Dynamic Stereochemistry of Chiral Compounds

Principles and Applications

Dynamic Stereochemistry of Chiral Compounds
Principles and Applications

Christian Wolf Department of Chemistry, Georgetown University, Washington, DC, USA

ISBN: 978-0-85404-246-3

A catalogue record for this book is available from the British Library r The Royal Society of Chemistry 2008 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org


Since the pioneering work of Pasteur, Le Bel and van’t Hoff stereochemistry has evolved to a multifaceted and interdisciplinary field that continues to grow at an exponential rate. Today, dynamic stereochemistry plays a fundamental role across the chemical sciences, ranging from asymmetric synthesis to drug discovery and nanomaterials. The immense interest and activity in these areas have led to the development of new methodologies and research directions in recent years. Chirality plays a pivotal role in efforts to control molecular motion and has paved the way for microscopic propellers, gears, switches, motors and other technomimetic devices. The concepts of Euclidian chirality have been extended to topological chirality of fascinating mechanically interlocked assemblies including rotaxanes, catenanes, and even molecular knots or pretzelanes. The impressive advance of asymmetric synthesis has been accompanied by significant progress in stereochemical analysis. Mechanistic insights into isomerization reactions and information about the conformational and configurational stability of chiral compounds are indispensable for today’s chemist, and new techniques such as dynamic chromatography and stopped-flow procedures that complement chiroptical and NMR spectroscopic methods have been established. A profound understanding of the stability of chiral target compounds, intermediates and starting materials to racemization and diastereomerization is indispensable for planning an efficient synthetic route. In many cases, interconversion of stereoisomers compromises the efficacy of asymmetric synthesis and ultimately results in the loss of stereochemical purity, but it can also be advantageous. While the usefulness and scope of asymmetric transformations of the first and second kind have been known for a long time, dynamic kinetic resolution, dynamic kinetic asymmetric transformation and dynamic thermodynamic resolution have become powerful synthetic alternatives. Many strategies that afford excellent control of stereolabile substrates and reaction intermediates have been developed and are nowadays routinely employed in the synthesis of a wide range of chiral compounds including natural products. Asymmetric synthesis of complex target compounds generally entails incorporation of several chiral elements in addition to strategic carbon-carbon bond formation. Once molecular chirality has been established it is often necessary to further manipulate it. Numerous methods for selective translocation of a chiral element along an existing carbon framework or interconversion of elements of chirality without loss of stereochemical purity have been introduced and provide invaluable synthetic prospects. Both, the progress and the diversity of stereodynamic chemistry, in particular asymmetric synthesis, are unrivaled and constantly fueled by an enormous amount of new scientific contributions. Over the last twenty years, several excellent books about asymmetric synthesis have appeared. Traditionally, asymmetric synthesis is discussed based on (1) reaction types, for example aldol v



reactions, hydroboration, epoxidation, dihydroxylation, hydrogenation, and so on, or (2) emerging concepts such as organocatalysis, biomimetic methods and phase-transfer catalysis. In addition, many reviews on broadly applicable asymmetric catalysts and methods can be found in the literature. While there is no need to duplicate these books and articles, I have felt that a conceptually different textbook that embraces asymmetric synthesis, interconversion of chiral compounds, analytical methods suitable for the study of racemization and diastereomerization reactions, as well as a discussion of topologically chiral assemblies and molecular propellers, switches and motors in the context of dynamic stereochemistry would be very helpful for both teaching and research. Stereoselective synthesis, analysis and stereodynamic properties and applications of chiral compounds are now combined in one text. The book is aimed at graduate students and is intended to serve as a guide for researchers with an interest in synthetic, analytical and mechanistic aspects of dynamic stereochemistry of chiral compounds. This book is organized into three parts that contain nine chapters and a glossary of important stereochemical terms and definitions. The first chapter provides an introduction to the significance and interdisciplinary character of dynamic stereochemistry. Chapter 2 covers principles, terminology and nomenclature of stereochemistry with an emphasis on Euclidian and topological chirality. The reader is familiarized with stereodynamic properties of chiral compounds and the relative contributions of interconverting configurational and conformational isomers to selectivity, reactivity and chiral recognition. Racemization, enantiomerization and diastereomerization including mutarotation and epimerization are discussed in Chapter 3. Mathematical treatments of reversible and irreversible isomerization kinetics are presented and the wealth of racemization and diastereomerization mechanisms is reviewed separately for each class of compounds to provide a systematic overview. Numerous examples of compounds with individual energy barriers to enantioconversion are given to highlight steric and electronic effects. The principles and scope of analytical techniques that are commonly used to determine the conformational and configurational stability of chiral compounds are discussed in Chapter 4. Special emphasis is given to chiroptical methods, variable-temperature NMR spectroscopy, dynamic chromatography, and stopped-flow analysis. The second part of this book focuses on asymmetric synthesis. Chapter 5 introduces the reader to the principles of asymmetric synthesis and outlines basic concepts of stereodifferentiation and reaction control. Chapter 6 covers asymmetric synthesis with chiral organolithium compounds and atroposelective synthesis of biaryls and nonbiaryls. This discussion leads to other strategies that are aimed at manipulation of chirality without concomitant racemization or diastereomerization, for example chirality transfer and interconversion of chiral elements during pericyclic rearrangements, SN2 0 and SE2 0 displacements, and self-regeneration of stereogenicity with temporary or transient chiral intermediates. Synthetic methods that utilize relays and stereodynamic catalysts for amplification of chirality and asymmetric induction link the above topics to the following chapter. Strategies that incorporate stereolabile chiral compounds and intermediates into asymmetric synthesis under thermodynamic (asymmetric transformations of the first and second kind, dynamic thermodynamic resolution) or kinetic reaction control (dynamic kinetic resolution and dynamic kinetic asymmetric transformation) are presented in Chapter 7. Because of the considerable overlap and relevance to some of the above methodologies, kinetic resolutions are also covered in detail. The scope and application spectrum of asymmetric reactions and concepts presented in Chapters 5 to 7 are highlighted with many examples and the stereochemical outcome is explained with a mechanistic rationale including transition state structures whenever possible. The third part of this book comprises stereodynamic devices, manipulation of molecular motion, and the chemistry of topologically chiral assemblies. Chapter 8 examines the central role that chirality plays in the design of molecular propellers, bevel gears, brakes, switches, sensors, and motors. The synthesis, chirality and stereodynamics of catenanes, rotaxanes and other mechanically interlocked compounds are presented in Chapter 9.



A single monograph can not comprehensively cover the enormous scope and the many facets of dynamic stereochemistry. Topics such as switching and amplification of chirality in polymers, gels and liquid crystals had to be excluded due to limitations of space and time. In writing this book during the last two and a half years, I have tried to adhere to well-defined and established stereochemical terminology and emphasized important limitations and conflicting definitions in the text. To assist the reader, a detailed glossary of stereochemical definitions and terms is included at the end of the book, and a list of abbreviations and acronyms is provided at the beginning. All topics are extensively referenced and the principal researcher is frequently named in the text to encourage further reading and to facilitate additional literature search. I would like to thank my colleagues, in particular Professors William H. Pirkle and the late Wilfried A. Konig, and my students for continuing inspiration and helpful discussions. I wish to ¨ thank Thomas J. Nguyen for the technical drawings illustrating the conceptual linkage between macroscopic mechanical devices and their molecular analogs. And I am particularly grateful to my wife Julia for her patience, encouragement and understanding during the endless hours involved in writing this book. Christian Wolf Washington, DC

This book is dedicated to my wife Julia


Chapter 1

Introduction References

1 4

Chapter 2

Principles of Chirality and Dynamic Stereochemistry 2.1 Stereochemistry of Chiral Compounds 2.2 Dynamic Stereochemistry of Cyclic and Acyclic Chiral Compounds References

6 6 15 27

Chapter 3

Racemization, Enantiomerization and Diastereomerization 3.1 Classification of Isomerization Reactions of Chiral Compounds 3.1.1 Racemization 3.1.2 Enantiomerization 3.1.3 Diastereomerization 3.1.4 Epimerization and Mutarotation 3.2 Stereomutations of Chiral Compounds: Mechanisms and Energy Barriers 3.2.1 Alkanes 3.2.2 Alkenes and Annulenes 3.2.3 Allenes and Cumulenes 3.2.4 Helicenes and Phenanthrenes 3.2.5 Alkyl Halides, Nitriles and Nitro Compounds 3.2.6 Amines 3.2.7 Aldehydes, Ketones and Imines 3.2.8 Alcohols, Ethers, Acetals, and Ketals 3.2.9 Carboxylic Acids and Derivatives 3.2.10 Amino Acids 3.2.11 Silicon, Phosphorus and Sulfur Compounds 3.2.12 Organometallic Compounds 3.2.13 Supramolecular Structures

29 30 31 34 36 40 44 44 46 52 53 54 56 58 60 65 68 71 74 80 ix

x 3.3 Atropisomerization 3.3.1 Biaryls, Triaryls and Diarylacetylenes 3.3.2 Nonbiaryl Atropisomers 3.3.3 Cyclophanes 3.3.4 Atropisomeric Xenobiotics 3.4 Pharmacological and Pharmacokinetic Significance of Racemization References

Contents 84 85 94 104 107 109 112

Chapter 4

Analytical Methods Chiroptical Methods NMR Spectroscopy Dynamic Chromatography 4.3.1 Dynamic High Performance Liquid Chromatography 4.3.2 Dynamic Gas Chromatography 4.3.3 Dynamic Supercritical Fluid Chromatography and Electrokinetic Chromatography 4.4 Chromatographic and Electrophoretic Stopped-flow Analysis 4.5 Comparison of Analytical Methods References 4.1 4.2 4.3

136 140 143 153 159 164 167 168 172 172

Chapter 5

Principles of Asymmetric Synthesis 5.1 5.2 5.3 Classification of Asymmetric Reactions Kinetic and Thermodynamic Control Asymmetric Induction 5.3.1 Control of Molecular Orientation and Conformation 5.3.2 Single and Double Stereodifferentiation References

180 180 183 186 189 194 198

Chapter 6

Asymmetric Synthesis with Stereodynamic Compounds: Introduction, Conversion and Transfer of Chirality Asymmetric Synthesis with Chiral Organolithium Reagents 6.1.1 a-Alkoxy- and a-Amino-substituted Organolithium Compounds 6.1.2 Sulfur-, Phosphorus- and Halogen-stabilized Organolithium Compounds 6.2 Atroposelective Synthesis of Axially Chiral Biaryls 6.2.1 Intramolecular Atroposelective Biaryl Synthesis 6.2.2 Intermolecular Atroposelective Biaryl Synthesis 6.2.3 Atroposelective Ring Construction 6.2.4 Desymmetrization of Conformationally Stable Prochiral Biaryls 6.2.5 Asymmetric Transformation of Stereodynamic Biaryls 6.3 Nonbiaryl Atropisomers 6.4 Chirality Transfer and Interconversion of Chiral Elements 6.1

204 205 207 212 215 217 220 224 225 226 231 233

4 Chiral Relays 6.5 Dynamic Kinetic Asymmetric Transformation 7.3.3 Conversion of Planar Chirality to Other Chiral Elements 6.7 Stereoselective Synthesis in the Solid State References 6.1 1.3 Stability and Reactivity of Stereodynamic Gears Structure and Ring Flipping of Molecular Propellers Dynamic Gearing in Biaryl-.5.2 Nonenzymatic Dynamic Kinetic Resolution Self-regeneration of Stereocenters 6.5 Self-regeneration of Stereogenicity and Chiral Relays 6.2-Chirality Transfer 6. Triaryl.6 Dynamic Thermodynamic Resolution References 7.4.6 Conversion of Axial Chirality to Other Chiral Elements 6.2 1.5.2 Stereolabile Axially Chiral Ligands 6.1 Stereodynamic Achiral Ligands 6.2 Asymmetric Transformation based on Chromatographic Separation 331 334 334 337 337 344 346 346 347 351 355 359 360 365 372 378 382 Chapter 8 From Chiral Propellers to Unidirectional Motors 8.2 Nonenzymatic Kinetic Resolution 7.2 xi 234 240 241 242 250 252 254 255 257 261 270 271 271 276 282 289 292 294 296 302 304 Chapter 7 Asymmetric Resolution and Transformation of Chiral Compounds under Thermodynamic and Kinetic Control Scope and Principles of Asymmetric Resolution and Transformation Asymmetric Transformation of the First Kind Asymmetric Transformation of the Second Kind Transfer of Stereogenicity Between Carbon and Heteroatoms 6.4.3 Parallel Kinetic Resolution 7.4-Chirality Transfer 6.4.4 Tetraaryl Propellers 399 399 403 405 .4.4.1 Enzyme-catalyzed Kinetic Resolution Transfer 6.4.2 Dynamic Kinetic Resolution 7.6 Asymmetric Catalysis with Stereolabile Ligands Intermolecular Chirality Transfer 6.1 Kinetic Resolution 7.1.5 Conversion of Central Chirality to Other Chiral Elements 6.3 Self-regeneration of Chiral Elements with Stereolabile Intermediates 6.1 Crystallization-induced Asymmetric Transformation 7.2 7.1 Transfer 6.Contents Chirality Transfer in SN2 0 and SE2 0 Reactions Rearrangements 6.1 Enzyme-catalyzed Dynamic Kinetic Resolution 7.4 Kinetic Resolution and Dynamic Kinetic Resolution 7.1 Stereocontrolled Substitution at a Chiral Center 6.

6 Propeller-like Coordination Complexes with Helicity Control 8. Switches.8 Molecular Brakes. Sensors.11 Chiral Molecular Motors References Contents 411 414 418 419 421 423 432 435 437 Chapter 9 Topological Isomerism and Chirality 9.1.1. and Rotors References 444 445 445 447 450 451 458 465 467 473 Glossary Stereochemical Definitions and Terms 480 Subject Index 503 .9 Chiral Molecular Switches 8.1 Synthesis of Catenanes and Rotaxanes 9.10 Stereodynamic Sensors 8.xii 8.2 Template-assisted Assembly 9.4 Knots and Borromean Rings 9.3 Topological Isomerization 9.3 Chiral Rotaxanes 9.5 Vinyl Propellers 8.4 Molecular Bevel Gears 8.7 Static Gearing and Cyclostereoisomerism 8.1.2 Chiral Catenanes 9.5 Topological Isomerism of Shuttles.1 Statistical Methods 9. Turnstiles and Scissors 8.

N-diisopropylcarbamoyl.4.5 Bc BHT Bn Boc BPDM Bu Bz 1C c CAL CAN Cat Cb Cby axial pseudoaxial asymmetric allylic alkylation antibody acetyl anticlinal acetylacetonate acetonitrile asymmetric dihydroxylation adamantyl asymmetric epoxidation azobisisobutyronitrile alanine antiperiplanar aqueous aryl aspartic acid atmospheric pressure adenosine triphosphate peak width at half height butyryl 2. conversion Candida antarctica lipase cerium ammonium nitrate catalyst N. (i-Pr)2NC(O)2. t-BuOC(O)benzphetamin N-demethylase n-butyl benzoyl degree Celsius concentration.Abbreviations and Acronyms a a0 AAA Ab Ac ac acac ACN AD Ad AE AIBN Ala ap aq Ar Asp atm ATP b0.4-tetramethyloxazolidine-3-carbonyl xiii .2.6-di-tert-butyl-4-methylphenol benzyl t-butoxycarbonyl.

absolute configuration (Fischer–Rosanoff convention) day(s) 1.4-benzoquinone diastereomeric excess diethyl azodicarboxylate dynamic chromatography dynamic high performance liquid chromatography diisopropyl azodicarboxylate N.N-dimethyl formamide dimethyl sulfoxide deoxyribonucleic acid 3.6-dicyano-1.2-dimethoxyethane dynamic micellar electrokinetic chromatography N. complete line shape analysis 1.10.0]undec-7-ene dicyclohexyl carbodiimide[2.0]non-5-ene 1.N-diisopropylethylamine dynamic kinetic resolution decimeter dimethyl azodicarboxylate 4-dimethylaminopyridine 1.4-dihydroxyphenylalanine 1.3.1 0 -bis(diphenylphosphino)ferrocene diastereomeric ratio dynamic supercritical fluid chromatography dynamic subcritical fluid chromatography dynamic thermodynamic resolution . BnOC(O)circular dichroism chiral derivatizing agent capillary electrochromatography crystallization-induced dynamic resolution Cahn–Ingold–Prelog chiral Lewis acid.3-dichloro-5.5-diazabicyclo[4.5-cyclooctadiene cyclopentadienyl circular polarization of emission circularly polarized light cross polarization magic angle spinning 1. c-C6H11 CZE D d DABCO dba DBB DBN DBU DCC DDQ de DEAD DGC DHPLC DIAD DIEA DKR dm DMAD DMAP DME DMEKC DMF DMSO DNA DNB DNMR DOPA dppf dr DSFC DSubFC DTR Abbreviations and Acronyms carbobenzyloxy.2.xiv Cbz CD CDA CEC CIDR CIP CLA cod Cp CPE CPL CP-MAS 18-crown-6 CSA CSP CSR Cy.8-diazabicyclo[5.4 0 -di-tert-butylbiphenyl 1.16-hexaoxacyclooctadecane chiral solvating agent chiral stationary phase chiral shift reagent cyclohexyl capillary zone electrophoresis sodium D-line (589 nm).7.2]octane dibenzylidene acetone 4.5-dinitrobenzoyl dynamic nuclear magnetic resonance 3.

and others NMR exchange spectroscopy flame ionization detection fluorenyl-9-methoxycarbonyl Gibbs free energy Gibbs activation energy gram anisotropy factor gas chromatography glycine enthalpy activation enthalpy hour(s). EXSY FID Fmoc G Ga g g GC Gly H Ha h HCH hfc HKR hn HOMO HPLC HSA i-Bu i. Planck’s constant hexachlorocyclohexane heptafluorobutyrylcamphorato hydrolytic kinetic resolution irradiation of light highest occupied molecular orbital high performance liquid chromatography human serum albumin isobutyl id est. en enant epi equiv er EROD ESR Et et al.g. i-Pr IR J J K K k k kB KHMDS dynamic kinetic asymmetric transformation electrophile enzymatic enantioselectivity factor entgegen.Abbreviations and Acronyms DYKAT E E (E) e e0 ECCD ee eepss e.e. that is isopropyl infrared joule coupling constant Kelvin equilibration constant kilo rate constant Boltzmann’s constant potassium hexamethyldisilazide xv . for example ethylenediamine enantiomerization epimer. epimerization equivalent enantiomeric ratio ethoxyresorufin-O-deethylase electron spin resonance ethyl et alii. relative configuration equatorial pseudoequatorial exciton-coupled circular dichroism enantiomeric excess enantiomeric excess at photostationary state exempli gratia.

.1. .3 . ligand. absolute configuration (Fischer-Rosanoff convention) length light amplification by stimulated emission of radiation lithium diisopropylamide leucine lithium hexamethyldisilazide natural logarithm lithium tetramethylpiperidide lowest unoccupied molecular orbital lysine molar denotes left-handed helicity (CIP convention) milli meta 3-methylcholanthrene 3-chloroperbenzoic acid methyl micellar electrokinetic chromatography mesityl methionine minute(s) methoxymethyl mobile phase mass spectrometry methylsulfonyl. nano 1. .2. CH3SO2methyl tert-butyl ether 0. C4F9SO2nonlinear effect nanometer N-methylmorpholine N-oxide nuclear magnetic resonance nuclear Overhauser effect spectroscopy nonsteroidal anti-inflammatory drug nucleophile ortho observed optical rotary dispersion oxidation denotes right-handed helicity (CIP convention) para phenobarbital polychlorinated biphenyl .3 .xvi KR L l LASER LDA Leu LHMDS ln LTMP LUMO Lys M (M) m m MC m-CPBA Me MEKC Mes Met min MOM MP MS Ms MTBE N n n nA NADH NADPH NBS Nf NLE nm NMO NMR NOESY NSAID Nu o obs ORD Ox (P) p PB PCB Abbreviations and Acronyms kinetic resolution liter.2. . population of state A nicotinamide adenine dinucleotide nicotinamide adenine dinucleotide phosphate N-bromosuccinimide nonaflate.

universal gas constant rectus. racemization reduction ribonucleic acid entropy sinister. denotes absolute configuration (CIP convention) racemic. t-BuOC(O)tributylsilyl tert-butyl 2. denotes absolute configuration (CIP convention) activation entropy second(s) enantioselectivity factor sec-butyl synclinal electrophilic substitution supercritical fluid chromatography 3-methyl-2-butyl simulated moving bed chromatography nucleophilic substitution intramolecular nucleophilic substitution stationary phase synperiplanar self-regeneration of stereocenters subcritical fluid chromatography temperature coalescence temperature time tetrabutylammonium fluoride tert-butyldimethylsilyl tert-butyldiphenylsilyl tert-butyl hydroperoxide t-butoxycarbonyl.3.7.8-tetrachlorodibenzo-p-dioxin triflate. CF3SO2- xvii .Abbreviations and Acronyms PCL Ph pH Phe Phg PhMe Piv PKR PLP PM3 PMB PPAR ppm Pr PS py R (R) rac Red RNA S (S) Sa s s s-Bu sc SE SFC sia SMB SN SNi SP sp SRS SubFC T Tc t TBAF TBDMS TBDPS TBHP t-Boc TBS t-Bu TCDD Tf Pseudomonas cepacia lipase phenyl Àlog10 [H3O1] phenylalanine phenylglycine toluene trimethylacetyl parallel kinetic resolution pyridoxal-5 0 -phosphate parametric method 3 (semi-empirical molecular modeling software) para-methoxybenzyl peroxisome proliferator-activated receptor parts per million n-propyl lipase from Pseudomonas stutzeri pyridine alkyl.

C-2 rotation angle. trifluoroacetyl trifluoroacetic anhydride trifluoroacetylcamphorato tetrahydrofuran tetrahydropyran triisopropylsilyl 2. Ph3Ctime-resolved circularly polarized luminescence transition state tosyl. C-3 C-4 heat. right-handed complex C-5 ellipticity molar ellipticity transmission coefficient left-handed complex wavelength micro frequency half-life time quantum yield for photoracemization mole fraction dextrorotatory levorotatory . relative configuration denotes anomer.6-triisopropylphenyl thin layer chromatography N.o b g D d e y k L l m n t1/2 F w (þ) (–) Abbreviations and Acronyms trifluoroacetic acid.N.xviii TFA TFAA tfc THF THP TIPS tipyl TLC TMEDA TMS Tol Tr TR-CPL TS Ts TTF Tyr URO UV UV-vis V VCD VE (Z) a a a.N 0 -tetramethylethylenediamine trimethylsilyl tolyl trityl. difference.4.N 0 . chromatographic enantioselectivity factor denotes chain termini denotes anomer. 4-CH3C6H4SO2tetrathiafulvalene tyrosine uroporphyrinogen ultraviolet ultraviolet-visible volt vibrational circular dichroism valence electron zusammen.

Structures and Acronyms of Chiral Ligands PPh2 PPh2 OH OH PPh2 PPh2 P Ph BIPHOS Ph P O N R N O N R BOX B Ph Ph O BINAP BINOL BIPHEB CBS oxazaborolidine NH2 NH2 DABN DAIB NMe2 OH H HO CO2i-Pr CO2Et OH H OH H HO H CO2Et CO2i-Pr DET Et DIPT O O DIOP PPh2 PPh2 Et R P Ph Ph NH2 P NH2 DPEN R DUPHOS R R MeO N O H N N Et N N N O H O N N OMe MeO Et O H O N N OMe O H N N (DHQD)2-PHAL (DHQD)2-AQN F3C OMe O O hfc C3F7 CO2H MTPA NOBIN O OH NH2 PPh2 N NMe2 R R N R R Fe H Me PPFA OH HO salen O O O PPh2 PPh2 N R R O O N PPh2 PPh2 O O O SYNPHOS OH OH O O tfc CF3 Ph NHTs TSDPEN Ph NHTs O SEGPHOS sparteine R R TADDOL xix .




In 1848, Louis Pasteur, one of the pioneering stereochemists, recognized the omnipresence and significance of chirality, which prompted his famous statement that the universe is chiral (l’univers est dissymme´trique).1 Today, we know that chirality can indeed be encountered at all levels in nature – in the form of the elementary particle known as the helical neutrino, inherently chiral proteins, carbohydrates and DNA, or helical bacteria, plants and sea shells. Pasteur realized that chiral objects exist as a pair of enantiomorphous mirror images that are nonsuperimposable and related to each other like a right-handed and left-handed glove. At the molecular level, chirality gives rise to enantiomers that can exhibit strikingly different chemical and physical properties in a chiral environment. Many biologically active compounds, for example pharmaceuticals, agrochemicals, flavors, fragrances, and nutrients, are chiral, and more than 50% of today’s top-selling drugs including Lipitor (cholesterol reducer, global sales in 2004: $12.0 billion), Zocor (cholesterol reducer, $5.9 billion), Plavix (antithrombic, $5.0 billion) and Nexium (antiulcerant, $4.8 billion) are sold as single enantiomers, Figure 1.1. The increasing demand for enantiopure chemicals has been accompanied by significant progress in asymmetric synthesis2–8 and catalysis,9–14 and by the development of analytical techniques for the determination of the stereochemical purity of chiral compounds. Stereoselective analysis usually entails chiroptical measurements,15 NMR and mass spectroscopic methods,16–18 electrophoresis,19 chiral chromatography20 or UV and fluorescence sensing assays,21–27 and it can provide invaluable information about the stability of chiral compounds to racemization and diastereomerization. A renowned example of a chiral drug that undergoes fast enantioconversion under physiological conditions is thalidomide (Thalidomid, Contergan) which was prescribed to pregnant women in the 1960s to alleviate morning sickness. One of the enantiomeric forms of thalidomide does indeed have sedative and antinausea effects, but the other enantiomer is a potent teratogen.i The racemic drug was approved in Europe for the treatment of pregnant women suffering from nausea and its use caused severe birth defects. Even formulation of the pure nontoxic (R)-enantiomer of thalidomide would have been unsafe because racemization takes place in vivo and the teratogenic (S)-enantiomer is rapidly generated in the human body, Scheme 1.1.ii Since the thalidomide tragedy, the significance of the stereochemical integrity of biologically active compounds has received increasing attention and the investigation of the stereodynamic


Teratogenic agents interfere with embryonic development and cause congenital malformations (birth defects) in babies. Despite its inherent toxicity and stereochemical instability, thalidomide has recently been approved by the US Food and Drug Administration under a specially restricted distribution program for cancer therapy and for the treatment of the painful disfiguring skin sores associated with leprosy.


OMe O N .. S N OMe (S)-omeprazole (proton pump inhibitor used for treatment of esophagitis, ulcer) HO2C NH2 OH (S)-ibuprofen (anti-inflammatory drug)

Chapter 1


HO2C F (S)-flurbiprofen (anti-inflammatory drug) OH O N N N Cl



(S)-propranolol (β-adrenergic blocker)



OH (S)-DOPA (S)-bupivacaine (neurotransmitter precursor used (local anaesthetic) for treatment of Parkinson's disease)

N (2R,3R)-paclobutrazol (fungicidal agent)

(S)-malathion (insecticidal agent)

Figure 1.1

Structures of chiral pharmaceuticals and agrochemicals.

O N NH O O (S)-(-)-thalidomide (teratogen) O


O N NH O O (R)-(+)-thalidomide (sedative and antinausea agent) O

Scheme 1.1

Interconversion of the enantiomers of thalidomide.

properties of chiral molecules has become an integral part of modern drug development. For example, a variety of 2-arylpropionic acids including ibuprofen (Advil), naproxen (Aleve), ketoprofen (Oruvail), and flurbiprofen (Ansaid) has found widespread use as pain relievers and nonsteroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory activity of these profens resides primarily with the (S)-enantiomer.iii The enantiomers of flurbiprofen possess different pharmacokinetic properties and show substantial racemization under physiological conditions. Although (S)-naproxen is the only profen that was originally marketed in enantiopure form, in vivo interconversion of the enantiomers of NSAIDs is an important issue in preclinical pharmacological and toxicological studies.28 Another noteworthy example that underscores the significance of racemization of chiral drugs is the potent gastric acid secretion inhibitor omeprazole (Prilosec) which has been used in its racemic form for the treatment of esophagitis and ulcer.29 The active form of this prodrug is an achiral sulfenamide derivative, and one could conclude that the presence of a chiral center in omeprazole does not affect its pharmacological activity. Nevertheless, the enantiomers of omeprazole have strikingly different pharmacokinetic profiles. The (S)-enantiomer of omeprazole affords higher bioavailability in humans because the (R)-form is more readily metabolized in the liver. To enhance the potency of this blockbuster drug, the pharmaceutical industry has launched esomeprazole (Nexium), the pure (S)-enantiomer of omeprazole. The unique structure and mode of action of the antibiotic glycopeptide vancomycin (Vancocin) has fascinated synthetic and medicinal chemists alike. The antibacterial activity of vancomycin, i.e.,

Some (S)-profens have distinct ulcerogenic properties that are increased in the presence of the (R)-enantiomer.



its ability to inhibit cell wall biosynthesis, stems from its rigid macrocyclic structure which is crucial for effective recognition and binding to the terminal D-alanine-D-alanine sequence of bacterial peptides. The cup-shaped structure of vancomycin is a consequence of the chirality of the amino acids in conjunction with the chiral axis of the actinoidinic acid moiety consisting of aryl rings A and B and the planar chirality of aryl ethers C and E, Scheme 1.2. The stereodynamics of these chiral elements have played a pivotal role in the total synthesis of the vancomycin aglycon (the part of the glycopeptide lacking carbohydrate units).30–33 An intriguing example is Evans’ synthesis of vancomycin from a bicyclic precursor bearing an unnatural (M)-actinoidinic acid moiety. Evans and coworkers recognized that the axial chirality of the atropisomeric actinoidinic acid unit is controlled by the global aglycon architecture, rather than by individual proximate stereogenic elements. They also realized that rotation about the central C–C bond between aryl rings A and B proceeds at ambient temperature and favors formation of the (P)-conformer with high selectivity. In fact, thermal equilibration at 55 1C results in atropisomerselective interconversion of the two diastereomeric tetrapeptides and establishes the desired axial chirality with 90% diastereomeric excess. This thermodynamically controlled transformation significantly enhances the overall efficiency of the total synthesis of vancomycin, Scheme 1.2. Similarly, Boger and others exploited thermally controlled atropisomerization reactions which have been strategically incorporated into several synthetic routes towards vancomycin and other complex antibiotics including teicoplanin.





OPiv D





Cl H N


95 : 5




Scheme 1.2

Structure of vancomycin (left), and stereoisomer interconversion favoring the formation of the natural (P)-diastereoisomer of a tetrapeptide precursor (right).

The unique stereodynamics of chiral compounds have paved the way to artificial machines and other molecular devices that lie at the interface of chemistry, engineering, physics, and molecular biology. The design of gears, rotors, switches, scissors, brakes, shuttles, turnstiles, and even motors showing unidirectional motion has certainly been inspired by the coordinated movement in biological systems such as muscle fibers, flagella and cilia.34–36 Feringa and coworkers developed light-driven molecular motors derived from sterically overcrowded chiral alkenes exhibiting thermal bistability and nondestructive read-out.37,38 The subtle interplay between the chiral center and the inherently helical conformation of this type of molecular motor provides control of the rotation about the carbon–carbon double bond in a series of thermally and photochemically initiated isomerization steps. In other words, both chirality and conformational flexibility are essential for unidirectional motion of the rotor around the stator, Scheme 1.3. The first isomerization step requires irradiation of UV light to a solution of the stable (3 0 S)-(P)-trans-form of the chiral alkene. This generates a photostationary state favoring 69.4% of the unstable (3 0 S)-(M)-cis-form that thermally relaxes to 94% of the stable (3 0 S)-(P)-cis-isomer in the second step. The same concept is exploited for photoisomerization of the (3 0 S)-(P)-cis-alkene to 48.9% of the (3 0 S)-(M)-trans-isomer

S Step 1

Chapter 1

rotor 3 4 1

OMe S stable (3′S)-(P)-trans-form 2 Step 4

photoinduced isomerization > 280 nm 30.6% : 69.4%

OMe S unstable (3′S)-(M)-cis-form Step 2
thermal helix inversion at 55˚C 6.0% : 94.0%

thermal helix inversion at 55˚C 83.4% : 16.6%


S Step 3 OMe S unstable (3′S)-(M)-trans-form
photoinduced isomerization > 280 nm 48.9% : 51.1%


OMe S stable (3′S)-(P)-cis-form

Scheme 1.3

Four isomerization steps of a unidirectional motor.

in the third step which is followed by thermal helix inversion to regenerate 83.4% of the (3 0 S)-(P)trans-isomer in the final step. Since the interconverting isomers exist as mixtures obeying Boltzmann distributions and reversible reaction kinetics, this molecular motor is not rotating in an exclusively monodirectional sense. However, the discrete and synergetic photochemical and thermal isomerization reactions of the diastereomeric mixtures result in an overall clockwise motion observed from the stator. Since the discovery of the ubiquity of chirality by Pasteur, stereochemistry has undoubtedly emerged as one of the most important and fascinating areas within the chemical sciences. Stereochemistry embraces a broad variety of closely intertwined static and dynamic aspects that are all related to the three-dimensional structure of molecules. While static stereochemistry deals with the spatial arrangement of atoms in molecules and the corresponding chemical and physical properties, dynamic stereochemistry emphasizes structural change and comprises asymmetric reactions as well as interconversion of configurational and conformational isomers. The few examples outlined above highlight both the significance of chirality and the fundamental role that dynamic stereochemistry plays in modern chemistry, spanning multiple disciplines from asymmetric synthesis and drug discovery to material sciences. The principles and applications of stereodynamic chemistry of chiral compounds are discussed in the chapters following.

1. Pasteur, L. Ann. Chim. Physique 1848, 24, 442-459. 2. Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E. Stereoselective Synthesis in Methods of Organic Chemistry, Houben-Weyl, Vol. 21a-21f, 4th ed., Thieme, Stuttgart, 1995. ´ 3. Gawley, R. E.; Aube, J. Principles of Asymmetric Synthesis, Tetrahedron Organic Chemistry Series, Elsevier, New York, 1996. 4. Ho, T.-L. Stereoselectivity in Synthesis, Wiley-VCH, New York, 1999. 5. Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and Applications of Asymmetric Synthesis, Wiley-VCH, New York, 2001. 6. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024-2032.



7. Song, C. E.; Lee, S.-G. Chem. Rev. 2002, 102, 3495-3524. 8. Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035. 9. Jonathan, M. J. W. Catalysis in Asymmetric Synthesis, Sheffield Academic Press, Sheffield, 1999. 10. Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed., Wiley-VCH, New York, 2000. 11. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008-2022. 12. Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187-2209. 13. Inanaga, J.; Furuno, H.; Hayano, T. Chem. Rev. 2002, 102, 2211-2225. 14. Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem., Int. Ed. 2002, 41, 3554-3571. 15. Ding, K.; Shii, A.; Mikami, K. Angew. Chem., Int. Ed. 1999, 38, 497-501. 16. Guo, J.; Wu, J.; Siuzdak, G.; Finn, M. G. Angew. Chem., Int. Ed. 1999, 38, 1755-1758. 17. Evans, M. A.; Morken, J. P. J. Am. Chem. Soc. 2002, 124, 9020-9021. 18. Markert, C.; Pfaltz, A. Angew. Chem., Int. Ed. 2004, 43, 2498-2500. 19. Reetz, M. T.; Kuhling, K. M.; Deege, A.; Hinrichs, H.; Belder, D. Angew. Chem., Int. Ed. 2000, 39, 3891-3893. 20. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, John Wiley & Sons, New York, 1994, pp. 214-274. 21. Pu, L. Chem. Rev. 2004, 104, 1687-1716. 22. Mei, X.; Wolf, C. Chem. Commun. 2004, 2078-2079. 23. Zhao, J.; Fyles, T. M.; James, T. D. Angew. Chem., Int. Ed. 2004, 43, 3461-3464. 24. Eelkema, R.; van Delden, R. A.; Feringa, B. L. Angew. Chem., Int. Ed. 2004, 43, 5013-5016. 25. Mei, X.; Wolf, C. J. Am. Chem. Soc. 2004, 126, 14736-14737. 26. Tumambac, G. E.; Wolf, C. Org. Lett. 2005, 7, 4045-4048. 27. Folmer-Andersen, J. F.; Lynch, V. M.; Anslyn, E. V. J. Am. Chem. Soc. 2005, 127, 7986-7987. 28. Leipold, D. D.; Kantoci, D.; Murray Jr., E. D.; Quiggle, D. D.; Wechter, W. J. Chirality 2004, 16, 379-387. 29. Lindberg, P.; Braendstroem, A.; Wallmark, B.; Mattsson, H.; Rikner, L.; Hoffman, K.-J. Med. Res. Rev. 1990, 10, 1-54. 30. Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700-2704. 31. Evans, D. A.; Dinsmore, C. J.; Watson, P. S.; Wood, M. R.; Richardson, T. I.; Trotter, B. W.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2704-3708. 32. Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Loiseleur, O.; Castle, S. L. J. Am. Chem. Soc. 1999, 121, 3226-3227. 33. Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 10004-10011. 34. Kelly, T. R.; DeSilva, H.; Silva, R. A. Nature 1999, 401, 150-152. 35. Koumura, N.; Zijlstra, R. W. J.; van Delden, R. A.; Harada, N.; Feringa, B. L. Nature 1999, 401, 152-155. 36. Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature 2003, 424, 174-179. 37. Koumura, N.; Geertsema, E. M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 12005-12006. 38. Van Delden, R. A.; ter Wiel, M. K. J.; de Jong, H.; Meetsma, A.; Feringa, B. L. Org. Biomol. Chem. 2004, 2, 1531-1541.


Principles of Chirality and Dynamic Stereochemistry

Stereochemistry has evolved into a multi-faceted discipline, and numerous concepts and descriptors have been introduced since the discovery and analysis of chiral organic compounds by van’t Hoff, Le Bel and Pasteur in the nineteenth century. Unfortunately, the stereochemical terminology used in the literature is not always well defined, and in some cases it can be ambiguous. The principles of stereoisomerism and chirality and the relationship between reactivity and stereodynamics of chiral compounds are discussed in this chapter and complemented with brief definitions in the glossary.

Stereoisomeric compounds exhibit the same constitution, i.e., molecular formula and connectivity of atoms, but have a different spatial arrangement. Stereoisomers are classified into enantiomers and diastereoisomers. Chiral molecules that have the relationship of mirror images are called enantiomers. All other stereoisomers are diastereoisomers, Figure 2.1. Enantiomers have the same chemical and physical properties when present in an achiral environment. But they show different chiroptical behavior and cause a clockwise (dextrorotatory (þ)-form) or counterclockwise (levorotatory (–)-form) rotation of the plane of linearly polarized light by equal amounts.i Enantiomers may have distinguishable properties in a chiral environment if they experience diastereomeric interactions. For example, the enantiomers of chiral drugs such as omeprazole, ibuprofen and DOPA exhibit different pharmacological and pharmacokinetic activities because they interact with enzymes and receptors consisting of amino acids and other chiral biomolecules. By contrast, diastereoisomers usually have different chemical and physical properties in both achiral and chiral environments. Many chiral compounds possess a tetrahedral carbon atom bearing four different substituents, Figure 2.2. The presence of one chiral carbon center in a molecule gives rise to a pair of two enantiomers. Other important stereogenic centers consist of a nitrogen, phosphorus, boron, silicon or sulfur atom carrying nonidentical substituents, Figure 2.3. Enantiomers and diastereoisomers can be chiral due to the presence of an asymmetric center, but this is not always the case. A compound is chiral if it is not superimposable on its mirror image. This unequivocal definition provides a necessary and sufficient condition for chirality. Chiral

The absolute configuration of a chiral compound, and the assignment of its three-dimensional structure based on CIP rules (descriptors R,S) must not be confused with its ability to rotate the plane of monochromatic linearly polarized light in a clockwise or counterclockwise direction (descriptors þ,À).


Principles of Chirality and Dynamic Stereochemistry
Cl Pt Cl H2N Pt HO OH diastereoisomers CO2H HO (R)-lactic acid HO2C OH HO2C (S)-lactic acid HO (2S,3S)-2,3-dihydroxybutyric acid (E)-2-butene (Z)-2-butene enantiomers diastereoisomers OH HO OH (2R,3R)-2,3-dihydroxybutyric acid enantiomers CO2H HO diastereoisomers Cl CO2H HO2C OH


H2N NH2 NH2 Cl cis-diamminedichloroplatinum trans-diamminedichloroplatinum

(2R,3S)-2,3-dihydroxybutyric acid (2S,3R)-2,3-dihydroxybutyric acid


Figure 2.1

Examples of enantiomers and diastereoisomers.
OH O Et NH2 Cl O O OH (R)-2-chlorobutyric acid Me H2N (S)-styrene oxide Ph OH (S)-leucine H2N (1S,4R)-camphor CO2H O HO O OH HO CH2OH (R)-glyceraldehyde (1R,2S)-norephedrine CHO (R)-1-aminoindan


(R)-2-bromobutane OH



(R)-2-methylsuccinic acid

Figure 2.2

Chiral compounds with asymmetric carbon atoms.
O O O P R OR′′ R′ phosphinic esters R′′′ S R O RO sulfinic esters N R R′′ R′ ammonium ions

OR′′′ P B R RO OH OR′′ R′ R′O phosphinous acids borates R′′′ P R R′′ R′ phosphonium ions S R R′′ R′ sulfonium ions

N N P P R R R′′ R R′′ R R′′ R′′ R′ R′ R′ R′ amines phosphines phosphine oxides amine oxides R′′′ OH

S Si Si R O R′′ R R′′ R R′ R′ R′ silanols silanes sulfoxides

Figure 2.3

Chiral compounds with stereogenic centers others than carbon atoms.

molecules may possess a rotation axis, but no symmetry plane, rotation-reflection axis and inversion center. This criterion may be fulfilled by the presence of an asymmetric center or other elements of chirality. Many organic compounds lack asymmetric atoms but possess axial, planar or helical chirality. For example, substituted allenes, biphenyls, spiranes, and alkylidenecycloalkanes have a chiral axis and exist in the form of two enantiomers. Certain ansa compounds,


Chapter 2

Cl •





CH3 (S)-spirobiindan

H Cl H H (S)-2,2'-dimethylbiphenyl (S)-1,3-dichloroallene (R)-4-methylcyclohexylideneacetic acid (S)-2,6-dimethylspiro[3.3]heptane CO2H O (CH2)9 (S)-(E)-cyclooctene (R)-[2.2]paracyclophanecarboxylic acid (R)-1,11-dioxa[11]cyclophanecarboxylic acid (R)-1-acetyl-2-methylferrocene CO2H O Fe COCH3


Figure 2.4

Molecules with a chiral axis, plane or helix.




HO2C HO2C (S,R)-form

OH symmetry plane OH

OH HO HO2C (R,R)-(+)-form CO2H (S,S)-(-)-form



meso form


N N (R,R)-form

N N (S,S)-form

N N (R,S)-form meso form

N N (S,R)-form



Figure 2.5

The stereoisomers of tartaric acid (top) and 1,8-bis(2 0 -methyl-4 0 -quinolyl)naphthalene (bottom).

paracyclophanes, trans-cycloalkenes with a twisted double bond, and metallocene complexes display a chiral plane, and helicenes afford a chiral helical structure, Figure 2.4. Chiral compounds may have one or more than one stereogenic center, axis, plane or helix. In most cases, each element of chirality gives rise to two distinct stereoisomers, and one can expect 2n stereoisomers for n chiral elements. However, the existence of a symmetry plane, rotation-reflection axis or inversion center results in degeneracies. A compound that possesses at least one of these symmetry elements is achiral because it is superimposable on its mirror image. Tartaric acid has two chiral centers and should exhibit two diastereoisomeric pairs of enantiomers. In fact, it exists only in the form of two enantiomeric (R,R)- and (S,S)-isomers and a third diastereoisomeric form that has a symmetry plane and is achiral because its mirror images are superimposable and therefore identical, Figure 2.5. Similarly, 1,8-bis(2 0 -methyl-4 0 -quinolyl)naphthalene has two chiral axes but affords three stereoisomers: two enantiomers and one meso form. These examples clearly demonstrate that the presence of a stereogenic element in a molecule such as a tetrahedral carbon

Principles of Chirality and Dynamic Stereochemistry


atom bearing four different substituents or a chiral axis does not necessarily render the molecule chiral. A discussion of the stereochemistry of chiral compounds requires a clear understanding of the relevant nomenclature. The Cahn–Ingold–Prelog (CIP) rules are used to give an unambiguous description of the absolute configuration of enantiomers and diastereoisomers.1,2 Because of its importance, the CIP convention and the descriptors R, S, M, and P are explained below in some detail, whereas definitions of other stereochemical terms can be found in the glossary. The descriptors R, S, M, and P are applicable to all kinds of chiral elements. First, the priority of the atoms attached to the chiral element is assigned based on the following sequence rules: 1. Atoms with a higher atomic number have a higher rank than atoms with a lower atomic number. Note that the substituent with the lowest priority at a tetrahedral carbon atom may be a hydrogen atom or a lone electron pair at a three-coordinate chiral heteroatom such as nitrogen, phosphorus or sulfur. Isotopes with higher atomic mass number precede isotopes with lower mass number, e.g., D 4 H and 13C 4 12C. When two or more substituents are the same element, one has to compare atoms in the next sphere until the priority of all groups has been established. It is important that all substituents in a given sphere must be evaluated before one proceeds further away from the core of the chiral element to the next array of atoms. Comparison of a dimethyl acetal moiety with an ethoxy group shows that the former has a higher priority because it carries two oxygens, in contrast to the ether moiety which bears only one oxygen atom. In other words, all atoms in one sphere must be fully analyzed before one continues to the next sphere. In the case of equal priority of a given sphere, one always proceeds by following the branch of the highest priority until a rank can finally be assigned, Figure 2.6. The rank of substituents carrying multiple bonds is established based on the principle of ligand complementation. Multiple bonds are complemented by phantom atoms through multiple representation of atoms that are doubly or triply bonded. An organometallic pcomplex is treated the same way. A metal carrying an alkene or alkine ligand is hypothetically replaced by one (two) metal(s) attached to each end of the ligand, e.g., a palladium p-complex bearing an olefinic group –CH¼CHR is represented by –C(Pd)H–C(Pd)HR. The rule of ligand complementation is also applicable to polydentate and cyclic ligands. A cyclic structure is disconnected and complemented with a phantom atom at the bonds where it reduplicates itself. For example, the priority of the substituted pyrrolidine shown in Figure 2.7 is assigned by cutting the ring into two hypothetical branches with peripheral phantom atoms in addition to the real branches. Disconnection at A gives –CH2NHCH2CH2(C) having the highest priority because –CH2NHCH2CH3, the group that is assigned second priority, carries a peripheral hydrogen which has a lower priority than a phantom carbon. Disconnection at B results in the formation of –CH2CH2NHCH2(C), which has the lowest rank. This case thus also illustrates that, for a given element, a real atom has precedence over a phantom atom: –CH2CH2NHCH2CH3 4 –CH2CH2NHCH2(C).



determines branch of the highest priority (3) (4 ) OMe (1) (R) OMe (S) I (3) (4) OH

(2) OEt

determines rank (Br > Cl)

Br (1) OH



Figure 2.6

Comparison of CIP spheres and determination of the branch of the highest priority.

HN A B N H N H ligand complementation HN (4) (C) (S) N H NH (1) (C) HN (3) (2)

Chapter 2

(C) = phantom carbon

Figure 2.7

Ligand complementation in cyclic compounds.
(3) (4) OMe (2) (S) (S) (3) (4) (S) (2)

(1) OMe (R)




Figure 2.8

CIP rules for stereoisomeric substituents.


If ligands possess a different stereochemical environment and can not be distinguished based on the above, the following rule applies: cis-configuration precedes trans-configuration, Z 4 E, R 4 S, M 4 P, Figure 2.8.

The CIP rules described above give the following priority of common functional groups: –I 4 –Br 4 –Cl 4 –SO3H 4 –SO2R 4 –SR 4 –SH 4 –P(O)R2 4 –PR2 4 –F 4 –OR 4 –NO2 4 –NR2 4 –NH2 4 –CO2R 4 –CO2H 4 –C(O)R 4 –CHO 4 –CH(OR)2 4 –CH(OH)2 4 –CH2OR 4 –CH2OH 4 –CN 4 –CH2NH2 4 o-tolyl 4 m-tolyl 4 p-tolyl 4 –C6H5 4 –CRCH 4 t-Bu 4 –CH(C6H13)2 4 cyclohexyl 4 vinyl 4 i-Pr 4 benzyl 4 allyl 4 n-alkyl 4 –H. Once the priority of the substituents or groups around the chiral center is established, the molecule is viewed in such a way that the moiety with the lowest priority is placed behind the central atom. The three remaining substituents or groups are thus oriented towards the viewer and afford a tripodal arrangement. If the sense of direction following the established priority of these three substituents describes a clockwise rotation, (R)-configuration (for Latin rectus, right) is assigned. If the rotation is counterclockwise, the chiral center has (S)-configuration (for Latin sinister, left), Figure 2.9. This nomenclature can also be applied to compounds possessing a chiral axis or plane. In both cases the priority of substituents must be assigned with the help of an additional CIP rule, which specifies that the groups on an arbitrarily chosen side of a chiral axis or plane always precede substituents on the other side of the stereogenic element. It is helpful to view the chiral axis of biphenyls, allenes and spiro compounds as a stretched tetrahedron. Because of the inherently lower symmetry of a stretched tetrahedron compared to a regular tetrahedron, it does not require the presence of four different substituents to constitute a chiral axis. For example, 2,2 0 -dimethylbiphenyl is chiral. The symmetric substitution pattern gives rise to a C2-symmetric structure, but incorporation of the same substituents to a tetrahedral carbon generates an achiral compound with a symmetry plane. To assign the CIP descriptor to an axially chiral compound, one can choose either side of the chiral axis to determine the first two priorities. This side always has precedence over the opposite side. Then the remaining ranks are assigned on the side of lower priority, and the clockwise (Ra) or counterclockwise (Sa) sense of rotation is established. Some classes of compounds, including (E )-cycloalkenes, cyclophanes and metallocenes, display a planar aryl or alkene group that may have one or several substituents residing outside that plane. A substitution pattern that destroys a perpendicular symmetry plane or an inversion center establishes planar chirality.

P). respectively. which gives rise to a pair of (P. correspond to each other.or (R)-spiro[3. only the substituents of the highest CIP rank on each side of the stereogenic axis (denoted 1 and 3 in Figure 2. . Again. As mentioned above.. In order to assign helical descriptors to a chiral plane. After determination of these two substituents. molecules with a helical shape may also be chiral. Figure 2. ii The use of suffixes a and p to indicate axial and planar chirality is optional. First.ii Although metallocenes exhibit planar chirality. The sense of chirality in molecules with a stereogenic axis or plane may also be characterized using descriptors M and P. Application of the two conventions to axially chiral compounds reveals that descriptors Ra and M.Principles of Chirality and Dynamic Stereochemistry H (4) (4) (4) (3) (3) HO2C H (2) (2) 11 C S P • (3) Me (3) Cl (3) Me I (1) O (1) Ph (1) CO2H (1) (4) H (2) Et (1) (2) t-Bu (4) (2) Br (P). bonds between the p-donor and the metal atom are complemented as described above and the atom of the highest priority is determined. the descriptors Rp and P.2'-dimethylbiphenyl (S )-bromochloroiodomethane (S)-ethylmethylphenylphosphine (S)-tert-butylmethylsulfoxide (3) NO2 (2) OH (3) D (4) H CO2H (1) (3) (1) pilot atom (3) (2) (2) (4) (M ). and Sp and M.5-diene (P). as well as Sa and P.or (R)-(E)-cyclooctene (1) (4) O N (1) H (2) 2 (P). Chiral axes of symmetrically substituted biaryls. are synonymous. The helical descriptors are then assigned through rotation of the front substituent in direction to the substituent located at the rear of the axis. decahelicene has two stereogenic elements. The sense of helicity is described as right-handed (P) if it resembles a screw that rotates clockwise away from the viewer.or (S )-2. one views the plane from the so-called pilot atom which is the out-of-plane atom closest to the stereogenic element. and left-handed (M ) if the rotation is counterclockwise. two helical turns. In the case of planar chirality. For axially chiral compounds. While hexahelicene exists in the form of two enantiomers. one views the molecule along the chiral axis from an arbitrarily chosen side. they are conventionally treated as molecules with a chiral center. The arrangement of the next three subsequent atoms located in the chiral plane determined according to the CIP rules will either describe a clockwise (Rp) or a counterclockwise (Sp) rotation. whereas M is assigned in the case of a counterclockwise rotation.9) are considered.or (S)-2. The asymmetric environment of this tetrahedral atom is then analyzed using the CIP rules to assign the absolute configuration. the descriptor P refers to a clockwise rotation and M to a counterclockwise movement. one looks from the pilot atom at the subsequent atoms using the CIP convention.e.P)-isomer having an inversion center.9.9 Description of axial. The descriptor P denotes a clockwise rotation.or (R)-4-deuteriocyclohexylideneacetic acid (the hydroxyl group is too remote from the chiral axis to matter) (3) CO2H (2) (1) pilot atom (P).or (R)-[2. Figure 2.or (S)-glutinic acid (P).2]paracyclophanecarboxylic acid Fe Fe (1) (2) atom of highest precedence (M) (P) (4) (3) (S )-2-ethyl-1.2'-dinitro-5-hydroxybiphenyl (M ). i.4-dimethylferrocene (M )-hexahelicene meso decahelicene Figure 2.3]heptane-1.M )-enantiomers and a meso (M.and (M.9. To assign CIP descriptors for molecules with a chiral plane. allenes and spiro compounds are arbitrarily viewed from the right-hand side to assign CIP priorities. planar and helical chirality based on CIP rules.

one describes the orientation of one ring with a polar vector while the other is viewed as a local thread and assigned an axial vector. and rotaxanes consist of a molecule that is threaded through at least one cyclic molecule which is trapped on the rod by bulky terminal groups. Figure 2.12 (a) + achiral achiral achiral achiral (b) + Chapter 2 achiral chiral Figure 2.and (S )-enantiomers of alanine in cyclohexaalanine. (R)-configuration is assigned.3. However.9 The .12. Figure 2. Figure 2.7 The chirality of catenanes and rotaxanes composed of oriented ring and thread components can be described through a combination of axial and polar vectors generating a right-handed or a lefthanded screw.10.6. In this case.5 Topologically chiral compounds may lack classical elements of chirality but still exist as a pair of enantiomers. For the determination of the configuration at ring B of the [3]rotaxane shown in Figure 2. but a chiral assembly existing in the form of two mirror images is obtained if the two achiral rings possess directionality. [2]Rotaxanes consisting of only one oriented component are of course achiral. Combination of this axial vector and the polar vector of ring B then establishes (R)-configuration. The assignment of the absolute configuration of topologically chiral molecules has been under debate for some time.12. and different procedures utilizing CIP rules have been proposed.8.13. In addition to classical or Euclidian elements of chirality. the direction from the atom of the highest priority to the atom of the second highest priority following the shortest distance is determined to define (a) an axial vector depicting the orientation of the thread and (b) a polar vector describing the orientation of the ring. introduction of directionality to mechanically interlocked molecules can generate so-called topological chirality. the presence of at least one directional ring on a [3]rotaxane exhibiting a nondirectional thread gives rise to topological chirality. one views the oriented wheel which absolute configuration is under consideration from the direction of the other wheel. Applying the same method to determine the chirality at ring A confirms that the [3]rotaxane possesses (R. the side of the nondirectional axle bearing ring A receives a higher priority to artificially assign an axial vector. The directionality of the interlocked units is assigned based on CIP priority rules. incorporation of directionality into both axle and wheel of a rotaxane generates topological chirality. In both ring and thread of a rotaxane. vide infra. assignment of the axial vector based on the local directionality of ring A and the polar vector based on the orientation of ring B affords (R)-configuration for the [2]catenane shown in Figure 2. Examples of nonclassical chirality can be encountered in catenanes and rotaxanes. was first introduced by Prelog and Gerlach. If the vector combination represents the motion of a right-handed screw. The concept used for the assignment of the absolute configuration outlined for chiral [2]rotaxanes can also be applied to cyclostereoisomeric [3]rotaxanes that are chiral only by virtue of directionality of at least one ring component. resulting in cycloenantiomerism. To apply the same concept to catenanes. The concept of cyclostereoisomerism resulting from ring directionality and the distribution pattern of chiral but otherwise identical building blocks in a cyclic molecule.10 Achiral (a) and chiral (b) catenanes devoid of classical elements of chirality. for example (R). The part of the thread bearing the second wheel has a higher priority than the part carrying the wheel under consideration.R)-configuration. The ring used to determine the direction of the axial and polar vector. the wheel attains either a clockwise or a counterclockwise orientation with respect to the axle.4 Similarly.11. can be chosen arbitrarily. whereas the (S )-enantiomer resembles a left-handed screw. Catenanes contain two or more interlocked rings. respectively. In this case. For example. Intertwining of two achiral rings often affords an achiral catenane.

For instance. Mislow therefore suggested that the term cyclostereoisomerism should be restricted to cases in which ring directionality generates additional stereoisomers.Principles of Chirality and Dynamic Stereochemistry achiral ring unit achiral thread atom with second highest CIP priority O N H H N O O H N 13 O2 S N H atom with highest CIP priority axle directionality atom with second highest CIP priority N H O2 S O N H atom with highest CIP priority (S)-[2]rotaxane ring directionality based based on shortest distance from S to N (R)-[2]rotaxane O N H H N O O H N O2 S N H N H O2 S H N O O H N O N H N H O2 S O N H N H O O2 S N H axial vector shows axle directionality (S)-configuration (R)-configuration axial vector shows axle directionality polar vector shows wheel directionality polar vector shows wheel directionality Figure 2. Figure 2. and demonstrated that this can be achieved with hexaisopropylbenzene derivatives. . amino acid sequence and connectivity of stereogenic centers exhibiting both (R).. ring A ring B H N O O H N O O2 S O O O H N H N O O O H N O O O N H N H H N O N H axle (no directionality) ring A ring B O2 S N H (R)-configuration (R)-configuration Figure 2. i.11 Assignment of the absolute configuration of the enantiomers of a [2]rotaxane.14. The presence of ring directionality in cyclopeptides consisting of both enantiomers of one amino acid does not change the overall number of possible stereoisomers.e.and (S)-configuration in cyclopeptides give rise to cycloenantiomers and cyclodiastereoisomers.12 Structure of an (R. a cyclic peptide exists in as many stereoisomers as the open chain form.R)-[3]rotaxane.

5. i. whereas the enantiomeric L-complex resembles a left-handed screw with a counterclockwise helical sense. Removal of directionality in either the axle or the wheel in the chiral rotaxane shown in Figure 2. as a result.4.5. tris(ethylenediamine)cobalt(III). see Chapter 8.13 Assignment of the absolute configuration of a [2]catenane based on CIP rules.2-bis(bromochloromethyl)3.e.5. The assignment of the absolute configuration of octahedral tris-chelate complexes is determined by the sense of the helical coordination sphere generated by the ligands. metal complexes containing two or more chelating ligands can display helical chirality. Figure 2. Note that the two molecules of cyclohexaalanine differ on account of the directional sense of the peptide bonds.15.4.10–12 The same situation arises with cyclostereoisomeric rotaxanes. For example.. even if all the individual components are achiral.14 (R)-[2]catenane achiral ring unit HN HN O MeO O HN O2S NH O NH MeO O O MeO O2S NH O H N O2S NH O NH O N H O Chapter 2 axial vector of A NH polar vector of B (R)-configuration atom with highest CIP priority HN polar vector of A axial vector of B ring B (R)-configuration atom with second highest CIP priority ring A cyclic directionality based on CIP rules Figure 2. R-S-S-R-S-S versus S’R’R’S’R’R. The view along one of the threefold rotation axes of the octahedral complex reveals a sense of clockwise rotation similar to a righthanded screw in a D-complex.4. is a chiral octahedral complex that exists in the form of two enantiomers.2-bis(bromochloromethyl)-3.2-bis(bromochloromethyl)-3. the directionality of 1. [Co(en)3]31. Me H H H N (S) O O O H Me NH (S) H Me (R) NH H Me cyclohexaalanine H Me HN (S) Me H Me HN (R) H H N (R) O O O O O O Me Cl (S) NH Me (R) NH Me H Me H Me H Me Me H Me Me H Br H (R) (S) Br Cl H Me Me H Br Cl H Me Me H Me Me H H Br (R) Cl (S) H Me Me H Me Me HN (R) Me H HN Me H (S) O O O (S) N H (R) N H 1. By analogy with topologically chiral rotaxanes and catenanes consisting of interlocked achiral components.6-tetraisopropylbenzene (right). .14 Structures of cycloenantiomeric cyclohexaalanine (left) and 1.6-tetraisopropylbenzene is due to static gearing between the aryl substituents. which effectively increases the number of possible stereoisomers.11 would eliminate topological chirality and thus reduce the number of stereoisomers.7. one would observe only a single achiral [2]rotaxane instead of two enantiomers.6-tetraisopropylbenzene Figure 2.

16. Stereoisomers can be classified into configurational and conformational isomers. for example during thermal interconversion of conformational isomers. gears and motors.2 0 -di-tert-butylbiphenyl has a high energy barrier to racemization which is observed only at temperatures above 150 1C but the enantiomers of 3.or base-catalyzed racemization. which slowly racemize at room temperature. Similarly. Troger’s base. these examples demonstrate that the categorization of structurally related molecules belonging to the same class of compounds into conformational and configurational isomers is somewhat arbitrary.2 DYNAMIC STEREOCHEMISTRY OF CYCLIC AND ACYCLIC CHIRAL COMPOUNDS Dynamic stereochemistry deals with reversible and irreversible changes of the three-dimensional structure of molecules. For instance. the enantiomers of methylethylpropylamine are often viewed as conformational isomers because they rapidly interconvert through nitrogen inversion. Accordingly. is possible if the process is not too time-consuming.13 Chromatographic isolation of the enantiomers.15 Assignment of the absolute configuration of chiral metal complexes. Although the isolation and stability criteria are practical. such as temperature and time scale. the enantiomers of iii The enantiomers of 2. 2. and they have been exploited in a wide range of applications involving chiral amplification with relays and switches or correlated motion in propellers. Figure 2.2 0 -diiodobiphenyl. and acid.Principles of Chirality and Dynamic Stereochemistry 15 N N N N right-handed screw N N N N N Co N N ∆-[Co(en)3]3+ N N N N N Co N N Λ-[Co(en)3]3+ N N N N N N left-handed screw N = ethylenediamine (en) N = threefold rotation axis Figure 2. Interconversion of configurational isomers often requires bond breaking.2 0 -diiodobiphenyl can be isolated if the chromatographic process is rapid. whereas conformational isomers usually (but not exclusively) isomerize without bond breaking. and butylmethyl¨ phenylphosphine are considered to be configurational isomers because they are stable to racemization at room temperature. that should be applied to distinguish configurational from conformational isomers does not exist. By contrast. Pure enantiomers of 2. The diversity and complexity of dynamic stereochemistry becomes evident through a discussion of conformational and configurational isomerism. photochemical isomerization. 2. and enantioconversion can proceed via rotation about the chiral axis or bond breaking. which has a rotational energy barrier of 97 kJ/mol. Stereodynamic properties of chiral compounds are critical to the success of asymmetric synthesis including dynamic kinetic resolution and chirality transfer processes. The thermodynamic stability and bond breaking criteria stress the physical organic properties of stereoisomers: the isolable enantiomers of bromochlorofluoroiodomethane. Biaryls may or may not be stable to racemization at room temperature. a clear definition of the isolation conditions. but racemization occurs upon standing or during HPLC if the separation process is slow. .3 0 -di-tert-butylbiphenyl can not be isolated at room temperature due to rapid rotation about the chiral axis.2 0 -diiodobiphenyl show on-column racemization during HPLC separation on triacetyl cellulose at ambient temperatures. The ambivalence of this definition is even more evident in the case of 2.iii However. the enantiomers of axially chiral biphenyls can either be classified as configurational or conformational isomers. which are sometimes distinguished based on their stereochemical stability. a relatively high energy barrier to racemization or diastereomerization is commonly associated with configurational isomerism. For example.

As has been discussed above for tartaric acid. the enantiomers of compounds with a chiral center. One shortcoming of this classification is that (E). For example. i. the distinction between configurational and conformational isomerism in the present book is based on differences in bond and torsion angles. Alternatively. a meso (2R. respectively.3S)-configuration. having a chiral axis or plane may thus be regarded as conformational isomers.17. A closer look at the three-dimensional structure of meso 2. Since the stability criterion and the corresponding isolation conditions are not clearly defined.3R)-2.and (Z)-alkenes. As the relative stability becomes irrelevant. but the mixture is always racemic in the absence of a chiral bias.16 t-Bu F Cl Br C I Me Bu P Ph N (S. the enantiomers of butylmethylphenylphosphine display bond angles of the same value. 1-arylpyrimidine-2-thiones and their oxygen analogs can be conveniently isolated by chiral chromatography but undergo racemization during [3.3]-electrocyclic rearrangement involving ring opening and bond breaking at elevated temperature. the stability and bond-breaking criteria are vague and sometimes incompatible. the presence of a . and are problematic in some cases. Organic compounds often exist as a mixture of constantly interconverting conformational isomers. The ratio of the achiral to the two equienergetic chiral conformations of meso 2. achiral compounds populate both achiral and racemic chiral conformations at equilibrium. including Troger’s base and ethylmethylpropylamine. albeit with opposite sign.3-diaminobutane has two chiral centers and forms three configurational isomers. or the enantiomers of allenes and (E)-cycloalkenes. while (2R. irrespective of their rotational energy barrier or isomerization mechanism. in other words.3-diaminobutane can be expected to change with temperature and to vary in the gas.2'-di-tert-butylbiphenyl N t-Bu Chapter 2 t-Bu rotation about the axis of 3. Figure 2.14.and (2S.3'-di-tert-butylbiphenyl O (S)-bromochlorofluoroiodomethane (S)-butylmethylphenylphosphine O Et Me Pr N Pr N N N • N O N Me Et N N N-inversion of ethylmethylpropylamine electrocyclic ring opening and isomerization of 1-(2'-methylphenyl)-4. It should be noted that bond and torsion angles can vary in amplitude and sign..16 Chiral compounds exhibiting conformational or configurational isomerism and racemization mechanisms. All axially ¨ chiral biaryls mentioned above afford conformational enantiomers.3-diaminobutane generates enantiomeric conformational isomers that become diastereomeric in a chiral environment. are considered configurational isomers. with torsion angles varying in either magnitude or sign. Both definitions are commonly used in the literature to classify stereoisomers. A comparison of the chemical and physical properties of acyclic configurational stereoisomers requires analysis of the corresponding mixtures of fluxional conformers.e. configurational isomers have been defined as stereoisomers possessing different bond angles while conformers differ in torsion angles.3-diaminobutane reveals that it adopts three conformational isomers.3S)-isomer and a pair of enantiomers with (2R. In many cases.15 Clearly. 2.S)-Tröger's base t-Bu (S)-2.3-diaminobutane and its enantiomer are inherently chiral and exist as a mixture of three interconverting diastereomeric rotamers. liquid and solid state. This seems somewhat counterintuitive to many chemists.6-dimethylpyrimidin-2-one Figure 2. It is important to realize that facile rotation about the carbon–carbon bond in compounds such as meso 2. The meso isomer can populate an achiral antiperiplanar and two enantiomeric synclinal conformers that rapidly rotate about the central carbon–carbon bond at room temperature.3R).

2 0 -disubstituted biaryls populate two diastereomeric syn.5 and 6.18 Energy profile of 2.3-diaminobutane NH2 H3C H NH2 achiral H CH3 H2N H H enantiomers diastereoisomers diastereoisomers NH2 CH3 CH3 H H CH3 NH2 NH2 CH3 H H NH2 NH2 CH3 H3C CH3 H H (2R. the anti-form is thermodynamically more stable but 2. By contrast.3R)-2.3S)-2.3-diaminobutane. and 100 to 150 1. In the ground state conformation.and anti-conformations. but it does not change the racemic equilibrium.3. with torsion angles in solution usually ranging from 30 to 80 1. for example maleic acid.17 A typical energy profile of 2.3R)-tartaric acid render the enantiomeric conformers of meso 2. respectively. see Chapters 6.Principles of Chirality and Dynamic Stereochemistry meso (2R.3-diaminobutane diastereomeric and selectively favor one over the other. it would also cause severe repulsion between ortho-substituents. hydrogen bond interactions or salt formation with a chiral acid such as (2R. the aryl planes are neither coplanar nor orthogonal due to a compromise between resonance stabilization and steric interactions.3R)-2.iv It is therefore not surprising that conformational equilibria of acyclic and cyclic compounds affect the stereochemical outcome of asymmetric transformations.18.16. selectively stabilizes and thus favors synclinal conformations over the antiperiplanar rotamer. the enantiomers of 2. While coplanarity of the aromatic rings would maximize resonance stabilization.2 0 -dihalobiphenyls have been reported to prefer the syn-conformation. The steric interactions between ortho-substituents are minimized in an orthogonal geometry.3-diaminobutane with an achiral compound.2 0 -disubstituted biphenyls.3S)-2. but at the expense of p-electron overlap which decreases with the cosine of the torsion angle.3S).and (2R. Chelating interactions of meso (2R.2 0 -disubstituted biphenyls is shown in Figure 2. R R R E R (M)-biphenyl R R anti-form R R syn-form (P)-biphenyl R R syn-form R R anti-form -180o -90o 0o 90o 180o Figure 2. As a result.17 Newman projection of the conformational isomers of (2R. see Chapter 3. . In most cases.3-diaminobutane NH2 NH2 H2N CH3 H CH3 NH2 H CH3 17 Figure 2. A well iv Incorporation of sterically demanding substituents into the ortho-positions of biphenyl significantly increases the energy barrier to rotation and favors a near-orthogonal ground state geometry.6. Axially chiral biphenyls undergo racemization via rotation about the pivotal aryl–aryl bond. nonracemic chiral additive can disturb the equilibrium between the enantiomers.

emphasize the importance of careful stereodynamic analysis of chiral substrates.2-asymmetric inductions has been developed. He postulated that the substrate resides throughout the reaction in a preferred conformation having the largest substituent L attached to the chiral center antiperiplanar to the adjacent carbonyl function.18 Assuming a noncatalytic. This simple but powerful rationale was later extended to the so-called Cram chelation model to accurately predict the selectivity of a nucleophilic attack on chiral substrates that possess a stereocenter bearing a heteroatom in a. The restricted conformational freedom leads to a highly diastereoselective transition state in which the nucleophile is delivered from the less sterically hindered face exhibiting the smaller ligand S.3S)-3-methoxy-2-phenylbutan-2-ol in excellent diastereomeric excess. known example is the asymmetric 1.3S)-2. producing (2R. kinetically controlled reaction. attack from the opposite side is impeded by the presence of the larger ligand L. and disregarding electronic effects and the Curtin–Hammett principle. In contrast. yielding (2R. The diastereofacial selectivity of a nucleophilic addition to a chiral ketone depends on the conformational dynamics of the substrate. Scheme 2. The organometallic reagent then approaches the carbonyl group from the less sterically hindered side with the smallest substituent S because the medium-sized substituent M affords greater steric hindrance. 6 and 7. based on Cram’s rule. Scheme 2.1.19 Cram and others showed that a-alkoxy ketones and Grignard reagents form a cyclic structure having the alkoxy group synperiplanar to the carbonyl function. which increases stereoselectivity.20 The preceding discussion. Since the proton provides less steric hindrance than the methyl substituent.3-diphenylbutan-2-ol in 80% diastereomeric excess.18 Cram's rule X R′ M O S L M (S) Ph Ph O H O CH3 PhMgBr Ph Me H Ph Ph OMgBr CH3 Me BrMgO (S) (R) Ph 80% de Ph Si-face attack Br Mg O H Chapter 2 CH3 R Ph Me favored transition state Cram's chelation rule R′ X M O OR S R L Ph O (S) OMe Me2Mg Me H Ph OMe OMgMe Me Ph (R) 99% de OMgMe (S) OMe Si-face attack Me Me Mg O OMe H Me Ph favored transition state Scheme 2. formation of an intermediate dimethylmagnesium complex of (S)-2-methoxy-1-phenylpropanone effectively locks the substrate into a single conformer and thus restricts the number of possible transition states. phenylation occurs preferentially from the Si-face. Cram reasoned that the stereoselectivity of nucleophilic attacks on acyclic ketones and aldehydes could be rationalized by considering a single substrate conformation. For example.1 Rationalization of the stereoselectivity of 1.1.2-addition of organometallic reagents and hydrides to carbonyl compounds possessing an adjacent chiral center.2-nucleophilic additions to chiral ketones. Comparison of the diastereotopic faces of the five-membered chelate explains why the nucleophilic attack on the carbonyl moiety preferentially occurs from the Si-face. A powerful rationale was introduced by Cram.or b-position to the carbonyl function. The diastereoselectivity of the Grignard reaction between phenylmagnesium bromide and (S)3-phenylbutan-2-one can be rationalized by looking at the Newman projection of the favored transition state. reagents and catalysts for . and a variety of models that attempt to predict the selectivity of such 1. and additional examples given in Chapters 5.

Allosteric regulation and homotrophic or heterotrophic cooperativity of enzymes is controlled by reversible binding of molecular activators and inhibitors. An impressive example of stereodynamic control resulting in highly selective chiral induction transmitted through 22 bonds of a conformationally responsive relay has been accomplished by Clayden and coworkers.and b-alkoxy carbonyls is further complicated by Schlenk equilibria.27 as well as for complicated ¨ conformational equilibria. Nevertheless.5.2.30 Conformational analysis of an array of three rigid amide-substituted xanthenes confirmed that the tertiary amide groups prefer anti-conformation to minimize the overall dipole moment and steric repulsion. and their derivatives. -78 oC N (S) N O Ph O (P) O O N (P) O (M) O N 25 Å (M) O N N O (P) O O N OH (P) (S) Ph 77%.25.or (P)-helicity. the simple rationale introduced by Cram has been further refined by Karabatsos.26 accounting for the Burgi–Dunitz trajectory.23 Anh. . 8.. Cram’s model is still commonly used to predict 1.22. Cram’s model correctly predicts the stereochemical outcome of many diastereoface-differentiating additions.21 Felkin. Hammond’s postulate. To overcome these limitations.2 Remote stereocontrol and asymmetric induction via conformational communication along a tris(xanthenedicarboxamide) relay. competition between acyclic and cyclic reaction pathways and solvation effects.24 and Heathcock. see Chapters 6.2asymmetric induction in nucleophilic additions to aldehydes.29 and competing steric and electronic effects.11. which ultimately affects a distant active site. imines. The mechanism of Grignard reactions of a. conformational communication in proteins is the basis for remote reaction control. except for reactions involving a-halogenated ketones and a-substituted cyclohexanones. i.1 and 8. As each of the six amide groups adopts an anti-conformational orientation relative to the previous one. ketones. The binding of a so-called effector induces a change in the three-dimensional enzyme structure.4. This local conformational induction then propagates by a domino effect through the contiguous xanthenedicarboxamide moieties showing either (M). including propellers and motors mimicking nature. the central chirality of the oxazolidine ring triggers formation of a N (S) N Ph O O (P) O O N (P) (M) N O O (M) O N N O (P) O O N (P) CHO PhMgBr.28 Curtin–Hammett kinetics.Principles of Chirality and Dynamic Stereochemistry 19 prediction or interpretation of asymmetric induction.e. Scheme 2. 95% de Scheme 2. Introduction of an ephedrinederived (S)-oxazolidine residue at one terminus of a tris(arenedicarboxamide) framework consisting of three xanthene rings induces a right-handed twist (P-helicity) on the first two amide groups attached to the neighboring arenedicarboxamide. The idea of stereoselective communication and remote chiral induction is fascinating to synthetic chemists and stereochemists alike. The stereodynamics of chiral compounds can afford sophisticated relays and molecular devices.

Disubstituted cyclohexanes can have cis. The stereodynamic behavior of cyclic molecules is more restricted than that of acyclic compounds.3disubstituted cyclohexanes that are stabilized by intramolecular interactions such as hydrogen bonding and trans-1. Grignard reaction with phenylmagnesium bromide at –78 1C gives the corresponding secondary (S)-alcohol in 77% yield and 95% de as a consequence of [1.3.20 kJ/mol cis-1.19 Relative stability of configurational (top) and conformational isomers (bottom) of dimethylcyclohexanes. dipole–dipole interactions and 1.2-. and is controlled by torsion (Pitzer) and angle (Baeyer) strain. intramolecular hydrogen bonding can have a dramatic effect on the relative stability of conformational isomers. trans-1. and trans-1.and six-membered rings form envelope and chair conformations to balance torsion and angle strain.4-cyclohexanes. In particular.31 In general. In the case of cis-1.20 1. the corresponding trans-1. substituents can occupy equatorial or axial positions.5 kJ/mol o Figure 2.4-disubstitued isomers interconvert between diaxial and diequatorial chair conformations. Cyclic molecules experience less conformational flexibility to balance both factors.4-di-O-pyrenecarbonylxylopyranoside by Yuasa and coworkers revealed that the 4 C1-conformer of this carbohydrate exhibiting all four substituents in equatorial positions is favored over the 1C4-conformation in DMSO and methanol.5 kJ/mol o ∆G = 15. one substituent occupies an axial and the other an equatorial position.4-transannular repulsion.83 kJ/mol trans-1. robust atropisomeric array and controls the outcome of diastereoselective reactions at the remote aldehyde group located at the other terminus. and other stabilizing or destabilizing forces such as hydrogen bonding. Spectroscopic analysis of the stereodynamics of methyl-b-D-2.95 kJ/mol trans-1. cis-1.19. and cis-1. Scheme 2. the chair bearing the substituent in equatorial position is thermodynamically favored.5 nm. The ring flip is therefore controlled by intramolecular hydrogen bonding and the presence or absence of solvents that interfere with this interaction.3-isomers 1.3-. The high degree of rotational freedom inherent to acyclic molecules allows effective minimization of steric and torsional strain. Isomerization of one chair to the other proceeds via transient boat and twist conformations.3-.4-isomer ee aa ee aa ee aa ∆G = 11. intramolecular hydrogen bonding between the free hydroxyl and the methoxy group stabilizes the 1 C4-conformation and excimer formation in chloroform and other aprotic solvents. Three-membered and a few four-membered rings are flat while the ring geometry of all other cycloalkanes is nonplanar and usually quite fluxional.2-.2-isomers 1. Puckering of fourmembered rings is common and reduces torsion strain.23]-asymmetric induction over a distance of 2. Five. converting axial into equatorial positions and vice versa. Monosubstitued cyclohexanes are achiral but exist as a mixture of two diastereomeric chair conformations that rapidly interconvert at room temperature via ring inversion. As a consequence. and this generates a variety of stereoisomers.3-isomer ∆G = 7. Figure 2. the latter being thermodynamically favored.2-dihalocyclohexanes which preferentially populate the diaxial conformation.4-isomers Chapter 2 cis o trans cis o trans cis o trans ∆G = 7. with the exception of some diaxial cis-1.5 kJ/mol o ∆G = 11.or transconfiguration. albeit at the expense of some angle strain.32 However. The more stable isomer is underlined.2-isomer ∆G = 8. By contrast.3-syndiaxial or 1. .

. The situation is different in cis-1.2. Reetz and Stanchev obtained the axial carbinol via organiron(II)-mediated diastereofacial addition of butylmagnesium chloride in 76% de.. The conformations of cis.2-diaminocyclohexane is inherently chiral. Reduction of 4-tert-butylcyclohexanone with lithium aluminum hydride proceeds preferentially via axial attack and produces the equatorial alcohol as the major product. very small nucleophiles such as hydrides or acetylides experience less steric interaction with the remote 4-tertbutyl group and favor the axial approach to avoid local interactions with the axial hydrogens at C-2 and C-6.4-disubstituted cyclohexanes have a plane of symmetry and are generally achiral.v Introduction of different substituents into 1.3-disubstituted cyclohexanes are chiral. All trans-1.20.Principles of Chirality and Dynamic Stereochemistry 4 21 1 C1-conformer O O HO O O OMe O C4-conformer O H O OMe CHCl3 DMSO O O O O Scheme 2. Most nucleophiles including Grignard and organolithium reagents approach the carbonyl group at an angle close to 109 1 (Burgi–Dunitz ¨ trajectory) from the site opposite to the bulky tert-butyl group. Figure 2.2diaminocyclohexane generates the corresponding diaxial conformer but it does not produce a mirror image. . Since the contribution from the less stable cyclohexanone conformer having the tert-butyl group in the axial position is negligible. irrespective of the structure of the substituents. The diaxial and diequatorial isomers of cis-1. trans-1.and trans-1.and trans-1. whereas both cis. For example. Nucleophilic additions to 4-substituted cyclohexanones often proceed with low selectivity because of the conformational flexibility of the six-membered ring and weak stereoselective induction from the remote substituent. The predominant formation of (1R. Scheme 2. e.33 By contrast.3 Ring inversion of methyl-b-D-2. This is generally attributed to a less shielded equatorial attack on the carbonyl of the predominant conformation of 4-tert-butylcyclohexanone.3-disubstituted cyclopentanes are chiral. trans-1.and cis-1. which in most cases improves diastereoselectivity.3-diaminocyclohexane possess a symmetry plane and are achiral.and trans-1. Incorporation of small groups into the a-position of cyclohexanone does not change the preference of lithium aluminum hydride for an axial attack. the enantiomeric conformers can not be isolated at room temperature due to rapid interconversion via chair inversion.g.2. ring flipping does not result in racemization and the enantiomers are isolable at room temperature.4-di-O-pyrenecarbonylxylopyranoside. the sterically demanding tert-butyl group prefers to reside in the equatorial position and effectively locks 4-tert-butylcyclohexanone into one conformation. In these cases. i. Although cis-1.and trans-1-amino-2-methylcyclohexane exist as two pairs of noninterconverting enantiomers.and 1. cis.and trans-1. Computation of the two conformations of (R)-2-methylcyclohexanone shows that the methyl group does not strongly interfere with an axial approach. ring inversion of the diequatorial isomer of trans-1. the prediction of diastereoselective reactions of 4-tert-butylcyclohexanone is simplified and requires stereochemical analysis of only a single conformer. even when the two substituents are identical.2.e.3-disubstituted cyclohexanes.2-cyclobutanes and trans-1.2-cyclopropanes are inherently chiral.3-disubstituted cyclohexanes provides a mixture of separable stereoisomers.2.4. However.3-cyclobutanes exhibiting identical substituents are achiral. Similarly.2R)-trans-2-methylcyclohexan-1-ol can be attributed to a relatively rapid hydride addition to the major conformer of (R)-2-methylcyclohexanone having v The same considerations apply to cyclopentanes.

5. these interactions exceed the repulsion between the approaching hydride and the axial hydrogens at C-2 and C-6. An increase in the steric bulk of the a-substituent further locks the ketone into the equatorial conformation and results in enhanced steric hindrance to an axial attack.22 trans-diaminocyclohexanes NH2 NH2 NH2 ee-conformation NH2 aa-conformation NH2 aa-conformation NH2 H2N H2N ee-conformation rapidly interconverting enantiomers noninterconverting enantiomers NH2 NH2 NH2 ea * H2N ae ae NH2 ea NH2 * H2N NH2 H2N NH2 NH2 NH2 NH2 ea-conformation cis-diaminocyclohexanes NH2 NH2 Chapter 2 NH2 H2N ae-conformation NH2 interconverting achiral conformations noninterconverting enantiomers *ring flipping produces identical structures trans-1-amino-2-methylcyclohexanes ee NH2 H2N ee ea cis-1-amino-2-methylcyclohexanes NH2 H2N ea NH2 aa NH2 aa ae NH2 NH2 ae noninterconverting enantiomers noninterconverting enantiomers Figure 2. Diastereoselective Gignard addition axial attack BuMgCl 109o O O interconverting chair conformations 109o equatorial attack (favored) BuMgCl Fe(acac)2 axial carbinol Bu OH equatorial carbinol minor isomer OH major isomer Bu Diastereoselective reduction axial attack (favored) H OH 109o O H H 109 o minor isomer H LiAlH4 axial carbinol H major isomer OH equatorial carbinol H equatorial attack Scheme 2. In the case of 2-tert-butylcyclohexanone. Scheme 2. and .4 Stereoselective Grignard reaction and reduction of 4-tert-butylcyclohexanone with LiAlH4. the methyl group in the equatorial position.20 Conformations and chirality of disubstituted cyclohexanes.

Because the double bond and the two adjacent saturated carbon atoms C-3 and C-6 are in one plane. For the same reason. although the energetic difference between equatorial and axial conformers is less pronounced in cyclohexenes as a consequence of the reduced steric repulsion experienced by axial substituents.37 In accordance to the anomeric effect observed with carbohydrates.2R)-2-methylcyclohexan-1-ol 42% Scheme 2.34 An interesting example that underscores the significance of the relative population and interconversion of configurational isomers is the diastereoselective N-oxidation of N-methyl-4-tertbutylpiperidine. . Figure 2.Principles of Chirality and Dynamic Stereochemistry axial attack (favored) 109o Me O 109o Me LiAlH4 H cis-(1S. the vi Because both N-inversion and oxidation are rapid processes with similar reaction rates.2R)-2-methylcyclohexan-1-ol 76% equatorial attack axial attack H t-Bu O t-Bu LiAlH4 H H H H equatorial attack (favored) cis-(1S. Electronegative substituents such as halides or amino. Reaction with hydrogen peroxide proceeds more quickly with the minor diastereoisomer because it provides a more accessible equatorial position for oxidation.6.2R)-2-methylcyclohexan-1-ol 58% OH axial attack (favored) t-Bu + H OH trans-(1R.2R)-2-methylcyclohexan-1-ol 24% axial attack (favored) equatorial attack OH Me + 23 H H H H H equatorial attack OH trans-(1R. the general preference of allylic substituents for a pseudoequatorial orientation is less pronounced than the difference in the relative stability of axial and equatorial positions in saturated rings.3-syndiaxial repulsion between the axial methyl group and two axial hydrogens. In cyclohexene rings. the relative population of the conformational piperidine isomers has a major effect on the stereochemical outcome of the oxidation.5 Diastereoselective reduction of (R)-2-alkylcyclohexanones. amido and alkoxy groups favor the pseudoaxial position. The reported oxidation product ratio of 19:1 in favor of the axial N-oxide can be attributed to competing nitrogen inversion and diffusion-controlled diastereoselective oxidation. whereas two 1. this compound exists as a mixture of two rapidly interconverting isomers having either an equatorial or an axial methyl group. Similar to cyclohexanes. The piperidine conformer that bears the methyl group in the equatorial position is approximately 60 times more thermodynamically stable than the axial conformer due to 1. Although N-inversion is a rapid process. substituents preferentially occupy equatorial positions.vi Cyclohexenes exist in two half-chair conformations that rapidly isomerize at room temperature.36 As a result of facile N-inversion. axial groups participate in only one 1.35. allylic substituents reside in pseudoequatorial and pseudoaxial positions while carbons C-4 and C-5 generate truly axial and equatorial positions.21. Scheme 2. the Curtin–Hammett principle does not apply.3-synpseudoaxial interaction. reduction with LiAlH4 affords 2-tert-butylcyclohexanol as a 58:42 diastereomeric mixture in favor of the cis-isomer.3-syndiaxial interactions with truly axial hydrogens destabilize the axial conformation in cyclohexanes.

The relative stability of the half-chair conformation of disubstituted cyclohexenes or tetralin (1.3-syndiaxial repulsion axial conformer 1. synpseudoaxial repulsion.3.6 Oxidation of N-methyl-4-tert-butylpiperidine.4-tetrahydronaphthalene) derivatives depends on a variety of intramolecular interactions in addition to torsion and angle strain.3. Figure 2. For example. this selector forms a chiral cleft which appears to be crucial for enantioselective recognition. NHR.3.5 0 -dinitrobenzamido)-1. OH.3-synpseudoaxial repulsion axial conformer X X = Cl.4-tetrahydrophenanthrene at carbons C- Most important are resonance between the double bond and the pseudoaxial allylic s-bond.3-syndiaxial repulsion H H N equatorial N-oxide 5% H2O2 O k4 H N axial N-methylpiperidine (minor isomer) Chapter 2 H H k1 k2 N H2O2 k3 O N axial N-oxide 95% equatorial N-methylpiperidine (major isomer) k3 < k4 k1/k2 ~ 60 Scheme 2. Wolf and Pirkle studied the conformational preference and rigidity of disubstituted 4-(3 0 .5 0 -dinitrobenzamido)-1. dipole–dipole interactions.24 1.4-tetrahydrophenanthrene derivatives which are structural analogs of the so-called Whelk-O selector.2. axis or plane in close proximity to a hydrogen bond acceptor (usually a carbonyl group).vii It is assumed that only one enantiomer of a given racemate can diffuse into the cleft to undergo simultaneous hydrogen bonding to the amide function and face-to-face and face-to-edge interactions with the aromatic moieties while maintaining a heavily populated low energy conformation.21 Substituent effects on the relative stability of cyclohexane and cyclohexene conformations.5 0 dinitrobenzamido)-1. and hydrogen bonding.39–44 The propensity of the DNB group to occupy the pseudoaxial position in 4-(3 0 . incorporation of a methyl group into the saturated moiety of 4-(3 0 .2. OR π σ* H equatorial conformer resonance stabilization in unsaturated rings with pseudoaxial electronegative substituents Figure 2. Br. C-2 and C-3 alters the relative stability of the conformer having the benzylic amido group in pseudoaxial position. isopropylcyclohexane H H H i-Pr i-Pr equatorial conformer H i-Pr H H H 4-isopropylcyclohexene H H H H H H i-Pr H H H H 1. Chiral HPLC separation of the racemic Whelk-O analogs shown in Table 2.2.4-tetrahydrophenanthrenes was evaluated based on chromatographic structure-activity relationships. preference for the pseudoaxial position has been explained with resonance stabilization due to overlap of the p-system of the double bond and an antibonding orbital of the allylic s-bond. .1 on an vii The Whelk-O selector has been used extensively for chromatographic enantioseparation of compounds exhibiting a stereogenic center.38 Initially developed to separate the enantiomers of naproxen and other profens.

3.5'-dinitrobenzamido)-3methyl-1. as depicted in Figure 2. 3597–3603. In this case. Introduction of a methyl group into positions C-1.5 0 -dinitrobenzamido)-1.3. 4R)-4-(3'. Hydrogens bonded to carbon atoms are not shown.22 Chiral cleft and favored conformation of the Whelk-O selector participating in simultaneous hydrogen bonding. The difference in the Gibbs free energy between the transient diastereomeric complexes formed by the enantiomers of 4-(3 0 . DDG1. one has to remember that the tetrahydrophenanthrene ring of these Whelk-O analogs resembles a cyclohexene or tetralin structure and that the benzylic electron-withdrawing benzamido group generally prefers the pseudoaxial position.1. In contrast. face-to-face and face-to-edge interactions. and DG1 is the Gibbs free energy of the formation of transient diastereomeric complexes. 58. Table 2.4R)-Whelk-O selector pseudoaxial DNB group O (S)-naproxen diamide Me2N (S)-naproxen dimethylamide 3) NO2 O 25 O NO2 1) equatorial methyl 1) hydrogen bonding 2) face-to-edge interaction 3) face-to-face interaction cis-(3R. These energetic differences can be correlated to the influence of the methyl group on the relative stability of the Whelk-O conformers.Principles of Chirality and Dynamic Stereochemistry (3R. In order to understand the chiral recognition mechanism. DDG ¼ ÀRT ln a ð2:1Þ where a is the chromatographic separation factor. face-to-face and face-to-edge interactions with (S)-naproxen dimethylamide. The high selectivity has been attributed to extensive population of the conformer that has the benzamido substituent in .2. of the transient diastereomeric complexes formed between the CSP and the enantiomeric solutes is reduced as none of them can accommodate simultaneous hydrogen bonding.87 kJ/mol. enantioselective recognition is diminished when the Whelk-O enantiomers are likely to adopt a structure with a pseudoequatorial DNB group. C-2 and C-3 of the 4-amidotetrahydrophenanthrene ring yields three pairs of diastereoisomers having either cis. Stabilization of a cleft-like structure bearing a pseudoaxial DNB group results in high enantioselectivity because (S)-naproxen fits perfectly into the chiral pocket of one of the chromatographed Whelk-O enantiomers. the difference in the Gibbs free energy.2.1.4-tetrahydrophenanthrene and the (S)naproxen-derived chiral stationary phase was determined as 3. of transient diastereomeric complexes according to Equation 2. [Reproduced with permission from Tetrahedron 2002. DDG1.] (S)-naproxen amide-derived chiral stationary phase allowed determination of the difference in the Gibbs free energy.22.or trans-configuration.4-tetrahydrophenanthrene 2) NH Figure 2.

77 cis-2.1 Energetic differences of transient diastereomeric complexes of Whelk-O analogs and immobilized (S)-naproxen diamide. The stereoselectivity observed with the transisomer is therefore reduced to 3.52 trans-2.26 Table 2.0 kJ/mol. By contrast.and trans-4-(3 0 .4-disubstituted Whelk-O derivative because it bears an axial methyl group.05 trans-3.3.4DNBHN 3. The cis-configuration preferentially populates the conformation with a pseudoaxial DNB group and an equatorial methyl group over the conformer having the DNB group in pseudoequatorial and the methyl substituent in axial position.2. DNB ¼ 3.5-dinitrobenzoyl group.92 Only one enantiomer of the racemic Whelk-O analogs is shown.5-DNB group perpendicular to the tetrahydrophenanthrene plane. thus forming a chiral cleft exhibiting the 3. the cleft-like conformation is less heavily populated in the trans-3.4DNBHN 3.4-tetrahydrophenanthrene.77 kJ/mol.4-tetrahydrophenanthrene can afford a conformation having the two substituents in .4DNBHN 4. The enantiomers of trans-4-(3 0 . pseudoaxial position.5 0 -dinitrobenzamido)-3-methyl-1.3.02 cis-1. Incorporation of a methyl group into the adjacent position provides cis.87 cis-3.2. The cis-3. which is a prerequisite for effective chiral recognition.4DNBHN 1.4-disubstituted Whelk-O analog therefore strongly favors the cleft-like conformation and undergoes highly enantioselective interactions with (S)-naproxen exceeding 4.4DNBHN 1.5 0 -dinitrobenzamido)2-methyl-1.56 trans-1.4DNBHN 3. Relative configuration DDG1 [kJ/mol] Chapter 2 Whelk-O derivative / DNBHN 3.

H. Vallverdu.. Sobanski. 2288-2294. pp. Chem. Hortelano. Am. A. F. 18. Am. 67. Am. L. E. Sekhar. B. 1994. 431. 77. Newell. 385-415. . 40. G. Chem. 116. C. A. 5828-5835. J.. Clearly. Chem. V. Tetrahedron Lett. Soc. Adjimi. Cherest. 9... 567-583. E... 7. S. Am. 1996. Nouv. Lodge.. ¨ 28. 26. Soc. Rissanen. Schefter. J.. C. J. Nierengarten.-C. E. 23. F. 334-338.-P. A. J. Heathcock. J. Owtschinnikow. Stand.4tetrahydrophenanthrene shows superior enantioselectivity (DDG1 ¼ 3. The cleftlike conformer is therefore more heavily populated by the trans-2. Soc. Prudent. Cram.. Chem. C. Helmchen.. Wiley. Staigers. Chem. Karabatsos. 21. 19.. Soc. 9. 95. K. H. K. 395-402. R. J. Konig. Am. J. L. Am. J. 3. Prelog. J. 1. 2294-2302. Chem. C. 17. 20. Eliel. Kopecky. Helv. Roussel. 15. Accordingly. E. W. Sauvage. O. Boyd. S. 1987. J. 10. Chen. Int. Chem. 1952. Chem. Chemlal. Chimia 1986. Soc. Chem.52 kJ/mol). 53. Angew. Handel... J. J. R. Sauvage.. D. Helv. H. Engl. 1997. K. Am.. 7. 6. T. J.5 0 -dinitrobenzamido)-1-methyl-1. Finneman. D. A.. 22. H. J. J. Dunitz. O. Roussel. Bur. J. Clayden. 29. M. I.. J.4-isomer must place the methyl group in axial position in order to form the cleft with a pseudoaxial DNB group. Dietrich-Buchecker. V. 1963. A. R. 610-611. N. Chem. C. 1674-1682. Harren. 4. ¨ ¨ ¨ 6. Acta 1964. C. J. Chim. M. 3353-3361. Wilen. 1667-1668. 961-963. H. Cram. 375-376. 74. 27. 2748-2755. REFERENCES 1. 25. Can. 1968. J. 1988. Reson. Chem. A. Soc. 2 2001. Prelog. Am. 5076-5080... 1982.-P. Sect. C. Res. X. 61-70. Mislow. Djafri. H. Engl. Lund. 25.. (S)-naproxen effectively differentiates between the enantiomers of the trans-isomer (DDG1 ¼ 3. Chem. 2199-2204.. Prelog. 21. A. N. L.02 kJ/mol) but enantioselective separation and recognition of the cisdiastereomer is diminished (1. Soc. 52-54. Eisenstein. D. D. Elhafez. Frye.. K. 105. Stereochemistry of Organic Compounds. Finally. Prelog. Soc. Am.. 1973. Magn. Chem. 9558-9559.. 2000. 47. 966-971. Acta 1964. M. Am. 1992. 1955. L. V.3. Ingold. ¨ 14.. M. V. 1966. the relative stability and stereoselectivity of the cleft-like Whelk-O conformers originate from an energetic compromise between the tendency of the DNB group to occupy a pseudoaxial position and the preference of the methyl group for an equatorial or pseudoequatorial orientation.. 24. Y.. Chambron. L. Baudais. Anh. Ed..92 kJ/mol) because the cleft-like conformer is destabilized in the latter due to synpseudoaxial interactions experienced by the methyl group. K. J. Vogtle. 11. Liebigs Ann. 12. Nature 2004. 119. 5. J. 591-599. 81.56 kJ/mol) over the trans-disubstituted analog (1. J. Helliwell. Chorev. 1292-1299.. R. Chirality 1995. 1367-1371. 5. Curtin. J. Chem. Chimie 1977. P. Cahn.. 16. M. New York. 1954. Flippin. 13. 89. A. J. Jager. J.. whereas the cis-2. Eur. 63. R. 1985.. 1968. 2. 266-272. Soc. G. 1992.. V. Tetrahedron Lett. J..4-isomer than by the cisderivative. T. cis-4-(3 0 . Gerlach.. F. M.. Rec. Goodman.. R. M.. Org. M. A. 1985. Felkin. G. 109. Heathcock. 47.. G. 23. Res. 111-128.Principles of Chirality and Dynamic Stereochemistry 27 the preferred pseudoaxial and equatorial orientations. 1176-1181.. 2205-2208. Tauber J. Int. Soc. M. 1967. 1778-1784. Chem. Burgi. A. C. Gerlach. Roberts. J. 30. Acc.. Chem. H. Soc. Chem.. Chem. Dynes. Progr. Eliel.. Chem. Vogtle. 15. V. K.2.. Chim. Perkin Trans. J. DeVries. 9. Mohry. Angew. ¨ 8. S. J. F.-F. 5065-5067. M. L. 1994. 1959. H. Nat. E. Cherest. 1983. C. L. Ed. Reuter.. Wolf. Felkin. S. 1201-1207.. J. 114... Hammond. A.

S.. W.. 177-184. Welch. Spence. H. 173-178. New York. P. J. L. Chromatogr. Chem. 328-330. H.. 799. M. Martino. Chem. Crowley. Volpe. W.. 6.. Nakatani. Shvo. J. 1997.. Cavender. Chromatogr. Izumi. W. 3854-3860. M. J.. Spence. 39. W. E. D. W. 3287-3290. 21. 917-924. 42. Org. M. R. 33. Pirkle. Stanchev. C. E. G. 1992. H. Miyagawa. Tetrahedron 1977. 41. V. Rozing. 44. 573-580. 1972. Lett. C. Robinson. C. F. Eliel.. 785. Y. C.. L. Commun. 55. M. M. 2004. Chem. Wolf. P.. H.. A 1997. J. 1993. Wilen.. 1971. 58. Kaufman. J. T. . C. S. J. Yuasa.. R.. Izumi. Lessard.. Reetz. 1015-1023. Ashby. C. Org. Derrico. Chromatogr. 40. Ward.. Lamm. Pranatharthiharan. L. M. 37. A 1998. H. Wolf. H. Chem... Org. J. Pirkle. P. 33. M. W. Tetrahedron. Derrico. 34. J. Chem.. Electrophoresis 2000... Tan. Pirkle. Pirkle. E. B. Hashimoto.. 35. Wiley. Wolf. Sevenair. E. 3597-3603. Wolf. 197-199. E. 43. J. Wolf. C. 28. Pirkle. D. Pirkle. C. H. H.. J. C. E. Soc.28 Chapter 2 31. Tetrahedron 2002. Stereochemistry of Organic Compounds. G. 36. P. M.. 175-179. 32. D. Chem. H. J. 686-725. A 1997. 782. Dobbs. M. 36. Org. T. Can. 1489-1492. K. J.. 38. P. 2003.. 915-925. J... L... pp. 1994. 57.. 68. Saunders. P. J. M. Cavender. N. Wolf.

the design of microscopic motors and machines. Me Et N Me i-Pr ∆G = 31. Because of the inherently low energy barrier to interconversion..1. amines that have three different substituents at the stereogenic nitrogen atom exist as a pair of configurationally unstable enantiomers..1 Interconversion of the stereoisomers of ethylmethylisopropylamine and chlorocyclohexane. . Compounds that exist as a mixture of rapidly interconverting stereoisomers are often conveniently. A closer look reveals that organic compounds are generally fluxional and adopt more than one conformation or configuration.4 kJ/mol. are indispensable for today’s chemist. drug discovery and medical diagnosis. Cl Scheme 3. enantiomerization and diastereomerization of chiral compounds play a key role across the chemical sciences and provide multiple opportunities for asymmetric synthesis. Both processes. Enantiomerization and Diastereomerization The development of mechanistic insights into isomerization reactions. racemization of ethylmethylisopropylamine and diastereomerization of chlorocyclohexane. and monosubstituted cyclohexanes populate two diastereomeric chair conformations (and negligible twist conformations) having the substituent in either equatorial or axial position. and the activation energy required for ring flipping of the isomers of chlorocyclohexane is about 44 kJ/mol. faster methods such as time-resolved microwave and IR spectroscopy generate an instantaneous rather than a time-averaged spectrum and can be used to study the structures and properties of stereolabile isomers even at room temperature. One can distinguish between diastereotopic proton signals of the individual isomers of monosubstituted cyclohexanes or chiral amines in the presence of a chiral shift reagent under cryogenic conditions when the rates of interconversion are relatively slow with respect to the NMR time scale. A basic understanding of the properties and reactions of chiral compounds requires in-depth analysis of the stereodynamics of coexisting isomers. albeit inaccurately. Alternatively. Scheme 3. it is often difficult to distinguish between the individual isomers of stereolabile compounds. and information about the conformational and configurational stability of chiral compounds under various conditions. The energy barrier to pyramidal inversion of ethylmethylisopropylamine is 31.CHAPTER 3 Racemization. Racemization. For example. viewed as one averaged structure. are fast and only one averaged species is observed by NMR spectroscopy at room temperature.4 kJ/mol ≠ Et N i-Pr Cl ∆G ≈ 44 kJ/mol ≠ . 29 .

The half-life time of enantiomerization is the time required for 50% interconversion. At the microscopic level. Since enantiomerization and racemization kinetics are frequently employed to describe the same process. Alternatively. for instance by dynamic kinetic resolution or asymmetric transformation of the second kind. the same process is perceived as a reversible enantiomerization reaction with a different rate constant kenant ¼ 0. isomerization reactions can be viewed at the molecular level.. whereas the microscopic view takes into account the individual rate constants of reversible reactions.S) k1 ≠ k-1 Figure 3. it is important to distinguish between the different mathematical treatment and the corresponding rate constants. a change from 100% ee to 0% ee. This process is completed when all molecules have been converted to the other enantiomer. while other methods such as dynamic chromatography or proton–deuterium substitution analysis by 1H NMR spectroscopy afford enantiomerization rates. Kinetic analysis of diastereomerization is more complex than the study of racemization or enantiomerization because the rate constant for the transformation of one diastereomer to another is different from the rate constant of the reverse reaction.i The macroscopic analogy to epimerization is mutarotation which describes the irreversible change in the optical rotation of an epimeric mixture until equilibrium is reached.5 krac.1 CLASSIFICATION OF ISOMERIZATION REACTIONS OF CHIRAL COMPOUNDS Stereomutations of conformationally and configurationally unstable chiral molecules can be treated as a macroscopic process. i.2. The macroscopic change is by definition irreversible. kenant and krac.30 Chapter 3 3.1 i Classification of isomerization reactions of chiral compounds. Racemization (R) (R) Enantiomerization (R) (R) (R) (R) (R) krac (S) (R) (R) (S) (R) (S) krac (S) (S) (S) (S) (S) (S) kenant (S ) kenant krac = 2 kenant Diastereomerization (R.1 Racemization is an irreversible process that is completed when 50% of an enantiopure compound has been converted to the other enantiomer. Diastereomers possess different thermodynamic stabilities and an equimolar ratio is not usually obtained at equilibrium. Epimers are defined as diastereoisomers that differ in only one configuration of two or more elements of chirality. The corresponding half-life time is the time during which the enantiomeric excess of a chiral mixture has been reduced to half its initial value. .3 Such unidirectionality can also be achieved if enantioconversion is coupled with stereoselective removal of one enantiomer from the equilibrium. in which an enantiopure or diastereomerically pure compound is transformed by thermal equilibration either to a racemate or to a diastereoisomeric mixture. Monitoring of the macroscopic change of a nonracemic mixture of stereolabile enantiomers using polarimetry or circular dichroism spectroscopy provides the rate of racemization. as it refers solely to the interconversion of epimers.e. Figure 3. respectively.1. For example. Epimerization is a special case of diastereomerization. (R)-profens are enantioselectively and irreversibly transformed to the (S)-enantiomer by coenzyme A conjugate. for example from 100% ee to 50% ee. Enantiomerization is usually reversible and leads to the formation of a racemate but many unidirectional processes resulting in complete enantioconversion are known.R) k1 k-1 (R.

The entropic driving force for racemization at 25 1C can be estimated as DG1 E –RT ln 2 which corresponds to –1. Racemization is treated according to irreversible first-order kinetics: dx ¼ krac ðR0 À xÞ dt ð3:1Þ where R0 is the initial concentration of the (R)-enantiomer. the equation becomes: t1=2 ¼ ln 2 2 kenant or t1=2 ¼ ln 2 krac ð3:5Þ Both detection and control of racemization are important tasks in asymmetric synthesis because it can affect the stereochemical outcome of a reaction and compromise the stereoisomeric purity of the product. Nevertheless. In particular. and krac is the rate constant of racemization. t1/2.Racemization. In other words. Chiral drugs that possess an asymmetric center carrying a proton next to a carbonyl moiety can racemize via base.1 Racemization Racemization is irreversible. racemization can be utilized as a powerful tool in obtaining enantiopure products from racemic starting materials via dynamic kinetic resolution (DKR). provided one can disregard enthalpic contributions from heterochiral interactions that can occur in racemic mixtures in addition to strictly homochiral interactions in enantiopure solutions. . x ¼ R0 – R. can be calculated using the rate constant of enantiomerization kenant (assuming S0 ¼ 0 at t ¼ 0):ii       xeq R0 RþS ln ð3:4Þ ¼ 2 kenant t ¼ ln ¼ ln RÀS xeq À x 2 R À R0 where R0 ¼ R þ S.7 kJ/mol. Enantiomerization and Diastereomerization 31 3. At 50% ee. Zx 0 dx ¼ Àkrac R0 À x Zt dt 0 ð3:2Þ Integration of both sides of the equation gives:   R0 ln ¼ krac t R0 À x ð3:3Þ The half-life of racemization. and is completed when the thermodynamic equilibrium (ee ¼ 0%) is reached. Similarly. A close look at the solvent-dependent enolization of 2-benzoyl cyclohexanone and the palladium-catalyzed interconversion of axially chiral allenes reflects these opposite perspectives on racemization. a basic understanding of the stereochemical integrity of a chiral drug is crucial for ruling out undesirable racemization which may potentially occur under physiological conditions or during long time storage. it is sometimes important to prevent enantioconversion of a chiral compound while in other cases it becomes advantageous if one can identify conditions and catalysts that facilitate racemization.1.or acid-catalyzed keto/enol-tautomerization. b-diketones and b-keto esters such as 2-benzoyl ii The half-life of racemization is the time it takes to reduce 100% ee to 50% ee. The driving force for racemization is the increase in entropy. This is important because stereoisomers are likely to have different pharmacological and pharmacokinetic properties.S (concentration of the racemate at time t).

0 1C.2 Enantioconversion pathways of 2-benzoyl cyclohexanone and analysis of the racemization kinetics in hexanes and ethanol at 66. Campbell and Gilow showed that 2-benzoyl cyclanones mainly exist in the keto form.0 min k3 k4 O O k4 k7 O krac = 0.32 O 5 4 3 2 0 100 200 300 400 500 1/2 Chapter 3 OH trans-exo-enol ln % ee = 552. and the corresponding half-life times in ethanol and hexanes.5 Protic solvents such as ethanol stabilize the three possible intermediate enol forms through hydrogen bonding and thus affect the thermodynamics and kinetics of the tautomerization.and solvent-dependent equilibria.0 1C.] cyclohexanone are prone to enolization. although this effect is somewhat reduced because the disruption of the intramolecular enol hydrogen bond and subsequent formation of intermolecular hydrogen bonds with the solvent is associated with negative entropy contributions. They determined the keto/enol ratio of 2-benzoyl cyclohexanone in methanol as 97:3. While the stereochemical stability in alkanes and other aprotic solvents iii The cis-exo-enol form has an extended conjugated system with an exocyclic double bond. Only the cis-enols undergo intramolecular hydrogen bonding which is probably disrupted in protic solvents. The interconversion of the enantiomers of 2-benzoyl cyclohexanone is further complicated by the fact that the intermediate cis-exo-enol form undergoes exo/endo-isomerization to the trans-exo-enol isomer. even in the absence of base or acid. Protic solvents favor formation of the intermediate enol tautomers and subsequent racemization which has been confirmed by NMR spectroscopy.iii The racemization can therefore proceed via parallel reaction pathways that are linked through complex temperature. 17.2.6 Enolization of b-keto esters is enthalpically favored in protic solvents. The results demonstrate that enantiopure b-diketones are potentially useful building blocks for asymmetric synthesis. as long as the choice of solvent is taken into consideration. reveals that the configurational stability of 2-benzoyl cyclohexanone is highly solvent-dependent. Comparison of the racemization rate constants.8 min cis-endo-enol 0 0 krac = 2. but tautomerize to some extent in protic solvents. The relative stability of the enol intermediates therefore depends on the nature of the solvent. .1·10-4 s-1 k8 k3 hexanes 600 700 O OH O time (min) k1 (S) H k2 k1 (R) H k2 cis-exo-enol k5 k6 k9 OH k10 k6 k5 6 O ln % ee 4 2 1/2 = 23. [Modified with permission from Chirality 2005. Scheme 3. and is expected to be more stable than the trans-isomer and the enol form having an endocyclic double bond.4·10-4 s-1 ethanol 20 40 60 80 100 120 140 time (min) Scheme 3. Tumambac and Wolf isolated enantiopure 2-benzoyl cyclohexanone by chiral HPLC and studied the configurational stability in hexanes and ethanol at 66.4. 171-176.

The discovery of facile racemization pathways for synthetically versatile building blocks such as allenes is therefore quite important.2.Racemization.1. see Chapter 3. rapid racemization of b-diketones and b-keto esters in alcohols can be exploited by dynamic kinetic resolution and other stereodynamic synthetic methods. the racemic starting material undergoes deracemization and is subsequently converted to an enantiopure product. From a synthetic standpoint. .3 h CH2OH 21 min CH2OAc 30 min CH2NHBoc 2. t1/2 Me CO2Me o1 min 15 min CH2OH 3. fast enantioconversion is attractive if it can be coupled with highly stereoselective transformation of one of the stereolabile enantiomers.1 Allene Ph • H Ph • H Me • H Me • H Me • H Me • H Racemization half-lives.3 Palladium-catalyzed allene racemization.25 h CH2NHTs might be a fundamental prerequisite to many asymmetric reactions. In this case. An attractive feature of such a dynamic kinetic resolution is that it allows quantitative conversion of a racemate to a single enantiomer. Enantiomerization and Diastereomerization Ph • H CH2OH (P)-allenic alcohol Br Ph PdL3 CH2OH Ph PdL2 Br CH2OH Ph Pd(OAc)2 + LiBr Ph • CH2OH 33 H (M )-allenic alcohol Br CH2OH PdL3 Scheme 3. Table 3.

The kinetics for the reversible first-order interconversion of enantiomers can be simplified because the rate constants for the forward and backward reaction are identical: dx ¼ Àk2 ðS0 þ xÞ þ k1 ðR0 À xÞ dt ð3:6Þ where R0 is the initial concentration of the (R)-enantiomer. and in most cases the other 50% has to be discarded or in ´ some way recycled. A polarimetric study provides the rate of racemization. x ¼ R0 – R. A further significant disadvantage of traditional enantioseparation is the inherently low atom economy. respectively. The mathematical treatment of enantiomerization and racemization is somewhat arbitrary and depends on the choice of method.4. The principles and value of enantiomerization and deracemization become evident in a discussion of dynamic kinetic resolution (DKR) and crystallization-induced dynamic resolution (CIDR). while dynamic chromatography can be used to monitor directly the reversible enantiomerization processes of the same reaction. see Chapter 7. The racemization proceeds via reversible formation of an achiral p-allyl palladium complex. vide infra. amines and alcohols racemize with half-life times. but this entails additional purification steps.1. where R is the enantiomer concentration at time t. S0 is the initial concentration of the (S)-enantiomer. Table 3. The maximum yield of the desired enantiomer is only 50%. 3. dx ¼ Àkenant fðS0 þ xÞ À ðR0 À xÞg dt ¼ kenant ðR0 À S0 À 2xÞ   R0 À S0 Àx 2 ð3:7Þ ð3:8Þ ¼ 2 kenant At equilibrium. t1/2. dx ¼ 0.3.7 They found that catalytic amounts of Pd(OAc)2 facilitate racemization of allenes exhibiting various functional groups through a bromopalladation/debromopalladation sequence in the presence of LiBr.34 Chapter 3 Axially chiral allenes are often produced as racemic mixtures. Horvath and Backvall studied the Pd(II)-catalyzed racemization of axially ¨ chiral allenes as a potential entry to dynamic kinetic resolution. The separation of allenic enantiomers can be accomplished by preferential crystallization of diastereomeric salts or by chiral chromatography.1. xeq ¼ dt It follows that: R0 ÀS0 2 ð3:9Þ dx ¼ 2 kenant ðxeq À xÞ dt ð3:10Þ .2 for examples. The combination of Pd(II)-controlled racemization with stereoselective transformation of one of the interconverting allenic enantiomers may ultimately lead to an enantioconvergent process with high atom economy. Allenic esters. ranging from less than one minute to a few hours. and k2 ¼ k1 ¼ kenant (rate constant of enantiomerization). Scheme 3.2 Enantiomerization Enantiomerization and racemization are closely related and correspond to microscopically reversible and macroscopically irreversible processes. utilizing 100% of the starting materials.

A major drawback to this approach is that the maximum yield is limited to only 50%. Chiral carboxylic acids and amino acids are often separated into enantiomers by formation of diastereoisomers with enantiopure resolving agents such as alkaloids. Noyori and coworkers observed that chiral b-keto esters are stereolabile under conditions that allow (BINAP)RuBr2-catalyzed asymmetric hydrogenation to b-hydroxy esters. In this case. 92% ee Scheme 3.8 The combination of rapid enantioconversion and stereoselective hydrogenation results in complete deracemization of b-keto carboxylic esters because one enantiomer is selectively recognized and significantly more rapidly reduced by the chiral ruthenium complex. 93% ee (M)-BINAP PPh2 PPh2 [(M)-BINAP]RuBr2 100 atm H2 (fast) OH O O 99%. unidirectional conversion of the racemate to a single enantiomer is driven by concomitant irreversible enantioselective consumption. Enantiomerization and Diastereomerization and Zx 0 35 dx ¼ 2 kenant xeq À x Zt dt 0 ð3:11Þ Integration gives: xeq ln xeq À x     R0 À Req ¼ 2 kenant t ¼ ln R À Req ð3:12Þ Dynamic kinetic resolution of rapidly interconverting enantiomers can be achieved if one of the enantiomers undergoes a selective reaction in the presence of a chiral catalyst or reagent.4.4 Stereoselective hydrogenation via dynamic kinetic resolution. . Scheme 3. The racemic b-keto ester is thus converted to a single stereosiomer by a convenient one-pot procedure. dynamic kinetic resolution of racemic methyl 2-oxo-cyclopentanecarboxylate. Preparative separation of enantiomers is usually achieved by chiral chromatography or selective crystallization of diastereomeric salts.Racemization. involving hydrogenation in the presence of [(M)-BINAP]RuBr2.2R)-trans-b-hydroxymethylester with high anti-diastereoselectivity in 99% yield and 92% ee. solvent O O O (fast) H O O O (fast) O O O [(M)-BINAP]RuBr2 100 atm H2 (slow) OH O O 1%. Through careful optimization of temperature. Coupling of such a resolution process with enantiomerization can result in complete transformation of a racemic mixture to one enantiomer. The thermodynamically controlled conversion of a mixture of stereoisomers to an enriched or pure single stereoisomer followed by physical separation based on crystallization or extraction is called asymmetric transformation of the second kind or crystallization-induced dynamic resolution. produces the corresponding (1R. For example.

and syn-isomers.2S)-2-amino-1. the study of diastereomerization reactions requires determination of at least two rate constants whose ratio is the equilibrium constant. through one transition state and without formation of intermediates. of 1.36 HO N N O O N N O Br CO2H 90%.2:1. 3.4.5 Crystallization-induced dynamic resolution of a-substituted carboxylic acids.8 1C. which requires two consecutive diastereomerization steps involving an achiral intermediate. Enantioconversion occurs at higher temperatures via two subsequent diastereomerization steps. Keq..5-dioxo-1-imidazolidinebutanoic acid in the presence of (1R. DG.e.6 kJ/mol according to the Boltzmann equation:iv nA ¼ eÀDG=RT 2 nB where nA and nB are the population of states A and B. The mathematical treatment of diastereomerization is inherently more complex because the rate constants for the forward and reverse reaction are not identical.4-trimethyl-2. and DG ¼ GA À GB. Tumambac and Wolf were able to isolate enantiopure anti-isomers of a 1. . i. Rotation of either ring about the aryl–naphthalene bond results in diastereomerization.10 At equilibrium. which corresponds to a difference in the Gibbs free energy of the anti.2-diphenylethanol and catalytic amounts of tetrabutylammonium bromide furnishes the (R).9 For instance. can be fully described with a single rate constant.8-bis(2 0 -phenyl-4 0 -quinolyl)naphthalene is 1. the ratio of the two enantiomeric anticonformers to the diastereomeric syn-conformer of 1.8-diarylnaphthalenes.6. Crystallographic analysis and computational studies have shown that this class of compounds affords highly congested structures with cofacial aryl groups residing almost perfectly perpendicular to the naphthalene ring. crystallization-induced dynamic resolution of racemic 2-bromo-3. concentration of the substrate and additives.8-diquinolylnaphthalene that is stable to isomerization at 25 1C. iv ð3:13Þ The factor of 2 accounts for the coexistence of two enantiomeric anti-isomers. and choice of a chiral resolving agent. and one achiral syn-isomer.1.5. Substitution of the peri-rings gives rise to three stereoisomers: two C2-symmetric and therefore chiral anti-isomers. composition.carboxylic acid in 88% ee. Since the interconverting stereoisomers have different thermodynamic stabilities. Scheme 3. 88% ee Br O CO2H Ph NH2 HO Ph Ph Ph O N Bu4N Br i-PrOAc:MTBE (1:1) 55 °C. 24 h NH3 O2C Br Chapter 3 O N Scheme 3. An interesting case arises from the reversible interconversion of enantiomeric 1. Scheme 3.3 Diastereomerization The kinetics of enantiomerization and racemization reactions that proceed in a single step. Kiau and coworkers developed a process that allows deracemization of stereolabile a-substituted carboxylic acids due to selective precipitation of diastereomeric ammonium salts. Equilibration of the diquinolylnaphthalene was performed at 97.

and for syn-to-anti-interconversion.8-bis(2 0 -phenyl-40 -quinolyl)naphthalene was calculated as 122. k1 is the rate constant for the antito-syn-interconversion. The mathematical treatment of the reversible first-order interconversion kinetics can be fully described by the two rate constants k1 and k2. and k2 is the rate constant for the syn-to-anti-interconversion.6 Isomerization of the stereoisomers of 1. Figure 3. respectively. k1.2 (121. occured at 97. isomerization of the meso isomer to either enantiomer proceeds at identical rates via equienergetic transition states: dx ¼ À2 k2 ðS0 þ xÞ þ 2 k1 ðA0 À xÞ ð3:14Þ dt where A0 is the initial concentration of the anti-isomer and S0 is the initial concentration of the syn-isomer. using the equilibrium constant K ¼ k1/k2 and the Eyring equation.to the syn(anti)-isomer. and was monitored by chiral HPLC at room temperature. Org. k2.09 Á 10–4 s–1.10 Á 10–5 s–1 and 1. x ¼ A0 – A (concentration of the anti-isomer at time t). dx ¼ À2 k2 S0 À 2 k2 x þ 2 k1 A0 À 2 k1 x ð3:15Þ dt ¼ 2 fðk1 A0 À k2 S0 Þ À ðk1 þ k2 Þgx   k1 A0 À k2 S0 Àx ¼ 2ðk1 þ k2 Þ k1 þ k2 0 Àk2 At equilibrium dx ¼ 0 and xeq ¼ k1 A1 þk2 S0 ¼ A0 À Aeq dt k ð3:16Þ ð3:17Þ Hence: Zx Integration gives: 0 dx ¼ 2 ðk1 þ k2 Þ ðxeq À xÞ dt Zt 0 ð3:18Þ dx ¼ ðxeq À xÞ 2 ðk1 þ k2 Þ dt ð3:19Þ   xeq ln ¼ 2ðk1 þ k2 Þ t xeq À x ð3:20Þ The rate constants for anti-to-syn-isomerization. were determined as 9. For the same reason. 2005. The conversion of one highly enantioenriched anti-isomer to the diastereomeric syn-isomer. 2930-2938.Racemization.8) kJ/mol for the conversion of the anti(syn).2. Chem. The rotational energy barrier of 1.M)-enantiomer syn-isomer (P. Enantiomerization and Diastereomerization 37 k1 k2 N N N N Ph k2 k1 Ph N N Ph Ph Ph Ph (M.] The three stereoisomers were separated by preparative chiral HPLC. since the equienergetic anti-isomers form a single meso intermediate and experience the same rotational energy barrier.P)-enantiomer Scheme 3. .8 1C. 70.8-bis(2 0 -phenyl-4 0 -quinolyl)naphthalene and the crystal structure of the anti-isomer. [Reproduced with permission from J.4 Æ0. and subsequently to the opposite enantiomer.

However.4 0 500 1000 time (min) 1500 Figure 3.2 Plot of the mole fraction. discussed in Chapter 3.2.6:1 at room temperature. Table 3. and this constitutes a useful entry to challenging aldol stereoisomers. Stereoselective aldol reactions have been intensively studied and exploited for asymmetric synthesis of a number of compounds. 70. generates achiral intermediates and results in irreversible racemization. excluding by-products from competing elimination and retro aldol reactions. 2930-2938.1.8 1C. The observable isomerization rate constant. and the corresponding half-life time. Imidazole-catalyzed tautomerization of the syn-isomer generates a chiral enol intermediate that forms an equilibrium with both diastereomeric aldol adducts. are governed by four different rate constants. it can be useful synthetically if it allows selective isomerization towards an otherwise elusive stereoisomer. The equilibration process is highly solventdependent and half-life times range from 12 to 160 hours. . and describe the macroscopically irreversible transformation of the pure or diastereomerically enriched syn-isomer to the final syn/anti-mixture at equilibrium: kobs ¼ ln 2 t1=2 ð3:21Þ where kobs is the first-order rate constant of diastereomerization. the MgBr2-promoted aldol reaction of tetrahydrothiopyran-4-onederived trimethylsilyl enol ethers and structurally similar carboxaldehydes generally favors formation of the syn-isomer.1. Chem. Ward and coworkers have shown that certain aldol adducts undergo effective syn/anti-isomerization in the presence of imidazole or 4-dimethylaminopyridine.11 Enolization of b-hydroxy ketones derived from tetrahydro-4H-thiopyran-4one proceeds under mild conditions. Org.7.38 1 experimental 0. w. kobs. [Reproduced with permission from J. Scheme 3.6 0. This is possible because aldol products are prone to retro aldol reaction and isomerization via enolization in the presence of base. of anti-1. and can only be accomplished through thermodynamically controlled diastereomerization of b-hydroxy aldehydes or ketones.] The enol formation of 2-benzoyl cyclohexanone. Repetitive separation of the diastereomers and isomerization of the recycled syn-isomer thus provides access to the anti-diastereoisomer which can not be prepared otherwise. The reversible isomerization of the syn-isomer involves a slow enolization step followed by rapid forward and reverse ketonization that either forms the anti-isomer or regenerates the syn-adduct. Although enolization of carbonyl compounds bearing an acidic proton at an asymmetric carbon in a-position is often undesirable.8 calculated Chapter 3 0. t1/2. The diastereomerization yields a syn/anti ratio of 1. For example.v v Determination of the overall diastereomerization rate and the equilibrium constant does not provide the individual rate constants for the enolization and ketonization processes. and curve fit based on reversible first-order isomerization kinetics. the preparation of some aldol stereoisomers still remains a major synthetic challenge. 2005.8-bis(2 0 -phenyl-4 0 -quinolyl)naphthalene versus time monitored at 97.

9 0.3 Structures of (þ)-cylindricene C.55 0. Table 3.Racemization.6:1 2.2 Solvent CDCl3 CD2Cl2 acetone-d6 DMF-d7 C6D6 Solvent effects on the syn/anti ratio and diastereomization of b-hydroxy ketones. Keq(syn/anti) 1.5:1 kobs [10À2 hÀ1] 5. .43 5. permethyl tellimagrandin I and vancomycin (from left to right).8:1 1. Enantiomerization and Diastereomerization Stereoselective aldol addition (provides syn-aldol adduct) OSiMe3 + S S O MgBr2 61% S syn-isomer N NH 39 Keto/enol-tautomerization (provides anti-aldol adduct) O OH O O O OH O O O O S S S O OH O O k-2 k2 OH OH O O O k-1 k1 OH O O S syn-isomer S S S S anti-isomer S kobs = (k1 k2 + k-1 k-2) / (k2 + k-1) Scheme 3.9 2.1:1 1.9:1 1.3 t1/2 [h] 12 24 130 160 13 OMe MeO MeO H MeO N OH H H C6H13 O MeO O OMe O OMe MeO OMe OMe MeO OMe O O O O O HO O O OMe O HO H2N HO HO O O O O Cl H N O O OH O O O N H O Cl OH H N O O NH NHMe H N NH HO2C HO OH OH NH2 Figure 3.7 Stereoselective aldol reaction and enolization of b-hydroxy ketone-derived tetrahydro-4Hthiopyran-4-ones.

If the pure anomers have a distinct specific optical rotation.40 Chapter 3 Diastereomerization under thermodynamic control. To achieve resolution of anomeric carbohydrates. k1 is the rate constant for the . Hsung et al. In both cases. reported the total synthesis of the alkaloid (þ)-cylindricine C in eight steps including diastereomerization of an aza-tricyclic precursor. k1 and k2.14 and several other groups have incorporated asymmetric transformations of intermediate stereolabile diastereomers into ingenious multi-step syntheses of vancomycin. Many saccharides. it is likely to cause band broadening or peak splitting. such as pentoses and hexoses. gives:     x1 C a0 À C a1 ln ð3:22Þ ¼ ðk1 þ k2 Þ t ¼ ln x1 À x Cat À Ca1 Since the term ln ðCa0 À Ca1 Þ is a constant. the change in the optical rotation of the aqueous mixture continues until equilibrium is reached. Formation of hemiacetals and hemiketals is generally reversible and the isomers interconvert rapidly in aqueous solution. The specific rotation of pure a-D-glucopyranose in water is þ1121 but the value decreases over time to þ52. For instance. Although mutarotation can impede chromatographic separation. For example. the equilibrium mixture consists of 64% of the b. CaN is the concentration of the a-anomer at t ¼ N (at equilibrium). fructose equilibrates between its open chain form and the anomers of fructopyranose and fructofuranose. Cat is the concentration of the a-anomer at t. the equilibrium mixture does not usually contain equal amounts of the two isomers.15–18 3.13.3. Figure 3. i. it can be exploited for analytical purposes.12 to a reversible first-order reaction. Mutarotation often complicates the chromatographic purification of carbohydrates as it competes with the separation process. The anomeric b-D-glucopyranose has a specific rotation of þ18. The diastereomers that are formed through intramolecular hemiacetal or hemiketal formation are referred to as anomers.3. For example.12 Meyers and coworkers combined diastereoselective Ullmann coupling and concomitant diastereomerization towards an atropisomeric (S)-hexamethoxybiphenyl derivative which was successfully converted to permethyl tellimagrandin I. computer simulation of elution profiles that originate from simultaneous separation and interconversion of anomers during liquid chromatography can be used to study the mutarotation kinetics.8).71.and 36% of the a-anomer because the former displays all substituents in the equatorial position and is therefore thermodynamically more stable. Application of Equation 3. see Chapter 4.4 Epimerization and Mutarotation Epimerization and mutarotation are generally associated with interconversion of carbohydrate diastereomers.71 which increases to the same value in water. asymmetric transformation of the first kind. the separation process must be much faster than the interconversion which can occur within a few minutes in an aqueous mobile phase. have to be considered (Scheme 3. For glucose. and are more stable than the open chain form which is often present in trace amounts. Since anomers are diastereomeric. This macroscopic observation is called mutarotation. The mutarotation of glucose is a consequence of the interconversion of two pyranose forms via an open chain intermediate but other carbohydrates undergo more complex isomerizations. has been used as a powerful strategy for asymmetric synthesis of complex chiral molecules. the interconversion process can be monitored by polarimetry. exist as a mixture of an open chain form and two diastereomeric cyclic structures exhibiting an additional chiral carbon center. Mutarotation is a special case of diastereomerization and two different rate constants.19 The mutarotation of (þ)-a-D-glucose in water can easily be monitored by polarimetry at room temperature and is treated similarly to enantiomerization and racemization reactions. the equation can be simplified to: ln ðCat À Ca1 Þ ¼ Àðk1 þ k2 Þ t þ C ð3:23Þ where Ca0 is the concentration of the a-anomer at t ¼ 0. with k1 a k2.1..e. If mutarotation proceeds within the chromatographic time scale.

and [a]b is the specific rotation of the b-anomer.7° OH OH [ ]D = +18. [a]a is the specific rotation of the a-anomer.Racemization. a is the observed rotation. Enantiomerization and Diastereomerization HOH2C HO HO β-anomer O OH OH HOH2C HO HO OH O HOH 2C HO HO α-anomer O 41 OH open chain form equilibrium mixture: [ ]D = +52. is given by: at ¼ ½aŠa l Cat þ ½aŠb l Cbt ¼ ½aŠa l Cat þ ½aŠb l ðCa0 À Cat Þ Rearrangement of Equation 3. and C ¼ ln ðCa0 À Ca1 Þ. In general. a-to-b isomerization. at. the rotation of an anomeric mixture at t.8 Mutarotation of D-glucose. l is the path length in dm. and c is the concentration in g/mL. Combination of these equations gives: Cat À Ca 1 ¼ at À ½aŠb l Ca0 a1 À ½aŠb l Ca0 À ð½aŠa À ½aŠb Þ l ð½aŠa À ½aŠb Þ l at À a1 ð½aŠa À ½aŠb Þ l ð3:28Þ Cat À Ca 1 ¼ ð3:29Þ ln ðCat À Ca 1 Þ ¼ ln at À a1 ¼ ln ðat À a1 Þ À ln ð½aŠa À ½aŠb Þ l ð½aŠa À ½aŠb Þ l ¼ ln ðat À a1 Þ þ C ð3:30Þ ð3:31Þ ð3:32Þ The equation finally becomes: ln ðat À a1 Þ ¼ Àðk1 þ k2 Þ t þ C where C is a constant.7° [ ]D = +112° Scheme 3. . a ð3:24Þ The specific rotation is defined as : ½aŠT ¼ D cl where [a] is the specific rotation measured with monochromatic light of wavelength l (usually the sodium D line at 589 nm) at temperature T. k2 is the rate constant for the b-to-a isomerization.25 provides Cat: Cat ¼ and at t ¼ N: Ca 1 ¼ a1 À ½aŠb l Ca0 ð½aŠa À ½aŠb Þ l ð3:27Þ at À ½aŠb l Ca0 ð½aŠa À ½aŠb Þ l ð3:26Þ ð3:25Þ where aN is the observed optical rotation at t ¼ N (at equilibrium).

21. can be calculated in accordance with Equation 3. epimerization generally refers to stereomutation of a single stereocenter in diastereomers that have at least two elements of chirality. Figure 3. The half-life time of mutarotation.201 which rapidly decreases to the equilibrium value of 4. Reduction of the trichloroethylidene to the corresponding ethylidene acetal facilitates acidic hydrolysis which is followed by basic removal of the carbamoyl protection group to afford methyl a-L-galactopyranoside.4 Mutarotation of (þ)-a-glucose at pH 7. t1/2.0 in 0.000 0 5 10 min 2 ln(αt .000 3. provided that the pyranoside and inositol display a cis/trans-sequence of three contiguous hydroxyl groups. A classical example is the interconversion between glucose and mannose. From a plot of ln ðat À a1 Þ versus t. .05 M NaH2PO4/Na2HPO4 at 23. Epimerization of natural carbohydrates and cyclic polyols is often achieved with epimerases that catalyze inversion of the absolute configuration at one particular chiral center.0 1C.000 α589 9.4.5 as: t1=2 ¼ ln 2 ln 2 ¼ ¼ 2:67 min k1 þ k2 0:26 minÀ1 The term epimerization was originally coined to describe the change in the absolute configuration at C-2 in aldoses. An aqueous solution of 0. the value of –(k1 þ k2) can be directly obtained from the slope. Scheme 3.9.42 12.20 Alternatively.961.α∞) 1 0 5 -1 -2 -3 10 15 min 20 15 Figure 3. Comparison of the 4 C1-conformation of the two L-pyranosides reveals regioselective epimeration at C-4. Today.000 23 Chapter 3 6.22 Treatment of methyl a-L-glucopyranoside with DCC and chloral and subsequent ring flip generate a reactive intermediate that forms a trichloroethylidene acetal through intramolecular nucleophilic substitution involving inversion of the configuration at C-4.000 0.10 g/mL of (þ)-a-D-glucose at neutral pH has an optical rotation of þ11. stereocontrolled epimerization can be accomplished via acetalization with highly active aldehydes in the presence of a carbodiimide such as DCC.

CF3COOH C6H11N OMe -C 6H11NH2 ring flip O HO C6H11HN OMe O O C6H11HN 1 HO HO CCl3CHO DCC OH C6H11N C1 O HO O CCl3 HO O O O O CCl3 O O O O O OH OMe OH OMe OH HO OMe OH C4 HO OH 4 C1 O ring flip Racemization. Bu3SnH/AIBN 2.9 Epimerization of methyl a-L-glucopyranoside.4 HO CCl3 CCl3 O O OH O C6H11HN Cl3C H OH O O O O O OH C6H11HN NHC6H11 O OMe OMe 3. NaOMe/MeOH OH 1. 43 . Enantiomerization and Diastereomerization HO HO OH OMe Scheme 3.

For example.44 Chapter 3 3. microwave-assisted racemization of (þ)-vincadifformine. see Chapter 9.2 and 91. One can classify the most prominent mechanisms as follows:26 1. proceeds via retro Diels–Alder reaction.2.1 Alkanes Thermal racemization of alkanes devoid of other functional groups is not observed unless very high temperatures are applied. and have been exploited for the development of molecular propellers and motors or asymmetric strategies based on dynamic kinetic and dynamic thermodynamic resolution.23 Epimerization of tilivalline occurs in the presence of a Lewis acid at 50 1C within 24 hours. stereomutations of chiral compounds involve either inversion of configuration or interconversion of conformational isomers.11 provides an interesting case. based on individual functional groups. 2.2 STEREOMUTATIONS OF CHIRAL COMPOUNDS: MECHANISMS AND ENERGY BARRIERS In general. Reversible ring opening affords a mixture of two diastereomers in a ratio of 87:13 at equilibrium. The free energy barriers to these independent processes are 79.vi This may require sequential cleavage and formation of one or more covalent bonds. To provide a systematic overview. . which is discussed in Chapter 3. rotaxanes and other topologically chiral compounds. 3. they can also be advantageous.27–33 The stereomutations of a series of cycloalkanes have been examined by Baldwin and others using vibrational circular dichroism to accurately monitor the change in the enantiomeric vi This is not necessarily the case with catenanes. 3. Numerous racemization and diastereomerization procedures have been reported to date.24 However. 7. to avoid side reactions of intermediate diradicals.3.25 This compound bears two elements of chirality. The dynamic stereochemistry of the tricyclic pyridone shown in Scheme 3.10. Thermal reactions Photochemical reactions Acid and base catalysis Radical reactions Oxidation-reduction sequences Enzyme catalysis Nucleophilic substitutions A mechanistic understanding of these processes is crucial for both prediction and control of the conformational and configurational stability of chiral compounds. Scheme 3. racemization and diastereomerization are undesirable if they reduce the efficiency of asymmetric synthesis or the pharmacological integrity of chiral drugs. stereomutations do not necessarily require bond cleavage and generation of an achiral intermediate. 5. Axially chiral biaryls and many other atropisomeric compounds racemize via thermally or photochemically induced rotation about a chiral axis. Both photochemically and thermally induced isomerizations generally occur via homolytic bond cleavage and radical formation. the wealth of racemization and diastereomerization reactions is discussed below. and exists as a mixture of four stereoisomers that interconvert via rotation about the chiral 2-tolylpyridone axis and flipping of the seven-membered ring.8 kJ/mol. respectively. However. 4. Racemization and cis/trans-isomerization via sequential ring opening and closure of chiral cyclopropanes is usually studied in the gas phase. As has been pointed out in the preceding chapters. The achiral intermediate readily undergoes intramolecular [4þ2]cycloaddition to regenerate the pentacyclic scaffold which is obtained as a racemate. which is facilitated in cycloalkanes exhibiting considerable ring strain (see Chapter 3.11 for an example of heterolytic cyclopropane ring opening). 6.2. a naturally occuring indole alkaloid.

11 Ring flipping and atropisomerism of a tricyclic pyridone. Racemization and concomitant diastereomerization of chiral cyclobutanes have been observed at temperatures above 400 1C.2.Racemization.and cis-isomers. Enantiomerization and Diastereomerization N N N 45 ∆ N H CO2Me (+)-vincadifformine H N H N N H ∆ N H CO2Me H N CO2Me H N H N ZnCl2 N 87% NH N O O ZnCl2 N 13% O tilivalline Scheme 3. which indicates that transient 1.10 Racemization of vincadifformine (top) and epimerization of tilivalline (bottom). composition of chiral trans.2-Tetraarylethanes adopt propeller-shaped ground state conformations resulting in helical chirality even when four equal aryl groups are present.2 kJ/mol (27 °C) O N S N ≠ N B rotation O N S N N B′ A and A′ are enantiomers A and B are diastereomers N A′ Scheme 3.1.3-diradicals are formed.35 The vicinal methine hydrogens remain on .12.8 kJ/mol (20 °C) ≠ O N S N N A ∆G = 79. and incorporation of functional groups that stabilize the intermediate diradical increases reaction rates. They observed that the rate of enantiomerization of trans-1. Activation energies range from 145 to 240 kJ/mol.34 1. Scheme 3. O N S N ring flip ∆G = 91.2-disubstituted cyclopropanes is correlated to the sum of the substituent radical stabilization energies.

2-tetrakis(2. Many other triarylmethanes and triarylmethyl radicals show similar stereomutations.2.2 Alkenes and Annulenes Sterically overcrowded alkenes possess a twisted ground state conformation rather than a planar structure.4 °C) R′=R″=vinyl: ∆G ≠ = 146.5 °C) R′=Me. selectively substituted nonplanar alkenes can . Racemization proceeds via a concerted ring flipping mechanism and does not involve bond cleavage.6-dimethyl-4-methoxy)ethane has an energy barrier of 93.4 kJ/mol (335.2-tetrakis(2. OMe MeO OMe Cl Cl Cl Cl Cl Cl Cl Cl ⊗ ⊗ Cl Cl MeO OMe Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl (racemic) Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl OMe MeO ∆G ≠ = 93.2. Scheme 3.0 kJ/mol at 21 1C.6-dimethyl-4-methoxy)ethane and perchlorinated triarylmethanes. if severe repulsion between the ethylene substituents renders the latter an energy maximum. The geared rotation of the aryl rings in C2-symmetric 1.2-disubstituted cyclopropanes.8 kJ/mol (408.4 kJ/mol (422.13 Stereomutations of helical kJ/mol (160.0 °C) R′=CN.4. R″=Et: ∆G ≠ = 229.13.1. opposite sides to minimize steric repulsion between the bulky aryl groups.4 kJ/mol at –5.0 °C) Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl (meso form) Cl Cl Cl Cl ∆G = 96. 3. tris(2.36 The structures and stereodynamics of other propeller-like molecules are discussed in Chapter 8.4 kJ/mol (-5.0 °C) Scheme 3.0 kJ/mol (21.6-trichlorophenyl)methane racemizes with an energy barrier of 80.0 °C) Cl Cl Cl Cl Cl Cl ∆G ≠ = 80.0 1C. R″=Me: ∆G ≠ = 211. For example.0 °C) ≠ Scheme 3.0 kJ/mol (44.12 MeO Enantiomerization barriers of 1.46 R″ R′ R′ R″ R′ R″ Chapter 3 R′=R″=D: ∆G ≠ = 239. By analogy with allenes and biphenyls.

14.45 bithioxanthylidenes.1 0 -disubstituted bifluorenylidene shown in Figure 3.Racemization.44 bixanthylidenes. and the corresponding energy barriers vary from 45 to 120 kJ/mol. one is a consequence of strong steric interactions in a planar structure. and p-conjugation.47.14 Twisted conformations and rotations of disubstituted bifluorenylidenes.E) R R R R (M.Z) R R R (P. Scheme 3.Z) E/ Z-isomerization R (M. bifluorenylidenes adopt a torsion angle of approximately 451. which is at a maximum in a coplanar structure. These sterically crowded alkenes can afford a complex mixture of conformers. including disubstituted bifluorenylidenes. Rotation about the 01 barrier causes enantiomerization whereas the 901 barrier separates E/Z-diastereomers. Investigation of both processes in the 1.37–40 biphenanthrylidenes. In this conformation substantial poverlap.vii Disubstituted bifluorenylidenes favor a twisted ground state geometry reminiscent of biphenyls.3 kJ/mol N 1. a decreased transition state energy or a combination of both.15. Scheme 3. racemization (P. bixanthylidenes and bianthrones. Rotation about the double bond is hindered by two different barriers.1′-disubstituted bifluorenylidene ∆G ≠rac ≈ ∆G ≠E/Z = 84 kJ/mol N N. A quite different situation arises with biacridanes. The barrier to rotation about the stereogenic axis in tetrasubstituted ethylenes is often surprisingly low.41–43 biacridanes. activation barriers to uncatalyzed E/Z-isomerization of unstrained alkenes such as 2-butene are usually higher than 250 kJ/mol. Figure 3. which is minimized in a perpendicular orientation of the fluorene planes.N′-dimethylbiacridane ∆G ≠ E→Z N = 87. is maintained while repulsive interactions are effectively reduced. so-called wingshaped folded conformations are more heavily populated than less stable twisted conformations. Isomerization of the folded (Z)-conformer A via eclipsing of the two smaller O N MeO2C CO2Me (E) (Z ) O bixanthylidene ∆G ≠E→Z = 73. .5.5 revealed that rotational barriers to these stereomutations are quite similar and approximately 84 kJ/mol. The structures and interconversion of the stereoisomers of several bistricyclic alkenes have been studied. Enantiomerization and Diastereomerization 47 be axially chiral.48 Rotation about the stereogenic axis can result in enantioconversion and E/Zisomerization. which decreases with the cosine of the torsion angle. vii For comparison.46 and bianthrones. and the other stems from loss of stabilizing p-overlap and conjugation at a perpendicular geometry. This can be a consequence of enhanced ground state energy due to considerable strain and nonbonding interactions between the vinyl substituents. In order to optimize both steric repulsion. Usually.1 kJ/mol Figure 3.E ) Scheme 3.5 Structures and rotational energy barriers of axially chiral alkenes.

15 Interconversion pathways of folded alkenes.Z )-conformer ≠ ≠ R R folded (Z )-conformer A R TS A TS B folded (Z)-conformer B E / Z-isomerization R R R R TS D R folded (E)-conformer D ≠ R R R folded (E)-conformer C R R TS C twisted (M.3 kJ/mol.7 and 114.57. there is less steric hindrance to swiveling of the double bond through the bridge. Accordingly.2 0 .55. see Chapters 8.and (Z)-1.9 and 8. the enantiomer of the original folded isomer A.1 kJ/mol at 155 1C. in which the crown conformation of the chiral cycloalkene is first changed to an intermediate chairlike structure that rearranges to the enantiomer of the original crown conformer. Since R/R-eclipsing causes more steric repulsion than H/H-eclipsing. Interconversion of the enantiomers of (E).53 In the case of twisted push-pull or capto-dative ethylenes. .59 As the ring size increases. The smallest trans-cycloalkene. substituents (transition state A) gives the twisted (M.56 In trans-cycloalkenes the aliphatic bridge is forced out of the plane of the twisted double bond which breaks the symmetry of the molecule.51 The Gibbs activation energy for racemization of the (Z)-and the (E)-olefin is 97. respectively. but it affords severe steric strain and rapidly forms the more stable (Z)-isomer at viii It should be noted that only one of two racemization courses is shown in Scheme 3.54 The reduced double bond character of the chiral axis greatly facilitates rotation. Scheme 3.18.4 0 biphenanthrylidene exhibiting two helical entities proceeds via consecutive inversion of each tetrahydrophenanthrene ring but without concurrent E/Z-isomerization. This is indeed a stepwise process.Z)-form which may undergo E/Z-isomerization or formation of conformer B. has been generated under cryogenic conditions.Z)-isomer which can then generate conformer B via a transition state exhibiting H/H-eclipsing (enantiomeric to transition state A).E )-conformer Scheme 3.15. respectively.8 kJ/mol. and the barrier to inversion depends on the ring size and steric interactions between the bridge and additional double bond substituents.3.58 The enantiomers of (E)-cyclooctene can be isolated at room temperature and undergo interconversion at elevated temperatures with an activation barrier of 146. (E)-cycloheptene.1 0 .2. Rotation of conformer A via a transition state showing R/R-eclipsing (enantiomeric to transition state B) generates the twisted (P. transition state B is less stable than transition state A. The formation of the distorted chair conformation is believed to be the rate-determining step. Scheme 3. and the corresponding energy barriers have been determined as 83. This process occurs via R/R-eclipsing (transition state B).4 0 -biphenanthrylidenes and other overcrowded chiral alkenes have been exploited for the development of molecular switches and motors.52. the combination of electron-donating and electron-withdrawing groups on opposite sides of the alkene moiety results in stabilization of a zwitterionic resonance structure and delocalization of the p-bond.4.60. Racemization of (E)-cyclononene and (E)-cyclodecene is fast at room temperature. The racemization processes involve a meso intermediate having either a symmetry plane or an inversion center.viii The corresponding (E)-conformer gives rise to similar stereomutations. Scheme 3. The intriguing stereodynamic chemistry and the thermo.50 Rapid interconversion of the enantiomers of the (Z)-isomer is observed at 25 1C while racemization of the less sterically crowded (E)-olefin requires temperatures above 55 1C.48 R R ≠ Chapter 3 R R R R R twisted (M.3 0 .7 and 44.4 0 -octahydro-4. trans-cycloalkenes display planar chirality and racemization can occur by swiveling of the double bond through the saturated ring component.and photochromic properties of octahydro-4.

4 -octahydro-4.62 Incorporation of a larger heteroatom such as silicon into the ring reduces the strain.2 . i.M )-(Z)-isomer (M. see Chapter 8. This has been demonstrated with (5S)-bicyclo[3. Inoue and coworkers demonstrated that photoisomerization of cyclooctene in the presence of a chiral sensitizer allows transformation of the achiral (Z)-isomer to nonracemic (E)-cyclooctene.16 Ph Racemization course of 1. Ph N N N N Ph O BnN Ph Ni-Pr Ph BnN N N O Ni-Pr Ph BnN Ph N N O Ni-Pr Ph O BnN Ni-Pr ∆G ≠ = 109.P)-(E)-isomer 0 0 0 0 (P.b]betweenanenes.3 . representing an anti-Bredt compound.71–73 . pilot atom R (S) R R (R) R R (S)-crown R distorted chair R (R)-crown R Scheme 3.10..2.18 Racemization course of trans-cycloalkenes.64–69 Bridging of a cycloalkene impedes the swiveling motion and significantly enhances conformational stability.1]-1(2)-nonene.5 °C) Scheme 3.P)-(Z )-isomer (P.P)-(E)-isomer Scheme 3.17 Racemization of a push-pull ethylene. have been exploited for asymmetric synthesis. room temperature.4 0 -biphenanthrylidenes. Replacement of the two vinyl hydrogens of trans-cycloalkenes by a second bridge generates planar chiral [a. their propensity for E/Z-isomerization and enantioconversion. Figure 3. and the enantiomers of trans-silacycloheptene have been isolated by preparative gas chromatography and proved to be thermally stable.1 .3. The presence of two rings dramatically increases the racemization barrier.10]betweenanene and other homologs can be isolated at room temperature.M )-(E)-isomer (M. a methylene-bridged derivative of (E)cyclooctene.63 The remarkable stereodynamics of cycloalkenes.P)-(Z )-isomer (M. Enantiomerization and Diastereomerization 49 (M.7 kJ/mol (69.e. and the enantiomers of [10.Racemization.

However. the chirality of D-homoandrost-5-ene and its isomers does not originate from the presence of an axially chiral double bond. androstane and pregnane series are known to occur under acidic conditions and usually generate a mixture of constitutional isomers.and b.and (Z)-2-meta-methoxymesityl-1. Cyclobutadiene and other annulenes containing 4N p-electrons are antiaromatic. For example. unlike the examples discussed above.78–82 Annulenes are cyclic hydrocarbons with alternating single and double bonds. Ring flipping between chiral conformations of triarylvinyl derivatives77 and cog-wheeling of chiral propeller molecules are discussed in greater detail in Chapter 8.20.1 kJ/mol (155 °C) Figure 3. For example.19 Racemization of D-homoandrost-5-ene.2-dimesitylvinyl acetates undergo two-ring flip enantiomerization and three-ring flip diastereomerization. Tetramesitylethylene represents a four-bladed molecular propeller that racemizes through correlated rotation of the four aryl rings with an energy barrier of 165. H H H H H H H H H H H D-homoandrost-5-ene H H meso compound H H H H H H Scheme 3. Scheme 3.76 Stereomutations of other molecular propellers can be more complicated and may involve competing processes. According to Huckel’s rule. Backbone rearrangements of olefinic steroids from the cholestane. cyclooctatetraene adopts a tub conformation with a ring inversion barrier of 57.b 0 -two-ring rotations. and structures of (5S)-bicyclo[3. Scheme 3. a. the alkene moiety still plays a crucial role in the racemization process.b]betweenanene (right). rather than E/Z-isomerization of the double bond.3. The dynamic stereochemistry of these compounds is due to rotation of the aryl substituents about the stereogenic vinyl–aryl axes. (E). antiaromatic and nonaromatic compounds. and are generally classified into aromatic. ¨ planar annulenes with (4Nþ2) p-electrons (where N is an integer) such as benzene are aromatic. Some crowded alkenes exhibiting aryl substituents possess helical chirality. reminiscent of propellers.1]-1(2)-nonene and an [a.3 kJ/mol. It is noteworthy that.75 The stereochemical outcome has been attributed to the formation of a meso compound which causes complete racemization at thermodynamic equilibrium.50 Chapter 3 ∆G ≠ = 146.19.b 0 .6 Racemization of (E)-cyclooctene (left).83 Incorporation of substituents into this puckered [8]annulene introduces chirality. An interesting exception is the reversible acid-catalyzed rearrangement of D-homoandrost-5-ene. The third class of annulenes comprises nonplanar and therefore nonaromatic species that often display interesting stereodynamics.8 kJ/mol.74.b-. The enantiomeric conformations of substituted cyclooctatetraenes can interconvert via . The three-ring flip has a lower energy barrier than a.

Enantiomerization and Diastereomerization OMe β α MeO α.2 kJ/mol.3.99 . ring inversion (a) bond shifting (b) bond shifting ring inversion: ∆G ≠ = 103. the energy barrier to bond shifting usually (but not necessarily) exceeds that for ring inversion.9-dibromo-1.β′-ring flip ∆G = 83.β′-ring flip OAc Scheme 3.4-tetramethylcyclooctatetraene are 133.1 and 134.5 kJ/mol (31. The activation energies for inversion and bond shifting of 1.2.20 Enantiomerization of tetramesitylethylene (left) and stereomutations of (E)-2-metamethoxymesityl-1.Racemization.0 °C) OAc ≠ OAc α.8 °C) ≠ MeO α.0 kJ/mol (25 °C) bond shifting: ∆G ≠ = 107.β.6:8.22 Stepwise interconversion of the isomers of 2.2-dimesitylvinyl acetate (right).3-trimethylcyclooctatetraene has a barrier to ring inversion and bond shifting of 103. respectively.98. bond shifting around the whole molecule.95–97 Introduction of another substituent significantly increases the conformational stability.0 and 107.0 °C) ≠ 51 OAc β′ four-ring flip α.2 kJ/mol (25 °C) ring inversion (d) (c) Scheme 3.13-bisoxido[14]annulene. found that 1.85–94 Paquette et al.21 Tub conformation and stereomutations of 1.β.3-trimethylcyclooctatetraene. or via ring inversion.7 kJ/mol (-10.0 kJ/mol.2. Note that (a) ¼ (c) and (b) ¼ (d).2.β′-ring flip ∆G = 97.1 kJ/mol (150 °C) Br O O Scheme 3. Scheme 3. whereas (a) and (b) are enantiomeric.β′-ring flip OMe ∆G = 165.21.8 kJ/mol (200.84 While both mechanisms might be operative at the same time. resulting in exchange of single and double bonds. Br Br Br O O O Br O Br ∆G ≠ = 133.

109 Imidozirconium complexes undergo stereospecific [2þ2]cycloaddition with chiral allenes to an azazirconacyclobutane intermediate that racemizes via reversible b-hydride Me H • Me H H H H Me H • H Me Me Me H H • t-Bu Me Me ∆G ≠rac = 187.6:8. the enantiomers of cis-2.24 Imidozirconium-promoted racemization of allenes. The rotation about the chiral axis in simple allenes is believed to be a twostep process involving a nonlinear allyl diradical intermediate with considerable carbene character. For example. but has been observed with a 1.13-bisoxido[14]annulene. 3.9-dibromo-1.4 kJ/mol (280 °C) MeO2C • Me t-Bu ∆G ≠rac = 192. The trans-intermediate possesses an inversion center and is achiral. The racemization requires consecutive passage of the oxygen bridges through the annulene plane.108 Mild racemization of allenes occurs in the presence of stoichiometric amounts of organocuprate and Grignard reagents. . H • 25 °C Ar N Cp2Zr H Cp2Zr H Ar N Cp2Zr H Ar N i-Pr i-PrN H • • Ni-Pr i-Pr H + i-Pr H • i-Pr i-Pr H Scheme has an interconversion barrier of only 128 kJ/mol. Scheme 3.107.104 Both conjugation and ring strain in cyclic allenes decrease the barrier to racemization.3 Allenes and Cumulenes Racemization of axially chiral allenes in the absence of a catalyst generally requires high temperatures. Scheme 3.3-dimethylallene possess rotational energy barriers above 180 kJ/mol.52 Chapter 3 An interesting situation arises with bridged annulenes that exist as cis.9 kJ/mol (308 °C) CO2Me MeO2C CO2Me O ∆G ≠rac = 128 kJ/mol (120 °C) OMe • MeO2C Scheme 3.13-bisoxido[14]annulene interconvert above 120 1C with an activation barrier of 133.and trans-isomers.23.1 kJ/mol.103 Aliphatic allenes such as 1.23 Ar N Cp2 Zr THF + i-Pr H Racemization of allenes.101 Interconversion between the planar and therefore aromatic cis-isomers and the puckered nonaromatic trans-form of doubly bridged [14]annulenes does not take place in the presence of methylene bridges.106 Allenes are also susceptible to photoracemization at room temperature.102 In fact.22. dimethyl 2. which has been attributed to a resonance-stabilized dipolar structure.100.6:8.

112 Alternatively.125–130 Racemization of these helicenes requires substantial molecular deformation towards a Cs-symmetric transition state. but the enantiomers of ketene immonium salts are isolable at 25 1C.5 kJ/mol (-19 °C) (-51 °C) i-Pr ∆G ≠rac = 36 kJ/mol (-100 °C) ∆G ≠rac = 28.110.5 kJ/mol (25 °C) i-Pr • Ph Ph ∆G≠rac = 114.4 Helicenes and Phenanthrenes Helicenes consist of ortho-condensed aryl rings that form a nonplanar helical structure.24. Chiral allenes generally do not show any sign of racemization in the absence of a catalyst such as Pd(OAc)2 at room temperature but higher cumulenes are less stable.7 minutes.119 2-azaallenium salts120 and carbodiimides121 is fast and can be observed under cryogenic conditions. Newman and Hussey reported the synthesis and partial separation of the enantiomers of (4.2. 7. As a rule of thumb.3 kJ/mol by .5. cumulenes with an odd number of double bonds are planar and therefore achiral. which explains the modest increase in conformational stability when additional benzene rings are incorporated into heptahelicene. Annulation of seven thiophene rings into a helicene structure provides a chiral oligothiophene that slowly racemizes at 199 1C.118.7 Thermal isomerization barriers of cumulenes.113.8 kJ/mol ∆G ≠rac = 51.116.133–146 The exact barrier to helical inversion of the first chiral phenanthrene was later determined as 78.111 Final cleavage of the metallacycle with diisopropylcarbodiimide thus produces a racemic allene.1. Synthetically more useful are rapid palladiumcatalyzed racemizations suitable to dynamic kinetic resolution (DKR) and dynamic kinetic asymmetric transformation (DYKAT). see Chapters 3. at 27 1C.8 kJ/mol (25 °C) Me2N • Ph ∆G≠Z → E = 86.and [9]helicenes possess Gibbs activation energies of 174. Interestingly.114 Properly substituted cumulenes with an even number of unsaturated bonds are chiral due to the orthogonal arrangement of the successive double bonds.and thiapentahelicenes is significantly faster. Figure 3.115 In contrast. deracemization of allenes has been accomplished with Eu(hfc)3 and other chiral lanthanide shift reagents. Scheme 3. This finding paved the way to the discovery of helicenes. racemization of monoaza.5.1.117 Racemization of other cumulenes including ketene imines. which corresponds to a half-life of 62.131 Stereomutations of helicenes involve extensive bond bending and torsion of the whole molecule.5 kJ/mol.8trimethyl-1-phenanthryl)acetic acid which undergoes racemization within a few seconds at room temperature. the energy barrier to rotation about the stereogenic axis of cumulenes decreases as the number of double bonds increases.4. The higher homologs exhibit considerable steric hindrance to this process and are much more stable. elimination at room temperature.124 The enantioconversion of pentahelicenes probably proceeds via stepwise slippage of the two ends through the mean plane of the helicene. and 7.Racemization.9 kJ/mol (25 °C) i-Pr N • i-Pr N N Ph N SbCl6 t-Bu N i-Pr i-Pr Me Ph t-Bu ∆G ≠rac = 61. Figure 3.2. The racemization barrier of [5]helicene is 100.0 kJ/mol (-140 °C) Figure and 182.1 kJ/mol.122 3. and [7]-. Scheme 3. Enantiomerization and Diastereomerization t-Bu • • 53 t-Bu • • • • Ph t-Bu • • • t-Bu Ph t-Bu t-Bu Ph ∆G ≠Z→ E = 122.132 The chirality of helicenes is closely related to that of overcrowded phenanthrenes. In 1947. For example.9 kJ/mol at 57 1C. and has contributed substantially to our current knowledge of molecular helicity.5. 177.7. [6]helicene has a barrier to racemization of 151.25. [8]. respectively.

5-dimethyl.4 kJ/mol (25 °C) ∆G≠ = 96. the neighboring methyl groups reduce the flexibility of the substituents at positions 4 and 5 and thereby increase steric repulsion in the transition state.25 Helical inversion of overcrowded phenanthrenes. Nitriles and Nitro Compounds Chiral alkyl halides racemize via copper(I)-catalyzed atom transfer reactions150 or through reversible bimolecular and unimolecular nucleophilic substitutions that are often accelerated by phasetransfer catalysts.1 kJ/mol (49 °C) Scheme 3.147 The nonplanarity and helicity of 4. Scheme 3. 6 7 8 5 4 3 2 1 9 (M ) 10 CO 2H ≠ ∆G = 78.148 However. in other words.4.5. Kinetic measurements of the racemization of 1-bromo-1-phenylethane in acetonitrile confirmed that both bimolecular and unimolecular bromide displacements occur concurrently.3 kJ/mol (-11 °C) (P ) CO2 H ∆G ≠ = 67.54 S S (M) (P) S S Br Br S Chapter 3 SiMe3 ∆G = 151. although the former is usually significantly more rapid .5 kJ/mol (27 °C) ≠ SiMe3 S S ∆G≠ = 163. comparison of the activation barriers obtained for 4.8 Structure and racemization of hexahelicene (left) and a thiaheptahelicene (right).149 Similarly. which has been attributed to steric interactions with the adjacent hydrogens at C-9 and C-10. The conformational stability is mostly determined by the bulkiness of these substituents which have to pass each other in the transition state.6-tetramethylphenanthrene reveals a strong buttressing effect.26. 3.2.5-dimethylphenanthrenes stems from severe nonbonding interactions between the proximate substituents at C-4 and C-5. Mannschreck and coworkers. the enantiomers of 1-bromo-1-arylalkanes are prone to rapid interconversion at ambient temperatures.3 kJ/mol (199 oC) Figure 3.7 kJ/mol (25 °C) ∆G≠ = 105. incorporation of substituents into the positions at C-1 and C-8 substantially enhances conformational stability.and 3.5 Alkyl Halides.151–155 In particular.

26 Reversible nucleophilic substitution of 1-bromo-1-phenylethane.3 kJ/mol (120 °C) ≠ (CH2)n Scheme 3.156 Stereomutations of configurationally unstable alkyl halides have been exploited for asymmetric synthesis. .158 In general.3 kJ/mol (120 °C) ∆G = 127.4 kJ/mol (120 °C) n=3: ∆G ≠ = 128. ketones and carboxylic acid derivatives. pKa values of a-hydrogens in ketones.2-dihalides are known to racemize on heating. 25 and 28.157 Acyclic and cyclic trans-1. the considerable acidity of a-hydrogens in nitriles (pKaE25) and nitro alkanes (pKaE9) facilitates deprotonation and subsequent racemization.7 kJ/mol (25 °C) SN1: ∆G ≠ = 113. in the case of benzyl halides. epimerization of an a-bromopropionyl imide in the presence of tetrabutylammonium bromide. esters and amides are approximately 20. Enantiomerization and Diastereomerization Br + − 55 Br O N N Br SN2: ∆G = 88. CIDR of interconverting diastereomers of an a-bromopropionyl imide and racemization of dihalides. It is therefore assumed that the 1. Interconversion of the enantiomers of 2-methyl-3-phenylpropionitrile is about 109 times faster in DMSO than in methanol. Scheme 3. Scheme 3.27 Racemization of 2-methyl-3-phenylpropionitrile (top) and sequential elimination and addition of cyanide observed with cyanohydrins and a-acetamido-a-vanillylpropionitrile (bottom).ix The rate of racemization depends on substrate structure. produces one diastereomer in remarkable 98% de. Ph CN KOMe Ph CN Ph • N MeOH Ph CN OH R NHAc MeO HO CN -CN 160 °C CN -CN R OH H +CN R OH CN AcHN MeO HO NHAc +CN MeO HO CN Scheme 3. base and solvent.8 kJ/mol (25 °C) ≠ Bu4N Br ACN Br − + O + − O Bu4N Br N N O Br Ph 98% de upon crystallization Ph Br Br Br Br − + Br Br Br Br n=1: ∆G ≠ = 129.Racemization. For example. and reaction rates in the dibromocycloalkane series decrease in the order C7 4 C5 4 C8 4 C6 which resembles the trend of debromination rates.26.2-interchange involves an intermediate bromonium/bromide ion pair.5 kJ/mol (120 °C) n=2: ∆G ≠ = 124.159–161 Racemization of cyanohydrins and a-amino or a-amidonitriles that are in equilibrium with the corresponding aldehyde. diaxial halides are more prone to racemization than diequatorial isomers. By analogy with aldehydes. and subsequent crystallization-induced dynamic resolution (CIDR). ketone and imine ix For comparison. respectively.27.

The nucleophilic displacement occurs at room temperature. Inversion at the sp3-hybridized nitrogen occurs via a planar sp2-hybridized transition state.4 kJ/mol.162–164 Configurationally unstable chiral amino nitriles have been employed as key intermediates in the asymmetric synthesis of amino acids based on dynamic kinetic resolution and related processes. Scheme 3. Scheme 3. The bond angles in N-chloramines are significantly reduced from the neartetrahedral value of aliphatic amines.179 In general. An increase in the p-character of the nitrogen bonds therefore impedes N-inversion. fixation of ethylmethylisopropylamine in the cavity of appropriately sized host molecules and hydrogen bonding or protonation can effectively inhibit inversion and afford configurational stability at room temperature. Such an increase can be accomplished by introduction of chlorine or other electronegative substituents to the nitrogen atom. racemic substitution products are obtained.29. precursors does not require deprotonation. are 102.172 Substitution of the alkyl nitro group of 2-(4-nitrophenyl)-2-nitrobutane by sodium azide. and formation of a transition state structure exhibiting 1201 bond angles requires a higher activation energy.28.and four-membered rings of aziridines and azetidines effectively enhances the activation energy for pyramidal inversion as a result of additional ring strain in the planar transition state.177.165–170 Nonenolizable a-methyl-a-acetamidonitriles including a-acetamido-a-vanillylpropionitrile show reversible elimination of HCN at high temperatures. the energy barrier to racemization of ethylmethylisopropylamine is 31. and involves a radical intermediate that either adopts a planar and thus achiral configuration or undergoes rapid pyramidal inversion.182–191 The enantiomerization barriers of 1-chloro-2.178 However.4-tetramethyldiaziridine. which interconverts via two consecutive nitrogen inversions. As a result.180 Incorporation of the stereogenic nitrogen into three. the barrier to nitrogen inversion decreases as the bulkiness of the substituents increases because of destabilizing steric repulsion in the pyramidal ground state.28 Base-catalyzed racemization (top) and radical-mediated electron-transfer substitution of nitro alkanes (bottom). Some cyanohydrins rapidly racemize due to sequential elimination and addition of cyanide at room temperature.174–176 For instance. thiophenoxide or other nucleophiles has been achieved via electron-transfer radical chain reactions.2.2-diphenylaziridine and 1.171 Racemization via retro aldol reaction of a chiral b-hydroxynitrile has also been reported.2.56 NO2 R′ R NO2 KOMe R′ R R NO2 NO2 SPh SPh -NO2 PhS R′ R O N O MeOH Chapter 3 NO2 R′ SPh SPh +e + NO2 NO2 -e + NO2 99% NO2 NO2 NO2 NO2 Scheme 3.3.1 kJ/mol .6 Amines Amines with three different substituents are chiral but racemization via pyramidal N-inversion is often too fast for separation of enantiomers at room temperature.173 3.181 The enantiomers of N-chloro.and N-alkoxyaziridines or diaziridines are configurationally stable at 25 1C but nitrogen inversion is observed upon heating.

0 kJ/mol.203 In the case of 1.30 Racemization pathways of amines. The two stereogenic nitrogen atoms in Troger’s base can not accomplish ¨ pyramidal inversion without bond cleavage.3. The barrier to racemization of 1.0 °C) ∆G≠ = 51.202 Several cyclic amines including 1.0 kJ/mol (60 °C) ∆G≠trans→cis = 106.30. Bn Me N X ∆G ≠ = 31.0 kJ/mol..9 kJ/mol (-35 °C) .204 Quaternary ammonium salts and rigid bicyclic amines containing the nitrogen as a bridgehead such as Troger’s base are usually con¨ figurationally stable. and 115.1 kJ/mol (60.0 °C) H ∆G≠ = 91. N N N N N N Ph Ph ∆G ≠ = 102. The barrier to cis/trans-isomerization of 2-tert-butyl-3-methyl-3-(4-nitrophenyl)oxaziridine is 108.Racemization.200 Interestingly.4 kJ/mol (-113 °C) .1 kJ/mol (-66 °C) X=OH: ∆G ≠ = 51.5 kJ/mol at 155 1C which is significantly lower than the inversion barrier of the corresponding diaziridine.2 °C) N H N NaH N H2O H N H + N Scheme 3. probably as a result of retro hetero-Diels–Alder ring opening or formation of a zwitterionic intermediate.201 An increase in ring size facilitates racemization due to reduced strain in the transition state.1 kJ/mol (60 °C) ∆G = 135.0 °C) O N cis t-Bu O N trans t-Bu t-Bu N t-Bu N t-Bu ≠ H N N t-Bu t-Bu N N t-Bu ∆G≠cis→trans = 108. respectively.4 kJ/mol (-83 °C) Scheme 3.0 kJ/mol (80.2-di-tert-butyldiaziridine have been reported to racemize through a dissociative mechanism and reversible bond breaking.5 kJ/mol (155.2-diazetidine is 91. Scheme 3.205–207 .2-di-tert-butyl-1.4oxadiazolidines and 1. Enantiomerization and Diastereomerization 57 X=Cl: ∆G ≠ = 43. This is observed at high temperatures. aryl.2-di-tert-butyldiaziridine.0 °C) t-Bu N PhS N SPh ∆G ≠ = 115.29 Facile N-inversion of acyclic amines.and alkylsulfenylaziridines readily racemize even under cryogenic conditions because the barrier to N-inversion is usually lower than 60 kJ/mol.5 kJ/mol (-61 °C) ∆G ≠ = 70..192–199 Oxaziridines exhibit similar configurational stability and show nitrogen inversion at ambient temperatures. Scheme 3.8 kJ/mol. thermal racemization occurs through reversible conrotatory electrocyclic ring opening with an activation energy of 135. X=OMe: ∆G ≠ = 41.30.8 kJ/mol (150.9 kJ/mol (-23 °C) N F3CS N SCF3 N N t-Bu N N O2N O2N ∆G ≠ = 43.7 °C) N N N N ≠ N ∆G = 133 kJ/mol (144. Me Et N i-Pr Et Me i-Pr N .3 kJ/mol (155..

The nitrogen atom is chirotopic but nonstereogenic. vide infra.216 A similar pathway. which has been utilized for crystallization-induced asymmetric transformation. has been exploited for chemoenzymatic deracemization of primary and secondary amines with enantioselective amine oxidases in the presence of a nonselective reducing agent. see Chapter 3. i. The base-catalyzed reaction usually follows an SE1 mechanism and the rate of enolate formation is equal to the rate of racemization. see Chapter 7.and acid-catalyzed racemization through keto/enol.2diphenylpropanone racemizes in ethanolic solution containing sodium ethoxide with a half-life time .4 kJ/mol (120 °C) 71%. At 120 1C. Scheme 3. an example of a three-bladed propeller. 99% ee NH Scheme 3. followed by b-elimination of a PdH species.220 Racemization reactions of molecular propellers and ring-flip mechanisms are discussed in Chapter 8.208 Some amines including nicotine racemize in the presence of a strong base.. The study of the stereochemical integrity of such pharmaceuticals has therefore become routine during drug discovery.2.209 In accordance with amino acids.211–215 Deuterium labeling experiments showed that the mechanism for racemization of a-methylbenzylamine proceeds via coordination to palladium.217. Amfepramone and other drugs exhibiting an enolizable stereocenter are often not stable to racemization under physiological conditions.210 Palladium. racemization of perchlorotriphenylamine occurs due to reversal of the propeller helicity but not because of N-inversion. enantioconversion of chiral amines via an achiral imine intermediate.4 kJ/mol. Troger’s base also racemizes in the presence of 1. and the chirality of this molecule originates solely from its propeller-like structure.58 Ph NH2 Ph Ph NH2 Pd NH PdH2 Ph NH2 PdH2 Cl Cl Cl Chapter 3 Cl NH Cl Cl N Cl Cl Cl Cl amine oxidase NH3 BH3 Cl N Cl NH3 BH3 Cl (rac) Cl Cl ∆G ≠ = 131. The so-called threshold mechanism presumably involves a two-ring flip with an energy barrier of 131.31 Palladium-catalyzed racemization of a-methylbenzylamine. 3. Scheme 3. ketones and imines with a stereogenic tertiary a-carbon undergo base.31. formation of a Schiff base provides another venue for racemization of amines.or imine/enamine-tautomerization.4. amine oxidase-catalyzed deracemization. ruthenium and iridium complexes catalyze racemization of amines through CH-bond activation and the formation of achiral enamine and imine complexes.218 An interesting case arises with perchlorotriphenylamine. a less reactive achiral enol is formed that tautomerizes to either enantiomer. probably via formation of a configurationally labile carbanion intermediate.221 Substituent effects on the reaction rate are quite important: 1.219. In the presence of acid. Ketones and Imines Aldehydes.2 0 -diyl hydrogenphosphate or ¨ other acids.e.7 Aldehydes. and the propeller-like structure of perchlorotriphenylamine.1 0 -binaphthyl-2.32.

240 Chiral a-substituted aldehydes and ketones bearing an electronwithdrawing group in b-position are susceptible to enol formation and racemization under mild conditions.224–228 Alternatively. is 0. Although interconversion of the stereosisomers of asubstituted aldehydes and ketones via enolization has been successfully incorporated into many synthetic strategies.252 Imine/enamine-tautomerization of chiral a-substituted imines253. and racemic cryptone is obtained upon acidic hydrolysis.3-diketones and their derivatives greatly facilitates enolization even in water.2-diphenylbutanone is 228 hours.242 and has been exploited in many other elegant dynamic kinetic resolutions.Racemization.and acid-catalyzed racemization of carbonyl compounds.3-dimethyl-1. see Chapter 3. of 18.35. see Scheme 3. Scheme 3.250 b-keto nitriles.241. Scheme 3.222 Treatment of (–)-menthone with sodium methoxide in methanol causes epimerization to a diastereomeric mixture exhibiting 40% de at equilibrium. Kenol/keto.239 Ketalization of the monoterpenoid (–)-cryptone with ethylene glycol results in destruction of asymmetry due to double bond migration and formation of an achiral D3-dioxolane intermediate. enolization of a-substituted aldehydes229 and ketones230–238 has been utilized to enhance stereoselectivity in a number of asymmetric syntheses.x providing an entry to chemoenzymatic DKR of b-diketones.34. it can be advantageous to use the corresponding imines and hydrazones.1.32 Base.3 and the equilibrium constant for enolization in water.223 Racemization of enolizable chiral carbonyl compounds can compromise the stereochemical purity of reaction products and requires careful attention during asymmetric synthesis. The configurational instability of b-dicarbonyl compounds is crucial to Noyori’s (BINAP)RuBr2-catalyzed asymmetric hydrogenation of rapidly interconverting enantiomers of b-keto esters. Racemization and diastereomerization of aldehydes and ketones often involves enolization but this is not necessarily the case.256 Condensation of methyl 5-oxo-4-phenylpentanoate and (R)-phenylglycinol gives a mixture of diastereomeric imines that readily interconvert via enamine x The pKa of acetylacetone is 13.33.2. transformation of (–)-menthone to its tosylhydrazone derivative greatly facilitates acidcatalyzed epimerization and provides a different diastereomeric ratio than equilibration of the original ketone. Scheme 3.23.254 and hydrazones255 causes racemization or diastereomerization.243–248 The high acidity of a-hydrogens in 1.249 b-keto esters. for example by base-catalyzed equilibration of diastereomers. For example.251 and b-keto amides.4 minutes while under the same conditions that of 3. Enantiomerization and Diastereomerization Base catalysis O R R′ H O NEt2 base R R′ O NEt2 59 O R R′ O R H R′ O O NEt2 amfepramone Acid catalysis O R R′ H R R′ H OH R R′ OH R H R′ O Scheme 3.33 for comparison. .

2 min τ1/2 = 12.260.60 O NaOEt H O O EtOH O Chapter 3 H τ1/2 = 18. and Ketals Secondary and tertiary chiral alcohols are configurationally stable under basic conditions but they are prone to acid-catalyzed racemization in aquous solution. MeOH O O O O 53% O O O O O O H O O + HO OH + H 2O (-)-cryptone racemic cryptone Scheme 3. The same strategy has been applied in the synthesis of other polysubstituted lactams from d-keto esters and d-oxo diesters. MeOH O 70% (-)-menthone 30% Scheme 3.257 Reversible oxazolidine formation followed by irreversible lactamization favors formation of the bicyclic (R.34 Epimerization of a chiral ketone and racemization of cryptone via a stable achiral intermediate. O KOt-Bu.2 h τ1/2 = 228 h O NaOMe. xi Racemization of tertiary alcohols is an SN1 process while secondary alcohols often prefer the SN2 mechanism.2. .258.R. Ethers. formation. MeOH O NaOMe.259 3.xi In the case of unimolecular dissociation.4 min O O O O O τ1/2 = 9 min τ1/2 = 32 min τ1/2 = 53.S)-isomer which is obtained in 49% yield. Acetals.8 Alcohols.33 Racemization of ketones via base-catalyzed enolization (top) and epimerization of (–)-menthone (bottom). reversible formation of a planar carbocation intermediate from a chiral alcohol in the presence of a Lewis or Brønsted acid is sometimes accompanied by undesirable rearrangements or elimination.

Racemization. HO R R″ R′ H H2 O R R″ -H O 2 R′ R R″ R′ H2O R″ R OH2 R′ R″ R OH R′ HO H .37.3-propanediols derived from pyridine. -H HO OH NHMe NHMe Scheme 3.35 Epimerization of a-substituted imines and hydrazones. thiazole.36. Scheme 3.279 In general. rearrangments are less likely with carbocations derived from chiral benzylic or allylic alcohols due to resonance stabilization. Scheme 3. Scheme 3.262 Protonation of the heteroaryl moiety facilitates cyclization which is followed by ring opening to an achiral intermediate that regenerates either enantiomer. Sequential oxidation and reduction based on reversible ruthenium-catalyzed hydrogen transfer provides a useful method for mild racemization of secondary alcohols.36 Acid-catalyzed enantioconversion of chiral alcohols. While formation of elimination products can be avoided at low temperatures.263–277 This can also be accomplished with rhenium.38. deprotonation of the substrate is followed by formation of a transition metal hydride intermediate and a prochiral ketone that is then nonselectively reduced to the racemic alcohol.261 A different mechanism has been proposed for the acid-catalyzed racemization of 1heteroaryloxy-2.278. and pyrimidine. Enantiomerization and Diastereomerization Ph NH2 OH MeO2C O H 61 + ∆ Ph MeO2C N OH Ph HN OH Ph Ph MeO2C N OH imine/enaminetautomerism Ph MeO2C Ph Ph Ph O N O Ph slow O Ph 9% O H OMe N H H Ph Ph MeO O N H O H H Ph fast O Ph N O Ph 49% H N NHTs N H NHTs N NHTs 29% 71% Scheme 3. pyrazine. iridium and rhodium complexes. Reversible . -H2O OH NHMe HO H2O.

Ph Ph OH R H Ph Ph Ru OC H OC O Gd(Oi-Pr)3 NaA. For example. Reversible crossed aldol reactions that establish a mixture of rapidly equilibrating b-hydroxy ´ aldehyde stereoisomers afford interesting synthetic opportunities. Meerwein–Ponndorf–Verley/Oppenauer redox reactions catalyzed by lanthanide triisopropoxides constitute another viable alternative for racemization of secondary alcohols. gadolinium and samarium isopropoxides allow mild racemization of 1-phenylethanol and have proved more effective than the aluminum salts traditionally used.280 Neodymium.282 . The reaction sequence is completed by ring closure.62 Chapter 3 H N O OH OH O NH NH OH OH HO O OH NH O N O OH OH -H O NH NH OH OH HO HO O OH OH Scheme 3. providing deoxysugars in excellent ee and de.38 Ruthenium-catalyzed hydrogen transfer with secondary alcohols (top) and reversible Meerwein–Ponndorf–Verley/Oppenauer redox reactions (bottom). 50 °C 16 h OH H H H Nd(Oi-Pr)3 NaA O MeO H H H MeO H OH Ph O Ph Ph R′ Ru OC OC + Ph Ph Ru OC OC OH + O − Ph O − OH H Ph + R′ + R Ph + R R′ OH O OH + + Gd(Oi-Pr)3 NaA. the enantiomeric excess of pure (R)-1phenylhex-5-en-3-ol decreases to 59% ee within 2 hours upon treatment with 10 mol% of 3-phenylpropanal and p-toluenesulfonic acid at 20 1C. The procedure can also be utilized for selective epimerization of steroidal b-estradiol methyl ether. Acetone is the preferred hydride acceptor and zeolite NaA is added to suppress the competing aldol reaction. Scheme 3.39. Reyes and Cordova found that the (S)-proline-catalyzed aldol addition of aldehydes to propanal is reversible at room temperature.281 Chiral homoallyl alcohols undergo racemization via reversible aldehyde-mediated allyl transfer in the presence of catalytic amounts of acid. and can be coupled to a stereoisomer-differentiating reaction between the enantiomeric b-hydroxyaldehydes and a proline-derived enamine. albeit with low yields.3-propanediol. 50 °C O O + OH H H MeO β-estradiol methyl ether α-estradiol methyl ether Scheme 3.37 Racemization of 1-(2 0 -pyridyloxy)-2.

290 Jacobsen’s group developed a protocol for (salen)Cr(III)N3-catalyzed racemization of epichlorohydrin in the presence of trimethylsilyl cyanide.285–289 Although metal-catalyzed stereointerconversion of epoxides is often of limited use because epoxides readily rearrange to ketones in the presence of a Lewis acid. 98% ee. Scheme 3. >95% de R=C6H11: 19%. the enantiomers of epichlorohydrin interconvert via formation of achiral 1. Cyclization of the achiral intermediate can produce either xii The diastereomer with an equatorial substituent at C-1 is thermodynamically more stable because the anomeric effect is not operative in C-glycopyranosides.H2O R allyl transfer R R=CH2CH2Ph O R Scheme 3.3-dichloro-2-propanol. An intriguing example is the stereomutation of C-galactopyranosides involving a sequence of base-promoted enolization.283. The mechanism entails formation of an achiral intermediate that is probably generated by heterolytic cleavage of the C(sp3)-O bond.292 Sequential ring opening and cyclization of chiral 2-aryl-2-methyl-2H-1-benzopyrans results in racemization.291 Alternatively.284.Racemization.xii Cyanostilbene oxide and other 1. The equilibrium favors formation of the C-glycopyranoside having the substituent at C-1 in equatorial position. a rutheniumcatalyzed cis/trans-isomerization procedure has been reported. 90% ee.39 Stereoselective synthesis of deoxysugars based on fast racemization of chiral aldol products (top) and enantioconversion of 1-phenylhex-5-en-3-ol (bottom).40. . Enantiomerization and Diastereomerization CO2H H 63 N OH R O H R OH OH O H R O OH slow OH (S)-proline O O + R H H (S)-proline N CO2H H OH R O H OH R OH O H R O OH R=i-Pr: 21%.RCHO R HO OH H2O O R OH .40. Scheme 3.293 Narwedine possesses a chiral axis in addition to two asymmetric carbon centers and racemizes via ring opening followed by Michael addition in the presence of base. Racemization or diastereomerization of chiral ethers provides access to important building blocks for asymmetric synthesis.2-diaryloxiranes undergo thermal and photochemical racemization via intermediate carbonyl ylides or diradicals. >95% de fast OH R OH R RCHO HO H R R OH R H . b-elimination and intramolecular Michael addition.

homothiophene and benzoheterocycles. Scheme 3. hemithioacetals.6-dioxaspiro[4.and (2R.309 Thermal racemization due to reversible ring opening is also common with ketals. The activation energy for enantiomerization of homofuran is 113. enantiomer but formation of diastereomers is not observed. Scheme 3.42.4]nonane are 108.311–314 The racemization mechanism of 2.294. Ring opening and subsequent ring closure of the spiroketal chalcogran.2 0 -indoline316 is described in Scheme 3.317 The corresponding low activation enthalpies and the highly negative activation entropies are indicative of a heterolytic dissociative mechanism xiii This is remarkable because stereolabile compounds exhibiting more than one chiral element usually form a mixture of diastereomers.and N. Scheme 3.O. .45. Racemization of 5-hydroxyfuranones. which are important chiral building blocks. CN O CN R CN Ph Scheme 3. an important beetle aggregation pheromone. The ring opening and closure are orbital symmetry-allowed and obey Woodward–Hoffmann rules.5R). hemiketals.40 Epimerization of an a-C-glycopyranoside (left) and stilbene oxide derivatives (right).308.1.2 0 -spirobichromene315 and a spiro 2H-1-benzopyran-2. and hemiaminals are prone to racemization via reversible ring opening.5S)-2-ethyl-1.3-dichloro-2-propanol (bottom).Oketals at room temperature has paved the way for the development of chiroptical switches.43 racemizes in refluxing methanol via formation of an achiral quaternary iminium ion.298–304 Related epimerization305.0 and 108. the oxazolebenzodiazepinone shown in Scheme 3.296 Similar stereomutations have been observed with homopyrrole. Scheme 3.xiii Enantioconversion of homofuran proceeds via an achiral carbonyl ylide-like intermediate generated by a disrotatory electrocyclic reaction upon heating. see Chapter 3.8 kJ/mol.44. The Gibbs free activation energies for the interconversion of (2R. occurs at 70–120 1C and causes epimerization.43. respectively.310 The photochromism and facile reversible ring opening of spiro O.295. Racemization of epichlorohydrin via 1.64 OH OH O BnO BnO enolization NaOMe OH O BnO BnO O BnO BnO favored anomer O O Ph R O Cl Cl Cl OH Cl Cl O Cl β-elimination BnO O − Chapter 3 O O BnO Michael addition OH O Ph Ph − R O Ph 100-150 °C + CN Ph R=H.306 and mutarotation processes307 play a fundamental role in carbohydrate chemistry. is fast at room temperature or upon mild heating even in the absence of catalytic amounts of acid or base. The reversibility of hemiacetal formation under aqueous conditions certainly facilitates the development of enzymatic dynamic kinetic resolution processes and several procedures have been reported.4. For example.5 kJ/mol. The mechanism is based on ring opening and subsequent intramolecular acetalization.41.297 Chiral hemiacetals.

Base-promoted removal of a proton from a stereogenic carbon center usually entails complete racemization . Acid-catalyzed ring opening of the spirohydantoin shown in Scheme 3. Enantiomerization and Diastereomerization Ph O Ph O Ph O Ph O O Ph 65 O ∆G ≠ = 111.1 kJ/mol (69.0 °C) O H O Et3N H O O Et3N N O MeO N Et3N O N MeO (-)-narwedine MeO (+)-narwedine Scheme 3.4 kJ/mol ∆G≠ = 99. with a zwitterionic enol ether intermediate. HO H N O O O HO O H N O HO O O H N O O Br O F N Br N F Br O O F N Scheme 3.N-ketal moiety is temporarily cleaved to form a transient achiral acyliminium ion.42 Stereomutations of homofuran and its derivatives.2. O O O O N CO2Me S ∆G≠ = 113.8 kJ/mol (90.318 3.4 °C) ≠ ∆G ≠ = 132.and acid-catalyzed enolization. It is assumed that the N.41 Racemization of cyclic ethers.0 °C) ∆G ≠ = 77.9 kJ/mol (69.4 °C) N ∆G = 111.4 kJ/mol (135.6 kJ/mol (80 °C) (28 to 61 °C) Scheme 3.43 Thermal racemization of 5-hydroxy-5H-furan-2-one and an oxazolebenzodiazepinone derivative.45 results in complete racemization within two hours upon heating to 90 1C in the presence of 10% HCl.9 Carboxylic Acids and Derivatives Carboxylic acids and their derivatives undergo base.Racemization.

329. A few examples are depicted in Figure 3.2 0 -spirobichromene and of a spiro 2H-1-benzopyran2. .341.45 Possible epimerization pathways of chalcogran (top) and racemization of a spirohydantoin (bottom).46.5 kJ/mol (25.0 °C) ∆H ≠ = 45.328 Numerous racemization and epimerization procedures based on enolate formation of carboxylic acids.0 °C) ∆H ≠ = 47.44 Interconversion of the enantiomers of 2.0 °C) O O N N Me O NO2 O O2N NO2 O N Me ∆G ≠ = 85.0 kJ/mol (25.9 kJ/mol (22.8 kJ/mol ∆S ≠ = -210 J/K mol O NH O NMe HCl N H O N H O HN NH O NMe O O Scheme 3.66 Chapter 3 O O O O ∆G ≠ = 100.4 times faster than the concomitant racemization. Scheme 3. O O O O (2R.5R)-epimer ∆G ≠ = 108.0 °C) Scheme 3.324 It has been reported that exchange of the a-proton in N-pivaloyl phenylalanine dimethylamide by deuterium proceeds with considerable retention of configuration.325 The remarkable configurationally stability of some carbanions can be exploited for asymmetric synthesis.2 0 -indoline.331–340 thioesters.330 esters.342 and amides343–348 have been developed and employed in the synthesis of a wide range of chiral compounds. nonracemic bromochlorofluoromethane has been prepared by haloform reaction of 1-bromo-1-chloro-1-fluoroacetone326.319–323 Nevertheless. Kinetic studies revealed that the isotope exchange process is about 2. due to the inherently low stereochemical integrity of carbanions. For example.5S)-epimer O OH ∆G ≠ = 108. carbanions are generally less prone to racemization than carbocations.0 kJ/mol (45.9.1 kJ/mol ∆S ≠ = -204 J/K mol O NH HN O NMe N H O HCl H2N O O O HO O (2R.327 and by decarboxylation of the (–)-strychnine salt of bromochlorofluoroacetic acid.

356 Ring opening of the acyl chloride of chrysanthemic acid results in the simultaneous loss of both chiral centers. or alternatively be trapped as an amide or ester with primary and secondary amines or alcohols. Dicarboxylic acid derivatives can racemize through formation of a meso intermediate. The reaction is accompanied by complete racemization of the originally enantiopure acid.352. Mild enantioconversion of allylic esters can be achieved through formation of achiral p-allylpalladium complexes.3-dimethylcyclopropyl-1.50.47. Nucleophilic attack by the methoxide at the meso anhydride occurs at either carbonyl group and yields the racemic monomethyl ester. Scheme 3.49.2-dicarboxylic acid monomethyl ester which shows internal displacement of the methoxy group upon heating in the presence of a strong base.48.353 Fast interconversion of stereolabile p-allyl species generated from g-acyloxybutenolides and a chiral palladium complex has been exploited by Trost and Toste for the synthesis of g-alkoxy derivatives based on dynamic kinetic asymmetric transformation.46 Partial racemization of N-pivaloyl phenylalanine dimethylamide during proton/deuterium exchange. Scheme 3.350 2-Hydroxy-2-methyl-3-oxobutanoic acid follows an unusual racemization course that is based on a reversible base-catalyzed tertiary ketol rearrangement.9 Stereoinversions of carboxylic acid derivatives.4:1 Ph D ND O N 67 O O O Scheme 3.355.351 The intramolecular migration of the carboxylate group has been verified by 13C NMR experiments with isotopically labeled a-acetolactic acid. Scheme 3. Scheme 3.349 This has been observed with 3. The reactive ketene can regenerate racemic starting materials in the absence of an appropriate nucleophile. O Cl Ph O O DIEA O O 0 °C Ph Cl O O O CO2Me CO2H O O O O H S N LDA -78 °C CO2Me 81% CO2H O O O O 94% de DBN 25 °C CO2Me H S O N N H H Ph 80% N 91% CO2Me NMe2 Et3N Ph O O Br 25 °C Ph O 94% de NMe2 H O Br N H H O N Ph t-BuOK 66 °C H Figure 3. see Chapter 7.354 Acyl chlorides bearing a stereogenic a-carbon atom readily form achiral ketenes by basepromoted elimination of hydrochloride. Enantiomerization and Diastereomerization O Ph t-Bu H NH N t-BuOK/t-BuOD 30 °C Ph t-Bu D ND O N + t-Bu 2.Racemization.5. The rearrangement of the dianion is degenerate.357 . in that both starting material and product have identical constitution but opposite configuration.

49 Enantioconversion via reversible formation of a p-allylpalladium complex. O R O N H O Cl Et3N.47 Enantioconversion involving a meso intermediate.51.358.10 Amino Acids Amino acids undergo base. Scheme 3.359 Several factors increase the rate of enantioconversion: the presence of electronegative substituents at the stereogenic carbon atom.and acid-catalyzed racemization. resonance stabilization of the intermediate carbanion. -HCl R BCl3 Cl O -10 °C O BCl3 Cl • O Cl O Cl Scheme 3. R R OAc + Pd R Pd R + AcO Pd R R OAc Scheme 3.361 coordination to .50 Acid. The reaction is reversible and occurs under mild conditions in the presence of catalytic amounts of Lewis-acidic boron trichloride.68 Chapter 3 KH/THF -MeO -MeO CO2 O O O2C CO2Me ∆ MeO2C CO2H MeO2C O MeO Scheme 3.and base-promoted racemization of acyl chlorides. Nucleophilic attack of the chloride ion at the achiral ketene intermediate is followed by ring closure and formation of the racemic trans-product in 90% yield.360.2. 3.48 Tertiary ketol rearrangement of 2-hydroxy-2-methyl-3-oxobutanoic acid. -HCl HCl O R • O HCl N O O O Cl H N O Et3N. O CO2H OH base O CO2 OH base O CO2 O HO CO2H O Scheme 3.

reprotonation generates (R)-alanine which is released through replacement with Lys39. and Lys39 catalyzes the opposite transformation.51 Base. and to investigate the stereochemistry of peptide folding. alanine racemase catalyzes interconversion of (S). Enantiomerization and Diastereomerization Base catalysis R H2N H CO2 R NH2 OH R OH H 3N H NH3 R OH NH3 CO2 R CO2 H NH2 OH R OH H NH3 OH R OH OH 69 Acid catalysis R H3N H CO2H Scheme 3.13.to (R)-alanine. Although the scope of racemases is often limited by their intrinsic substrate specificity. In the absence of a substrate in the active site of the enzyme. For example.386.2.and (R)-alanine through a two-base mechanism. . Introduction of protecting groups can reduce the configurational stability of amino acids.4. a wide range of chiral compounds other than amino acids are suitable to enzymatic and microbial racemization or diastereomerization.383–385 Many enzymes have been isolated and successfully employed in organic synthesis. Many enzymes utilize aromatic pyridoxal-5 0 -phosphate (PLP) as a cofactor for Schiff basemediated racemization of amino acids. Finally.53. see Chapter 3. As illustrated in Scheme 3. see Chapter 3.365 or this can alternatively provide an entry to crystallization-induced asymmetric transformation and dynamic kinetic resolution. the aromatic aldehyde is fixed as an aldimine derived from the terminal amino function of Lys39.362 and derivatization of the amino and carboxylic acid groups to amides and esters.392.388–391 Even external chiral stimuli can initiate so-called asymmetric noncovalent domino effects and induce helicity in achiral peptide chains.Racemization. oxazolidinediones and succinimides facilitates deprotonation and thus racemization. Racemization pathways involving formation of intermediate azlactones370–373 and Schiff bases374–382 that are prone to tautomerization or deprotonation are shown in Scheme 3.387 The scope of these asymmetric biotransformations is discussed in Chapter 7. Tyr265 is the catalytic base for the interconversion of (S). abstraction of the a-proton involves Tyr265. When this amino acid is replaced by the substrate.366–369 Derivatization of amino acids to hydantoins.xiv Achiral amino acids have been incorporated into chiral peptides to stabilize helical structures through asymmetric induction.364.52. In particular. This step is facilitated by formation of a resonance-stabilized quinoid-type structure. metal ions.363 This is consistent with the observation that epimerization of peptides is generally faster than racemization of free amino acids.393 xiv Achiral compounds that can adopt chiral conformations can be utilized for amplification and switching of chirality. PLP is transferred to either (S). the low stereochemical integrity of N-acyl derivatives can be problematic during peptide synthesis. for example in supramolecular assemblies.and acid-catalyzed racemization of amino acids. Similarly. In the case of (S)-alanine. The stereodynamic properties of amino acids lacking an asymmetric carbon atom are noteworthy.or (R)-alanine. epimerization of peptides occurs more readily with diketopiperazine derivatives. since they can easily be introduced to peptides to alter their 3-dimensional structure and biological activity.

70 Racemization via azlactone R H2N H Ph CO2H PhCOCl R O N H H CO2H ∆ -H2O R O N Ph CO2H AcOH N H Ph Ph N H H AcO NH R CO2H N Ph O R O N Ph OH R O O R Chapter 3 CO2H NH2 Racemization via Schiff base R H2N H CO2H PhCHO R R CO2H + AcOH R H 2N H CO2H PhCHO R N H CO2H AcOH R N H H Ph AcO CO2H Ph Ph Scheme 3.53 Mechanism of PLP-dependent alanine racemase.52 Racemization pathways of amino acids via azlactone (top) and Schiff base intermediates (bottom). . Tyr 265 O Lys 39 N + − − H N+ CO2 (S)-Ala H O − H O P + − P + N H (R)-Ala Tyr 265 H Lys 39 NH2 N + N H CO2 − OH + CO2 Lys 39 NH3 N H O P − H O P + − N H N H Scheme 3.

Enantiomerization and Diastereomerization 71 3. even though high temperatures may be required.404 and sulfonium salts405–407 are configurationally stable at room temperature. The barrier to racemization of tert-butylmethylphenylphosphine is 136. Due to facile ligand-site exchange processes.1. Silyllithium species are configurationally stable under cryogenic conditions and have been used as key intermediates in the asymmetric synthesis of several chiral silanes. see Chapter 2. 1-chloro-1-phenyl-1. tetrahedral chiral-at-silicon compounds are generally stable to racemization.409. Phosphorus and Sulfur Compounds Chiral compounds bearing a stereogenic third-row element play an important role as reagents. Thermodynamically controlled pyramidal inversion of tertiary phosphines can be useful synthetically. and inversion barriers of acyland alkoxycarbonylphosphines are generally lower than 100 kJ/mol. and are key components of pharmaceuticals such as esomeprazole. Chiral phosphines403. these so-called l5.408 Incorporation of an acyl substituent significantly reduces configurational stability.54 Asymmetric transformation and racemization of chlorosilanes (top) and O.2.55.394 For example. Since the bond angle in trivalent phosphorus and sulfur is typically about 1001.7 kJ/mol (50 °C) Berry pseudorotation Cl Ph Cl Cl .9 kJ/mol.Racemization. chiral silyl chlorides are known to undergo facile chloride-induced racemization which has been attributed to the formation of achiral pentacoordinate silicon dichloride derivatives.395–398 However.3.and l6-silicates show rapid racemization in solution. and the corresponding hypervalent silicon species may interconvert via Berry pseudorotation exchanging equatorial and axial positions.O-exchange at a l6-silicate (bottom). in particular through Si-N dissociation and subsequent recombination.O-exchange mechanism has also been reported.401 Inversion of chirality at the silicon center via an O. whereas acyclic amines readily racemize. phosphorus and sulfur centers has therefore received considerable attention.and hexavalent complexes.410 Pyramidal inversion at Cl Bu Si Cl BuLi -20 °C Ph 74%. Scheme 3. The racemization process probably entails apical and equatorial attack of the chloride anion.54.4-tetrahydro-1-silanaphthalene racemizes at 0 1C within one hour. 92% ee NMe2 O Cl Si O Cl Me2N ≠ Si Si Si Cl Cl Si Cl Ph NMe2 O Cl Si O Cl Me2N ∆G = 88. a greater amount of distortion is required to reach the planar transition state. treatment of (S)-methyl(1-naphthyl)phenylsilyl chloride with butyllithium at –20 1C generates (R)-(n-butyl)methyl(1-naphthyl)phenylsilane in 72% yield and 92% ee.402 Third-row elements have considerably higher pyramidal inversion barriers than amines.400. Scheme 3. The configurational stability of chiral silicon. auxiliaries or catalysts in asymmetric synthesis.54. Coordination of achiral chelating ligands to silicon can result in the formation of chiral penta. Scheme 3.11 Silicon.2-bis(2 0 -benzylphospholano)benzene proceeds with excellent diastereoselectivity at 190 1C.399 In the presence of LiCl. Epimerization of 1. . By analogy with compounds possessing an asymmetric carbon center.2. and have been successfully employed in stereoselective substituent displacement reactions.Cl Si Ph Scheme 3.

.72 Chapter 3 .412 Monochlorophosphoramidates and other configurationally unstable phosphorus compounds have been employed in DYKAT and similar stereodynamic synthetic strategies.419 Benzyl p-tolyl sulfoxide racemizes approximately 1000 times faster than comparable alkyl aryl sulfoxides. Activation barriers range from 140 to 180 kJ/mol.57. P O H H H R R′ P H -H H .. Scheme 3. Ring closure and allylic rearrangement of the phosphate group generates the other enantiomer through formal inversion at all chiral carbon and phosphorus centers. P R R′ . ∆G ≠ = 81.416 Rotto and Coates uncovered an intriguing stereomutation of a chiral tricyclic phosphate that is configurationally stable in organic solvents but shows thermal diastereomerization and racemization upon heating to 145 1C..55 Pyramidal inversion of phosphines.. the stereogenic phosphorus atom is not the only stereomutation pathway of chiral phosphines. ∆G ≠ = 136.55..417 This can be explained by formation of a symmetric zwitterion exhibiting both an allylic carbocation and a phosphate anion moiety.413–415 Isotope experiments proved that chiral phosphates can racemize through a dissociative mechanism with an achiral metaphosphate intermediate. Scheme 3. The mechanism for racemization of benzylic sulfoxides involves homolytic cleavage of the carbon-sulfur bond and subsequent recombination of the radical pair.xv The energy barrier to xv The dissociative mechanism has a positive activation entropy which explains the relatively low energy barrier to racemization of benzyl p-tolyl sulfoxide. Facile acid-catalyzed racemization of secondary phosphines involves formation of an achiral phosphonium ion and often renders isolation of enantiomers difficult. Scheme 3. Most chiral sulfoxides are configurationally stable but undergo pyramidal inversion at high temperatures. Me t-Bu P Ph t-Bu Me Bn Ph P P Bn P 190 °C 8h Bn P Bn P 100% de . This unimolecular process obeys first-order kinetics and is observed with both aliphatic and aromatic sulfoxides at approximately 200 1C. Ph i-Pr P O i-Pr Ph .2 kJ/mol (110 °C) MeO2C N O P Cl C11H23 kepi MeO2C N O O2N O2N R R′ P MeO2C O O P N C11H23 OC6H4NO2 kepi > k1 > k2 k1 70%.9 kJ/mol (130 °C) ..418 Interestingly.. the barrier to pyramidal inversion of benzothiophene oxides is as low as 100 kJ/mol and enantioconversion can be observed at ambient temperatures.56. racemization of secondary phosphines via achiral phosphonium ions and DYKAT of a monochlorophosphoramidate.411. 97% de O P N O MeO2C P Cl C11H23 k2 C11H23 OC6H4NO2 Scheme 3.

0 °C) ∆G = 168.1 kJ/mol (50.0 °C) O S S O S N S ∆G = 101.8 kJ/mol.OR 16 16 − 73 OPh OPh O + − O P 18 O − P − 18 O OR − OR 17 O 18 P O O 145 °C PhNO2 O O P − + O O P O O 17 17 O O− O − P − O 16 O Scheme 3. photoracemization originates exclusively from direct sulfur inversion.7 °C) O S S O S N S O S N S ∆G ≠ = 96.6 kJ/mol (200.5 kJ/mol (200.56 O S Enantioconversion of isotopically labeled and allylic phosphates.3. O S O S O S O S ∆G = 172.428.421 Although homolytic a-cleavage and recombination of radical pairs is a common photochemical reaction of sulfoxides.430 Sulfoxide derivatives such as N-aryl or N-benzyl-1.420 Aryl sulfinamides have also been reported to racemize via a radical mechanism.57 Racemization pathways of sulfoxides and their derivatives.432 and aryl arenethiolsulfinates433 are less configurationally stable than sulfoxides and are prone to sulfur stereoinversion .7 kJ/mol (50.3 kJ/mol (200.0 °C) ≠ Scheme 3.2-benzodithiazole-1-oxides431.8 kJ/mol (25.0 °C) O S O S ≠ ≠ ∆G = 137.Racemization.0 °C) O S N S ∆G ≠ = 95.0 kJ/mol (145.0 °C) ≠ O S O S Ph O S ∆G = 105.3]-rearrangement to an achiral allyl sulfenate intermediate with an energy barrier of 102.0 °C) O S ≠ ∆G = 102.422–427 Enantioconversion of chiral sulfoxides is usually based on homolysis or pyramidal inversion but thermal racemization of allylic and allenic sulfoxides entails a different concerted mechanism.1 kJ/mol (35.7 kJ/mol (200.9 kJ/mol (36. and carbon–sulfur bond scission has been ruled out as an alternative mechanism. racemization of benzyl p-tolyl sulfoxide is 137. Enantiomerization and Diastereomerization OPh OR .0 kJ/mol.0 °C) O S Ph ≠ ≠ ≠ ∆G = 145.0 °C) ∆G = 161.429 Kinetic studies and isotope labeling experiments with allyl p-tolyl sulfoxide proved that the reaction proceeds via reversible sigmatropic [2.

59. This may occur via formation of a solvent-separated ion pair or through a nondissociative process when a proximate Lewis basic site coordinating to the lithium cation is present.74 Chapter 3 O2S NaOMe/MeOH 100 °C O2 S O2S C6H13 C6H13 SO2Ph CO2Me 125 °C SO2Ph CO2Me CO2Me SO2Ph Scheme 3. recognized the ability of the sulfone group to stabilize adjacent carbanions. Stereoinversion at the chiral center requires migration of the lithium atom from one enantiotopic site to the other. and 7Li NMR spectroscopy. Scheme 3. see Chapter 3. 3. the sulfur atom in sulfones is not the origin of chirality but it can affect the configurational stability of an adjacent asymmetric carbon center.443 During the last 50 years. 6Li.12 Organometallic Compounds The dynamic stereochemistry of chiral transition metal complexes is quite versatile and adds a new dimension to asymmetric synthesis and supramolecular chemistry including stereoselective selfassociation and chiral amplification. Aryl.2. The configurational stability of chiral organolithium compounds has been studied by variabletemperature 1H. The racemization course of sulfones usually resembles that of carboxylic acid derivatives and is strikingly different from the stereomutations of sulfoxides discussed above.444–451 The configurational stability is often solvent-dependent and varies significantly with the steric bulk and chelating properties of neighboring groups.58 Enantioconversion of chiral sulfones.2. 13C. the ever-increasing impact of organometallic compounds on stereoselective synthesis and chiral recognition has fueled the development of numerous chiral metal complexes.2.434–437 In contrast to sulfoxides. Scheme 3.442.1.58.440 Cram et al. under mild conditions. Since the pKa value of the a-proton in aliphatic sulfones is about 30.3. The substituents effectively favor formation of an intermediate achiral zwitterion and racemization can be observed in DMSO at 125 1C which is substantially lower than the temperatures usually required for stereomutations of cyclopropanes.452–456 While some organolithium compounds racemize rapidly . and designed a cyclopropane that favors thermal racemization via heterolytic ring opening and subsequent cyclization over the radical mechanism generally observed with cyclopropanes. Atropisomerization of axially chiral sulfoxides and sulfones is discussed in Chapter 3. This proves a remarkable stereochemical integrity of the intermediate carbanion which is apparently not planar and does not readily undergo pyramidal inversion.and alkylsulfinyl chlorides easily racemize in the presence of amines and this has been utilized for asymmetric synthesis of chiral sulfinate esters and sulfoxides.2-dimethyl-1-phenylsulfonylcyclopropane-1-carboxylic acid exhibits carbanion-stabilizing and carbonium ion-stabilizing groups on either side of the strained three-membered ring. A close look at the configurational stability and reactivity of Grignard and organolithium reagents underscores the fact that synthetic applications of metal complexes are defined by their stereodynamic properties.439.438 Deuterium exchange experiments conducted with aryl 2-octyl sulfones at 100 1C revealed that the rate of isotope exchange is significantly faster than the rate of racemization. base-catalyzed racemization via an intermediate carbanion is possible at elevated temperatures.441 The methyl ester of 2.

It is therefore sufficient to know the relative configurational stability with respect to the rate of reaction with a trapping electrophile. According to the Curtin– Hammett principle. This information can be obtained by the Hoffmann test which is based on the principles of KR. .9 kJ/mol (2 °C) Li H ∆G = 33. when an enantiopure electrophile is used the diastereoselectivity will be different. it is often not necessary to determine accurately the racemization rate of an organometallic species. DKR and DYKAT. The corresponding energy profiles for an organolithium compound that racemizes rapidly compared to the reaction with the racemic or enantiopure electrophile. If the stereochemical outcome is different. If an enantiopure organolithium reagent is consumed by an electrophile before it can undergo measurable racemization. is depicted in Figure 3.5. the stereochemical outcome of both scenarios depends solely on the difference in energy of the diastereomeric transition states. chiral nonracemic Grignard and organolithium compounds can not be isolated at room temperature.457–462 This test requires two experiments that are usually conducted with an excess of an electrophile to guarantee complete conversion: the racemic organolithium species is first treated with a racemic electrophile and then with the enantiomerically pure electrophile. and the diastereoselectivities obtained by the two experiments must be the same. even under cryogenic conditions.xvi For synthetic purposes. Based on the Hoffmann test.4 and 7. One would obtain the same ratio of diastereomers with the enantiopure organolithium compound.59 Racemization pathways of organolithium compounds and energy barriers to racemization of selected examples. In the context of asymmetric synthesis. the overall stereoselectivity of the asymmetric reaction is not compromised.Racemization. DDGa.xviii However. see Chapters 7. organometallic species are considered configurationally stable if racemization is relatively slow compared to a trapping reaction with an electrophile.xvii This is no longer the case when the organolithium compound is configurationally stable or has a racemization half-life time comparable to the rate of reaction with the electrophile. Quantitative trapping with a racemic electrophile still affords a mixture of diastereomers that is determined by the energetic difference of the diastereomeric transition states.10.5 kJ/mol (-15 to -135 °C) Li ∆G ≠ = 72. one can conclude that a chiral organolithium reagent undergoes fast racemization relative to the reaction with an electrophile if both experiments provide the same diastereoselectivity. Figure 3. and the product ratio will be unity if equilibration between the organolithium enantiomers does not occur during the reaction.9 kJ/mol (-34 °C) Scheme 3. xviii This is not a consequence of the Curtin–Hammett principle. Enantiomerization and Diastereomerization Racemization via a solvent-separated ion pair Li Ph Ph Li inversion Ph Ph Li Li 75 Racemization via a nondissociative process involving a heteroatom-stabilized coordination complex Li Ph N Ph Li N inversion Ph Li N Ph Li N O S Ph ≠ O S CF3 Si Ph Ph SePh Ph Li H ∆G ≠ = 51. others such as a-lithio sulfones can have energy barriers above 70 kJ/mol.11. xvii Note that enantiomeric pathways do not alter the diastereoselectivity of the reaction. DDGa. xvi Usually. but is a result of matched and mismatched stereoselection. This is often the case at very low temperatures.

60. although enantiopure crystals obtained by crystallization-induced asymmetric transformation have been employed in enantioselective additions to aldehydes with some success.2-dimethoxyethane ligands have been described. kE′ ER + ES kE. The six-coordinate magnesium atom is the only chiral center in these complexes which rapidly racemize in solution. see Chapter 6.76 a) Reaction of a stereolabile organolithium compound with a racemic electrophile AS ER + ES kE.1. providing (1R. Hoffmann’s group showed that the preparation of a nonracemic Grignard complex is possible through sulfoxide/magnesium exchange at low temperatures. treatment of (RS. The chiral Grignard reagent can then be trapped with benzaldehyde.467. For instance. Scheme 3.60.3-diphenyl-2-chloro-1-hydroxypropane in 77% yield and 93% ee. Grignard compounds are certainly among the most widely used organometallic reagents but few asymmetric reactions with nonracemic organomagnesium reagents are known.464–466 For example.1R)-p-tolyl-1-chloro-2-phenylethyl sulfoxide with ethylmagnesium bromide at –78 1C gives the corresponding (R)-a-chloroalkylmagnesium bromide with retention of configuration. or if equal amounts of diastereomers are obtained with an enantiopure electrophile the organolithium species is configurationally stable under the reaction conditions used. both racemization and reaction with the electrophile must occur on a similar time scale. kE′ krac > kE.2R)-1. nonracemic organolithium compounds have found numerous applications in asymmetric synthesis. AR = enantiomeric RLi P = stereoisomeric products E = chiral electrophile PSR + PSS ∆∆G ≠ Chapter 3 krac AR PRR + PRS ∆G ≠SS ∆G ≠SR AS ≠ ∆G ≠RS AR ∆G rac ∆G ≠RR PRR PRS b) Reaction of a stereolabile organolithium compound with an enantiopure electrophile AS krac AR ER kE′ krac > kE.468 In contrast to Grignard complexes. Even chiral-at-metal magnesium complexes that display two chelating 1. transmetalation between (R)-1-benzyloxymethoxy-1tributylstannylpropane and butyllithium at –78 1C followed by methylation with dimethyl sulfate produces (R)-2-benzyloxymethoxybutane in 95% ee. kE′ PSR PRR + PSS PRS + PSR = PRR PSR PRR ∆G ≠SR AS ≠ ER kE PSR ∆∆G ≠ ∆G ≠RR AR PRR ∆G rac Figure 3. The configurational stability of lithiated carbanions can be significantly enhanced by intramolecular coordination of proximate heteroatoms to the lithium atom.10 Energy profiles for the reactions between a stereolabile organolithium species and a racemic or enantiopure electrophile. Scheme 3. kE′ PSS PSR AS. This approach reduces the risk of racemization which would ultimately compromise the stereoselectivity of a subsequent reaction with an electrophile.469 .463 This is a consequence of the low configurational stability of chiral carbanions under conditions that are normally required to produce Grignard reagents from alkyl halides.

Racemization, Enantiomerization and Diastereomerization
a) Reaction of a configurationally stable organolithium compound with a racemic electrophile
∆G ≠ rac AS ER + ES kE, kE′ ER + ES kE, kE′ krac < kE, kE′ PSS PSR AS, AR = enantiomeric RLi P = stereoisomeric products E = chiral electrophile PSR + PSS ∆∆G ≠



b) Reaction of a configurationally stable organolithium compound with an enantiopure electrophile

∆G≠ rac AS krac AR ER kE′ krac < kE, kE′ PSR PRR + PSS PRS + PSR ≠ PRR PSR PRR PSR = 1 (if krac << kE, kE′) PRR ∆G≠SR AS AR PRR ∆G≠RR ER kE PSR ∆∆G≠

Figure 3.11

Kinetics of the reactions of a configurationally stable organolithium species with a racemic or enantiopure electrophile.

O S Cl

Ph EtMgBr -78 °C

O S BrMg + Cl O O Mg -70 °C 30-45%, 5-21% ee H O Li OBn Me2SO4 H O OBn H OH Ph PhCHO Me2AlCl Ph


Cl 77%, 80% de, 93% ee

O O O p-Tol Br ∆-[p-Tol)MgBr(DME)2] H O SnBu3 OBn n-BuLi -78 °C

>95%, >95% ee

Scheme 3.60

Asymmetric synthesis with chiral Grignard and organolithium reagents.

NMe2 B Ph X B-N dissociation B NMe2 X Ph C-B rotation NMe2 Ph X

Chapter 3

X=F: ∆G = 94 kJ/mol (120 °C) X=Me: ∆G≠ = 103 kJ/mol (140 °C) X=O2CCF3: ∆G≠ = 112 kJ/mol (73 °C) X=Cl: ∆G = 112 kJ/mol (135 °C)

NMe2 B X Ph B-N dissociation B

X=O2CCF2CF3: ∆G≠ = 116 kJ/mol (83 °C)

O O O i-Pr B O i-Pr H HO

O B O O i-Pr HO O O i-Pr -H i-Pr O B OH O i-Pr O i-Pr O B O i-Pr i-Pr

O i-Pr O O B

Scheme 3.61

Racemization of tetrahedral boron complexes.

Chiral-at-boron complexes are usually not configurationally stable in solution due to rapid dissociation of boron–nitrogen and boron–oxygen bonds.470 The stereodynamics of several fourcoordinate oxazaborolidinone-derived boron complexes have been exploited for asymmetric transformation of the second kind.471–473 Toyota and coworkers demonstrated that substituents have a major influence on the barrier to racemization of amine-borane complexes, Scheme 3.61.474 The configurational stability of [2-(dimethylaminomethyl)phenyl](pentafluoropropionyloxy)phenylborane was determined as 116 kJ/mol. The remarkable stability to racemization of perfluoroacyl-derived complexes coincides with shorter B–N bond lengths and increased thermal stability.xix A dissociative acid-catalyzed mechanism has been proposed for the enantioconversion of chiral borates.475 Racemization and diastereomerization of kinetically unstable transition metal complexes often involve ligand exchange processes. In the case of K3[Yb{(M)-BINOL)}3], stepwise replacement of all (M)-BINOL ligands upon addition of a molar excess of the (P)-enantiomer results in complete chirality inversion because the homochiral complexes are thermodynamically favored over the heterochiral intermediates. Although near-IR CD and NMR studies revealed that the bidentate ligands are rapidly exchanged one-by-one, this is not a trivial process: each replacement requires additional proton transfer steps that may occur via a concerted or sequential mechanism, Scheme 3.62.476


The increased stability to boron–nitrogen bond dissociation is a consequence of the enhanced Lewis acidity of the corresponding trivalent boron complex.

Racemization, Enantiomerization and Diastereomerization
3(M) O O (M) O O (M) Yb O (M)-BINOL O (P)-BINOL O (P) O O (M) OH (P)-BINOL (M)-BINOL 3(P)


O O Yb O


(M) OH

3(P) (M)-BINOL O O (P) Yb O (P)-BINOL O (M) heterochiral enantiomers (thermodynamically less stable) O O

O (P) O Yb O O


homochiral enantiomers (thermodynamically more stable)

Scheme 3.62

Enantioconversion of [Yb(BINOL)3]3– complexes by ligand exchange.

Most stereomutations of kinetically unstable transition metal complexes occur through a dissociation/association sequence and an intermediate unsaturated 16-electron species that allows rapid reorientation of one or more ligands. Faller postulated two possible mechanisms for the interconversion of chiral ruthenium complexes.477 The chiral-at-metal complex shown in Scheme 3.63 can racemize either via dissociation and subsequent association of water or by conversion of the chelating P,O-donor to a monodentate ligand followed by internal rotation about the Ru-P bond and rechelation. In both pathways, formation of an intermediate achiral 16-electron complex yields racemization. Some chiral-at-metal complexes are configurationally stable in solution while others undergo rapid racemization or epimerization if another chiral element is present in the ligand sphere.478–490 Prediction of the configurational stability of transition metal complexes is difficult and half-lives vary substantially among different metals and ligands, Scheme 3.64.491–494 Inversion of the planar chirality of aryl metallocenes can occur via migration of the metal moiety to the opposite arene face. Heating of syn-(Z-1,2,3,4,5,6-tricarbonyl-2-hydroxymethyl-6-methoxy2 0 -methylbiphenyl)chromium in a nonaromatic solvent affords a mixture of two anti-diastereomers due to rotation about the chiral axis (atropisomerization) and stereoselective tricarbonylchromium migration to the less sterically hindered arene face. The latter results in inversion of planar chirality and is the predominant reaction. It has been proposed that the migration is assisted by the hydroxymethyl group and that it proceeds in an intermolecular fashion.495,496 An intramolecular migration of tricarbonylchromium along a naphthohydroquinone skeleton has been incorporated into the design of a reversible chiral switch.497 The naphthohydroquinone-derived tricarbonylchromium complex shown in Scheme 3.65 forms the thermodynamically disfavored (R)-isomer by an asymmetric photo-induced metal shift along the aromatic ring. The reaction outcome can be reversed by thermally controlled metal migration to the more stable (S)-regioisomeric complex. Both haptotropic migrations proceed without any sign of racemization. Induction and inversion of chirality play an important role in nature and are known to affect the properties and functions of DNA and proteins. The versatile coordination chemistry and stereodynamics of chiral metal complexes can be used to mimic such processes, to devise chiral switches

+ i-Pr Ru H2O + i-Pr Ru H2O O Ph2 P - H2O P Ph2 O Ph2P Ru PPh2 PPh2

Chapter 3

η 2 to η 1

O P Ph2 + i-Pr

η 1 to η 2
i-Pr Ru H2O H2O Ph2P O PPh2


Scheme 3.63

Possible racemization pathways of a chiral ruthenium complex.
i-Pr M NBn Cl NMe2

R Fe(CO)2L


R Fe(CO)2 L


Rh N

R=Me, L=P(OMe)3: τ1,2 = 25.7 s (-193 °C) R=CO 2Me, L=CO: τ1,2 = 173.3 s (119 °C)

τ1,2 = 23 ms (115.1 °C)

M=Ru: τ1,2 = 34 min (6 °C) M=Os: τ1,2 = 62 min (5 °C)

Scheme 3.64

Configurational stability of transition metal complexes.

that respond to external stimuli, and to develop supramolecular architectures exhibiting chiral amplification and memory.498–504 Miyake’s group demonstrated that the helicity of kinetically labile octahedral Co(II), Cu(II) and Ni(II) complexes can be reversed upon addition of an achiral stimulus.505,506 Coordination of a chiral amino acid-derived tetradentate ligand to cobalt(II) affords a thermodynamically favored L-isomer with a positive CD signal, Scheme 3.66. However, addition of two equivalents of tetrabutylammonium nitrate completely reverses the CD signal due to displacement of two solvent ligands and cooperative stabilization of the diastereomeric D-form.xx Because of the kinetic instability of the cobalt(II) complex, the stereochemical response to the presence of nitrate anions resulting in helicity inversion within the metal coordination sphere requires less than a minute.

3.2.13 Supramolecular Structures
The dynamics, cooperative effects and correlated motions of chiral supramolecular structures held together by weak intermolecular interactions such as hydrogen bonding, metal coordination, p–p interactions, Coulomb forces, dipole–dipole interactions, and van der Waals forces have led to the development of complex molecular assemblies that can be used for switching507–510 and amplification511–515 of chirality. Lehn’s group demonstrated that self-association of achiral compounds adopting a helical conformation can lead to chiral supramolecular aggregates.516 Intramolecular hydrogen bonding of linear heptamers derived from repeating 2 0 -pyridyl-2-pyridinecarboxamide

The ratio of the diastereomeric Co(II) complexes is also sensitive to the solvent composition. In this case, dynamic helicity inversion is based on solvato-diastereomerism.

Racemization, Enantiomerization and Diastereomerization
HO 140 °C 55% (CO) 3Cr OMe syn-isomer OMe HO (CO)3Cr + (CO)3Cr anti-isomers 95:5 OMe Et Cr(CO)3 Et OSiMe2t-Bu (R)-regioisomer 1. hν, cyclooctene 2. CO (OC)3Cr Et OSiMe2 t-Bu (S)-regioisomer Et OMe HO



Scheme 3.65

Isomerization of chiral aryl tricarbonylchromium complexes.
O O N O O N Co N O ∆-form tetradentate ligand NHMe MeHN N N O NHMe 2+



solvent solvent Λ-form

2 NO3 - 2 NO3




Scheme 3.66

Dynamic helicity inversion of a stereolabile Co(II) complex.

units establishes a racemic mixture of short helical structures consisting of approximately one and a half turns, Figure 3.12. Dimerization of homochiral helices was observed by variabletemperature NMR spectroscopy and has been attributed to spiral sliding of one oligopyridinecarboxamide coil into another. This artificial double helix has remarkable stereodynamic features. Partial unwinding due to lateral movements of the individual strands gives rise to translational isomerism which can be monitored at ambient temperatures up to 55 1C. Dissociation of the double-stranded helix requires complete unwinding through translational movement of one coil relative to the other. The dimers are remarkably stable in solution due to cooperative intermolecular p-stacking but dissociation is fast and thermodynamically favored above 105 1C.xxi Chiral inversion and induction processes play an important role in host-guest chemistry, selfassembly and molecular recognition. The fascinating structure and properties of double-stranded helical DNA has inspired Lehn and others to design artificial analogs, in which molecular chirality is transformed into supramolecular helicity.517–522 For example, charge-assisted hydrogen bonding

At room temperature, the dimer of the heptamer depicted in Figure 3.12 remains the major species in solution, even at concentrations as low as 300 mM. The dimerization constant in CDCl3 is 6.5 Á 104 L mol–1.

a) Folding of the oligopyridinecarboxamide
OC10H21 OC10H21 H N N O OC10H21 O O OC10H21
C10 H21O O O C10H21O O C10H21O N NH O C9H19 C10H21O O NH O NH N HN N N HN NH N N OC10H21 HN N O HN C9H19 O OC10H21

Chapter 3

OC10H21 H N H N N O OC10H21 O OC10H21 H N H N O










spontaneous helix formation in chloroform


b) Double helix formation and translational isomerism

slow up to 55 oC

slow up to 105 oC

Figure 3.12

Dynamic exchange of artificial single and double helices derived from oligopyridinecarboxamide strands. [Modified with permission from Nature 2000, 407, 720-723.]

between two sulfate anions and two enantiomerically pure bisguanidinium strands results in the assembly of a well-defined supramolecular structure. The handedness of the helical arrangement is controlled by the central chirality of the homochiral guanidinium moieties, Figure 3.13.523 The same principle can be applied to the synthesis of hetero-stranded double helices. Furusho and Yashima reported spontaneous self-assembly of an enantiopure double helix from two complementary m-terphenyl strands exhibiting amidine and carboxylate groups, respectively. Cooperative charge-assisted hydrogen bonding between the chiral bisamidine strand and the complementary dicarboxylate strand affords an artificial double helix that is stable in solution and in the solid state. The sense of chirality of the supramolecular structure is determined by the absolute configuration of the amidine units and enantiomeric bisamidine strands have been found to generate assemblies of opposite helicity.524 Chiral induction is a widespread phenomenon that is not only observed with supramolecular assemblies. Numerous examples of switching and amplification of chirality in oligomers,525–528 polymers,529–543 and gels or liquid crystals have been reported.544–557 Cyclodextrins consist of six, seven or eight glucose units linked by a-1,4 glycosidic bonds. These naturally occurring macrocycles have been known for a long time and are commonly employed in chromatography, electrophoresis and many other purposes. Cyclodextrins have the shape of a truncated cone that is chiral due to the presence of five stereogenic centers in each glucose unit, Figure 3.14. Inclusion of UV-active achiral molecules into the chiral cavity of cyclodextrins can force the guest into a nonracemic chiral conformation which gives rise to induced circular

Racemization, Enantiomerization and Diastereomerization


O Me3Si Me3Si Ph N H O N H Ph O Ph H N

O H N Ph SiMe3 SiMe3

Figure 3.13

Artificial double-stranded helices.

dichroism.558 Polycyclic aromatic hydrocarbons,559 benzophenones560,561 and diarylmethanes562 have been reported to adopt a helical structure upon complexation by native b- or g-cyclodextrins. The asymmetric perturbation and relative orientation of aromatic guest molecules in the chiral cavity can be conveniently measured by circular dichroism spectroscopy because native cyclodextrins are CD-silent. The usefulness of cyclodextrin-derived inclusion complexes has inspired the study of molecular recognition and chiral induction with artificial hosts such as crown ethers, calixarenes and other cavitands.xxii Both induction of chirality from a chiral guest to an achiral host, and from a chiral host to a guest molecule that can adopt chiral conformations, have been reported.563–567 Some macrocycles possess flexible structures that can racemize without bond cleavage. This has been demonstrated with calixarenes derived from selectively substituted arene units. Collet and others found that a partially O-methylated calix[4]arene consisting of four 3,4-dimethylphenol units adopts a chiral cone conformation despite the lack of a chiral center, Scheme 3.67.568,569 Due to intramolecular hydrogen bonding, this calixarene affords only two enantiomeric cone structures while achiral 1,2-alternate and 1,3-alternate conformations exhibiting C1- and S4-symmetry, respectively, have not been detected. The enantiomers can be separated by chiral chromatography, but racemize via cone-to-cone ring inversion at ambient temperatures.570


Cavitands are macrocyclic compounds with an open cavity that can be occupied by small molecules. Calix[n]arenes are a sub-class of cavitands and consist of n arene units linked by methylene bridges. Calixarenes exhibit a hydrophobic interior and have found widespread applications in host-guest chemistry.


Chapter 3




Figure 3.14

Structures of native g-cyclodextrin and guest molecules that undergo chiral induction upon complexation.


HO MeO OMe OH ∆G = 101.7 kJ/mol (30.0 °C)

Scheme 3.67

Racemization of a calix[4]arene via cone-to-cone ring inversion.

In 1922, Christie and Kenner reported the separation of the enantiomers of 6,6 0 -dinitrobiphenyl2,2 0 -dicarboxylic acid and its 4,4 0 ,6,6 0 -tetranitrobiphenyl derivative by preferential crystallization of diastereomeric brucine salts, Figure 3.15.571 But they were unable to resolve the enantiomers of biphenyl-2,2 0 -dicarboxylic acid. We know today that the latter can not be separated into enantiomers at room temperature because this biphenyl readily racemizes due to facile rotation about the chiral axis. For practical reasons, Kuhn introduced the concept of atropisomerism to describe stereoisomers that result from restricted rotation about a single bond and that can be separated at room temperature.572 This definition is solely based on the rotational stability of isolable stereoisomers, and suffers from the same drawbacks as the physicochemical classification of configurational and conformational isomers discussed in Chapter 2.2.573 For example, 2,2 0 diiodobiphenyl has a rotational energy barrier of 97.0 kJ/mol at 34 1C and can be separated into enantiomers at room temperature but it slowly racemizes in solution.574 Since Kuhn’s stability criterion is vague, i.e., there is no clearly defined minimum half-life time or free energy barrier to rotation associated with atropisomerism, it remains unclear whether 2,2 0 -diiodobiphenyl fulfills the requirements of this type of stereoisomerism. A strict interpretation of Kuhn’s original definition would include axially chiral biphenyls that are stable to racemization and have been separated into stereoisomers, for example 2,2 0 ,3,4,4 0 ,5 0 ,6-heptachlorobiphenyl (PCB 183). On the other hand, the enantiomers of conformationally stable 2,2 0 ,3,3 0 ,4,4 0 ,5,6 0 -octachlorobiphenyl (PCB 196) would not be considered atropisomeric because they have not been separated to date. Although the concept of atropisomerism is not clearly defined, it is widely used in the literature, irrespective of the

Racemization, Enantiomerization and Diastereomerization
NO2 O2N O2N CO2H CO2H NO2 Cl CO2H CO2H Cl Cl PCB 183 Cl Cl Cl Cl Cl Cl PCB 196 Cl Cl Cl Cl Cl



Figure 3.15

Structures of axially chiral biphenyls.

separation criterion, and generously applied to stereoisomers that exhibit hindered rotation about a single bond.xxiii

3.3.1 Biaryls, Triaryls and Diarylacetylenes
Since the early findings of Christie and Kenner, the unique relationship between structure and stereodynamics of atropisomeric biaryls and triaryls has received significant attention. Interconversion of the enantiomers of 1,8-bis(2 0 -phenyl-4 0 -quinoyl)naphthalene proceeds via a diastereomeric meso intermediate and involves two rotations obeying reversible first-order kinetics, Chapter 3.1.3. In contrast, racemization of chiral biphenyls constitutes a one-step process and is kinetically less complicated which greatly facilitates investigation of stereodynamic properties.575–578 Wolf and coworkers conducted a systematic study of steric and electronic effects of ortho-, meta- and para-substituents on the rotational energy barrier of axially chiral 2,2 0 -dialkylbiphenyls utilizing polarimetry and dynamic gas chromatography, Figures 3.16 and 3.19.579–582 The conformational stability of unbridged biphenyls is mainly determined by the number and size of ortho-substituents that experience strong steric repulsion in the periplanar transition state and thus impede rotation about the pivotal bond.xxiv Most tri- and tetra-ortho-substituted biphenyls are conformationally stable and can be conveniently resolved into enantiomers at room temperature, unless small fluoro or methoxy ortho-substituents are present. With the exception of 2,2 0 -disubstituted biphenyls bearing bulky isopropyl, phenyl or tert-butyl groups, axially chiral biphenyls that have fewer than three ortho-substituents are often not stable to racemization at 25 1C. Rotation about the chiral axis of 2,2 0 -disubstituted biphenyls can in principle occur via two different transition states, in which the substituents pass either one another or a hydrogen atom of the adjacent aryl ring. The latter entails significantly less steric repulsion and is the energetically favored and therefore predominant pathway of atropisomerization, Figure 3.17. A closer look at tri- and tetrasubstituted biphenyls shows that the relative position of ortho-substituents is also important. For example, 2-tert-butyl-2 0 -methyl-6-isopropylbiphenyl can access two transition states. Rotation via a transition state in which the 2 0 -methyl and the 6-isopropyl substituents pass each other will be energetically favored because it avoids the severe steric hindrance that would result from the interaction between the 2 0 -methyl and the bulky 2-tert-butyl group. In the case of 2-tert-butyl-2 0 -methyl-6 0 -isopropylbiphenyl, enantiomerization requires that either the 2 0 -methyl or the 6 0 -isopropyl group passes the 2-tert-butyl group of the other phenyl ring. With this biphenyl, the least steric repulsion is encountered in the transition state that has the methyl and the tert-butyl group passing each other. A comparison of the accessible transition states of these two constitutional isomers reveals that 2-tert-butyl-2 0 -methyl-6 0 -isopropylbiphenyl is conformationally more stable.

Atropisomerism is a special case of conformational isomerism. Atropisomers are necessarily conformational isomers but not all conformational isomers fulfill the criteria of atropisomerism, for example the overcrowded alkenes described in Chapter 3.2.2. xxiv The transition state is not perfectly planar and has a slightly twisted geometry, see Figure 3.18.


Chapter 3


[α ]

62.7 oC 365 nm






0.2 0.1



0 0 15 30 45 60


Figure 3.16

Energy profile of the atropisomerization of biphenyls (left) and polarimetric study of the racemization of 4,4 0 -dimethoxy-2,2 0 -bis(trifluoromethyl)biphenyl (right).

H t-Bu H H

Me i-Pr energetically favored TS

R R energetically disfavored TS R H H

t-Bu Me


Me i-Pr Me t-Bu H




H R energetically favored TS


R i-Pr H energetically favored TS t-Bu Me i-Pr t-Bu





i-Pr H

Me H

Figure 3.17

Rotation pathways of di- and trisubstituted biphenyls.

The energy barrier to atropisomerization of biphenyls steadily increases with the bulkiness of the substituents due to both enthalpic and negative entropic contributions. The latter originates from the compromised rotational freedom of ortho-substituents in the crowded transition state. For example, 2,2 0 -diisopropylbiphenyl has a Gibbs free energy of activation, DGa, of 116.6 kJ/mol and an activation entropy, DSa, of –46 J/K mol at 159.9 1C. Replacement of one isopropyl substituent with a bulky tert-butyl group affords 2-tert-butyl-2 0 -isopropylbiphenyl which has a rotational energy barrier of 136.9 kJ/mol at the same temperature. On the other hand, the enantiomers of 2-ethyl-2 0 -isopropylbiphenyl interconvert rapidly and can not be isolated at room temperature. Substituents in the meta-position exhibit a so-called buttressing effect: they reduce the flexibility of the adjacent ortho-substituent and therefore enhance steric repulsion during rotation about the chiral axis. The buttressing effect can provide a significant contribution to the overall steric hindrance to rotation. Incorporation of a relatively small ethyl group into the meta-position at C-3

The distortion of the aryl rings decreases steric hindrance between ortho-substituents when the aryl rings go through the same plane in the transition state. and opposite electronic effects on the conformational stability have been observed with para-substituted 2. incorporation of one methoxy and one nitro group into opposite para-positions significantly accelerates racemization. and on the bulkiness of the adjacent ortho-substituent. This facilitates out-of-plane bending and thus reduces steric interactions in the crowded transition state.2 0 -disubstituted biphenyls by up to 10%. established the following order of destabilizing para-substituents: NH2 44 NHAc 4 OH 4 OMe 4 CH3 4 H E Br 4 NH31 4 CF3 4 Cl 4 NO2 E F.18.2 0 -bis(trifluoromethyl)biphenyl has been explained by effective push-pull conjugation which stabilizes the transition state and therefore increases the rate of rotation. Figure 3.5 kJ/mol. The low conformational stability of 4-methoxy-4 0 -nitro-2.19.9 1C.18 Racemization pathway and twisted transition state of 1. Enantiomerization and Diastereomerization ≠ E H R RH 87 R R R R Figure 3. Figure 3.2 0 -bis(trifluoromethyl)biphenyl yields a negligible buttressing effect on the adjacent hydrogen attached to C-6 and a rotational energy barrier of only 114. Changes in the stability of the ground state and of the transition state have to be considered for analysis of substituent effects on the atropisomerization barrier. However.Racemization. The buttressing effect depends on the size and geometry of the meta-group. Quantum mechanical computations of biaryls indicate that rotation about the chiral axis occurs via a transition state that is not perfectly coplanar. Figure 3.2 kJ/mol to 126. .. The order of destabilizing para-substituents established for 2. In this case. Interestingly.1 0 -binaphthyls.1 0 -binaphthyls. the enantioconversion process involves a transition state with twisted geometry. in 2.2 0 bis(trifluoromethyl)biphenyl and the corresponding 4. The presence of these groups therefore increases the barrier to atropisomerization. Figure 3. whereas electron-donating groups decrease the rotational barrier.3 kJ/mol at 128.20. Kinetic studies of a range of 2. A comparison of the Gibbs free energy of activation of 2.2 0 -bis(trifluoromethyl)biphenyl increases the rotational energy barrier from 114. The destabilizing effect of methoxy groups and other electron donors has been attributed to enhanced electron density at carbons C-1 and C-1 0 . Figure 3.2 0 -diisopropylbiphenyls.4 0 -disubstituted analogs reveals that electronwithdrawing groups increase conformational stability. conducted by Wolf et al.19.20.2 0 -bis(trifluoromethyl)biphenyls.583 Electronic effects of para-substituents are less pronounced than steric interactions and alter the rotational energy barrier of 2. As is shown for 1.xxv Introduction of ethyl at the opposite metaposition at C-5 in 2. electronic contributions can be more complex in biaryls that undergo CH/p-interactions. electron donors such as amino groups increase the xxv The van der Waals radius of a chloro substituent is slightly smaller than that of a methyl group but it provides a stronger buttressing effect because of its spherical geometry.2 0 -bis(trifluoromethyl)biphenyls is in agreement with similar trends observed in a wide range of biphenyls. Electron acceptors decrease the electron density at the pivotal carbon atoms and impede outof-plane bending.

0 o C) i-Pr NO 2 i-Pr 103.0 ˚C) Figure 3. CF3 H3CO F3C NO2 H3CO CF3 NO2 F3 C H2N H3C H3C H NH2 H2N H CH3 CH3 H3C H3C H NH2 H CH3 CH3 push-pull conjugation CF3 H2 N F3C NH2 H H3C H H2N H H CH3 NH2 H2N H3C H H H H CH3 NH2 out-of-plane bending CH/π-interactions Figure 3.0 ˚C) CF3 Chapter 3 OCH3 F3 C 102. the amino groups in 4.0 o C) i-Pr NH2 i-Pr 112.0 oC) i-Pr NH3 i-Pr 109. Figure 3.0 ˚C) CF3 CF3 F3 C 107.9 ˚C) Et CF3 CF3 H3 C F3 C Et 126.7 kJ/mol (25.4 k J/mol (25.5 kJ/mol (128. Electron-donating groups increase the p-basicity of the aryl moieties and thus enhance intramolecular CH/p-interactions.4 0 -diamino-2. Electron-withdrawing groups reduce the aryl p-basicity which results in a less stable ground state and consequently in reduced conformational stability.6 kJ/mol (25. several CH/pinteractions involving the methine and methyl protons of both isopropyl groups and the ipso.5 kJ/mol (25.2 0 diisopropylbiphenyl strongly increase the stability of the ground state.2 0 -dialkylbiphenyls are only possible in the ground state but not in the periplanar transition state.7 kJ/mol (25.8 kJ/mol (25.0 ˚C) CF3 H3CO CF3 CF3 F O 2N F3C 109.0 ˚C) H3N AcHN CF3 OH F3C 102.0 ˚C) CF3 NH2 H 3CO F3C 99.584 For geometric reasons.4 kJ/mol (25.585 For 2.0 ˚C) NHAc F3C 101.20 Electronic effects of para-substituents on the conformational stability of biphenyls and ground state stabilizing intramolecular CH/p-interactions in 2.0 ˚C) H 2N F3C F3C CF3 CH 3 HO F3C 103.2 0 -diisopropylbiphenyls.7 kJ/mol (25.0 ˚C) CF3 NO 2 H2 N F3 C 109.7 kJ/mol (25.88 CF3 F F3C 106. Energies related to CH/p-bonds are usually less than 10 kJ/mol but these interactions are known to significantly affect the relative stability of conformational isomers of various compounds.0 ˚C) 166.9 ˚C) Br CF3 Br F3C 106. Accordingly.9 kJ/mol (25.0 ˚C) NO 2 F3 C 103.6 kJ/mol (159.and . CH/p-interactions between soft Lewis-acidic C–H bonds of the ortho-alkyl groups and the soft Lewis-basic p-system of the adjacent phenyl ring in 2.8 kJ/mol (25.20.6 kJ/mol (25.and para-substituted dialkylbiphenyls.0 ˚C) i-Pr O2N i-Pr 110. rotational energy barrier while introduction of electron-withdrawing nitro and ammonium groups facilitates atropisomerization.9 kJ/mol (25. It is assumed that the electronic effects on the stability of the transition state discussed above are overcompensated by intramolecular CH/p-interactions that selectively stabilize the ground state.9 kJ/mol (25.3 kJ/mol (128.2 kJ/mol (128.2 0 -diisopropylbiphenyls.7 kJ/mol (25.9 ˚C) 114.9 ˚C) CF3 Cl Cl F3C 107.19 Rotational energy barriers of meta.0 ˚C) 114.0 kJ/mol (25.

Because the rotational energy barrier of 1. are 57. in which the edge of the rotating pyridine is directed towards the adjacent pyridyl ring. the presence of electron-donating groups leads to substantial stabilization of the ground state.612. and N-oxidation increases the electron density at the pivotal carbon atoms.613 An increase in bridge length enhances the torsion angle between the two aryl rings and raises the energy barrier to racemization.or six-membered bridge may still undergo rotation about the chiral axis. The conformational stability of bridged biaryls varies significantly with the ring size. ortho-aryl carbons can be anticipated. The conformational stability of many other biaryls586–601 and triaryls602–611 has been investigated.2 0 -diisopropylbiphenyl. DG2. biaryls with a five. . DHa. The isomerization process involves a sterically crowded T-shaped transition state. As a rule of thumb.N 0 -dioxides has been attributed to two synergistic effects on the relative stability of the ground and transition states: repulsive dipole/dipole-interactions between the cofacial rings of 1. unless bulky ortho-substituents are present in the bridged biaryl xxvi As discussed above for biaryls. Nevertheless.4 kJ/mol.and anti-diastereomers proceeds rapidly at room temperature. The syn/anti-isomerization of 1.21 Illustration of the energetic effects of electron-donating para-substituents on the rotational barrier of 2. electronic substituent effects on the rotational barrier of triaryls are significantly smaller than steric effects.xxvi The reduced rotational energy barrier of diheteroarylnaphthalene N. Figure 3.20. Scheme 3.8-bis(2 0 -phenyl4 0 -pyridyl)naphthalene has been studied over a temperature range of more than 100 1C by chromatographic and NMR spectroscopic methods.5 kJ/mol and –43. respectively.N 0 -dioxides selectively destabilize the ground state and thus decrease the rotational energy barrier (1). DG1.Racemization. Consequently. Rotation of either pyridyl ring of this atropisomer about the pyridyl–naphthalene axis entails interconversion of a meso syn. The considerably negative activation entropy is indicative of a highly ordered transition state which is typical for atropisomerizations of biaryls and triaryls. interconversion between the syn.21. DSa.8-diheteroarylnaphthalene N. facilitating out-of-plane bending and rotation about the axially chiral naphthyl-heteroaryl bond via a less sterically hindered transition state (2). biaryls that possess one bridging atom are not stable to rotation at room temperature even if the remaining two ortho-positions are occupied by bulky groups. due to enhanced CH/p-interactions which becomes the predominant effect on the rotational energy barrier as it overcompensates the concurrent stabilization of the transition state via facilitated out-of-plane bending.4 J/K mol.22. Enantiomerization and Diastereomerization ∆G2 i-Pr 89 ∆G≠2 ∆G≠1 i-Pr i-Pr i-Pr H2N i-Pr NH2 ∆G1 H2N i-Pr i-Pr NH2 i-Pr ∆G1: stabilization of the ground state due to increased CH/π-interactions ∆G2: stabilization of the transition state due to facilitated out-of-plane bending ∆G1 > ∆G2 ⇒ ∆G≠1 > ∆G≠2 Figure 3.8-bis(2 0 -phenyl-4 0 -pyridyl)naphthalene is only 70. and activation entropy. The corresponding activation enthalpy. N-oxidation of diheteroarylnaphthalenes decreases the conformational stability.68. Figure 3. Figure 3. Interestingly. and the rotational energy barriers can usually be explained on the basis of the steric and electronic substituent effects discussed above.and two chiral anti-isomers.

1 °C) OMe 99.9 °C) 100.7 kJ/mol (43.22 Structures and rotational energy barriers of selected biaryls.0 kJ/mol (67.0 °C) MeO2C F 106.2.68 Diastereoisomerization of axially chiral 1. framework.1 °C) CO2H 107. Figure 3.0 kJ/mol 126.9 °C) (25.1 °C) OMe 98.621–625 The transient formation of a short bridge can significantly compromise the conformational stability of biaryls.a 112.0 kJ/mol (40.626.0 °C) CO2Et OMe i-Pr i-Pr OMe F F CO2Me OH Br Br MeO CO2Et F F OH O CO2H 86.2.3 oC) R=Ph: ∆G ≠ = 74.9 oC) a) anti-to-syn-isomerization.8 kJ/mol (67.0 kJ/mol (109.1 °C) CO2H 78.1 °C) OH MeO 108.1 to 89.5 oC) R=Me: ∆G ≠ = 67.2 kJ/mol (28.90 HO2C HO2C I Chapter 3 i-Pr MeO O2 N t-Bu HO2C t-Bu I I I I I I MeO CHO 77.4 kJ/mol (67.8 kJ/mol (25.9 °C) Figure 3.5 C) o anti-isomer syn-isomer R=Ph: ∆G ≠ = 69 kJ/mol (27.0 oC) R=i-Pr: ∆G ≠ = 117.7 kJ/mol (58.1 kJ/molb (71.5 kJ/mol (194.9 kJ/mol (61.0 °C) F I CO2H 125.0 kJ/mol (25.627 According to the discussion above.614–620 This has been demonstrated with a series of benzonaphthopyranones. b) syn-to-anti-isomerization ∆G ≠ >180 kJ/mol Scheme 3.a 111.0 °C) NO2 73.0 °C) OMe 74.3 kJ/mol (50.0 °C) 155. Biaryls containing seven-membered or larger rings are generally at least as stable as their unbridged analogs.0 oC) a) b) R N N R N R N R R N O N O R a) b) N O N O N R R N R R R=Me: ∆G ≠ = 116.0.1 kJ/molb (66.0 kJ/molb (56.23.8 kJ/molb (97.8-diheteroarylnaphthalenes.0 kJ/mol (27.1 °C) O 91.8 oC) R=i-Pr: ∆G ≠ = 115. one would expect that incorporation of four ortho-substituents into a biaryl framework establishes considerable conformational .6 kJ/mol (67.0 kJ/mol (67.2 oC) R=Ph: ∆G ≠ = 122.a 121.0 kJ/mol (67.a 109. ≠ R R N N R N R N R R N O N O R N O R N O R N O N O T-shaped TS R R=Me: ∆G ≠ = 65.4.

Racemization. LASER photolysis experiments revealed that it undergoes facile racemization in the excited triplet state.1 °C) 102.632–637 An interesting example is 1. but this is apparently overcompensated by the large electron stabilization energy.1 to 70.3 kJ/mol (25. OH (M) CHO OH O O OH OHC HO (P) ∆G≠ = 99 kJ/mol (23. it is believed that the increase in electron density at the central carbon atoms of the naphthoxide moieties facilitates rotation via out-of-plane bending in the transition state.1 kJ/mol (23.2 N hydrochloric acid within this period of time.4 kJ/mol (25.3 °C) Figure 3.7 kJ/mol at 43. which reduces both the torsion angle between the two aryl rings and the barrier to rotation about the chiral axis. The rotational energy barrier in the triplet state has been estimated to be as low as 8 kJ/mol. Atropisomerizations are not necessarily thermal rotation processes and smooth photoracemization of several biaryls has been observed.631 By analogy with the rationalization of electronic effects of electron-donating substituents on the rotational energy barrier of biphenyls.628 An important example is the acid-catalyzed racemization of BINOL. However.24.0 °C) R O O HN O NH CO2H 104.9 1C. Scheme 3. Figure 3. This biaryl does not show any sign of racemization on heating at 100 1C for 24 hours under neutral conditions but it racemizes at 100 1C in 1. Enantiomerization and Diastereomerization 91 O O P R R′ 60.629. Atropisomerization is an intramolecular process that is controlled by steric and electronic substituent effects.0 kJ/mol (6. The higher bond order and the shorter distance between the aryl planes should enhance steric hindrance and thus increase the rotational barrier. The biaryl has a formyl and a hydroxyl group in opposite aryl rings and forms an intermediate five-membered lactol ring. .69 Atropisomerization of a 2-hydroxy-2 0 -formylbiaryl via lactol formation. Bringmann and coworkers reported that an enantiopure sample of the tetraortho-substituted biaryl depicted in Scheme 3.630 This has been attributed to formation of a protonated nonaromatic intermediate exhibiting a C(sp2)–C(sp3) bond which reduces steric repulsion during rotation about the pivotal axis. Racemization of BINOL is also catalyzed under basic conditions due to deprotonation and dianion formation. R′=Me: 92.639 The diradical character of the photochemically induced triplet state results in increased aryl–aryl bond order and smaller biaryl torsion angle.1 0 -binaphthyl which has a rotational energy barrier of 100. the barrier to rotation can be altered by external factors.6 kJ/mol (50.9 °C) R=neomenthyl R=OMe. R′=i-Pr: 73.23 Rotational energy barriers of bridged biaryls.0 °C) R=i-Pr.9 kJ/mol (25. In some cases.0 °C) R=Me.70.0 °C) R=Et. stability.638.1 °C) Scheme 3. R′=Et: 54.7 kJ/mol (25.69 racemizes at room temperature even under neutral conditions due to a surprisingly low rotational energy barrier of 99 kJ/mol. R′=i-Pr: 83.

70 Acid-catalyzed atropisomerization of BINOL. whereas reversal of the directionality of all ten substituents affords topomerization. The enantiomers of 1-arylpyrimidine-2-thiones and their oxygen analogs are stable to interconversion at room temperature and can be conveniently isolated by chiral chromatography. Decasubstituted biphenyls such as decakis(dichloromethyl)biphenyl are chiral due to the directionality of the geared dichloromethyl groups.642 The five dichloromethyl groups in each phenyl ring can not rotate individually but do so together in a concerted process. although this is not always the case.e.T 0 torsion angle T Figure 3.1 0 -binaphthyl.7 kJ/mol ground state - . flavonoids. i.71. Reversal of the sense of directionality of the dichloromethyl groups in one aryl moiety generates the other enantiomer.641 Decakis(dichloromethyl)biphenyl gives rise to so-called dynamic molecular gearing.640.92 Chapter 3 OH OH H OH OH HO HO Scheme 3. Atropisomerization of this class of compounds entails ring opening as a consequence of a reversible [3.3]electrocyclic rearrangement and does not require rotation about the chiral axis.651–653 Natural atropisomers can have distinct physiological activities and often occur in plants or microorganisms in enantiopure form. Bringmann and coworkers investigated the isomerization of macrocyclic bisbiphenyls having . lignans and peptides.643–650 The demand for total synthesis and structure elucidation of naturally occurring atropisomers has been fueled by the discovery of important pharmacological properties and applications.24 Photoracemization of 1. Thermal and photochemical racemization of the vast majority of stereolabile chiral biaryls involves rotation about the aryl–aryl bond. ≠ hν hν triplet E triplet state ∼8 kJ/mol 100. in which the methine protons are wedged between the two chloro substituents of an adjacent dichloromethyl group. Racemization does not proceed via rotation about the chiral axis but through concerted rotation of five dichloromethyl groups in one phenyl ring. Atropisomeric biphenyls are important building blocks of many biologically active compounds including alkaloids. Scheme 3.. degenerate isomerization due to exchange of the positions of identical ligands.

antibacterial and antimycotic properties.656 gyroscopes657. A C B (P) OH OH OH OH Figure 3.6 °C) H H H H H H H H H H chloro substituents are omitted for clarity the arrows represent ring directionality H ∆G≠ = 99. see also Chapter 8.654 A closer look at the structure of isoplagiochin C reveals the presence of three chiral elements: two axially chiral biphenyl units. A and B.658 and similar molecular devices. Chromatographic and CD spectroscopic analysis proved that isoplagiochin C exists as a separable atropisomeric 85:15 mixture favoring (P)-conformation of axis A in Plagiochila deflexa liverworts. Since quantum mechanical calculations suggest fast interconversion between the two helical forms of the chiral cis-stilbene unit.25. The rotational energy barrier of biaryl A is 101. one would expect up to eight nonresolvable conformational stereoisomers of isoplagiochin C.6 kJ/mol.0 °C) H H H H H H the arrows indicate simultaneous rotation of geared dichloromethyl groups H H H Cl Cl H Cl Cl Cl Cl H Cl Cl H H Scheme 3.2 0 -disubstituted biphenyls. Because of the elongated . circular dichroism and variable-temperature NMR measurements in conjunction with computational studies revealed that the rigid cyclic structure of this bisbiphenyl affords significant conformational stability of chiral axis A while chiral elements B and C are fluxional at room temperature. and found that atropisomeric conformations coexist in liverworts. Enantiomerization and Diastereomerization X N N N • 93 X X N N N X=O: ∆G≠ = 118. remarkable antitumor.8.0 A. According to the preceding discussion of the conformational stability of 2. rotation about the chiral axes should proceed rapidly at room temperature. Incorporation of an acetylene ˚ unit into a biaryl system extends the axis to approximately 4.2 kJ/mol (86. The rotational isomerism of diarylacetylenes is of interest for the design of turnstiles.2 kJ/mol (25.25 Structure of (P)-isoplagiochin C.655 Surprisingly. Figure 3.6-dimethylpyrimidin-2-one (top) and dynamic gearing of decakis(dichloromethyl)biphenyl (bottom).7 kJ/mol (61. C.71 Electrocyclic ring opening of 1-(2 0 -methylphenyl)-4. and one twisted double bond.Racemization.5 °C) X=S: ∆G≠ = 107.

and molecular gears.2 Nonbiaryl Atropisomers The unique combination of axial chirality. The former therefore occurs independently and without concomitant C–N rotation. and sulfones. Finally.3.3 kJ/mol (0 °C) Scheme 3. and correlation of the two isomerization processes can be observed. sulfoxides. stereodynamics and reactivity of nonbiaryl atropisomers has been exploited for many purposes including dynamic kinetic resolution and dynamic thermodynamic resolution. while some of the less restricted rotation about the amide bond now proceeds freely and at a faster rate.672–675 Aryl–carbonyl rotation in aromatic amides that display unbranched nitrogen substituents is usually significantly faster than rotation about the amide bond. The rotational barrier is mostly governed by two factors: the bulkiness of the ortho-aryl substituents and the size of the amide moiety.and exo-conformations that xxvii The rotational energy barrier of diphenylacetylene is only 2-3 kJ/mol.665–671 Even moderate steric repulsion between the aryl ring and the amide group enforces a dihedral angle of approximately 901 on the aryl–carbonyl axis.72. steric hindrance to rotation is considerably reduced and diarylacetylenes are conformationally unstable. separation of the two aryl rings.5-cis-dimethyl)pyrrolidinylcarbonyl]-2-methylnaphthalene provide a typical example of atropisomerism and gearing of aryl amides.676–679 By analogy with aryl amides.3 kJ/mol.72 Rotamers of a chiral diarylacetylene. A closer look reveals that aryl amides also undergo restricted C–N rotation. Incorporation of branched nitrogen substituents into the amide moiety increases the energy barrier to rotation about the aryl–carbonyl bond and atropisomerization predominantly proceeds in correlation with C–N rotation. Tertiary aryl amides carrying different aromatic ortho-substituents are nonplanar and axially chiral.682 This chiral aryl amide exists in the form of two diastereomeric endo. Scheme 3. stereochemical relays.681.73. Scheme 3.680 The stereodynamics of 1-[N-(2. the conformational stability of aryl thioamides increases when sterically demanding groups are introduced.663 3.659–662 The congested structure of bis(1-phenyl-9-anthryl)ethynes has an energy barrier to rotation about the chiral axis of 75.26. Rotation about the aryl-carbonyl bond causes enantiomerization or diastereomerization if another chiral element is present in the molecule.94 Chapter 3 i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr ∆G≠ = 75.664 Among the most prominent examples of nonbiaryl atropisomers are aromatic amides. Aryl thioamides have a considerably higher barrier to rotation about the aryl–thiocarbonyl bond than do the corresponding oxygen analogs. . Figure 3. introduction of severe steric hindrance to rotation about the aryl-carbonyl bond is observed with 2-substituted 1-naphthamides which do not show any uncorrelated aryl–carbonyl rotation.xxvii The steric hindrance can be increased by introduction of bulky substituents. but isolable atropisomers of this class of compounds are still elusive. Correlated rotation about the aryl–thiocarbonyl and the thioamide bond has been observed with acrylic thioamides. ketones.

8-diacylnaphthalenes display two chiral axes.1 kJ/mol (30.688 predominantly populate the anti-conformation.7 kJ/mol (159. Figure 3.9 °C) Me2N S Me2N S Me2N S t-Bu N ∆G≠ = 93. Rotation about the amide bond is the faster process and also occurs without simultaneous aryl–carbonyl rotation.8-dibenzoylnaphthalenes.8 kJ/mol (44 oC) ∆G≠ = 112.4 °C) ∆G≠ = 100.9 kJ/mol (22. Rotation about the aryl–carbonyl axis generally proceeds rapidly at room temperature.692–694 Rotation about the chiral carbon–sulfur axis of 1-naphthyl sulfones is fast and can be monitored at low temperatures.4. even in the case of tert-butyl 1-(2-methylnaphthyl) ketone. 1.1 kJ/mol ∆G = 103. Enantiomerization and Diastereomerization a) O k1 k2 N b) O k1 k2 N c) O k1 k2 N 95 k1 > k2 k1 ≈ k2 k 1 < k2 a) Ar-CO rotation is relatively fast and mainly occurs independently (not geared) b) Ar-CO and C-N rotation have similar rates and are mostly correlated c) Ar-CO rotation is relatively slow and proceeds solely in correlation with C-N rotation while some uncorrelated C-N rotation can occur O Et NEt2 O NEt2 O Ni-Pr2 O NEt2 O NEt2 OEt O Ni-Pr2 O Me2 N Ni-Pr2 CHO ≠ ≠ ≠ ∆G≠ = 59. Comparison of the rates of isomerization proves that sterically hindered 2-substituted 1-naphthamides afford considerable gearing between the two rotational processes but display significantly more slippage (uncorrelated motion) than the triptycyl-derived three-toothed gears discussed in Chapter 8.2-Diacylbenzenes and 1.4 kJ/mol ∆G = 63.1 °C) Figure 3.26 Isomerization of tertiary aromatic amides (top) and energy barriers to rotation about the arylcarbonyl bond of selected examples (bottom).Racemization.3 kJ/mol (29.1 °C) X NMe2 X=O: ∆G≠ = 100. either in concert or sequentially. at least 90% of the latter must proceed in concert with C–N rotation.3 kJ/mol (54. interconvert via rotation about the aryl–carbonyl axis and the amide bond.1 kJ/mol ∆G≠ = 80. Enantiomerization requires completion of both processes. and can in principle exist as a mixture of two chiral anti-isomers and one meso syn-conformer. Naphthyl sulfoxides possess a chiral center at the sulfur atom in addition to .and 1.1 kJ/mol ∆G = 99.5.9 kJ/mol (12.689–691 The structure of aryl sulfoxides and aryl sulfones gives rise to similar atropisomerism.683–687 1.27. NMR spectroscopic analysis revealed that 1. In contrast to ortho-substituted aromatic aldehydes that possess an essentially planar achiral conformation. Since the rate constants for enantiomerization are a magnitude larger than for aryl–carbonyl rotation.7 kJ/mol (50 oC) X NMe2 X=O: ∆G≠ = 86. aryl ketones afford enantiomeric rotamers with almost perfectly orthogonal carbonyl and aryl planes.6 °C) ∆G≠ = 98. with the exception of 1.5 kJ/mol (36 °C) (47 °C) (65 °C) (35 °C) (22 °C) ∆G≠ = 104.5 °C) X=S: ∆G≠ = 126.4-.2-diacylbenzenes and 1. However.8-diacylnaphthalenes.3 kJ/mol (89.9 °C) X=S: ∆G≠ = 138.

3 kJ/mol (-50 °C) OO ≠ ≠ R=Me: ∆G≠ = 42.1 kJ/mol (-55 °C) t-Bu: ∆G ≠ = 92.2 kJ/mol (-110 °C) -CH2Ph: ∆G ≠ = 37.9 · 10 s . ∆G ≠ endo: (M.696 Introduction of two different nitrogen substituents to prochiral ortho-substituted anilines and 1-aminonaphthalenes provides aryl amines that are axially chiral by virtue of hindered rotation about the aryl–nitrogen bond.28.1 kJ/mol (-80 °C) i-Pr: ∆G ≠ = 56.8 kJ/mol 110 kJ/mol Ar-CO rotation concerted rotation Ar-CO rotation kAr-CO: 0.9 kJ/mol (-92 °C) i-Pr: ∆G ≠ = 47.1 · 10 s .27 Rotational energy barrier of atropisomeric acylarenes.0 kJ/mol (-140 °C) -CH2Et: ∆G ≠ = 31.5-cis-dimethyl)pyrrolidinylcarbonyl]-2-methylnaphthalene.7 kJ/mol (-95 °C) Figure 3.0 · 10-5 s-1. The energy barriers to diastereomerization of 1-(alkylsulfinyl)-2-methylnaphthalenes range from 44 to 77 kJ/mol. exo) Scheme 3.3 kJ/mol 101.695 Secondary (2-methyl-1-naphthyl)phosphine oxides bearing a configurationally stable chiral phosphorus center undergo diastereomerization due to facile rotation about the chiral aryl–phosphorus axis. ∆G -5 -1 -5 -1 ≠ C-N: 100.5 kJ/mol (-55 °C) i-Pr: ∆G ≠ = 47. the chiral carbon–sulfur axis and therefore exist as a pair of two diastereomeric E/Z-conformers.3 kJ/mol (-55 °C) t-Bu: ∆G = 55. endo) Diastereomerization processes: kC-N: 3.6 kJ/mol O N C-N rotation O N kendo: 2.8 kJ/mol (-70 °C) Et: ∆G ≠ = 43. In general.73 Interconversion of stereoisomers and geared rotation of 1-[N-(2.8 kJ/mol (-118 °C) -CHMe2: ∆G ≠ = 35.5 kJ/mol (22 °C) ≠ R R=-CH2Me: ∆G = 28. endo) (M.9 · 10 s . Figure 3.96 Chapter 3 O N C-N rotation O N (P. ∆G -5 -1 ≠ exo: 104. chiral sulfoxides exhibit high configurational stability at ambient temperature. O O R R O O R R R O O R=Me: ∆G = 33.7 kJ/mol (-78 °C) O RO R R ≠ ≠ R O R R=Me: ∆G = 33. exo) (P. ∆G ≠ Ar-CO: Enantiomerization processes: kexo: 1.3 kJ/mol (-55 °C) t-Bu: ∆G = 83. although racemization via pyramidal sulfur inversion of electron-deficient aryl sulfoxides can occur at 25 1C.9 kJ/mol (-110 °C) Et: ∆G ≠ = 38.697 In order to minimize steric repulsion between nitrogen .7 kJ/mol (-120 °C) Et: ∆G ≠ = 48.

: S S O R : (E.1 kJ/mol (-25 to -17 °C) R=t-Bu: ∆G ≠ = 77.R) R S (E.0 kJ/mol (80 to 100 °C) t-Bu H P O ∆G≠ = 62.1 kJ/mol (-13 to 15 °C) ≠ R=Me: ∆G ≠ = 44.R)-rotamer R (Z.2 kJ/mol (-65.0 °C) Racemization.4 kJ/mol (-70 to -60 °C) R=Et: ∆G≠ = 51.R) ≠ ≠ O O S O R O S O O R R=Et: ∆G = 30. Enantiomerization and Diastereomerization t-Bu O P H Figure 3. sulfones and a secondary phosphine oxide.1 kJ/mol (-136 to -120 °C) R=i-Pr: ∆G≠ = 44.R)-rotamer O R S (Z.0 kJ/mol (-60 to -50 °C) R=t-Bu: ∆G = 61. 97 .28 Diastereomerization of a 2-methylnaphthyl sulfoxide and rotational energy barriers of naphthyl sulfoxides.1 kJ/mol (-40 to -35 °C) R=i-Pr: ∆G = 56.

Ndialkyl-1-naphthylamines.724–728 the conformational stability of axially chiral ureas is significantly lower than that of amides. Figure 3.4. Figure 3. rhodanines and barbiturates. The two hydroxymethyl groups xxviii By contrast. 2. Steric repulsion is significantly reduced in (E)-aryloximes which rapidly rotate about the chiral axis.3 kJ/mol and an activation entropy. The interconversion of the conformational enantiomers of a series of N.2 0 .29.and (Z)-conformers and the energy barrier to E/Z-isomerization are difficult to predict.N-dialkyl arylamines adopt twisted conformations in the ground state. the Gibbs activation energy for nitrogen inversion of N-methylaniline is 6.705 The atropisomerism of anilides.6-diol are stable to racemization in the solid state but show slow rotation about the chiral axis via an s-trans (transoid) transition state in solution at room temperature. irrespective of the substitution pattern.742 The four bromo substituents impede a coplanar orientation of the double bonds and therefore induce chirality and steric hindrance to racemization.and (Z)-conformers of acetanilides carrying a 2.xxviii The enantiomers of 2.and meta-substituents attached to the same aryl group can be identical.707 Rotation about the planar amide function causes E/Z-isomerization. .736 Thermal racemization studies at 50–75 1C revealed a rotational barrier. N.30.6-disubstituted phenyl ring can be isolated at room temperature provided at least one of the substituents is a tert-butyl group.712 As expected.739–741. acetanilides populate a conformation in which the aryl ring and the amide group are orthogonal to each other. The nonplanarity of highly substituted 1. not all ortho. The presence of different ortho-substituents in the aryl ring of a twisted styrene renders the molecule chiral.5-tetrabromo-2. Substituent and solvent effects on both the ratio of the (E).713–723 In contrast to imides. A similar situation arises with ortho-substituted benzophenone oximes and benzyl aryl ketoximes. whereas rotation about the aryl-nitrogen axis results in interconversion of enantiomeric conformers. concurrent nitrogen inversion of these compounds has a very low energy barrier and is only observable under cryogenic conditions.729. and enantiomers can be resolved in the case of sufficient steric hindrance to rotation about the aryl–vinyl bond. of –80 J/K mol at 66.730 Styrene derivatives with bulky vinyl substituents adopt twisted conformations that interconvert via a planar transition state.706 To minimize steric repulsion. although gearing of the two processes is possible.3-dienes gives rise to axial chirality and atropisomerism.98 Chapter 3 substituents and the aryl ring. Nonplanar dienes always belong to the point groups C1 and C2 and are inherently chiral. imides.8 1C. of 106.698–701 N-aryl tetrahydropyrimidines702 and N-aryl-4-pyridones703 has been studied.6-disubstituted anilines or 2-tert-butyl aniline can be isolated at room temperature.738 The Gibbs activation energy for the enantiomerization of axially chiral orthohalogenated (Z)-O-methyl benzyl aryloximes increases with the bulkiness of the substituents due to increased steric hindrance in the periplanar transition state.31.31.7 kJ/mol whereas the energy barrier to rotation about the aryl–nitrogen bond is 30. Figure 3.e. which has been attributed to enhanced ground state strain.4hexadiene-1.3 kJ/mol. and urea derivatives of anilines bearing different ortho-substituents is closely related to that of the benzamides and naphthamides discussed above. a prerequisite for chirality of biphenyls and styrenes is that the aryl rings are not symmetrically substituted. The (E). The considerable negative entropic contribution is reminiscent of the racemization of biaryls.2dimethylstyrene which has been separated into enantiomers by chiral HPLC. DSa.3.6trimethylbiphenyl has a symmetry plane and is achiral because it bears one symmetrically substituted aryl ring. the rotation about the axially chiral aryl–nitrogen bond is governed by steric interactions between ortho-aryl groups and substituents attached to the nitrogen atom.b-diisopropyl-a. This greatly facilitates determination of the free energy of activation for the rotation about the chiral carbon–nitrogen axis. The atropisomers of amides and lactams derived from either 2. DGa. and can be attributed to a loss of vibrational and rotational freedom of the vinyl and aryl substituents in the congested transition state.704. For example.731–735 A typical example is b.708–711 Rotation about the amide bond is usually faster than rotation about the aryl–nitrogen axis.. For example. Notably. barbiturates. Figure 3.737. i.

8 kJ/mol (40.4 kJ/mol (24.7 kJ/mol (-100 °C) R=Me: ∆G = 65.29 Favored conformation of N.0 °C) (140 °C) O NH O ∆G≠ = 113.30 Stereodynamics of anilides.0 kJ/mol (25.5 kJ/mol (25.9 kJ/mol (-38 °C) R=Me: ∆G≠ = 82.0 °C) X=S: ∆G≠ = 115.0 °C) R=i-Pr: ∆G≠ = 70.0 kJ/mol (108 to 125 °C) ≠ ≠ ≠ R=H: ∆G≠ = 46. Enantiomerization and Diastereomerization Me N R R Et Et N Me i-Pr N R Et 99 R=H: ∆G≠ = 34.0 kJ/mol (27.8 kJ/mol ∆G≠ = 118.3 kJ/mol (109 to 114 °C) R=i-Pr: ∆G = 93.8 kJ/mol (25.0 °C) R=Br: ∆G≠ = 61.9 kJ/mol ∆G≠ = 112.8 kJ/mol (-9.5 kJ/mol ∆G≠ = 106. .7 kJ/mol (25.4 °C) O N i-Pr (23.1 kJ/mol (28 to 42 °C) R=i-Pr: ∆G = 72.0 °C) (27.0 °C) (100 to 110 °C) O t-Bu O Ph R N NH R=Cl: ∆G≠ = 58.Racemization.0 kJ/mol (75 to 89 °C) R=Et: ∆G≠ = 88.6 kJ/mol (65.P)-rotamer O Ph N OTMS Bn O N I N I O N t-Bu N OMe O t-Bu t-Bu ∆G≠ = 110.8 kJ/mol (25.0 °C) Me OMe ∆G≠ = 109.8 kJ/mol (70. E/Z-Isomerization O O R″ R″ N R′ (Z)-conformer (E)-conformer O Ph N t-Bu Enantiomerization O N R′ R R″ R N R′ R″ O N R′ R R (E.2 kJ/mol (60.0 °C) N X ∆G = 119. barbiturates.0 to 80.N-dialkyl-1-naphthylamines and rotational energy barriers of atropisomeric aniline derivatives.7 kJ/mol (16 to 37 °C) R=Et: ∆G = 69.0 °C) Figure 3.0 °C) ≠ X=O: ∆G≠ = 102.0 °C) S S N O Cl ∆G≠ = 136. and ureas.0 °C) R=Me: ∆G≠ = 64.5 kJ/mol (25. imides.0 °C) R=I: ∆G≠ = 67.5 kJ/mol ∆G≠ = 128.7 °C) Me OMe ∆G≠ = 94.3 kJ/mol (135 to 150 °C) R=t-Bu: ∆G = 96.0 kJ/mol (50 to 65 °C) ≠ R=t-Bu: ∆G = 82.3 kJ/mol (137 to 150 °C) OMe N O N O ≠ ≠ N N Cl Cl ∆G≠ = 62.M)-rotamer O (E.3 kJ/mol (72.6 °C) Figure 3.

32.2 kJ/mol (20. Racemization studies of this atropisomer. the atropisomers of N-aryl ketimines can undergo nitrogen inversion in addition to aryl–nitrogen rotation.4-dinitrobenzenesulfenyl)-2-isopropylacridone via rotation about the S–N bond has an activation barrier of 95.0 °C) t-BuMe2Si SnPh3 Figure 3.0]hexane.74.8 °C) Br Br Chapter 3 N R O O O (E) N I SPh R=Cl: ∆G = 52.0 °C) MeO2C CO2Me MeO2C CO2Me Ph3Sn SiMe2t-Bu ∆G≠ = 56.748 Few studies of rotation about the chiral nitrogen–nitrogen axis of C2-symmetric hydrazines. Some axially chiral 1.3-dienes.4-disubstituted (Z. whereas the enantiomers of the di-tert-butyl analog interconvert through nitrogen inversion.5-dimethyl-3-azabicyclo[3.31 Atropisomeric styrenes.1.9 kJ/mol Bn Bn Br Br HOH2C Br CH2OH Br HOH2C Br HOH2C Br Br Br Br CH2OH Bn X Bn X R=Cl: ∆G≠ ~ 88 kJ/mol (~140 °C) ≠ R=Br: ∆G > 92 kJ/mol (~165 °C) ≠ R=I: ∆G > 100 kJ/mol (~195 °C) s-trans TS ∆G≠ = 99.100 (Z ) N i-Pr i-Pr i-Pr i-Pr ∆G≠ = 106. Figure 3. By analogy with amines.6 kJ/mol ≠ ∆G = 61.749–751 An interesting example is 3-nitroso-1.7 kJ/mol R=Br: ∆G≠ = 58.746 Variabletemperature NMR studies confirmed that the favored pathway for enantiomerization of an N1-naphthyl ketimine derivative bearing two terminal isopropyl groups is rotation about the aryl– nitrogen bond.7 kJ/mol (27. revealed an energy barrier of 94.3 0 -biquinazoline-4. a chiral N-nitroso amine that can be separated into enantiomers at room temperature. Scheme 3.752.Z)-1.0 kJ/mol. Stereomutations of N-aryl imines are mechanistically more complicated than the rotational racemization pathways of styrenes and similar systems discussed above.2-dialkylidenecycloalkane derivatives including 1.4 0 -diones and N-nitroso amines have been conducted.5 kJ/mol (-20. O-alkyl aryloximes and 1.3 kJ/mol (66.743–745 The surprisingly low energy barrier to racemization of these compounds is probably a consequence of destabilizing steric repulsion between the bulky substituents in a highly distorted ground state. 3. exert a buttressing effect similar to that observed with meta-substituents in biaryls and further enhance the rotational energy barrier. Sulfenamides adopt a chiral ground state conformation in which the substituents on the nitrogen and sulfur atoms reside in two perpendicular planes.3-dienes with terminal silyl and stannyl substituents undergo facile enantioconversion.747. .0 °C) CH2OH Br ≠ ≠ ∆G≠ = 23. which is chiral due to hindered rotation of the nitroso group about the nitrogen–nitrogen axis.753 Interconversion of the enantiomers of N-(2.6 kJ/mol R=I: ∆G≠ = 66.2 kJ/mol.

0 kJ/mol (30. respectively.3.755 One would expect that 1.8 and 19.0]hexane and N-(2. Figure 3.8-disubstituted naphthalene derivatives.1.757 A closer look reveals that the ground state of 1. A careful evaluation of the structure and relative stability of ground and transition states is also indispensable for a discussion of the hindered rotation about the C(sp2)–C(sp3) bond of axially chiral 1-monosubstituted and 1. a decrease in conformational stability can either result from stabilization of the transition state or destabilization of the ground state. 3-nitroso-1. The conformational stability of atropisomers is solely determined by the energetic difference between ground and transition states. i-Pr O N N N N O N N O O N N O 2N O N S NO2 ∆G ≠ = 96 kJ/mol (25. For example.8-di-tert-butylnaphthalene is considerably : : : i-Pr : t-Bu t-Bu .8bis(trimethylsilyl)naphthalene. According to the analysis of electronic effects of parasubstituents on the rotational energy barrier of axially chiral biphenyls.0 °C) t-Bu N Scheme 3.0 °C) ∆G≠ = 94.4 0 -dione.4 kJ/mol. alkyl rotation in 1. 22.0. decreases further to 25.3 0 -biquinazoline-4. 1-neopentylnaphthalene exists as a mixture of two relatively unstrained enantiomeric conformers exhibiting the tert-butyl group almost exactly perpendicular to the naphthyl ring.6 kJ/mol. The barrier to rotation about the aryl–alkyl bond of 1-alkylnaphthalenes devoid of bulky orthoaryl substituents is usually quite low.4-dinitrobenzenesulfenyl)-2-isopropylacridone.32 Atropisomerization of 3.754 Interconversion of these two conformers requires that the alkyl group passes at the unsubstituted side at C-2 through the naphthalene plane to avoid enhanced steric repulsion with the peri-hydrogen at C-8.5 °C) Figure 3.74 Racemization pathways of N-aryl imines. Enantiomerization and Diastereomerization Rotation ≠ N-Inversion t-Bu N i-Pr i-Pr ∆G≠ = 44.Racemization.7 kJ/mol. This is not possible when both peri-positions are occupied by sp3-hybridized substituents.5-dimethyl-3-azabicyclo[3.756 The barrier to the same process in 1.0 °C) ∆G ≠ = 95.1.8-dialkylated naphthalenes have significantly higher rotational barriers.0 kJ/mol (-95.0 kJ/mol (-100.33. in which these planar groups are oriented perpendicular to the naphthalene ring and thus undergo few steric interactions.2 kJ/mol (23. see Chapter 3.8-di-tert-butylnaphthalene has an activation energy of only 26. The ground state of 1. Nevertheless. The energy barrier to this enantiomerization process is 21.0 °C) N t-Bu ≠ 101 : N i-Pr i-Pr N i-Pr N t-Bu ∆G≠ = 41. and in the corresponding germanium and tin derivatives. Both aryl rings and acyl moieties can adopt relatively stable ground states.8-dialkylnaphthalenes is quite different from that of naphthalene derivatives bearing sp2-hybridized substituents in the peri-positions.

The surprisingly low rotational energy barrier of this compound can therefore be attributed to an overcrowded ground state. To minimize steric hindrance in the transition state.33 Stereomutations of 1-neopentylnaphthalene and 1. Because of steric repulsion between the methyl group attached . For example.102 ∆G≠rot = 26.8-di-tert-butylnaphthalene.N-dibutyl-1-(1-naphthyl)ethylamine affords two diastereomeric rotamers exhibiting the amino group in almost perpendicular orientation to the naphthalene ring.2-dimethylpropan-1-ol and intramolecular CH/pinteractions. (S)-N. [Reproduced with permission from Tetrahedron Lett. 1-(1-naphthyl)ethylamines possess a chiral center in addition to a stereolabile chiral axis but they exist as a pair of rapidly interconverting diastereoisomers.758 The conformers are stabilized by intramolecular CH/p-interactions between C–H bonds of the tertbutyl group and the adjacent aromatic p-system. Rotation about the chiral axis results in interconversion of diastereomeric conformers.M)-rotamer HO H H H H H H HO H (hydrogens are omitted for clarity) Figure 3.35.] destabilized due to strong repulsion between the two bulky tetrahedral groups.8-di-tert-butylnaphthalene C2-symmetric and enantiomerization via ring flipping. Interestingly.4 kJ/mol t-Bu t-Bu H H ∆G≠ = 21. Similarly.P)-rotamer (S.34 Diastereomerization of 1-(1-naphthyl)-2. 8563-8567. 1-(1-naphthyl)-2. Figure 3. Quantum mechanical calculations of the ground state structures of 1-naphthyl-derived carbinols such as 1-(1-naphthyl)-2. 43.6 kJ/mol (-156 °C) H H H t-Bu t-Bu 32° ∆G≠flip = 94 kJ/mol (144 °C) ≠ Chapter 3 (-140 °C) ring flipping H t-Bu Figure 3. 2002.2-dimethylpropan-1-ol is conformationally stable and has a rotational energy barrier of 158 kJ/mol. all nine hydrogens of the tert-butyl group are available to participate in multiple CH/p-interactions involving Cipso and Cortho of the naphthalene ring.34. Figure 3. the distortion renders 1. H t-Bu OH HO t-Bu H 158 kJ/mol H (170 °C) (S. with an energy barrier of 94 kJ/mol.759 Notably. As a consequence of considerable ground state stabilization due to CH/p-interactions and strong repulsion between the sterically demanding tert-butyl group and the naphthalene ring in the transition state. has been observed by variable-temperature NMR spectroscopy. the bulky tertbutyl group is likely to pass the ortho-hydrogen rather than the peri-hydrogen of the naphthalene ring. the tert-butyl groups are placed on opposite sides of the naphthalene ring and rotation about the C(sp2)–C(sp3) bond is fast.2-dimethylpropan-1-ol suggest that these atropisomers populate two conformations in which the bulky tert-butyl group is perpendicular to the naphthalene ring. As a result of severe molecular distortion.

The rotation about C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds of atropisomeric 9-arylfluorenes and triptycene derivatives has been studied in some depth.2]octadiene shown in Scheme 3. X A 1) A has the highest priority (by definition if B=C): synperiplanar (sp) conformer 2) B (or C) has the highest priority and B≠C: anticlinal (ac) conformer C Y A Y B 1) A has the highest priority: antiperiplanar (ap) conformer 2) B (or C) has the highest priority and B≠C: synclinal (sc) conformer C A Y C Z 1) A and X have the highest priority: antiperiplanar (ap) conformer 2) A and Z (or Y) have the highest priority: synclinal (sc) conformer X B X B Figure 3.P)-isomer Figure 3.760–764 The conformational isomerism of these compounds is often described based on the Prelog–Klyne rules. 9-Arylfluorenes derived from selectively substituted aryl and fluorenyl moieties possess axial and central chirality. Yamamoto and Oki discovered that sterically hindered dibenzobicyclo[2.36. Enantiomerization and Diastereomerization 103 Bu2N Me H ∆G = 75. see Chapters 8. Rotation about the chiral C(sp2)– C(sp3) axis results in diastereomerization whereas enantiomerization is not observed due to the configurational stability of the asymmetric carbon atom.4. and exploited for the development of molecular gears and propellers.6 kJ/mol (S. Scheme 3.9 kJ/mol (22. Figure 3.2]octadienes and 9-substituted triptycenes can be separated into a meso ap-isomer and sc-enantiomers.0 which is slightly higher than the statistical ratio of 2.7 to 84.36 Prelog–Klyne designation of atropisomerism about C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds.9 kJ/mol.N-dibutyl-1-(1-naphthyl)ethylamine. the (S.7 °C) (S.Racemization.P)-diastereoisomer.2.1 and 8.765–768 The rotational energy barrier of 9-arylfluorenes carrying two ortho-substituents in the 9-aryl ring is sufficient for isolation of atropisomers but mono-ortho-substituted derivatives are usually not conformationally stable at room temperature.2.770 The dibenzobicyclo[2. the sc/ap ratio is 3. The energy barrier to conversion of the more stable to the less populated atropisomer has been determined as 75.6 kJ/mol less stable than the (S.and sc-rotamers. It has been hypothesized that the more flexible methoxycarbonyl group . to the chiral center and the peri-hydrogen of the naphthalene ring.75.0 kJ/mol.771–773 At equilibrium.M)-isomer ≠ H NBu2 Me ∆G = 4.M)-rotamer is about 4. and exist as a mixture of diastereomeric ac.769.35 Diastereomerization of N.76 has a barrier to rotation about the chiral axis of 139.

and carbocyclic [11]paracyclophanes have interconversion barriers between 110 and 135 kJ/mol which are pH-dependent in the case of diaza derivatives. 3.780 The chirality of these compounds stems from the fact that the handle.5 is only obtained in the presence of peri-hydrogens.104 Chapter 3 R H H (R)-ac-conformer H R ∆G≠ac→sc = 137. As a rule of thumb. The energy barrier to racemization is generally controlled by the length and rigidity of the handle and the bulkiness of the aryl substituents. Figure 3.11-dioxa[11]paracyclophanes possess a higher steric .3 kJ/mol (166 °C) Scheme 3. which may contain another aryl unit. defined by the bonds that connect the aryl ring to the bridge.3. handle) were discovered by Luttringhaus ¨ in 1941. Replacement of the tertiary by a secondary alkyl group significantly reduces the rotational energy barrier of triptycenes. which has been attributed to steric repulsion between the peri-substituent and the tetrahedral triptycyl group in the congested ground state. this process can be described as a flip of the handle from one side of the chiral plane to the other.775–778 Interestingly. and the proximate benzyl group experience less steric repulsion in the sc-conformers than do the fused benzene rings and the benzyl group in the less stable ap-atropisomer. results in enantiomerization. The energy barrier to rotation about the pivotal C(sp3)–C(sp3) bond increases with decreasing size of X. Crystallographic analysis and comparison of the conformational stability of a number of 9-tert-alkyl triptycenes indicate that incorporation of peri-substituents.75 Diastereomerization of 9-(1-naphthyl)fluorenes.3 Cyclophanes Cyclophanes or so-called ansa compounds (Latin ansa.779.3 kJ/mol (170 °C) (R)-sc-conformer R=H: ∆G≠ac→sc = 89.37. Introduction of other substituents X disfavors population of the sc-rotamers due to enhanced steric repulsion between X and the neighboring benzyl group.774 The statistical ap/sc ratio of 0. the size of aryl substituents in monosubstituted paracyclophanes has only a minor effect on the rotational energy barrier.786 Typically. Again. into one benzene moiety causes considerable strain and favors population of the ap-isomer.782–785 Monosubstituted diaza-. More examples of atropisomerism involving rotation about C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds are presented in the context of molecular propellers. rather than stabilization of the transition state. resides outside the plane of a selectively substituted aryl ring.781 The enantiomers of [11]paracyclophanes can often be isolated at room temperature but racemization occurs upon heating. 1. Rotation about the axis. dioxa.76. Scheme 3. as the handle preferably flips around the unsubstituted and consequently less sterically hindered side of the chiral plane. see Chapter 8. Alternatively. the ap-isomer of 9isopropyltriptycenes is usually not observed and the predominant sc-enantiomers undergo facile interconversion at ambient temperatures. is responsible for a decrease in the isomerization barrier. X. However.5 kJ/mol (160 °C) R=Me: ∆G≠ac→sc = 139. destabilization of the ground state. paracyclophanes with a bridge consisting of fewer than eleven atoms are stable to enantiomerization while chiral [12]paracyclophanes undergo rapid racemization at 25 1C.

and sc-diastereoisomers of a dibenzobicyclo[2. Y=Cl: ∆G≠ap→sc = 169. ap/sc ratio: 0.1 kJ/mol (227.0 °C).76 Atropisomerization of ap. 105 .70 (259 °C) Scheme 3. Y=H: ∆G ap→sc = 161.6 kJ/mol (227.0 °C). Y=F: ∆G≠ap→sc = 185.4 kJ/mol (227. ap/sc ratio: 2.5 kJ/mol (227. Y=H: ∆G≠ap→sc = 177.5 (259 °C) X=OMe.0-152. ap/sc ratio: 0.44 (212 °C) X=F.0 °C) Cl Cl Cl Bn X Me ap-conformer ≠ X=H.82 (259 °C) X=CH3.0 °C).2]octadiene (top) and 9-substituted triptycenes (bottom).0 C) ≠ Racemization.0 °C).+ (P)-sc-enantiomer Me Y Me Cl Cl Me Cl Cl H (M)-sc-enantiomer Me H Cl Me (P)-sc-enantiomer ∆G≠ = 106. ap/sc ratio: 0.7 kJ/mol (25. Enantiomerization and Diastereomerization Bn X X Y ≥1:2 Me Me Y Y X Bn (M)-sc.CO2Me 1:3 Me CO2Me Bn Bn (M)-sc-conformer (P)-sc-conformer meso ap-conformer Me CO2Me MeO2C Me Bn Me Me CO2Me MeO2C + Me Bn Me CO2Me MeO2C CO2Me Bn o Me Me Me Me Me ∆G ap→sc = 139.0 kJ/mol (111.2.

11-diaza[11]paracyclophane is significantly lower than that of other 2 0 -substituted derivatives. The aromatic carbon atoms directly connected to the bridge are bent out of the plane of the arene moiety and afford a benzene boat conformation.0 °C) ∆G≠ = 120.4]paracyclophane derivative. Scheme 3.1 kJ/mol (145. hindrance to racemization than their carbocyclic analogs due to the relatively short C–O bond distance.9 kJ/mol (95. It is assumed that the nitro group stabilizes the planar transition state by push-pull conjugation.5) (CH2)9 HN NH HN (CH2)9 NH ∆G≠ = 111. chiral metacyclophanes show significantly less steric hindrance to atropisomerization and probably interconvert through a chair inversion process.2]paracyclophanes.37 Interconversion barriers of [11]paracyclophanes. Cyclophanes with a short handle are considerably distorted.0) (CH2)9 HN Cl ∆G≠ = 122.6 °C) (CH2)9 HN NH (CH2)9 HN O N NH O NH HN O N O (CH2)9 NH ≠ Me ∆G≠ = 125. This is probably a consequence of facile pyramidal nitrogen inversion which increases the flexibility of the handle and its ability to accommodate a planar transition state. pH 4.2 kJ/mol (146.5) HN (CH2)9 NH NO2 O2N Br ∆G≠ = 122.5 °C.5 °C.5 °C.11-diaza[11]paracyclophanes is similar to that of carbocyclic paracyclophanes.5 kJ/mol (133. pH 4.792–799 xxix ˚ ˚ The C–O bond length in paracyclophanes is 1.50 A. 4-carbomethoxy[2. The racemization barrier of 2 0 nitro-1. which is about 130 kJ/mol in [2.4 kJ/mol (95.43 A. A typical C(sp2)–C(sp3) bond length is 1. pH 4. facilitates photochemical and thermal racemization via biradial open chain intermediates. This value is slightly lower than the racemization barrier of the corresponding [3.77.5 °C. pH 3. The high strain energy.8 kJ/mol (107.xxix The rotational energy barrier of 1.1 kJ/mol (95. .787–791 In general.2 kJ/mol (95. Incorporation of strong electron-withdrawing groups into the aryl ring effectively reduces the conformational stability of diazaparacyclophanes. For example.106 CO2Me O (CH2)9 O MeO2C O (CH2)9 O O (CH2)9 Br O O (CH2)9 i-Pr O H2C (CH2)9 Br Chapter 3 CH2 ∆G≠ = 129.0 °C) ∆G≠ = 130.0 °C) ∆G≠ = 133.2]paracyclophane racemizes at 200 1C with an activation energy of approximately 160 kJ/mol.5) Figure 3.

84. 183. Table 3. 139.809. . 175. Enantiomerization and Diastereomerization MeO2C H2 C CH2 MeO2C ∆G ≠ = 160 kJ/mol (200 oC) SO2 HO2C ∆G ≠ = 132 kJ/mol (150 oC) CO2H S CO2Me 107 S EtO2C O ∆G ≠ = 107 kJ/mol (60 to 90 oC) ∆G ≠ = 127 kJ/mol (100 oC) Scheme 3. 3-methylcholanthrene-type PCBs (MC-type) and phenobarbital-type PCBs (PB-type). 132.2. 3. a widely used pesticide mixture.77 Racemization of a [2. and most of these so-called PB-type PCBs have been separated into enantiomers by chiral chromatography on selectively substituted cyclodextrins. Scheme 3.78. 131. 135. 176. 149. 136. Their uptake by invertebrates and fish has introduced PCBs into the food chain. and 19 PCBs (45.811 MC-type PCBs do not exhibit chloro atoms in ortho-position and are not conformationally stable. exhibit different toxicity and metabolic pathways in biological samples. namely.xxx Although their production has been banned by the United Nations treaty on persistent organic pollutants. a chiral congener of the pesticide lindane (g-HCH). hydraulic fluids. PCBs have been applied as electrical insulators in capacitors and transformers.3. impregnants for wood and paper.6-hexachlorocyclohexane (a-HCH). 91.4 Atropisomeric Xenobiotics The pharmacological and toxicological activities of some pesticides and herbicides are closely related to their chirality.4. metabolism and excretion proceed enantioselectively. MCtype PCBs have been reported to increase benzo[a]pyrene hydroxylase activity and expression of cytochrome P450c and P450d in liver cells. The energy barrier to racemization of these 19 PCBs is greater than 180 kJ/mol.802.Racemization. The enantiomers of a-1. PCBs have numerous toxic effects including immunosuppression and thymic atrophy. 197) afford at least three chloro substituents in the ortho-position which is a requirement for conformational stability under abiotic conditions.803 Only 78 of the 209 possible PCBs are chiral. one can distinguish between two major classes.810 Based on characteristic structure–activity relationships.804–808 Pharmacological and toxicological studies of PCBs proved that the biological activities of these xenobiotics vary significantly with the number and position of chloro atoms. penguin. 144. They also cause accumulation of uroporphyrinogen (URO). and as plastic and paint additives. 174. 171.3.2]paracyclophane and chair inversion of metacyclophanes. It is assumed that these PCBs can easily adopt a coplanar structure similar to TCDD (dioxin). In addition. hyperkeratosis. The pharmacological and toxicological properties of PCBs depend on their axial chirality as well as on the stability to racemization. seal) revealed stereoselective metabolism of chlordane. 88. 95. In addition to their carcinogenic potential. Since 1929.801 Apparently the enantiomeric composition of these environmental pollutants changes during biological transformation because uptake.3. more than a million tonnes of PCBs have been produced worldwide.800 Analysis of human tissue as well as aquatic samples (salmon. and hepatotoxicity. 196. PCBs have become ubiquitous environmental xenobiotics. The unique chemical and physical properties of polychlorinated biphenyls (PCBs) have led to the extensive use of these xenobiotics as refrigerants. probably as a consequence of decreasing activity of URO decarboxylase and induction of xxx Technical mixtures such as Acroclor and Clophen A contain considerable amounts (often 30–60%) of PCBs.5.

6 0 2.3.2 0 .6 0 2. Enantioselective bioenrichment has been observed.812–814 Their biological activity seems to be related to the coplanar structure as well as to the number and position of chloro substituents in meta.6 2.5 0 .6 2.108 PCB 44 Cl fast Cl Chapter 3 Cl Cl Cl Cl Cl enantiomers of PCB 44 interconvert at 25oC Cl Cl Cl Cl Cl PCB 136 Cl Cl Cl Cl Cl Cl Cl Cl conformationally stable and isolable enantiomers of PCB 136 Scheme 3.und para-position.2 0 .3 0 .6 0 PB-Type PCBs found in butter and human milk.5 0 . Table 3.3.2 0 .6 0 2.2 0 .3 0 .3 0 .3. cytochrome P448.3.3 0 .b 139 144a 149a.4.820 the enantiomers of PB-type PCBs show . 0 .4.6 2.3.2 0 .4.5 0 .3.5 0 .3.4 0 .6.4.4 0 .5.6 0 2.6 2.6 2.5.2 0 .3.b 136a.3 0 .6 2.2 0 .4.b 175 176b 183 196a 197 a b Substitution pattern 2.6 2.3 0 . 5 4 6 1 3 2 1′ 6′ 5′ 4′ 2′ 3′ Cl Cl PCB 45 84 88 91b 95a.2 0 .3.6 2.3 0 .3.4.2 0 .2 0 .3.4 0 . 135a.6 0 2.3.3 0 .2 0 .78 Axially chiral PB-type PCBs 44 and 136.2 0 .816–818 Similarly to a-HCH819 and metolachlor.2 0 .6.2 0 .2 0 .3 0 .815 Phenobarbital-type PCBs have three or four chloro atoms in the ortho-positions and are conformationally stable.3.3.2 0 .6 2.4 0 .b 131a 132a.6 0 2.6.2 0 .4 0 .3.4 0 .b 171 174a.6 2.3 0 .2 0 .4 0 .3 Ballschmiter nomenclature for conformationally stable chiral PCBs.2 0 .5 0 .6 2.4.4.

95. By contrast. and intermolecular interactions with proteins.828 Enantioenrichment of PCBs 91. They induce cytochrome P450b. biphenyls are metabolized via hydroxylation or arene oxide formation of the aryl moieties by hepatic oxygenase systems. The (þ)-enantiomer of PCB 139 causes URO accumulation which correlates with substantial increase in EROD activity.821  Enantiomeric enrichment of (þ)-PCB 139 in rat liver observed by Puttmann and coworkers is ¨ only possible in the absence of an active PCB racemase. as it compromises the purity and shelf-life of chiral drugs. distribution. From a pharmacological and toxicological standpoint this is quite important because stereoisomers can have distinct biological properties. studied inductive effects of PCBs 88. Rodman et al.823 They reported enhanced induction of cytochrome P450 by (þ)-PCB 139.825 The pronounced enantioselective metabolism in aquatic sediment and biota results in accumulation of nonracemic PCB mixtures in the food chain. Some of the PB-type PCBs mentioned are components of Clophen A or Acroclor and have been found in butter and human milk. 149. 135. 139 and 197 using chick embryo hepatocyte cultures to minimize pharmacokinetic effects on cytochrome P450 induction. would have to cleave or elongate the pivotal C–C bond between the two chlorinated benzene rings.  A PCB racemase. However. 3. The (þ)-enantiomers of PCBs 88. 174. The bio. For several reasons it is believed that PB-type PCBs do not undergo racemization under physiological conditions:  The energy barrier to racemization is mostly determined by intramolecular steric interactions.829. To date. (þ)-PCB 197 induces production of aminopyrine N-demethylase more strongly than does (–)-PCB 197. . and the (þ)-enantiomer of PCB 139 exhibits stronger inducing potency for benzphetamin N-demethylase (BPDM) than its (–)-enantiomer.4 PHARMACOLOGICAL AND PHARMACOKINETIC SIGNIFICANCE OF RACEMIZATION Some chiral pharmaceuticals including thalidomide racemize either within minutes or several hours under physiological conditions (37 1C.822 ¨ They found that (þ)-PCB 139 induces expression of aminopyrine N-demethylase. and cause proliferation of liver endoplasmic reticulum. 132. Similarly. metabolism or excretion)..xxxi xxxi Racemization that does not occur within the pharmacological time scale but over a period of months or years after formulation is also important. P450e. the (–)-enantiomers of PCBs 88 and 197 are more effective inducers of BPDM than their (þ)-enantiomers. pH 7.79. The most striking enantioselective effects are observed with induction of ethoxyresorufin-O-deethylase (EROD).Racemization. and 176 has been observed in river sediments. see Chapter 1. enantioenrichment has been reported for PCB 149 in blue mussels. Scheme 3. membranes and solvents are expected to have negligible affects on the conformational stability. aldrin epoxidase and cytochrome P450 more effectively than the (–)-enantiomer.830 Significant health and environmental risks could be related to enantioselective enrichment of PB-type PCBs in nature. Enantiomeric enrichment of (þ)-PCB 139 was discovered in rat liver and attributed to pharmacokinetic effects (absorption. 139 and 197 induce EROD more effectively than the corresponding (–)-enantiomers. The results of this study clearly demonstrate that the chirality of PCBs plays a role during induction of cytochrome P450 and accumulation of URO. and aminopyrine N-demethylase. Oxazepam has a racemization half-life of less than five minutes at 37 1C. and 176 in dolphins.827 and for PCBs 95.and geoaccumulation of PCBs originate from their persistence to degradation and high lipophilicity.e. 149. i. aldrin epoxidase. 132.831. Puttmann studied the biological activity of conformationally stable PB-type PCBs 139 and 197. 136. Enantiomerization and Diastereomerization 109 distinctive biological effects and metabolism.826 for PCB 132 in human milk.824. enzyme attacks occur remote from the chiral C–C bond.4). if existing.

832 In vitro studies with camazepam and other racemic 3-hydroxybenzodiazepinones showed that the (R)-enantiomer is selectively metabolized by human liver microsomes. oxazolidinediones. Racemization of (S)-aspartic acid proceeds in vivo via succinimide formation and is believed to constitute a biological clock for peptide and protein aging. The deuteration process can easily be monitored by 1 H NMR spectroscopy using racemic samples.833 Although the stereochemical integrity of new chiral drugs can often be deduced from previously studied compounds exhibiting similar functionalities. ritalin. tolperisone.80. and NMR spectroscopy with chiral shift reagents. and cyclandelate possess a chiral center carrying an acidic proton and are susceptible to base-catalyzed racemization.846 Numerous studies have shown that epimerization of dipeptides proceeds faster than racemization of free amino acids due to neighboring effects and formation of diketopiperazines. electrophoresis with chiral additives. Figure 3. For example. and in most cases the rate of deuteration is equal to that of racemization. thiazolines. oxazolines. 3-hydroxybenzodiazepinone-derived anti-anxiety agents experience enantioselective metabolism and undergo reversible ring opening via an achiral intermediate. SFC and GC on chiral stationary phases. proglumide. hyoscyamine. it is indispensable to carefully evaluate the effect of endogenous factors such as pH.835 Welch et al.81. investigated the configurational stability of a 5-aryl-thiazolidinedione. and other widespread pharmacophores racemize due to facile enolization. in particular epimerases and racemases. succinimides. profens. Chlorthalidone racemizes through acid-catalyzed elimination and base-catalyzed ring opening. bupivacaine.847–849 The accumulation of (R)-aspartic acid in tissue with no turnover (tooth enamel and bone osteocalcin) allows accurate age determination for forensic purposes. hydantoins. ionic strength and the presence of plasma proteins.38. and rapid racemization in both dog and human plasma was confirmed by enantioselective HPLC-MS analysis. chiroptical methods.844 Racemization of drugs can also be studied by HPLC. Scheme 3. a peroxisome proliferator-activated receptor (PPAR) agonist. Many pharmaceuticals such as thalidomide.850 Measurements of the extent of racemization of (S)-aspartic acid in urinary molecular fragments .79 Racemization mechanism of oxazepam and structures of 3-hydroxybenzodiazepinones. see Chapter 4. tropicamide.838–843 The configurational stability of enolizable drugs is often evaluated by proton/ deuterium exchange in deuterium oxide.845.836 The drug proved to be stereolabile in various solvents irrespective of pH.837 Chiral barbiturates. ibuprofen.110 H N Cl N O H OH Cl H N O O NH Cl N H N O OH H Chapter 3 (R)-oxazepam H N Cl N O H O O NMe2 Cl N O H OH (S)-oxazepam O H O O NMe2 Cl N Cl H N O H OH N N Cl N norcamazepam temazepam camazepam lorazepam Scheme 3.834 The ultimate analysis of the stereochemical stability of a chiral drug candidate during preclinical studies requires racemization studies in biological media. Scheme 3. Nonenzymatic interconversion of (S)-amino acids to the biologically rare (R)-enantiomer possibly plays an important role in aging. under various conditions. imidazolines. scopolamine.

38 Enolizable pharmacophores.Racemization. .81 Racemization of (S)-aspartic acid via succinimide formation. CO2H H N H H N R O (S)-Asp peptide CO2H H N H H N O R (R)-Asp peptide O H N H N O O H N H N O O O O R (S)-succinimide peptide O O N H OH N R O R (R)-succinimide peptide Scheme 3. -H O OH O Ph NH H . O H R HN O hydantoin O H R O NH N O H barbiturate Ar CO2H H Me profen NH R O O oxazolidinedione O succinimide H NH R O H NH O Figure 3. -H O Ph OH NH NH O (S)-chlorthalidone (diuretic agent) O O (R)-chlorthalidone (diuretic agent) Scheme 3. Enantiomerization and Diastereomerization HO N O (S)-tropicamide (antimuscarinic agent) 111 HO N N HO N OH N N OH O O (R)-tropicamide (antimuscarinic agent) O Bu N N H (S)-bupivacaine (anaesthetic agent) O N O N O proglumide (antiulcer agent) OH O N O O cyclandelate (vasodilator) (R.R)-ritalin (psychomotor stimulant) N H (R)-tolperisone (muscle relaxant) (S)-ibuprofen (analgesic agent) N O O (S)-hyoscyamine (cholinergic agent) OH O N O O (S)-scopolamine (cholinergic agent) Ph OH H .80 Racemization pathways of chiral drugs.

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Rate constants and activation parameters (DGa. Tumambac and Wolf were able to separate the meso syn.1 optical calorimetry measurements. and the capacity of the method to differentiate between interconverting stereoisomers. using 136 ¼ 6 ð4:1Þ . switches.1. circular dichroism and optical rotary dispersion) and chromatographic methods are often employed in kinetic studies of more stable compounds.6 Slow atropisomerization of the enantiopure anti-isomer was observed upon heating to 71. Figure 4. dynamic chromatography and chromatographic stopped-flow techniques render the isolation of pure enantiomers or diastereoisomers unnecessary.8-bis(2 0 -methyl-4 0 -quinolyl)naphthalene by semipreparative chiral chromatography. infrared. For example.2 stopped-flow methods. whereas chiroptical techniques (polarimetry.CHAPTER 4 Analytical Methods The study of racemization and diastereomerization reactions of chiral compounds is a fundamental aspect of dynamic stereochemistry. The choice of a suitable technique for the study of an enantiomerization or diastereomerization reaction mainly depends on the reaction rate. which greatly facilitates stereodynamic analysis. Integration and quantification. DHa.5. such as microwave.4 The interconversion of stereoisomers exhibiting activation barriers between 20 and 100 kJ/mol is usually monitored by variabletemperature (dynamic) NMR spectroscopy.and enantiomeric anti-isomers of axially chiral 1. Fast dynamic molecular processes can be investigated by femtosecond or picosecond pumpprobe methods.0 1C and monitored by chiral HPLC at room temperature. fluorescence. motors and other stereodynamic devices.3. DSa) are routinely obtained by spectroscopic. electron spin resonance (ESR). and flash photolysis. the availability of isolated enantiomers or diastereomers. variable-temperature NMR spectroscopy. Stereoisomers with an interconversion barrier above 100 kJ/mol can often be isolated by chromatography or crystallization at room temperature.89 Á 10À5 sÀ1 at 25 1C. In the case of an irreversible first-order reaction. In contrast to chiroptical methods. an activation energy of 100 kJ/mol corresponds to a reaction rate of 1. In general: k ¼ 2:084 Á 1010 T eÀDG =8:314 T where T is the temperature in Kelvin and DGa is the activation energy in J/mol. routine methods can be used. If the reaction time-scale permits. The determination of the relative thermodynamic stability of stereoisomers and kinetic studies that are aimed at a mechanistic understanding of enantiomer and diastereomer interconversion play a crucial role in the development of asymmetric reactions and molecular gears. chiroptical and chromatographic techniques to provide today’s chemist with invaluable information about the configurational and conformational stability of chiral compounds. in conjunction with time-resolved spectroscopy or spectrometry. and nuclear magnetic resonance (NMR) spectroscopy.

.Analytical Methods 137 k1 k2 N k2 k1 N N N N N anti-enantiomers syn-diastereomer 4 5 6 7 min 2760 min 4 5 6 7 min 780 min 4 5 6 7 min 4 5 6 7 min 540 min 300 min isolated enantiomer 4 5 6 7 min 180 min 4 60 min 5 6 7 min 4 5 6 7 min (HPLC retention time) 0 min (heating period) Figure 4. 2004. 69.4% of each anti-conformer and 11. of 3.5% within the first three hours and then continued to change very slowly to its final value as the rate of conversion of the syn-isomer to the anti-isomers increased significantly relative to its rate of formation. small aliquots of the reaction mixture (71 1C) were rapidly cooled to room temperature and the three stereoisomers were separated by HPLC on a Chiralpak AD column.2% of the meso syn-isomer was obtained.ii [Reproduced with permission from J.] individual UV response factors for each conformer.1 Chromatographic analysis of the atropisomerization of 1. For stereoselective analysis. Chem.8-bis(2 0 -methyl-4 0 -quinolyl)naphthalene at 71 1C. After 46 hours. which corresponds to a difference in Gibbs free energy. Org. The concentration of the syn-isomer increased to 7. DG. an equilibrium consisting of 44. The fast initial increase in the concentration of the intermediate syn-isomer followed by a slow change to the final steady state value is typical for consecutive reversible reactions. 2048-2055. allowed accurate analysis of the isomer composition at various reaction times.4 kJ/mol according to the Boltzmann equation:i nsyn ¼ eÀDG=RT 2 nanti i ii ð4:2Þ The factor of 2 accounts for the coexistence of two enantiomeric anti-conformations.

3144 J KÀ1 molÀ1). Using reversible first-order reaction kinetics that account for interconversion of stereoisomers via two consecutive reaction steps.138 Chapter 4 where R is the universal gas constant (8.8 Helical inversion of this molecular propeller involves correlated rotation of the four aryl rings via conrotatory ring flipping with an iii Reversal of the sense of directionality of the dichloromethyl groups in one aryl ring results in enantiomerization of decakis(dichloromethyl)biphenyl.2 kJ/mol.2 kJ/mol.1. the rate constants for the reversible isomerization reaction of 1.1 kJ/mol for the conversion of the syn. nsyn and nanti describe the population of the syn. and the activation barrier to racemization was determined as 99.3. At equilibrium. kB is the Boltzmann constant (1.2. Scheme 4. was calculated as 116. h is Planck’s constant (6. Figure 4. Interestingly.and as 1.3144 J KÀ1 molÀ1). The diastereoisomers show distinguishable 1H NMR spectra and the interconversion process can be directly monitored by NMR spectroscopy in deuterated DMSO at 56.to the anti-isomer.7 The same HPLC method was then used to monitor the decreasing enantiomeric excess as a function of time.8-bis(2 0 -methyl-4 0 -quinolyl)naphthalene. With knowledge of the syn/anti ratio at equilibrium. and k is the transmission coefficient. whereas reversal of the directionality of all ten substituents affords topomerization (degenerate isomerization) due to exchange of the positions of identical ligands. the conformers of 1. k¼k kB T ÀDG6¼=RT e h ð4:3Þ where k is the rate constant at the temperature T in Kelvin.8-diheteroarylnaphthalene discussed above. Similar approaches have been employed in kinetic studies of many other compounds. T is the temperature in Kelvin.0 kJ/mol.and anti-conformation. for instance decasubstituted biphenyls exhibiting dynamic molecular gearing and crowded helical alkenes that behave like molecular propellers.to the syn-isomer and 112.9 kJ/mol. In contrast to the 1. an example of a tetraarylvinyl propeller. were determined as 3.38 Á 10À4 sÀ1 for the syn-to-anti-atropisomerization.and anti-diastereoisomers are separable by crystallization.N 0 -dioxide can not be resolved by chiral chromatography.5-dimethylphenylcarbamate). isolation of stereoisomers by crystallization and NMR spectroscopic analysis of the isomerization course can provide a viable alternative.3.8-diheteroarylnaphthalenes discussed above was accomplished with chromatographic and spectroscopic methods that were well suited to monitoring racemization and diastereomerization of isolated isomers. k1 and k2. Rappoport and others resolved the enantiomers of tetramesitylethylene. which corresponds to a difference in Gibbs free energy.45 Á 10À5 sÀ1 for the anti-to-syn. DGa. of 4.iii Biali.3807 Á 10À23 J KÀ1).6261 Á 10À34 J s). Using the Eyring equation 4. by HPLC on poly(triphenylmethyl)methacrylate. Chromatography is not always suitable for preparative separation of stereoisomers or for the study of racemization and distereomerization reactions of chiral compounds. and DG ¼ GsynÀGanti. the diastereomers afford an anti/syn ratio of 9. In these cases. as described in Chapter 3. the free Gibbs activation energy. and that to syn-to-anti-atropisomerization was 109.0 for the conversion of the anti. the energy barrier to anti-to-synatropisomerization was determined as 115. R is the universal gas constant (8.1.9 1C. .8-bis(2 0 -isopropyl-4 0 -quinolyl)naphthalene N. interconversion of the enantiomers does not proceed via rotation about the chiral biphenyl axis but through concerted internal rotation of five dichloromethyl groups in one phenyl moiety. The stereodynamic analysis of 1.6:1. Mislow and coworkers separated semipreparative amounts of the enantiomers of decakis(dichloromethyl)biphenyl by HPLC on cellulose tris(3. DG. but the syn. DGa is the Gibbs activation energy in J molÀ1.

and curve fit using the mathematical treatment for reversible first-order interconversion of axially chiral triaryls discussed in Chapter 3. This value was obtained by external heating of an isolated enantiomer and chiral HPLC analysis of small aliquots of the reaction mixture at room temperature. Nevertheless.8-bis(2 0 -isopropyl-4 0 -quinolyl)naphthalene N.0 C) H H o H ∆G ≠ = 165.9 5 0 500 1000 1500 2000 2500 0.2 kJ/mol H (25.P) anti-isomers 90 χ 10 0. This is often possible when NMR spectroscopy. 2930-2938.] H H H H H H H H H H ∆G ≠ = 99.N 0 -dioxide versus time (left).M) 0.92 experimental calculated syn-isomer χ 0. it is desirable to avoid time-consuming preparative separation steps prior to kinetic analysis. of the syn. the stereodynamics of a broad variety of chiral compounds have been studied by thermal interconversion of isolated stereoisomers in combination with chiroptical measurements. . w. 2005. 70.1. Chem.8 kJ/mol. activation energy of 165.0 oC) H H H H four-ring flip chloro substituents are omitted for clarity the arrows represent ring directionality Scheme 4.3 (right).8 kJ/mol H H (200.88 0 500 1000 1500 2000 2500 time (min) time (min) Figure 4. dynamic chromatography and chromatographic stopped-flow methods can be used.2 Plot of the mole fraction.and anti-isomers of 1.Analytical Methods 139 k1 k2 N i-Pr O k2 k1 N i-Pr O N O i-Pr N O i-Pr i-Pr N O N i-Pr O 95 (M.94 (P. Org. [Reproduced with permission from J.1 Enantioconversion of decakis(dichloromethyl)biphenyl and tetramesitylethylene. In general.

A major drawback of polarimetry. and circular polarization of emission (CPE). Mannschreck and coworkers utilized preparative HPLC on cellulose. This concept has even been applied to alcohols that are chiral only by virtue of isotopic substitution (RCHDOH).4. In addition to structural analysis.N-dimethyl thiobenzamides28 to investigate the mechanism and barrier to thermal interconversion by .23 2-aryl-2-methyl-2H-1-benzopyrans.10 The optical rotation of a chiral compound does not always increase linearly with the enantiomeric purity and is therefore not necessarily representative of the actual enantiomeric composition.1 CHIROPTICAL METHODS Polarimetry has traditionally been used for analysis of the enantiomeric purity of chiral compounds with known specific rotation based on Equation 4. which can be applied in the study of stereomutations with energy barriers between 80 and 180 kJ/mol. circular dichroism (CD). l is the length of l the cuvette in dm.and polymethacrylatederived chiral stationary phases for separation of the enantiomers of spiro 2H-1-benzopyran-2. The presence of small amounts of (chiral) impurities can significantly affect the accuracy of polarimetric measurements. polarimetry is generally not used for determination of absolute configurations unless a reference is available. Small amounts of chiral impurities must be carefully removed prior to analysis in order to exclude interference with chiroptical measurements.140 Chapter 4 4. and c is the sample concentration in g/mL.11–13 Other chiroptical techniques. allows deduction of the absolute configuration of the secondary alcohol. Accordingly.15 In particular.4. chiroptical methods have found widespread use in kinetic studies of racemization and diastereomerization reactions. According to Horeau’s rule.2 0 indolines. polarimetric analysis of the decrease in the optical rotation of an enantiopure or enantiomerically enriched sample provides convenient access to racemization and diastereomerization rate constants.14. but NMR spectroscopy and chiral chromatography are preferred nowadays since they provide more accurate results.26 twisted push-pull ethylenes. vibrational ORD and CD. followed by polarimetric analysis of the free carboxylic acid obtained after hydrolysis of residual anhydride (or acyl chloride). which is enantiomerically enriched due to kinetic resolution. in particular when compounds with small rotation angles are analyzed. CD16–20 and ORD21.24 sterically crowded tetrasubstituted phenanthrenes.22 spectroscopy have become invaluable tools for elucidation of the absolute configuration of chiral compounds. A noteworthy exception is the diastereoselective esterification of chiral secondary alcohols with an excess of racemic 2-phenylbutyric anhydride (or 2-phenylbutyric chloride). temperature. It is important to remember that there is no simple relationship between the sign of the optical rotation of a chiral compound and its absolute configuration. afford more structural information about chiral compounds than polarimetric measurements. As discussed in Chapter 3. in the case of associating chiral analytes such as carboxylic acids. including optical rotary dispersion (ORD). the sign of optical rotation of the remaining 2-phenylbutyric acid. although crystallography remains the ultimate method of choice. half-life times and the corresponding activation parameters. Some of these techniques have been used for determination of enantiomeric composition as well as for conformational and configurational analysis based on the octant rule and other semiempirical methods.9.25 N-aryl-4-pyridones. Horeau and others have pointed out that. and sample concentration. determination of the optical rotation for stereochemical analysis can be misleading.27 and atropisomeric N. The optical rotation of a chiral compound depends on the wavelength of the linearly polarized light and the solvent.1. ½aŠT ¼ l ½aŠ cl ð4:4Þ where [a]T is the specific rotation and [a] is the measured optical rotation in degrees. is that at least semipreparative amounts (410 mg) of purified stereoisomers are required.

combined with polarimetric racemization studies.b 0 -two-ring circuits in which the nonflipping ring passes through the double bond plane.and (Z )2-meta-methoxymesityl-1.7 oC) N S N S N Me OMe ∆G ≠ = 94.29 Similarly. a.2 0 -bis(trifluoromethyl)biphenyl at various temperatures. and b.0 oC) O N NBn S ∆G ≠ = 93.30 Stereochemical analysis of sterically crowded triarylvinyl acetates and thioxanthene-derived alkenes by NMR and CD spectroscopy.2 0.4 365 nm 0.4 Polarimetric studies of the racemization of enantiomerically enriched 4.0 oC) Ph N N N N Ph O BnN Ph Ni-Pr Ph i-PrN N N CO2H Ph Ph Me OMe ∆G ≠ = 109. Figure 4.3 kJ/mol (-11. has provided insights into ring flipping mechanisms of molecular propellers and paved the way for the development of chiroptical switches.6 kJ/mol (55.2. polarimetry.1 oC) 60 min Figure 4.4 kJ/mol (24. based on DNMR and polarimetric studies.b-.9 kJ/mol (69.Analytical Methods Me Ph N O Me NO2 ≠ 141 Me O Ph O O Me Ph O ∆G = 111.4 kJ/mol (135.3 kJ/mol (29. Wolf et al.2-dimesitylvinyl acetates. Polarimetry has also been used for stereodynamic analysis of atropisomeric amides.36 biquinazolines exhibiting hindered rotation about a chiral N–N bond.b 0 -.0 oC) Cl OMe N ∆G ≠ = 78.1 oC) Figure 4.4 oC) ∆G ≠ = 132. CF3 MeO OMe F3C [ ] 0. were able to deconvolute the energy barriers to two-ring flip enantiomerization and three-ring flip diastereomerization of (E ).0 oC) N Me ∆G = 111.4 oC) ≠ HO2C ∆G ≠ = 78.35 chiral tricyclic phosphates.3 kJ/mol (50.1 kJ/mol (30.37 and biologically relevant compounds such as adrenaline.1 0 0 15 30 45 ∆G ≠ = 104.9 kJ/mol (22.6 oC) OH O N O ≠ O2N O N ∆G = 85.38 . Scheme 4.9 kJ/mol (62. Figure 4.6 kJ/mol (65.5 oC) ∆G ≠ = 98. separated or enriched the enantiomers of axially chiral biphenyls by HPLC on microcrystalline triacetyl cellulose to determine the rotational barrier by monitoring the decay of the optical rotation at various temperatures.3.4 oC) ∆G≠ = 100.3 Racemization barriers of selected chiral compounds determined by polarimetric analysis of chromatographically enriched or isolated enantiomers.31–34 Rappoport et al.9 kJ/mol (22.7 oC) ∆G ≠ = 104.1 kJ/mol (69.4 0 -dimethoxy2.7 kJ/mol (69.6 oC) O BnN Ni-Pr ∆G ≠ = 109.7 oC) ∆G ≠ = 104.4.3 0. They found that the three-ring flip affords a lower energy barrier than a.0 kJ/mol (-10.

Time-resolved CPL measures molecular iv Chiroptical and NMR measurements proved that enantioconversion of neither alkene coincides with cis/trans-isomerization.and (Z )-isomers of a crowded octahydrobiphenanthrylidene by HPLC on (þ)-poly(triphenylmethylmethacrylate).4 0 octahydro-4.39 The barrier to enantioconversion of (Z)-1. Alternatively.2. . have been examined by vibrational CD spectroscopy which extends the application scope of chiroptical methods to compounds devoid of a chromophore.43 and azapentahelicenes. racemization can be monitored by CD spectroscopy.46 Gas phase racemization and epimerization kinetics of cyclopropanes.5 kJ/mol (31.β′-ring flip OMe α.2 Rotational energy barriers for the a. Although TR-CPL provides an additional means for kinetic studies with racemic samples. Thermal racemization studies revealed that enantioconversion of the (Z)-isomer occurs at room temperature.β.8 oC) MeO α. However.40 In addition to racemization studies of polysubstituted helical phenanthrenes.0 oC) OAc Chapter 4 α. this method is only applicable to luminescent samples such as trisdipicolinate europium complexes.142 OMe β α MeO α.2 0 .4 0 -biphenanthrylidene was determined as 97. The detection of emission of circularly polarized light by enantiomerically enriched excited species allows determination of racemization kinetics based on time-resolved circularly polarized luminescence (TR-CPL). Metcalf and Richardson introduced time-resolved chiroptical luminescence spectroscopy as an elegant alternative.48 The examples of stereochemical and stereodynamic analysis given above underscore the usefulness of chiroptical measurements. Figure 4. chiral only by virtue of isotope substitution.9 1C.44 circular dichroism has also been used to monitor imidozirconium-promoted enantioconversion of allenes45 and stereomutations of supramolecular assemblies. the need for semipreparative isolation of stereoisomers prior to kinetic analysis is a major drawback of these methods.b.42 axially chiral biphenyls.β′-ring flip ∆G ≠ = 97.7 kJ/mol at 24.4.1 0 .2-dimesitylvinyl acetate.β. Excitation of a racemic mixture of chiral lanthanide complexes having stereolabile three-bladed propeller-like structures by a pulse of circularly polarized light (CPL) generates a nonracemic excited state population.41 propeller-shaped tetraarylethanes.β′-ring flip OAc β' ∆G ≠ = 83.b 0 -ring flip diastereomerization and a.β′-ring flip OAc OAc Scheme 4. Figure 4. To overcome this problem. while stereomutation of the (E )-olefin requires temperatures above 55 1C.7 kJ/mol (-10.iv Resolution of the enantiomers of N-nitroso piperidines via crystallization of diastereomeric ´ TADDOL salts enabled Polonski and coworkers to apply CD spectroscopy in racemization studies of these atropisomers which are chiral due to hindered rotation of the nitroso group about the N–N bond.3 0 .47.b 0 -ring flip enantiomerization of (E)-2-meta-methoxymesityl- Harada’s group isolated the enantiomers of the (E ).

49–52 4.Analytical Methods 143 + 200 0h (M.2. Although 1H and 13C are the . 7249-7255.] dynamics of excited states.100 50 UV: λmax 222.5-dimethyl-3-azabicyclo[3.1.9 oC) (M. Chem.7 kJ/mol (24.P)-(E)-isomer (P. In addition.200 0 0 2 4 6h (M.0 5 min 300 350 400 (nm) Figure 4.5 Racemization pathways of 1. NMR spectroscopy is invaluable for conformational and configurational analysis of chiral compounds in solution.2 kJ/mol (23. Soc.P)-(Z)-isomer 0 % 100 . 119.2 NMR SPECTROSCOPY The determination of the composition of enantiomeric or diastereomeric mixtures is routinely performed by NMR spectroscopy.0 oC) O N N -2. Org.4 0 -octahydro-4. 1997.P)-(Z)-isomer ∆ε + 100 1h 2h 3h 4h 5h ∆G≠ = 97.6 Racemization and CD signal decay of 3-nitroso-1. [Reproduced with permission from J.8 nm CD: λext 238. 2001.4.P)-(E)-isomer 200 250 300 350 (nm) Figure 4. Chem. but it does not afford information about interconversion of species in the ground state.M)-(Z)-isomer (P.1 nm .2 0 . 66.M)-(E)-isomer (M. Am.3 0 .1 0 .0]hexane.5 90 min 70 min 50 min 30 min -5.3.] 0 -3 Θ [10 ] 130 min 110 min N N O ∆G ≠ = 94.9 1C. [Reproduced with permission from J.M)-(Z)-isomer at 24. 501-506.4 0 -biphenanthrylidenes and decrease in the CD signal of the (M.

one observes averaged NMR signals for each diastereomeric complex and its corresponding free enantiomer. Since CSA/solute association is an equilibrium process. 31P. The protons are therefore chemically equivalent and part of an A2B system. 19F. and frequently suffers from severe peak broadening due to fast chemical v The usefulness of nuclei with spin quantum numbers greater than I ¼ 1/2 such as 33S is somewhat limited because the quadrupole moment of these nuclei can cause significant line broadening and thus compromise resolution. The development of rationally designed chiral derivatizing agents (CDAs). The formation of diastereomeric complexes from enantiomeric analytes and a CSA often gives rise to anisochronous NMR shifts. . 15N. Figure 4.81–86 or paramagnetic CSR87–90 such as lanthanide (Eu. The usefulness of CSRs for enantiomeric analysis is limited to compounds that form a coordination complex with Lewis-acidic lanthanides.9. 29Si. by reducing the temperature if the solubility of the analyte is not compromised. For example.7 Chemical (non)equivalence of methylene protons in 2. Pr. even if not enantiopure. The observed difference in chemical shifts upon formation of diastereomeric adducts is usually quite small and diminishes with increasing solvent polarity. whereas the meso isomer carries diastereotopic methylene protons that establish an ABC system. Figure 4. The absolute configuration of chiral compounds can be deduced in many cases from empirical chemical shift correlation of covalent or noncovalent adducts. Yb) chelate complexes. Chemical nonequivalence can originate from the presence of a proximate stereogenic element.8.53–61 chiral solvating agents (CSAs). However. and 33S NMR measurements are also quite useful.72 Diastereoisomers have different chemical and physical properties and often afford distinguishable NMR spectra. This can be compensated with a stronger magnetic field. This problem can be avoided by formation of noncovalent adducts with a CSA or CSR which.62–67 and chiral lanthanide shift reagents (CSRs)68–70 has extended the application spectrum of structural NMR analysis to a wide range of compounds.v The elucidation of the three-dimensional structure or stereoisomeric composition of chiral molecules by NMR spectroscopy requires assessment of homotopic and heterotopic moieties. the methylene protons of (S.144 C2 axis HA H HA H H HA HB H Chapter 4 HO2C OH HO CO2H HO CO2H OH CO2H meso isomer (S. give accurate results if signal integration is not compromised due to reduced signal resolution. Conformational analysis of chiral compounds generally entails correlation of chemical shifts and coupling constants in conjunction with nuclear Overhauser effect spectroscopy (NOESY) and other NMR experiments.4-dihydroxyglutaric acids. but diastereotopic nuclei are chemically nonequivalent and usually exhibit different (anisochronous) chemical shifts.73–80 CSA. or by addition of an achiral lanthanide shift reagent. which greatly simplifies analysis of diastereomeric mixtures and diastereomerization processes. Since NMR spectra of enantiomers are identical.S)-2. Figure 4.7.71. most relevant nuclei.4-dihydroxyglutaric acid can be exchanged by rotation about a C2-axis. Homotopic and enantiotopic groups have isochronous NMR signals. nuclei remain equivalent when they are exchangeable by a symmetry operation that applies to the whole molecule.S)-isomer Figure 4. The determination of the enantiomeric composition of a sample requires the use of a 100% enantiopure CDA and quantitative conversion of enantiomers to diastereoisomers in order to avoid chiral discrimination effects that can originate from kinetic resolution. stereodifferentiation requires formation of diastereomers using a CDA.

i.94 Subsequent replacement of the a-proton attached to the chiral center of a-aminoe-caprolactam by deuterium results in the disappearance of the corresponding 1H NMR signal. Polarimetric analysis using isolated enantiomers of a-amino-e-caprolactam under the same conditions showed that the actual rates of racemization are substantially higher.8.95 In an achiral environment. can often be conveniently monitored by 1H NMR spectroscopy in deuterated protic solvents. respectively.(S)-α-metyhoxy-α-trifluoro. In rare cases. which makes it difficult to detect and quantify impurities below 2%. Eu(hfc)3. O Eu/3 O Eu(tfc)3 CF3 O Eu/3 O Eu(hfc)3 C3F7 Figure 4.5-dinitrobenzoyl)-α-methylbenzylamine Figure 4. A major shortcoming of NMR spectroscopy is its inherently low sensitivity.. Comparison of the individual exchange rates obtained by NMR spectroscopy with racemization rates determined by polarimetry thus reveals a pronounced primary isotope effect.9 Structures of chiral NMR lanthanide shift reagents tris(3-trifluoroacetylcamphorato)europium.97 The study of .2′-diyl.and (S)-enantiomer were determined as 170 and 98 minÀ1. however. exchange processes and short longitudinal relaxation times.e.2. Eu(tfc)3. Isomerization reactions that involve proton exchange. for example keto/enol-tautomerization.96.Analytical Methods 145 OMe CO2H (R)-O-methylmandelic acid F3C OMe CO2H O P O O OH F3C OMe NCO NH2 OH MTPA (Mosher's reagent) (P)-binaphthyl-2. this method provides proton/deuterium exchange rates that sometimes deviate from the corresponding rate of racemization. The isotope exchange was monitored by integration of the proton NMR signal and the proton/ deuterium exchange rates of the (R). Soda and coworkers examined the enzyme-catalyzed racemization of a-amino-e-caprolactam in the presence of a pyridoxal-P racemase in deuterium oxide at p2H 8.8 Chiral derivatizing agents (top) and chiral solvating agents (bottom) commonly employed in stereochemical NMR analysis.(S)-phenylglycinol hydrogen phosphate methylbenzyl isocyanate CF3 OH NH2 OH OH N H O NO2 NO2 (S)-1-(9′-anthryl)-2. Dynamic processes exhibiting an energy barrier between 20 and 100 kJ/mol can often be studied by analysis of temperature-dependent NMR spectra of the interconverting species. pronounced diastereomeric solute/ solute-interactions in nonracemic mixtures give rise to distinctive NMR spectra.2trifluoroethanol (R)-1-(1′-naphthyl)ethylamine (P)-BINOL (R)-N-(3.91–93 However. and the heptafluorobutyryl analog. the NMR spectra of enantiomers are indistinguishable and this is usually also observed with mixtures of enantiomers. 220 and 170 minÀ1.

1.9 kJ/mol (61. At increased temperature.3.4 kJ/mol (86. see Chapter 3. The interconversion of stereoisomers exhibiting diastereotopic nuclei can be monitored by variable-temperature NMR spectroscopy (dynamic NMR) when the reaction is slow on the NMR time scale. A particularly simple situation arises when two nuclei (AB case) provide sharp signals with equal intensity and undergo chemical exchange resulting in line broadening and coalescence upon heating. the first-order interconversion rate constant can be calculated as: Dn kTc ¼ p pffiffiffi 2 vi ð4:6Þ It is important to realize that both CSR and CSA can alter the actual reaction rate and the thermodynamic equilibrium of the interconverting species.0 oC) NO2 Figure 4.10 Enantioconversion of 2-isopropyl-2 0 -methoxybiphenyls studied by DNMR. Figure 4.0 oC) OMe OMe ∆G ≠ = 77.11. As the temperature is increased. become diastereotopic and therefore magnetically nonequivalent if the molecule contains a chiral element.146 diastereotopic groups Chapter 4 MeO MeO ∆G ≠ = 80. Analysis of the temperature-dependent NMR spectra of 2-isopropyl2 0 -methoxybiphenyl gave an activation energy of 80. The study of enantiomerization reactions is greatly facilitated when interconverting species possess diastereotopic nuclei even in the absence of a chiral additive. In the absence of any coupling. such as the two methyl moieties in an isopropyl group. For example. This is the case when: Dn k ( p pffiffiffi 2 ð4:5Þ where k is the interconversion rate constant and Dn is the NMR shift separation of the signals at low temperatures at which exchange does not occur.0 oC) OMe MeO OMe ∆G ≠ = 73.98 Examination of the 1H NMR spectra of 2-isopropyl-2 0 -methoxybiphenyl and its derivatives showed that the presence of the chiral axis renders the methyl protons of the isopropyl group diastereotopic. although achiral lanthanide shift reagents have been used to increase anisochrony for deconvolution of diastereotopic signals. one can obtain well resolved signals at low temperatures where the two nuclei do not show measurable exchange. the exchange rate becomes fast relative to the NMR time scale and only one averaged species is observed due to signal coalescence. which can be explained by facilitated out-of-plane bending and push-pull conjugation in the coplanar transition state. the two substituents Y in –CXY2. This has been observed by Oki and Yamamoto with 2-isopropyl-2 0 methoxybiphenyl derivatives. rotation about the chiral biphenyl axis is relatively fast compared to the NMR time scale and one observes coalescence of the diastereotopic methyl signals.10.7 kJ/mol (58.0 oC) MeO OMe ∆G ≠ = 74. enantiomerization reactions requires that enantiotopic atoms or groups of the interconverting species are rendered diastereotopic and chemically nonequivalent.4 kJ/mol (74.vi Diastereomerization reactions can often be monitored in the absence of any additives. Introduction of methoxy and nitro groups into the para-positions of 2-isopropyl-2 0 -methoxybiphenyl reduces the rotational energy barrier. This can be accomplished with a nonracemic CSR or CSA. .4 kJ/mol at 86 1C. Figure 4. In such a case.

Tc is the coalescence temperature in Kelvin.8-bis(2 0 -methyl-4 0 pyridyl)naphthalene N.and anti-isomers.12.3 1C and 11.N 0 -dioxide shown in Figure 4. Equations 4. It is noteworthy that the pyridyl signals of the N. respectively.8-dipyridylnaphthalenes which exist as almost equimolar mixtures of syn. the corresponding rotational energy barriers were calculated as 67 kJ/mol and 64 kJ/mol. and Dn is the difference in the chemical shifts of the two signals without exchange (at low temperatures. the rate constant can be estimated using the following equation: p 2 kTc % 2:22 ðDn2 þ 6 JAB Þ ð4:8Þ where JAB is the coupling constant between nuclei A and B in Hz.N 0 -dioxide are also well resolved and coalesce at 27.12. The inherently larger NMR scale of these nuclei provides superior resolution of chemical shifts and facilitates quantitative analysis of rapidly exchanging signals. which increases with the NMR measurement frequency and the applied magnetic field. Dn.Analytical Methods νA + νB νA νB slow exchange fast exchange coalescence 2 147 T Figure 4. Figure 4.7. According to Equation 4.11 Variable-temperature NMR spectra of an uncoupled dynamic AB system.6 to 4. vii This has been verified by analysis of the exchanging pyridyl and methyl protons. a coalescence phenomenon is associated with a specific set of signals. Both kTc and Tc therefore increase with the magnetic field strength.8 must yield the same activation energy within experimental error.3 provides the free energy of activation: DG6¼ ¼ 19:1 Á 10À3 Tc ð9:97 þ lg Tc À lg jnA À nB jÞ ð4:7Þ where DGa is the free energy of activation in kJ/mol. If coupling between the exchanging nuclei occurs. T { Tc).8-bis(2 0 -methyl-4 0 -pyridyl)naphthalene and its N. Using Equations 4.5 to 1. and a compound can have more than one pair of exchanging nuclei with individual coalescence temperatures. . As described above. Incorporation of Equation 4. the diastereotopic methyl proton signals of 1.vii Although dynamic processes are usually studied by 1 H NMR spectroscopy.99 The sharp proton NMR signals of the naphthalene ring undergo only minor changes within the temperature range studied. and 13C provide valuable alternatives. The difference in the rotational energy barrier of 1 kJ/mol is within the limited accuracy of the coalescence DNMR method.0 kJ/mol due to difficulties in determination of the exact coalescence temperature. and nA and nB are the chemical shifts of nuclei A and B in Hz.N 0 -dioxide are well resolved at À17. DNMR experiments with other nuclei including 19F.8 1C but show broadening at increasing temperature and coalescence at 40. kTc depends on the difference in the chemical shifts of the exchanging signals. If coalescence events are a consequence of the same stereomutation. In contrast. where kTc is the rate constant at the coalescence temperature Tc.6.2 1C. which corresponds to an energy barrier of 65 kJ/mol. respectively. The accuracy of the coalescence method is often limited to approximately Æ0.6 and 4.5 1C. Variable-temperature NMR spectroscopy was employed by Wolf and Ghebremariam in the study of the diastereomerization of axially chiral 1. 31P. of 1.

However. 1153-1156. Because of increasing steric repulsion between the methyl group attached to the chiral center and the perihydrogen at C-8 in the naphthalene ring.148 Chapter 4 N N N N N O N O N O N O Figure 4. [Reproduced with permission from Tetrahedron: Asymm. The atropisomerization of 1-(1-naphthyl)ethylamines. provides a good example.12 Variable-temperature NMR spectra of 1. N. the (S)-(M)-rotamer is considered to be less stable than the (S)-(P)-diastereoisomer.] The simplicity of the coalescence method has certainly contributed to its widespread use. In these cases.N 0 -dioxide derivative (right). The diastereomers have different NMR spectra and integration of well .8-bis(2 0 -methyl-4 0 -pyridyl)naphthalene (left) and the N. Figure 4. this method is not applicable to interconversions of species with different thermodynamic stability.N-dibutyl-1-(1-naphthyl)ethylamine affords two diastereomeric rotamers having the amine moiety in almost perpendicular orientation to the naphthalene ring. accurate results can be obtained by NMR line shape analysis. 2002.13.100 According to PM3 calculations. nor to compounds that possess complicate NMR spectra with multiple coupling patterns. which exist as a pair of diastereoisomeric racemates bearing a chiral center and a stereolabile chiral axis. 13.

43.Ndibutyl-1-(1-naphthyl)ethylamine are resolved in ortho-xylene-d10. 2002. and computer simulations and corresponding rate constants for the interconversion of the more stable to the less stable rotamer (right). 56. it has become a powerful tool for analysis of single bond rotations. Charlton and coworkers investigated hindered rotation about the chiral axis of arylnaphthalene lignans having half-lives of less than 10 minutes.14.0 · 10-3 s-1. Similarly to the NMR study of 2-isopropyl-2 0 -methoxybiphenyls mentioned above.] resolved signals gave an atropisomeric ratio of 6. The energy range covered by DNMR is limited by the NMR time scale.13 Experimental 1H NMR spectra of the methine protons of N.5:1.5 s-1. Variable-temperature NMR spectroscopy has been applied extensively in kinetic studies of stereodynamic processes with energy barriers between 20 and 130 kJ/mol.6 can and not be used for kinetic analysis of this atropisomerization reaction because the rotamers exist in unequal amounts and afford two distinct interconversion rates. 84.101 Lunazzi and others examined stereomutations of diastereomeric diarylbenzenes viii The coalescence method and Equation 4. 38.N-dibutyl-1-(1-naphthyl)ethylamine (left).6 kJ/mol based on the Boltzmann equation.4 °C (S)-(P)-isomer (S)-(M)-isomer 1380 1360 1340 Hz 1380 1360 1340 Hz k = 1. [Reproduced with permission from Tetrahedron Lett.Analytical Methods 149 k = 50.7 °C 1400 1370 1340 Hz 1400 1370 1340 Hz Figure 4. atropisomerization barriers of many other biaryls have been determined by the coalescence method and line shape analysis. Figure 4.9 (Æ0. Since DNMR can be used to study stereolabile compounds that rapidly interconvert at room temperature.9 °C (R)-(M)-isomer + NBu2 H Me (R)-(P)-isomer + Bu2N H Me 1375 1355 Hz 1375 1355 Hz k = 1. which corresponds to a difference in the Gibbs free energy of 4. and variable-temperature NMR spectroscopy yielded coalescence at 84. 22. They observed coalescence of diastereotopic protons of justicidin A and other natural products and determined energy barriers to rotation about the chiral biaryl axis. ranging from 70 to 90 kJ/mol. Screening of various solvents revealed that the diastereotopic quartet signals of the methine protons attached to the chiral center of N.0 s-1.7 °C 1375 1355 Hz 1375 1355 Hz H NBu2 Me Bu2N H Me k = 6.2) kJ/mol using Equation 4.viii Individual rate constants were obtained by line shape analysis of experimentally obtained 1H NMR spectra and the rotational energy barrier for the isomerization of the more stable to the less stable atropisomer was calculated as 75.3.0 s-1. signal resolution and the practical NMR temperature range (À150 1C to þ160 1C) which ultimately depends on the melting and boiling points of available deuterated solvents. .7 1C. 8563-8567.

The absence of a diastereotopic probe in the tert-butyl sulfone derivative requires the use of a chiral solvating agent such as (S)-2. Diastereomerization of several 1-(alkylsulfinyl)-2-methylnaphthalenes has been examined between À70 and þ100 1C.15. which is achiral in both conformations due to the presence of a symmetry plane in the syn. and therefore exist as a pair of diastereomeric E/Z-conformers that can easily be distinguished by NMR spectroscopy in the absence of a chiral additive. The atropisomerism of a series of hindered N. or if necessary with the help of chiral solvating agents.104–106 Activation energies obtained by simulation of the exchange of different proton and carbon nuclei were in excellent agreement and solvent effects on the carbonyl rotation proved to be negligible.2-bis(2 0 -methyl-1 0 -naphthyl)benzene.6 kJ/mol (25. these triaryls exist as a mixture of meso syn.0 °C) (25.2-trifluoro1-(9 0 -anthryl)ethanol for NMR analysis.4 kJ/mol ∆G ≠anti→syn = 81. Line shape analysis of experimentally obtained NMR spectra revealed that the energy barriers for the anti-to-syn-isomerization of these atropisomers span a range of 80 to more than 130 kJ/mol.N-dialkyl-1naphthylamines has been examined by Lunazzi and coworkers using line shape analysis of NMR spectra recorded between 16 and 165 1C. An exception is 1.14 Rotational energy barrier of diastereomeric lignan biaryls and triaryls determined by line shape analysis.0 °C) ≠ ≠ O O ∆G = 77. The two processes therefore do not interfere.103 By analogy with 1. Scheme 4.and an inversion center in the anti-rotamer. Figure 4. alkyl aryl sulfoxides possess a chiral center at the sulfur atom in addition to the chiral C–S axis.15.113 Rotation about the chiral carbon–sulfur axis of 1-naphthyl sulfones is evident from the exchange of the diastereotopic signals of the geminal hydrogens in 1-(ethanesulfonyl)-2-methylnaphthalene and of the geminal methyl groups in 1-(isopropylsulfonyl)-2-methylnaphthalene. Figure 4. Interconversion of diastereoisomeric diacyl arenes and atropisomerization of bridged biaryl lactones have also been explored by DNMR.4-bis(2 0 -methyl-1 0 naphthyl)benzene.0 °C) MeO OMe ∆G = 89.2. By contrast.112.150 Chapter 4 OH MeO MeO CO2(S)-Lac MeO OMe MeO O CO2(S)-Lac MeO O MeO O O ∆G ≠anti→syn = 130.107–110 The dynamic stereochemistry of many other nonbiaryl atropisomers has been studied by variable-temperature NMR spectroscopy. which facilitates determination of the free energy of activation for the rotation about the chiral carbon–nitrogen axis.0 °C) Me (S)-Lac = H CO2Me ≠ O O ∆G = 70.111. Alkyl aryl ketones afford a mixture of enantiomeric conformations exhibiting almost perfectly orthogonal carbonyl and aryl planes.3.0 °C) ∆G≠ anti→syn = 85.6 kJ/mol (130. Gasparrini.and chiral anti-isomers.ix Similar structures and conformational equilibria have been observed with aryl sulfoxides and aryl sulfones. Lunazzi and others showed that the existence of twisted conformations and rotation about the aryl–carbonyl bond can be detected by 1H and 13 C NMR spectroscopy when prochiral probes such as an isopropyl group are present.7 kJ/mol (23. such as 1. ix Concurrent nitrogen inversion of these compounds has a very low energy barrier and is only observable under cryogenic conditions. .102.4 kJ/mol (23.8-diarylnaphthalenes.6 kJ/mol (23.0 °C) Figure 4. An interesting situation arises with naphthylamines that adopt twisted conformations in the ground state to minimize steric repulsion between nitrogen substituents and the aryl ring.

120 pyridine-derived adamantanes.119 highly substituted 1.4 kJ/mol (-70 to -60 oC) R=Et: ∆G = 30.0 kJ/mol (80 to 100 oC) ≠ ≠ t-Bu: ∆G = 61.1 kJ/mol (-13 to 15 C) o ≠ Figure 4.8 kJ/mol (−70 oC) Et: ∆G≠ = 43.9 kJ/mol (25 oC) R=Et. R′= i-Pr: ∆G≠ = 83.5 kJ/mol (−55 oC) i-Pr: ∆G = 47.3 kJ/mol (109 to 114 C) i-Pr: ∆G ≠ = 93.9 kJ/mol (−110 oC) Et: ∆G≠ = 38.0 kJ/mol (-60 to -50 C) o ≠ ≠ o Et: ∆G = 51.7 kJ/mol (16 to 37 oC) Et: ∆G ≠ = 69. R′=i-Pr: ∆G≠ = 73.0 kJ/mol (75 to 89 oC) Et: ∆G = 88. PM3 computed ground states.3 kJ/mol (−55 C) t-Bu: ∆G≠ = 55.3 kJ/mol (137 to 150 oC) R S O R S O ≠ ≠ o ≠ R=Me: ∆G ≠ = 44.7 kJ/mol (−78 oC) O RO R R OO ≠ o R O R R=Me: ∆G≠ = 33.1 kJ/mol (-136 to -120 C) i-Pr: ∆G = 44.3-dienes.3 Rotational energy barrier of atropisomeric acyl arenes and biaryl lactones.3 kJ/mol (−50 oC) R ≠ o R=Me: ∆G≠ = 42. R′=Et: ∆G≠ = 54.0 kJ/mol (−140 oC) CH2Et: ∆G≠ = 31.0 kJ/mol (25 oC) R=OMe.1 kJ/mol (28 to 42 oC) i-Pr: ∆G = 72.5 kJ/mol (22 oC) O R R=CH2Me: ∆G≠ = 28.1 kJ/mol (25 oC) Scheme 4.Analytical Methods O O R R O O R R R O 151 O R=Me: ∆G≠ = 33.116.114 3-(ortho-aryl)-5-methylrhodanines.3 kJ/mol (135 to 150 oC) t-Bu: ∆G = 96.3 kJ/mol (−55 C) t-Bu: ∆G≠ = 83.1 kJ/mol (-25 to -17 oC) t-Bu: ∆G ≠ = 77.0 kJ/mol (108 to 125 oC) R O S O R O S O ≠ R=Me: ∆G = 82. Line shape analysis of temperature-dependent NMR spectra has been applied to numerous atropisomers including bis(1-phenyl-9-anthryl)ethynes.9 kJ/mol (−92 oC) i-Pr: ∆G = 47.8 kJ/mol (−118 oC) CHMe2: ∆G≠ = 35.0 kJ/mol (50 to 65 oC) t-Bu: ∆G ≠ = 82.1 kJ/mol (−80 oC) i-Pr: ∆G≠ = 56.15 Atropisomerism.118 N-naphthyl imines.115 orthosubstituted (Z)-benzophenone oximes and benzyl aryl oximes.1 kJ/mol (-40 to -35 oC) i-Pr: ∆G = 56.2 kJ/mol (−110 oC) CH2Ph: ∆G = 37.1 kJ/mol (−55 oC) t-Bu: ∆G≠ = 92. Me Et N R R Et N Me i-Pr Et N R R=Me: ∆G ≠ = 65. sulfones and sulfoxides. and rotational energy barriers of selected naphthylamines.4 kJ/mol (25 oC) R=Me.7 kJ/mol (−120 oC) Et: ∆G≠ = 48. R′=Et: ∆G≠ = 72.117 N-aryl tetrahydropyrimidines.121 and secondary .7 kJ/mol (−95 C) ≠ o O R O R′ O R′ R=Me.

2 kJ/mol (-65. Chem.3 kJ/mol (0.0 ppm Figure 4. 2001.122 Deconvolution of concurrent atropisomerization and ring flipping of tricyclic pyridones derived from a nonplanar seven-membered ring has been accomplished by a combination of HPLC racemization studies of isolated enantiomers and twodimensional NMR analysis (EXSY) of relatively fast diastereomerization resulting from rotation about the chiral axis.0 C 4.0 oC) N N Cl Ph3Sn ∆G ≠ = 62.0 C k = 95 s .3-bridged cyclooctatetraenes.0 oC) Figure 4. 6679-6684.0 oC) t-BuMe2Si SnPh3 ∆G ≠ = 26. Hydrogens are omitted for clarity. to determine the rates of ring inversion and bond shifting in chiral 1.2 kJ/mol (60.0 kJ/mol (-100.0 C -1 o -1 o -1 o -1 o k = 0 s .0 C k = 45 s .5. 66.0 to -30. 80. Org.6 kJ/mol (-25.124 Other stereodynamic processes that have been investigated by DNMR spectroscopy include enantiomerization of chiral cyclohexene oxide conformers in solution and in the solid state.0 oC) ∆G = 58.6-tetrahydropyrimidine (left).0 to 80.16 Stereomutations studied by DNMR spectroscopy. 20. 30.123 Dynamic EXSY has also been used by Paquette et al.16 and 4.17 Computed ground states of the interconverting enantiomers of 1-(2 0 -chlorophenyl)-2-phenyl1. and experimental and simulated NMR signals of the tetrahydropyrimidine methylene protons at various temperatures (right).0 oC) N i-Pr i-Pr MeO2C CO2Me MeO2C CO2Me HO O N P t-Bu H SiMe2t-Bu ∆G ≠ = 56.7 kJ/mol (27.152 Chapter 4 S i-Pr i-Pr i-Pr i-Pr S N O Cl i-Pr i-Pr i-Pr i-Pr ∆G ≠ = 119. Scheme 4. 40.0 3.5 3.] phosphine oxides.127 interconversion of helical conformations of overcrowded naphthalenes.0 · 10 s . [Reproduced with permission from J.0 oC) ∆G ≠ = 61.8 kJ/mol (-9.0 oC) ∆G ≠ = 62. k = 3.4.0 oC) ≠ N O SPh N O Br ∆G ≠ = 75.17. -9.4.0 C 3 -1 o N N Cl k = 200 s .128 ring flipping between chiral conformations of .126 electrocyclic rearrangements of homofuran and its derivatives.0 oC) ∆G ≠ = 44.125.5 kJ/mol (-20.4 kJ/mol (-152. Figures 4.

MEKC.g.139..130–134 helical inversion of dinuclear bis(oxazolinyl)pyrrole-derived palladium complexes. and HPLC separation. Similarly.3 DYNAMIC CHROMATOGRAPHY Chromatography (GC. SFC. chromatographic analysis of an enantiomeric mixture was accomplished by formation of diastereoisomers with an enantiopure chiral derivatizing agent (CDA) and subsequent separation on an achiral column.18.0 oC) O N S N N S O N ∆G = 91.8 kJ/mol (HPLC. 27. and TLC) and capillary zone electrophoresis (CZE) provide a powerful means for the determination of the enantiomeric and diastereomeric purity of chiral compounds.129 cog-wheeling of propeller molecules. or sufficient solubility for SFC. Basic requirements for common GC/FID analysis.136 and stereomutations of supramolecular assemblies such as helical inversion of donor-acceptor catenanes. triarylvinyl derivatives. SubFC.4 Stereodynamics of a tricyclic pyridone. MEKC.Analytical Methods O N S N ring flip N atropisomerization ∆G ≠ = 79.0 kJ/mol (EXSY. This can be avoided by direct enantioseparation in the presence of chiral mobile phase additives that form transient diastereomeric complexes during chromatographic separation. The choice of a suitable CDA depends on the structure and functional groups of the analyte. also need to be addressed. A shortcoming of this approach is that detection of diastereomers by UV spectroscopy or other methods necessitates cumbersome correction of integration results with individual response factors in order to obtain accurate ee values. Repetitive batch and simulated moving bed chromatography (SMB) are commonly used for HPLC.135 epimerization of a uranyl-salophen complex. 20. enantiomeric impurities in a CDA alter the diastereomeric product composition and lead to incorrect calculation of the ee.138 Chiral chromatography is also very well suited for preparative isolation of stereoisomers.2.140 Prior to the development of chiral stationary phases. enantiomer discrimination due to incomplete derivatization or partial isolation of the diastereomeric mixture gives false results. But the scope of this . HPLC. The preparation of separable diastereomers for analysis of the enantiomeric composition of a chiral sample is not a trivial task. CEC. Figure 4. e.0 oC) ≠ 153 S N O N N N N Scheme 4. TLC. SubFC and SFC separation of stereoisomers on the semipreparative (mg to g amounts) or industrial scale (kg quantities).137 4. SubFC. As is discussed in Chapter 4. thermal stability and volatility. CEC. stereochemical analysis with chiral derivatizing agents is generally not very attractive because it entails an additional synthetic step and has other severe drawbacks.

approach is limited due to the low stability and insufficient resolution of noncovalent adducts.18 Chiral derivatizing agents used for chromatographic analysis of enantiomeric mixtures. A similar situation arises with the term asymmetric synthesis which is widely used to describe enantioselective and diastereoselective synthesis.143–146 In particular.x Numerous CSPs derived from a-.154 O O OCOCl Ph Ph NH2 HO NCO NCO NH2 N O Cl O Chapter 4 MeO CO2H OH CO2H Figure 4. Enantioselective chromatography greatly facilitates quantification because enantiomers have the same individual response factors (in an achiral environment) and the ratio can readily be obtained by peak area integration.19 Structures and dimensions of native cyclodextrins that can be selectively derivatized in positions 2. alkylated or silylated cyclodextrins and metal camphorate complexes has been established by Konig. short peptides. To date. and chiral metal chelates have been introduced to gas chromatography (GC).142 The shortcomings of the methods described above have been overcome by the introduction of chiral stationary phases (CSPs). Chromatography is of course enantioselective and is not inherently chiral.20. Figures 4. Figure 4.19 and 4. 3 and 6 of each glucose unit.and g-cyclodextrins.147–151 Water-soluble cyclodextrin derivatives are frequently employed ¨ x For convenience. Schurig and others. b. GC on selectively acylated.141. a broad variety of CSPs has been developed for direct separation of enantiomers. the term chiral chromatography has been coined to refer to separation of enantiomers on a CSP and is commonly used instead of the more accurate term enantioselective chromatography. .

3-di-O-methyl)-β-cyclodextrin Figure 4.182 Gas chromatography (GC). The separation is thus a result of different partitioning of the enantiomers between an achiral mobile phase and a CSP. chromatographic separation results from enantioselective partitioning and different electrophoretic mobilities of the free solutes and their micellar complexes. both the reaction rate and the height of the plateau increase with temperature.165–170 SubFC. This technique is based on selective distribution of solutes between an electroosmotically driven mobile phase and chiral micelles. Alternatively. high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) are the most widely used techniques for separation of enantiomers on both analytical and preparative scales. including microcrystalline cellulose triacetate. When the interconversion is .21. allow convenient enantioseparation of a broad range of chiral compounds by HPLC. Direct chromatographic resolution of enantiomers is based on the formation of transient diastereomeric complexes between enantiomeric solutes and a chiral stationary phase.Analytical Methods 155 O Si O Si O n O HN O O Si O Si O n (CH2)7 (MeO)6 O Si O Si O n 3 6 6' O O Ni/2 O C3F7 Chirasil-Nickel (OPe)8 6 6 β-CD 2 NH (MeO)7 (OMe)7 Chirasil-Dex (OMe)7 (OMe)8 6 Chrompack (OTBDMS)7 6 γ-CD 3 2 3 β-CD 2 3 γ-CD 2 3 β-CD 2 (BcO)8 (OPe)8 (MeO)7 (OMe)7 (PeO)8 (OPe)8 (MeO)7 (OMe)7 octakis(3-O-butyryl-2. Chiralcel OD and Chiralpak AD. peak coalescence phenomena can be observed in chromatography as a consequence of simultaneous resolution and on-column interconversion. such as Whelk-O 1.171–174 and CEC. as chiral additives in enantioselective CZE. In MEKC.175–180 Figure 4. and so-called brush-type CSPs developed by Pirkle and coworkers.181.5-dinitrobenzoyl)phenylglycine and other amino acid derivatives.152–156 Cellulose and amylose derivatives. Since plateau formation is due to on-column isomerization. Importantly.3. rationally designed CSPs exhibiting a reasonably well understood chiral recognition mechanism can be used to elucidate the absolute configuration of chiral compounds based on predictable elution orders. However. N-(3. A successful chromatographic separation of stereoisomers affords two distinct peaks. enantioseparation can be achieved by MEKC with sodium cholate or other chiral mobile phase additives. stereolabile compounds can undergo interconversion during the chromatographic process.157–164 SFC. By analogy with variable-temperature NMR spectroscopy.3di-O-pentyl)-γ-cyclodextrin heptakis(6-O-tert-butyldimethylsilyl2.6di-O-pentyl)-γ-cyclodextrin (Lipodex E) heptakis(2.6-tri-O-methyl)β-cyclodextrin octakis(6-O-methyl-2. Competition between separation and isomerization gives rise to elution profiles showing a plateau between the peaks. or in combination with surfactants in micellar electrokinetic chromatography (MEKC).20 Structures of CSPs commonly used for GC enantioseparations.

Finally. 2. Figure 4. 2-tert-butyl2 0 -isopropyl-.21 Structures of CSPs commonly employed in enantioselective HPLC. As is discussed in Chapter 3. temperature increases Figure 4. Computer simulation of chromatographic elution profiles provides individual rate constants and activation parameters of the isomerization. OB. SFC and SubFC. OG.2 0 -diisopropylbiphenyl. These three cases are observed when a mixture of 2. (b) competition between chromatographic resolution and enantiomerization generates a temperature-dependent plateau between the two peaks.23. AS are coated on silica gel) O HN RO HN O SiO2 O Si α-Burke 2 NO2 NO2 N H NO2 O2 N O N H H N O Chapter 4 O Si O OEt SiO2 (S)-N-(3. Upon completion of the partitioning . and 2.5-Dinitrobenzoyl)phenylglycine-derived CSP Chiralcel OD Chiralcel OG Chiralcel OB O Chiralcel CA1 O Me (microcrystalline) RO O OR O n Chiralpak AD HN Chiralpak AS HN O RO O Figure 4.183 Based on the rate of enantioconversion of a stereolabile compound one can expect three different chromatographic scenarios: (a) two baseline-separated peaks are obtained if enantiomerization is slow compared to the chromatographic time scale. replacement of the sterically demanding tert-butyl moiety by the smaller isopropyl group decreases the rotational energy barrier. and (c) only one peak is observed when enantiomerization is fast relative to the time required for the separation.184 Because of the high conformational stability of 2. and Chiralpak AD. Each plate affords selective distribution of the analytes between the mobile and the stationary phase.2 0 -diisopropyl-.2 0 -di-tert-butylbiphenyl. which can be separated into enantiomers on cyclodextrin-derived CSPs at lower temperatures. is not stable to enantiomerization at 165 1C and only one racemic peak is observed.4R)-Whelk-O 1 RO O OR n O O (Chiralcel OD.156 MeO MeO P O O SiO2 HN O2 N O Si NO2 (3S.2 0 -di-tert-butylbiphenyl is analyzed by chiral GC at 165 1C. Chromatography is often described as a discontinuous process using a theoretical plate model in which the column is segmented into N theoretical plates. both enantiomers are separated and show no sign of interconversion.22.22 Temperature-dependent plateaus and peak coalescence due to simultaneous chromatographic resolution and on-column isomerization.3. and 2-tert-butyl-2 0 -isopropylbiphenyl undergoes significant isomerization in under 10 minutes at 165 1C.1. Figure 4. much faster than the chromatographic separation one observes peak coalescence.

23 GC resolution of 2. Enantioconversion occurs in the gas phase and in the achiral and chiral part of the stationary phase. b0. The retention increment. as well as the enantioselectivity factor. SP. N.185–188 Schurig and coworkers were first to incorporate both resolution and enantiomerization of chiral compounds into a computer program based on the theoretical plate model. To account for isomerization that is competing with the chromatographic separation processes. 781-786.] (R)MP KL (R)SP R(R) (R)CSP kMP kMP kSP kSP kCSP k'CSP (S)MP mobile phase KL (S)SP stationary phase R(S) (S)CSP Scheme 4. MP. from the retention time of a peak. which can be obtained . describes the distribution of the enantiomers between the mobile phase.5. kMP. The simulation of elution profiles requires determination of the number of theoretical plates. 1995. kSP.2 0 -disubstituted biphenyls at 165 1C on heptakis(6-O-tert-butyldimethylsilyl2.3-di-O-methyl)-b-cyclodextrin. each theoretical plate is considered a chemical reactor.5 Equilibria between enantiomers of a chiral compound in a theoretical plate. The partition coefficient. and k 0 CSP. and so on.5. process in each plate. a. Scheme 4. KL. tR.189 Their seminal work was followed by the development of user-friendly software packages that simplify simulation of enantioconversion and partitioning equilibria. and the peak width at half height. [Reproduced with permission from Liebigs Ann. kCSP.Analytical Methods i-P r 157 i-P r i-P r t-B u t-B u t-B u 0 5 10 min Figure 4. the mobile phase and its components are shifted to the next theoretical plate to participate in another separation step. and achiral sites in the stationary phase. which is described by four different rate constants. including achiral and chiral contributions to chromatographic retention. originates from selective partitioning of the enantiomers between the achiral and the chiral sites within the stationary phase. R.

Dynamic chromatography allows determination of reaction rates and activation parameters with high precision.3 C o 115 120 min 115 120 min Figure 4. Wolf and coworkers observed plateau formation during GC enantioseparation of 2. Figure 4. and the retention times of the enantiomers. t0.2 kJ/mol can easily be visualized.8 C o 60 65 min 60 65 min 64.4 C o 80 85 90 min 80 85 90 min 59. dynamic chromatography has become a widely used technique. t1 and t2.25. Figure 4. Since all parameters required for the computer simulation are readily obtained from the chromatogram.10:  2 tR ð4:9Þ N ¼ 5:54 b0:5 a¼ t1 À t0 where t1 4t2 t2 À t0 ð4:10Þ Iterative optimization of enantiomerization rates provides simulated elution profiles that are superimposable with experimentally obtained chromatograms. A comparison of computer simulations obtained by variation of the energy barrier to enantiomerization demonstrates that an energetic difference of less than 0.190 Repetitive computer simulation of the experimentally obtained chromatograms with varying rates of enantiomerization furnished identical elution profiles.24.2 0 bis(trifluoromethyl)biphenyl.] . according to Equations 4.3-di-O-pentyl)-g-cyclodextrin at different temperatures.2) kJ/mol. DGC and DHPLC have been exploited for the determination of enantiomerization barriers of a broad variety of chiral compounds and constitute a powerful alternative to NMR and chiroptical CF3 F3C 68.9 and 4.2 0 -bis(trifluoromethyl)biphenyl on octakis(6-O-methyl-2. These results were confirmed by polarimetric studies of enantioenriched samples.24 Comparison of experimentally obtained (left) and simulated chromatograms (right) of 2. [Reproduced with permission from Liebigs Ann. 357-363.158 Chapter 4 from the void volume. 1996. proving compatibility of the two techniques.7 (Æ0. In particular. and a rotational energy barrier of 109.

6-trichlorophenyl)methane and obtained an enantiomerization barrier of 80. Using various chiral stationary phases in conjunction with both photometric and polarimetric detection. This was confirmed by polarimetric studies of the racemization of enantiomerically enriched samples of 2.203 Other interesting .202. Furthermore. GC.9 kJ/mol ∆G = 110. Figure 4. a CSP capable of separating the enantiomers of interest at various temperatures remains an indispensable prerequisite. On the other hand.1 kJ/mol ∆G = 110. SubFC. and MEKC.201 Cabrera et al. see also Chapter 3. Mannschreck’s group also examined the enantiomerization of axially chiral 1-dimethylamino-8-dimethylcarbamoylnaphthalene and helical 1. Because of the inherently different time scales and operating temperatures.4 kJ/mol at À5.2 0 -spirobichromene under the same conditions.3 kJ/mol Figure 4. vide infra. they discovered that the enantiomers of 2.1 Dynamic High Performance Liquid Chromatography ´ In 1982.29. only minute amounts of a racemic sample are used.and trans-diastereoisomers of (S )-alanine-(S )-proline and (S )-valine-(S )-proline dipeptides.29. They were able to determine the two rate constants for the reversible first-order interconversion of cis. Horvath and coworkers observed cis/trans-isomerization of small peptides using reversed phase HPLC. ´ Investigating peptide isomerization by chromatographic means. stereomutations spanning a wide range of activation energies can be investigated with dynamic HPLC.3.2 0 -spirobichromenes interconvert during the chromatographic process due to reversible thermal ring opening.Analytical Methods CF3 159 F3C 60 ≠ 65 min 60 ≠ 65 min 60 ≠ 65 min ∆G = 109. and found that the stereochemical stability and pharmacokinetic integrity of these chiral drugs strongly depend on the solvent and pH.0 1C using a (þ)-poly(triphenylmethylmethacrylate) column.0 1C. They found that proline-derived peptides undergo rotation about the amide bond during chromatographic separation under neutral and acidic conditions at ambient temperatures.198 Simulation of the elution profiles obtained by HPLC on tribenzoyl cellulose revealed an energy barrier to ring opening of 100.4.200 Veciana and Crespo exploited DHPLC for stereodynamic analysis of tris(2.195–197 Mannschreck’s group then extended dynamic HPLC to enantiomerization reactions.7-trimethylbenzo[c]phenanthrene by HPLC on triacetyl cellulose.4. Horvath’s team was first to employ HPLC in kinetic studies of interconverting stereoisomers.194 4. and chiral or achiral impurities do not interfere with the measurements as they are usually removed during the chromatographic process.199.191–193 A major advantage of dynamic chromatography over chiroptical methods is that preparative separation of enantiomers is not necessary. techniques. introduced DHPLC on ChiraDex to enantiomerization studies of chiral pharmaceutical drugs such as chlorthalidone.3. Figure 4. oxazepam and prominal.0 kJ/mol at 45. SFC. It is important to realize that on-column enantiomerization proceeds partly in a chiral environment which can alter activation parameters.25 Comparison of elution profiles computed with different rate constants and energy barriers.

Figure 4. of 57. and the activation parameters.3 1C.8-bis(2 0 -phenyl-4 0 -pyridyl)naphthalene having either parallel (syn-isomer) or antiparallel (anti-isomer) 2-phenylpyridyl rings. of 92 kJ/mol. Figure 4.4 J/K mol. DGa.0 1C as a result of rapid diastereomerization relative to the HPLC time scale. DSa. Chromatographic baseline separation of the syn.8-bis(2 0 -phenyl-4 0 -pyridyl)naphthalene over a temperature range of more than 100 1C using dynamic HPLC and variable-temperature NMR spectroscopy. Computer simulation of DHPLC elution profiles obtained at various temperatures gave a free activation energy. DHa. DHa and DSa. The plot demonstrates that DHPLC and DNMR data are in excellent agreement and that they can be combined for stereodynamic analysis over a temperature range spanning more than 100 1C.0 1C. Figure 4.28.8-bis(2 0 -phenyl-4 0 -pyridyl)naphthalene proceeds rapidly at room temperature and has an energy barrier to rotation about the chiral naphthyl–pyridyl axis of 73 kJ/mol at 40. Scheme 4. A comparison of DHPLC and NMR data reveals that the conformational stability of 1. The enantiomers interconvert by consecutive ring opening of each oxazine ring via an iminium intermediate and ring closure involving the opposite hydroxyl group of the resorcinol unit. respectively. which can be attributed to a congested transition state exhibiting a considerably negative entropy of activation. Computer simulation of the experimentally obtained chromatograms allowed accurate determination of the activation energy over a wide temperature range.205 Wolf and Tumambac explored the isomerization of 1. Rotation of either pyridyl ring about the pyridyl–naphthalene bond results in interconversion of a meso syn. The low activation enthalpy and the highly negative activation entropy are in agreement with the postulated dissociative enantiomerization mechanism. and an activation entropy.1. were determined as 53 kJ/mol and À131 J/K mol. respectively.207 .7.26.8-bis(2 0 phenyl-4 0 -pyridyl)naphthalene increases steadily with temperature.5 kJ/mol and À43. DHPLC studies have been performed with stereolabile trityloxymethyl butyrolactol204 and with axially chiral biaryl derivatives of 4-(dimethylamino)pyridine in order to identify conformationally stable catalyst candidates for kinetic resolution of secondary alcohols. and peak coalescence was observed at À39. The Eyring plot for the isomerization of this atropisomer provides an activation enthalpy.206 The reaction involves a sterically crowded T-shaped transition state in which the edge of the rotating pyridyl ring is directed towards the adjacent pyridyl moiety.and anti-isomers of this atropisomer was achieved on an achiral HPLC column at À70. Scheme 4. Dynamic NMR studies showed that diastereomerization between the almost equienergetic rotamers of 1. This macrocycle displays a labile hemiaminal group that is readily cleaved under slightly acidic conditions.0 1C.6.and two axially chiral anti-isomers. Trapp and coworkers examined the reversible enantiomerization of a chiral tetrabenzoxazine resorcarene and observed plateau formation by HPLC on Chiralpak AD.27 and Table 4.6 Isomerization of the conformational isomers of 1. Plateau formation occurred when the column temperature was above À65.160 Chapter 4 Ph N N Ph N PhN Ph anti-isomer syn-isomer Scheme 4.

Phys.50 Á 10À3 9.0 À48.8 68.0 °C −55. Chem. 2003.22⋅10−3 s−1 6 8 min 6 8 min Figure 4.0 °C −48.0 40. Phys. 815-817.27 Experimental (left) and simulated (right) elution profile of 1. 2003.0 k [sÀ1] 8. Chem.0 °C 8 10 12 min 8 10 min 6 8 min Figure 4. 815-817.0 Á 10À4 1.22 Á 10À3 2.3 DGa [kJ/mol] 67. [Reproduced with permission from J.] Table 4.5 68.26 Cryogenic HPLC separation of the syn.0 À33.8-bis(2 0 -phenyl-4 0 -pyridyl)naphthalene and plateau formation at various temperatures. [Reproduced with permission from J.8-bis(2 0 -phenyl4 0 -pyridyl)naphthalene obtained by DHPLC and DNMR.8-bis(2 0 -phenyl-4 0 -pyridyl)naphthalene.3 Á 10À5 4.0 À55. T [1C] À65.and anti-isomers of 1. 107.7 73.1 Rotational energy barrier of 1.9 °C 6 8 min 6 8 min −65.Analytical Methods 161 −43.3 68.03 Method DHPLC DHPLC DHPLC DHPLC DNMR . 107.0 °C k = 1.] −48.0 °C −30.

4S)-Whelk-O 1 CSP.209 Comparison of the rotational energy barriers determined by computer simulation of elution profiles obtained by DHPLC with results from off-column racemization experiments revealed that the CSP increases the energy barrier of these atropisomers by 1-4 kJ/mol.3. 815-817. Chem.0 oC) O H O N N O H O N O H O N O O H +H HO N Bn O -H 4 +H HO N Bn OH -H 4 O N Bn OH 4 Scheme 4.211 Again.162 ln -20 -25 -30 -35 -40 -45 0.003 0. 107.0035 0. Oxelbark and Allenmark determined the configurational stability of N-aryl. investigated the stereodynamics of numerous axially chiral 2-methyl.and 2-ethoxy1-naphthyl carboxamides. Similarly.] N O H O O H O N N O H O N O O H ∆G ≠ = 92 kJ/mol (25. the CSP was found to increase the barrier to enantiomerization by .005 1/ T DNMR DHPLC Chapter 4 hk kB T Figure 4.0045 0.210.2benzodithiazole-1-oxides by both DHPLC and off-column racemization monitored by CD spectroscopy.7 Enantiomerization of a chiral tetrabenzoxazine resorcarene derivative and mechanism of reversible oxazine ring opening.004 0. Phys.208. sulfones and sulfoxides by DHPLC using a (3R.28 Eyring plot of DNMR and DHPLC data. 2003. [Reproduced with permission from J.and N-benzyl-1. Villani et al.

1 kJ/mol (35.0 °C) O O S NH N O ∆G≠ = 93.0 °C.0 °C) Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl ∆G≠ = 96.1 kJ/mol (35.0 °C) NEt2 Et2N N O Cl Cl Cl ≠ O Cl Cl Cl Cl Cl ∆G = 80.2 kJ/mol (25. pH 4.5 kJ/mol (20.0 kJ/mol (44.5 kJ/mol (75.8 kJ/mol (−65.Analytical Methods 163 O O O O ∆G≠ = 100.0 °C) O S N S O S O2N N S Ph N N Ph ≠ ∆G≠ = 95.7 °C) O S N S NO2 O S N S O S N S ∆G≠ = 96.0 °C) Figure 4.9 kJ/mol (45.29 Isomerization reactions studied by DHPLC.5 kJ/mol (15.7 °C) N Ph N Ph ∆G = 67. .0 °C) Cl Cl Cl Cl Cl (meso form) Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl (racemic) Cl Cl N N Cl Cl Cl Cl Cl Cl Cl N Cl ∆G≠ = 89.0 °C) Cl Cl Cl Cl Cl Cl Cl Cl SO2NH2 Cl NH O H N N O H OH HO Cl Cl ∆G≠ = 99.0 °C) O S N S ∆G≠ = 95.0 °C) Cl Cl ∆G≠ = 105.9 kJ/mol (36.1) ∆G≠ = 89.4 kJ/mol (− 5.0 kJ/mol (45.

2-benzodithiazole-1-oxide was determined as 96.9 kJ/mol at 36. Computer simulation of elution profiles yielded individual Gibbs free activation energies of 108. the enantiomerization barrier of 2-benzyl-1. 4. individual energy barriers for the forward and backward reaction had to be considered. respectively.218–220 Computer simulation of elution profiles revealed an enantiomerization barrier for 1. an important beetle aggregation pheromone. of 115.0 and 108.31.4S)-WhelkO 1 column.213 Having developed the theoretical background for dynamic chromatography and the necessary tools for peak shape analysis. enantiomerization barriers of homofuran obtained by DGC and polarimetry are in excellent agreement.7 kJ/mol was obtained in the absence of the chiral selector.3. The increase in the stereochemical stability of these compounds is commonly attributed to stabilization of the ground state of the interconverting stereoisomers during complexation by the CSP. Other chiral stationary phases such as poly(triphenylmethylmethacrylate) and triacetyl cellulose have been reported to exhibit small destabilizing effects on the conformational or configurational stability of chiral compounds.164 Chapter 4 approximately 2 kJ/mol.221 The corresponding low activation enthalpies and the highly negative activation entropies are indicative .214 Klarner and Schroer determined the ¨ ¨ enantiomerization barrier of homofuran as 113.5 kJ/mol.3. For example. and independent of the DHPLC studies reported by Horvath in 1982. confirming similar observations with DHPLC measurements. Trapp and Schurig extended DGC to epimerization reactions. see Figure 4.0 1C.6-dioxaspiro[4.29.0 1C gave an energy barrier of 132 kJ/mol.4]nonane during complexation gas chromatography using bis[(1R)-3-heptafluorobutyrylcamphorate]nickel(II) dissolved in squalane as chiral stationary phase. Chirasil–Dex accelerates the rate of enantiomerization of 1.4-tetramethyldiaziridine. Investigating the isomerization of spiroketal chalcogran.9 kJ/mol at 60. but DGC measurements using Chirasil–Nickel and Chirasil–Dex furnished energy barriers of 117. Schurig’s group employed Chirasil–Dex (permethylated b-cyclodextrin immobilized on dimethylpolysiloxane) and Chirasil–Nickel (polysiloxane-anchored bis[(1R)-3-heptafluorobutyrylcamphorate]nickel(II)) in DGC analysis of several diaziridines and allenes. Figure 4. Figure 4. which interconverts via two consecutive nitrogen inversions.5 and 114. A more pronounced effect was uncovered with axially chiral dimethyl 2.and (2R.2. for the interconversion of (2R.216 Dynamic gas chromatography has also been applied to syn/anti-isomerizations of axially chiral phenanthrenes and anthracenes.8 kJ/mol at 90.212 To date.2-dimethylaziridine is 104.3-pentadienedioate.4-tetramethyldiaziridine and reduces the activation energy by 1–3 kJ/mol. Importantly.215. Because of the inherently different ground state energy of epimers.9 kJ/mol. but an energy barrier of 94.2.5S)-2-ethyl-1.4]nonane. Chiral stationary phases commonly used in DGC can have measurable effects on isomerization rates.0 1C by DHPLC on a (3R.2 Dynamic Gas Chromatography ´ At the same time.3.10bis(2-methylphenyl)phenanthrene at 240. DHPLC and computer simulation has been applied in kinetic studies of a variety of enantiomerization and diastereomerization reactions with Gibbs activation energies ranging from 60 to 120 kJ/mol.0 1C and concluded that the reaction proceeds via a carbonyl ylide-like intermediate that is formed by orbital symmetry-allowed disrotatory electrocyclic ring opening obeying Woodward-Hoffmann rules. For example. peak shape analysis of the plateau formed by on-column interconversion of the anti-isomers and the meso syn-form of 9.5R).31. This is by no means a general trend. This allene has an interconversion barrier of 128 kJ/mol at 120 1C according to stopped-flow multidimensional gas chromatographic analysis conducted in the absence of a CSP. respectively.2-dimethylaziridine and 1. Schurig and coworkers observed plateau formation due to on-column enantiomerization of 1-chloro-2. Comparison of isomerization barriers obtained by dynamic chromatography and variable-temperature NMR spectroscopy or polarimetric studies usually shows excellent agreement between the methods.6-dioxaspiro[4.3. at the same temperature.0 1C. they found that the enantiomerization barrier of 1-chloro2.217 For instance.0 kJ/mol at 80.

Figure 4.5 kJ/mol (25. 1995.0 oC) ∆H≠ = 45.5S)-epimer O O (2R.8.0 kJ/mol (25. [Reproduced with permission from Liebigs Ann.8 kJ/mol ∆S≠ = -210 J/K mol ≠ Scheme 4. 781-786. Wolf and coworkers studied the rotational energy barrier of several axially chiral biphenyls by DGC on selectively modified cyclodextrins.Analytical Methods 165 of a dissociative heterolytic mechanism proceeding via a zwitterionic enol ether intermediate.222 Energy barriers determined by DGC were in excellent agreement with results obtained by polarimetric analysis of enantioenriched O O O O HO O (2R.1 kJ/mol ∆S≠ = -204 J/K mol ≠ o O O OH O ∆G = 108.30 DGC elution profiles of 2-isopropyl-2 0 -trifluoromethylbiphenyl using octakis(6-O-methyl-2. CF3 i-Pr 110 oC 10 12 min 105 oC 13 100 oC 16 95 oC 23 90 C 28 32 min 38 o o 14 min 18 min 25 min 85 oC 42 min 80 C 50 75 oC 70 70 oC 80 min 60 min 90 105 115 min Figure 4.0 C) ∆H≠ = 47.30.8 Dissociative epimerization mechanism of chalcogran.] .3di-O-pentyl)-g-cyclodextrin as CSP. Scheme 4.5R)-epimer ∆G = 108.

even at 170 1C. [11]. The stereodynamics of several [11]paracyclophanes with enantiomerization barriers between 115 and 135 kJ/mol have been analyzed by DGC.1 oC) CF3 Cl Cl F3C F3C Et ∆G≠ = 109.1) kJ/mol.166 Chapter 4 samples.5 kJ/mol (133.1 1C) was obtained with octakis(6-O-methyl-2.0 oC) Br CO2Me O (CH2)9 O O (CH2)9 i-Pr O CO2Me O (CH2)9 ∆G≠ = 132.5 kJ/mol (120.4 oC) ∆G≠ = 136.4 (Æ0.2 0 -diisopropylbiphenyl are negligible. Since additional polarimetric studies in various solvents including ethanol and hexanes showed that solvent effects on the conformational stability of 2. xi In principle.2) kJ/mol (78. the difference in the energy barriers calculated by DGC on cyclodextrins can be attributed to small. Chirasil-Nickel) ∆G≠ = 114.0 oC) MeO2C • N N ≠ O N Cl ∆G = 104. Chirasil-Dex) + • ∆G≠ = 113.2) kJ/mol (78.6 (Æ0.223.3-di-O-pentyl)-g-cyclodextrin.3 kJ/mol (78. whereas a value of 114.and ¨ [12]paracyclophanes exhibiting a chiral plane.6 kJ/mol (89.8 kJ/mol (90.9 kJ/mol (120.1 kJ/mol (145. Since its introduction by Schurig in 1982.224 They reported baseline separations of the enantiomers of various [10]paracyclophanes but did not observe any sign of on-column interconversion. albeit unpredictable.4 kJ/mol (59.0 kJ/mol (80.2 oC) F3C ∆G≠ = 110. were conducted in the same temperature range and gave an energy barrier of 112. but this lies outside the scope of DGC due to insufficient volatility of the analytes below 40 1C.0 oC) Et CF3 ∆G≠ = 130.8 kJ/mol (80. but small effects of CSPs on the biaryl atropisomerization barrier were reported.7 oC) CF3 Cl F3C ∆G≠ = 111.1 kJ/mol (124.5 oC) Figure 4.4 oC) i-Pr ∆G≠ = 112.0 oC) CF3 ∆G≠ = 129.xi As expected.3-di-O-pentyl)-b-cyclodextrin as CSP gave an energy barrier of 112. Hochmuth and Konig used DGC to study the enantiomerization of substituted [10]-.9 kJ/mol (157.0 oC) CF3 ∆G≠ = 125. enantiomerization of substituted dioxa. Polarimetric studies of enantiomerically enriched 2.0 oC.2 0 -diisopropylbiphenyl.4 to 88.4 oC) t-Bu F3C ∆G≠ = 111.8 (Æ0. As a N N ∆G = 115. the stereodynamics of [12]paracyclophanes can be studied at lower temperatures.5 oC) F3C ∆G≠ = 109.0 kJ/mol (240.2 kJ/mol (146. DGC has been applied in kinetic studies of a variety of enantiomerization and diastereomerization reactions.5 to 83.3 kJ/mol (68.0 oC) i-Pr i-Pr i-Pr O MeO2C O (CH2)9 O ∆G≠ = 133.0 oC) ≠ + − + O − N Cl O O MeO2C CO2Me OMe MeO2C − O ∆G≠ = 117.2 0 -diisopropylbiphenyl using heptakis(6-Otert-butyldimethylsilyl-2. stabilization or destabilization effects of the CSPs used.9 kJ/mol (73. Figure 4. Simulation of experimentally recorded elution profiles of 2.31. due to the high conformational stability of these atropisomers. isolated by HPLC on microcrystalline triacetyl cellulose.and carbocyclic [11]paracyclophanes is suitable for DGC analysis and formation of a temperaturedependent plateau during separation on cyclodextrin-derived CSPs can be observed. In contrast. [12]paracyclophanes undergo fast interconversion compared to the GC time scale and enantiomers can not be resolved above 40 1C.9 kJ/mol (60.5 1C).1 oC.31 Stereomutations studied by DGC. .

Analytical Methods 167 rule of thumb. HPLC is commonly performed between 0 and 120 1C.225 Enantioseparation of stereolabile axially chiral arylnaphthalene lignans under cryogenic conditions was accomplished on a polyWhelk-O CSP. OH MeO MeO CO2Et CO2Et MeO OH MeO O OH O O MeO O MeO O O O ∆G≠ = 91. Although competition between isomerization and separation of chiral compounds has mainly been observed by HPLC and GC. The application spectrum of DHPLC and DGC is confined by the chromatographic time scale.and supercritical fluid chromatography significantly expand the application spectrum of DGC and DHPLC. .and subcritical fluid chromatography and electroosmotically driven separations further extend the usefulness of dynamic chromatography. Because of decreasing analyte solubility and increasing viscosity of the mobile phase causing high back pressures at low temperature.32. In contrast.0 oC) H N N Cl O H OH Cl Cl ∆G≠ = 91. between 100 and 150 kJ/mol can be examined by this method. pH 8. and chiral separations are usually conducted between 40 and 180 1C.2 kJ/mol (28.0 oC.0 oC.4 kJ/mol (20.6 kJ/mol (20. although some brush-type CSPs are compatible with operating temperatures as low as À50 1C. The intrinsically high diffusivity and low viscosity of subcritical fluids provide a significant advantage of subcritical fluid chromatography (SubFC) over HPLC when cryogenic conditions are required.0 kJ/mol (-25. Sub.0 oC.3 Dynamic Supercritical Fluid Chromatography and Electrokinetic Chromatography The principles of dynamic chromatography and computer simulation have been applied in several separation techniques. pH 8.0) ∆G≠ = 91.0 oC) oxazepam H N N O H OH Cl O O ∆G≠ = 77. A further extension of this temperature range is not possible because of the thermal instability of CSPs above 180 1C.0) ∆G≠ = 91.0 oC) temazepam N N O H OH lorazepam O O ∆G≠ = 75.3 kJ/mol (20. Figure 4.0 to 92. Simulation of the temperature-dependent elution profiles gave rotational energy barriers ranging from 75. solubility and thermal stability of analytes. stereomutations with Gibbs free activation energies. GC requires sufficient volatility and thermal stability of the analyte.0) Figure 4.7 kJ/mol (-21.0 (Æ0. other pressure-driven methods such as super. these techniques can be applied to isomerization processes having energy barriers between 60 and 150 kJ/mol. Wolf and coworkers were first to use dynamic subcritical fluid chromatography (DSubFC) for the study of rapidly interconverting stereoisomers. DGa.32 Enantiomerization of chiral compounds studied by DSubFC (top) and DMEKC (bottom). pH 8.2) kJ/mol. Because SubFC and SFC cover the combined temperature range of HPLC and GC. and the temperature range inherent to these techniques. 4.3.

Wolf and Konig has introduced another powerful methodology. Engl. MEKC provides an important opportunity to study isomerization processes under biologically relevant conditions.226 Dynamic MEKC is applicable to reactions exhibiting energy barriers between 80 and 120 kJ/mol.6 oC 25. 1995. 1635-1636. the on-column interconversion was stopped and the buffer was cooled to the original a i-Pr H3N 0 30 60 90 min NH3 i-Pr enantiomers b 0 30 60 90 min first enantiomer second enantiomer 20 kV 0 kV 82. the enantiomers were already well separated and located at a similar distance either in front of or behind the midpoint of the capillary.168 Chapter 4 Schurig et al.4 0 diammonium-2. 4. Int.6-triO-methyl)-b-cyclodextrin is added to the electrophoretic buffer. A racemic sample of 4.4 0 -diammonium-2.227 They ¨ discovered that the enantiomers of 4. At this point.4 0 -diammonium-2. After a certain time. The development of stopped-flow procedures suitable to isomerization studies of chiral compounds by Weseloh.2 0 -diisopropylbiphenyl: (a) on-column enantiomerization experiment and (b) enantiomeric composition of each peak. Enantioseparation proceeds in sections A while enantiomerization takes place in section B.2 0 -diisopropylbiphenyl was injected electrokinetically into the CZE capillary and the enantiomers were separated at 25 1C.0 oC racemate c d Figure 4.2 0 -diisopropylbiphenyl can be separated with high selectivity and efficiency by capillary zone electrophoresis (CZE) when heptakis(2.] .33. temazepam and lorazepam using dynamic micellar electrokinetic chromatography (DMEKC) and sodium cholate as micelle-forming surfactant..3. Figure 4.4 CHROMATOGRAPHIC AND ELECTROPHORETIC STOPPED-FLOW ANALYSIS Chiral chromatography is invaluable for analytical and preparative separation of stereoisomers and for kinetic analysis of stereomutations via computer simulation of temperature-dependent elution profiles. The voltage was switched off at exactly the middle of the electrophoretic separation process and the temperature was increased to 82. Since separations can be performed with aqueous buffers and at ambient temperatures. 34. Ed. Chem. The applied voltage and temperature are illustrated at the bottom (c and d) and a typical electropherogram is shown at the right. [Reproduced with permission from Angew. investigated the racemization of chiral benzodiazepine drugs such as oxazepam.6 1C to allow interconversion of the atropisomers.33 54 58 62 min Illustration of the electrophoretic separation and interconversion of the enantiomers of 4.

Figure 4.2 kJ/mol).. The preceding discussion of DHPLC and DGC reveals that the presence of a chiral selector can cause a measurable increase or decrease in enantiomerization barriers due to ground state stabilization or catalysis of the interconversion process. one observes an additional racemic peak between the signals that correspond to the enantiomeric portions that do not undergo on-column enantiomerization during the allotted reaction time.4 0 -diammonium-2. the applied temperature and the period of heating. which is in excellent agreement with polarimetric studies of an enantioenriched sample under similar conditions. The investigation of the stereodynamics of 4. 1635-1636. The rotational energy barrier of 4. Engl. 1995. and the enantiomerization experiment was conducted in the middle section which did not contain any chiral additive. The stopped-flow experiment illustrated in Figure 4.33 affords an electropherogram with three peaks.4 by this modified stopped-flow procedure gave a rotational energy barrier of 106. Chem.34. Since electrophoretic stopped-flow analysis is usually conducted with aqueous buffers.2 0 -bis(trifluoromethyl)biphenyl were separated in the first and third buffer zone containing the cyclodextrin selector.2 kJ/mol.4 0 -diammonium-2. Int.34 Electropherograms obtained by variation of the on-column enantiomerization time. In contrast to a typical CZE enantioseparation. based on integrated peak areas. Figure 4.35. isomerization reactions can be investigated at temperatures up to 95 1C and energy barriers to isomerization ranging from 100 to 130 kJ/mol have been determined with high accuracy (Æ0. Segmentation of the capillary into different buffer and heating zones thus enables one to determine selectively the rotational energy barrier of either enantiomer in the presence and in the absence of a chiral additive.9 kJ/mol at 71. Ed. The electrophoretic process was then resumed by switching on the applied voltage of 20 kV and the separation continued through the second part of the capillary.] temperature. The stopped-flow method was therefore modified to allow kinetic analysis in the absence of a chiral additive and to exclude stabilizing or destabilizing interactions between the analyte and the chiral cyclodextrin host.228 Through careful rinsing procedures and control of the electroosmotic flow.2 0 diisopropylbiphenyl was calculated as 115. [Reproduced with permission from Angew.4 0 -diammonium-2. Following the stopped-flow procedure described above. An attractive feature of this method is that it requires only minute amounts of racemate but eliminates the need for computer simulation. The stopped-flow technique is a highly versatile analytical tool for investigation of stereomutations in the presence and absence of a . the CZE capillary was segmented into three different buffer zones.0 1C in the absence of a cyclodextrin additive. It is noteworthy that heating of only one part of the capillary provides a means for selective racemization of one enantiomer. The central peak corresponds to the amount of racemate formed. the enantiomers of 4.Analytical Methods A (mV) 169 100 50 150 90 0 60 42 45 48 30 54 15 60 0 75 120 rete ntio n ti reac tim tion e (m in) me (mi n) Figure 4.2 0 -bis(trifluoromethyl)biphenyl in a 30 mM phosphate buffer at pH 2. which is indispensable for kinetic analysis based on dynamic chromatography. 34.

5 oC.2 oC) N F3C ∆G≠(-)→(+) = 93. pH 4. while addition of hydroxypropyl-b-cyclodextrin increased the conformational stability to 108.8 kJ/mol (150.5 kJ/mol (80.5 oC.36 Enantiomerization of chiral compounds studied by chromatographic and electrophoretic stopped-flow analysis. 1635-1636.6 kJ/mol (15. and electropherograms obtained after different times of racemization (right). 8.3 kJ/mol. pH 4.5) H H N t-Bu N t-Bu Cl ∆G≠ = 122. pH 4.0) t-Bu N t-Bu N F ∆G≠ = 126.2 0 -bis(trifluoromethyl)biphenyl (left).4 0 diammonium-2. stopped-flow CZE confirmed that cyclodextrins can alter the rate of biaryl atropisomerization.1 kJ/mol (95. By analogy with dynamic chromatography.5 C.2 kJ/mol (95.4 0 -diammonium-2. Ed.] PCB 95 H3N i-Pr i-Pr ∆G = 115. enantiomer 2.4 kJ/mol (95.5 oC. Int.5) H25C12O ∆G≠ = 110. pH 4. Analysis of the conformational stability of 4.5) t-Bu N N t-Bu Br ∆G≠ = 122. 34.0 oC) Figure 4.35 Illustration of CZE enantioseparation and on-column racemization of one enantiomer of 4. [Reproduced with permission from Chirality 1996. 441–445 and Angew. Chem.6 oC) ≠ Cl Cl PCB 132 Cl Cl PCB 149 Cl Cl Cl NH3 H3N CF CF3 3 ∆G = 106.9 kJ/mol (71. 1995. pH 3. The emerging peak in the middle corresponds to the amount of enantiomer formed during selective on-column heating of the less retained enantiomer.0 oC) N NO2 ∆G≠ = 135.2 0 -bis(trifluoromethyl)biphenyl in the presence of permethylated b-cyclodextrin at 71 1C revealed a rotational energy barrier of 105.0 kJ/mol ≠ ∆G (+)→(-) = 94.2 kJ/mol (82. enantiomer racemate r et e n t io 8 n ti 6 me (m i n) t r ea c im e ion t (m in ) Figure 4.5) O 2N ∆G≠ = 111.1 kJ/mol o (95.7 oC) ∆G≠ = 133 kJ/mol (144. .5 oC..0 oC) ≠ NH3 Cl Cl ∆G = 184 kJ/mol (300 oC) (CH2)9 NH HN NH HN (CH2)9 ≠ Cl Cl Cl Cl Cl ≠ ∆G = 189 kJ/mol (300 oC) (CH2)9 NH HN NH Cl Cl ∆G = 184 kJ/mol (300 oC) Cl N ≠ Cl (CH2)9 HN NH HN (CH2)9 Me ∆G≠ = 125.9 kJ/mol (95. temperature CF CF3 + + H3N F3C N H3 40 cm 20 cm 0 10 20 30 40 50 60 70 80 90 min lar pil ca A (mV) gth en yl 100 retention time 50 20 kV 0 kV 0 20 30 25 12 10 15 5 10 40 50 1.170 Chapter 4 chiral additive and can be utilized for studying stereoselective interactions between stereolabile compounds and cyclodextrin hosts or other chiral selectors. Engl.2 kJ/mol.

0 Accuracy (kJ/mol) Æ0.0 171 .5 (interactions between the analyte and the CSP or chiral additive can increase or decrease the energy barrier) Precision (kJ/mol) Æ0.5–1.2 Æ0.2 Comparison of methods frequently used for investigation of isomerization reactions of chiral compounds.2 Æ0.2 o10 mg Impurities are usually separated during chromatography and do not affect the enantiomerization or diastereomerization process Sample amount 410 mg o10 mg Æ0. simulation of experimentally obtained elution profiles provides rate constants Polarimetry DNMR DGC DSubFC/ DSFC DHPLC DMEKC Stopped-flow analysis Chromatographic or electrophoretic separation and intermediate oncolumn isomerization 80–150 Chromatographic or electrophoretic conditions for baseline separation of enantiomers.Table 4.0 (coalescence method) Æ0.2–1. Analytical Methods Method Coalescence of NMR signals is analyzed by complete line shape analysis (CLA) 20–130 Sufficient resolution of diastereotopic signals for accurate integration 100–150 60–150 60–120 80–120 Simultaneous chromatographic separation of stereoisomers and on-column interconversion results in plateau formation.5 Æ0. control of diffusion during heating No interference if resolved Principle Isomerization of one stereoisomer is monitored by polarimetry Energy range (kJ/mol) 80–180 Requirements Semipreparative isolation or enrichment of stereoisomers Chromatographic conditions that allow baseline separation of stereoisomers Chiral impurities Interfere Might not interfere if signals are resolved and interactions with the analyte are negligible 1–10 mg Æ0.2–1.2 (CLA) Æ0.

Soc. Okamoto. Ed. and Troger’s base. Tumambac. Ed. Int. B. Figure 4. The principles and scope of their application are summarized in Table 4. Wiersma. E. Steffen. ¨ ¨ Chem. Wolf. a widely used chiral solvating agent... However. Angew.. Engl.36. dynamic chromatography.2) kJ/mol at 150. Kessler. C. 1970. M. The difference in the rotational energy barriers of the enantiomers of 2 0 -dodecyloxy-6-nitrobiphenyl-2-carboxylic acid in the presence of the quinine CSP was exploited for on-column deracemization based on asymmetric transformation of the second kind. 6. Similarly. J.. B. 7. Y.2-dimethylaziridine on a cyclodextrin column and subsequent selective introduction of one enantiomer to a second achiral column.7 1C. 219-235. Chem. W. 110. 116. stopped-flow multi-dimensional gas chromatography is suitable for investigation of isomerization reactions with activation energies between 70 and 200 kJ/mol. Chem. J. Ma.-W.5) kJ/mol. Chem. stopped-flow multi-dimensional gas chromatography proved that the enantiomers of Troger’s base interconvert at 144 1C with an activation energy of 133 ¨ (Æ1.. 1994. Grevels. Jacke. R.8 (Æ0. Int.5 COMPARISON OF ANALYTICAL METHODS Polarimetry. Dutt. E. K. B.. E.. Duppen. Phys. 885-887. 4. The rotational barrier of hexachlorobiphenyl PCB 132 was determined in the presence of a cyclodextrin-derived chiral stationary phase to be approximately 184 (Æ2) kJ/mol. This ¨ chiral amine has two asymmetric bridgehead nitrogen atoms that are stable to pyramidal inversion at room temperature. D. B.. H. see Chapter 7. Zijlstra. C. 132 and 136. The majority of enantiomerization and diastereomerization reactions discussed in Chapter 3 has been examined using these methods.235 Using a quinine-derived chiral stationary phase they determined the activation barrier to enantiomerization of the levorotatory and dextrorotatory enantiomer to be 93. L.172 Chapter 4 Stopped-flow electrophoresis has also been used to explore the stereodynamics of other chiral compounds including 1. K.. Aburatani.0 and 94. A 1997.. 3. Kruger. 1987. 1988. G. Wolf. Klotzbucher. 101.230 In general. Org. T.. H. 2.5) kJ/mol based on the known racemization temperature and the time that the analyte spent in the achiral reactor column. extended the concept of stopped-flow chromatographic analysis to HPLC and capillary electrochromatography (CEC) to study the rotational energy barrier of 2 0 -dodecyloxy-6-nitrobiphenyl-2-carboxylic acid. was determined as 135. Tumambac. respectively.6 kJ/mol. K. S. Org.-H. 70. J.. 10619-10629. G.233 Stoppedflow multi-dimensional gas chromatography has also been used to examine the conformational stability of PCBs 95. variable-temperature NMR spectroscopy. which probably undergoes reversible conrotatory electrocyclic ring opening.5 (Æ0. C.3.11-diaza[11]paracyclophanes. Seevogel. J.231. J.2-di-tert-butyldiaziridine.. Engl. J. 69.. 5. G. F. Chem. 2930-2938.. Mislow. D.232 This technique has been used for analytical separation of the enantiomers of 1-chloro-2. 3. Chem. J. Biali. Am. Figure 4. Zimmt. Tsay. 9828-9836.36. 2005. Integration of peak areas allowed determination of the barrier to N-inversion as 110. P.. Am. Kahr.. 2004. E. the enantiomerization barrier of 1. Waldeck.. Soc. Angew. REFERENCES 1. . W.. 4. This enantiomer was then subjected to racemization at high temperature and the partially racemized sample was subsequently separated into enantiomers on a third chiral column at lower temperatures. Y.2. A. R.. van Duijnen. 1917-1922. Feringa.229 Schurig applied the concept of stopped-flow analysis to gas chromatography. Chem. 26. 2048-2055..2. T.234 Lindner et al. J. and stoppedflow chromatography and electrophoresis are widely used techniques for stereodynamic analysis of chiral compounds.

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Chapter 4 Langer, S. H.; Yurchak, J. Y.; Patton, J. E. Ind. Eng. Chem. 1969, 61, 11-21. Kramer, R. J. Chromatogr. 1975, 107, 241-252. Burkle, W.; Karfunkel, H.; Schurig, V. J. Chromatogr. 1984, 288, 1-14. ¨ Wolf, C.; Hochmuth, D. H.; Konig, W. A.; Roussel, C. Liebigs Ann. 1996, 357-363. ¨ Keller, R. A.; Giddings, J. C. J. Chromatogr. 1960, 3, 205-220. Jung, M. QCPE Bull. 1992, 3, 12. Trapp, O.; Schurig, V. Comput. Chem. 2001, 25, 187-195. Trapp, O.; Schoetz, G.; Schurig, V. Chirality 2001, 13, 403-414. ´ Melander, W. R.; Lin, H.-J.; Jacobsen, J.; Horvath, C. J. Chromatogr. 1982, 234, 269-276. ´ Melander, W. R.; Lin, H.-J.; Jacobsen, J.; Horvath, C. J. Phys. Chem. 1984, 88, 4527-4536. ´ Jacobsen, J.; Melander, W.; Vaisnis, G.; Horvath, C. J. Phys. Chem. 1984, 88, 4536-4542. Stephan, B.; Zinner, H.; Kastner, F.; Mannschreck, A. Chimia 1990, 44, 336-338. Mannschreck, A.; Zinner, H.; Pustet, N. Chimia 1989, 43, 165-166. Mannschreck, A.; Kießl, L. Chromatographia 1989, 28, 263-266. Veciana, J.; Crespo, M. I. Angew. Chem., Int. Ed. Engl. 1991, 30, 74-77. Cabrera, K.; Lubda, D. J. Chromatogr. A 1994, 666, 433-438. Cabrera, K.; Jung, M.; Fluck, M.; Schurig, V. J. Chromatogr. A 1996, 731, 315-321. Li, L.; Thompson, R.; Sowa Jr., J. R.; Clausen, A.; Dowling, T. J. Chromatogr. A 2004, 1043, 171-175. Spivey, A. C.; Charbonneau, P.; Fekner, T.; Hochmuth, D. H.; Maddaford, A.; Malardier-Jugroot, C.; Redgrave, A. J.; Whitehead, M. A. J. Org. Chem. 2001, 66, 7394-7401. Wolf, C.; Tumambac, G. E. J. Phys. Chem. 2003, 107, 815-817. Trapp, O.; Caccamese, S.; Schmidt, C.; Bohmer, V.; Schurig, V. Tetrahedron: Asymm. 2001, ¨ 12, 1395-1398. Villani, C.; Pirkle, W. H. Tetrahedron: Asymm. 1995, 6, 27-30. Gasparrini, F.; Misiti, D.; Pierini, M.; Villani, C. Tetrahedron: Asymm. 1997, 8, 2069-2073. Oxelbark, J.; Allenmark, S. J. Org. Chem. 1999, 64, 1483-1486. Oxelbark, J.; Allenmark, S. J. Chem. Soc., Perkin Trans. 2 1999, 1587-1589. Gasparrini, F.; Lunazzi, L.; Misiti, D.; Villani, C. Acc. Chem. Res. 1995, 28, 163-170. Schurig, V.; Burkle, W. J. Am. Chem. Soc. 1982, 104, 7573-7580. ¨ Burkle, W.; Karfunkel, H.; Schurig, V. J. Chromatogr. 1984, 288, 1-14. ¨ Klarner, F.-G.; Schroer, D. Angew. Chem., Int. Ed. Engl. 1987, 26, 1294-1295. ¨ ¨ Schurig, V.; Jung, M.; Schleimer, M.; Klarner, F.-G. Chem. Ber. 1992, 125, 1301-1303. ¨ Marriott, P. J.; Lai, Y.-H. J. Chromatogr. 1988, 447, 29-41. Jung, M.; Schurig, V. J. Am. Chem. Soc. 1992, 114, 529-534. Schurig, V.; Keller, F.; Reich, S.; Fluck, M. Tetrahedron: Asymm. 1997, 8, 3475-3480. Trapp, O.; Schurig, V. Chirality 2002, 14, 465-470. Trapp, O.; Schurig, V. Chem. Eur. J. 2001, 7, 1495-1502. Wolf, C.; Hochmuth, D. H.; Konig, W. A.; Roussel, C. Liebigs Ann. 1996, 357-363. ¨ Hochmuth, D. H.; Konig, W. A. Liebigs Ann. 1996, 947-951. ¨ Hochmuth, D. H.; Konig, W. A. Tetrahedron: Asymm. 1999, 10, 1089-1097. ¨ Wolf, C.; Pirkle, W. H.; Welch, C. J.; Hochmuth, D. H.; Konig, W. A.; Chee, G.-L.; Charlton, ¨ J. L. J. Org. Chem. 1997, 62, 5208-5210. Schoetz, G.; Trapp, O.; Schurig, V. Anal. Chem. 2000, 72, 2758-2764. Weseloh, G.; Wolf C.; Konig, W. A. Angew. Chem., Int. Ed. Engl. 1995, 34, 1635-1636. ¨ Weseloh, G.; Wolf, C.; Konig, W. A. Chirality 1996, 8, 441-445. ¨ Scharwachter, K. P.; Hochmuth, D. H.; Dittmann, H.; Konig, W. A. Chirality 2001, 13, ¨ ¨ 679-690.

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Principles of Asymmetric Synthesis

Many pharmaceuticals, agrochemicals, flavors, fragrances, nutrients, and other biologically active compounds are chiral, and the majority of today’s top-selling drugs is formulated and marketed in enantiopure form. The omnipresence and significance of chirality has led to an ever-increasing industrial and academic demand for enantiopure compounds and methods to make them. This can in principle be accomplished by formation of racemic products and subsequent preparative enantioseparation or through asymmetric synthesis. The former approach is generally less attractive because it requires an additional separation step and is limited to a maximum yield of 50% unless the undesired enantiomer can be recycled and employed in an enantioconvergent process. Asymmetric synthesis is aimed at selective formation of a single stereoisomer and therefore affords superior atom economy. Numerous synthetic methods utilizing a wealth of chiral catalysts, auxiliaries and reagents have been developed to date.1–4 Asymmetric catalysis is particularly attractive because it provides efficient access to enantiopure compounds.5,6 An asymmetric reaction can be defined as follows: An asymmetric reaction selectively introduces one or more than one element of chirality to a substrate, in such a way that stereoisomers are formed in unequal amounts.

Asymmetric synthesis requires the use of a chiral catalyst, auxiliary or reagent that either recognizes heterotopic atoms, groups and faces of a substrate, or distinguishes between competing stereoisomers. While asymmetric synthesis entails selective introduction and manipulation of elements of chirality, the more broadly defined term stereoselective synthesis includes formation of achiral diastereomers such as (Z)- and (E)-alkenes. It is helpful to differentiate between enantioselective and diastereoselective processes:7 A. Enantioselective synthesis: 1. 2. 3. Enantiotopos-differentiating reactions Enantioface-differentiating reactions Enantiomer-differentiating reactions


Principles of Asymmetric Synthesis B. Diastereoselective synthesis: 1. 2. 3. Diastereotopos-differentiating reactions Diastereoface-differentiating reactions Diastereomer-differentiating reactions


Selective modification or replacement of heterotopic atoms or groups can introduce a range of new stereogenic elements to a substrate, for instance a chiral center, a chiral axis or a 1,2-disubstituted double bond, Scheme 5.1. An enantiotopos-selective (diastereotopos-selective) reaction generates unequal amounts of enantiomers (diastereomers). Typical examples of heterotopos-differentiating reactions are (À)-sparteine-mediated deprotonation of achiral carbamates and desymmetrization of prochiral biaryls, see Chapters 6.1 and 6.2.4. Compounds with heterotopic faces, for example aldehydes and ketones with different substituents attached to the carbonyl group, can either undergo enantioface-selective (if no chiral element is present) or diastereoface-selective (if the substrate is chiral) reactions. Common examples are chiral Lewis acid-catalyzed Diels–Alder reactions, aldol-type reactions and Grignard additions to chiral aldehydes and ketones, see Chapter 5.3. Stereoisomer differentiation occurs when enantiomers or diastereomers undergo the same
1) Topos differentiation
X R Y X→Y R′ R R′

pro-S X X

pro-R Y X→Y R R′ X (CIP sequence is X>R>R′ )

a) enantiotopos-differentiating if R and R' do not contain a chiral element and R ≠ R ′ b) diastereotopos-differentiating if R or R' (or both) contain at least one chiral element H R -HX R H H R H X R H H X H R -HX R R H H

H R diastereotopos-differentiating

2) Face differentiation
Y R X R′ X Y Re-face attack R Y Si-face R′ attack X R R′ Y (CIP sequence is X>R>R ′)

a) enantioface-differentiating if R and R' do not contain a chiral element and R ≠ R' b) diastereoface-differentiating if R or R' (or both) contain at least one chiral element

3) Stereoisomer differentiation
H R H R X R′ R X R′ X H R′ X H R′ PKR X →Y X →Z R KR X→Y R R H Y R′ H Y R′ R Z H R′ X H R′





a) enantiomer-differentiating if R and R′ do not contain a chiral element and R≠ R ′ b) diastereomer-differentiating if R or R ′ (or both) contain at least one chiral element

Scheme 5.1

Categories of stereoselective reactions.


Chapter 5

reaction with different rates or when they are selectively transformed to nonisomeric products by different processes. This is observed during kinetic resolution (KR), parallel kinetic resolution (PKR), dynamic kinetic resolution (DKR) and dynamic kinetic asymmetric transformation (DYKAT). The principles and scope of these methods are discussed in Chapter 7. Organic reactions are also commonly classified into stereoselective and stereospecific processes, Scheme 5.2. By convention, the term stereospecific is solely reserved for reactions that produce different stereoisomers from stereoisomeric starting materials under identical conditions. It follows from this definition and the discussion above that stereospecificity is a sufficient condition for stereoselectivity but that a stereoselective reaction is not necessarily stereospecific. The family of stereospecific reactions includes trans-addition of bromine to (E)- and (Z)-alkenes, cheletropic synaddition of singlet carbenes to alkenes, electrocyclic reactions such as disrotatory ring closures, and the sigmatropic Claisen rearrangement of the cis- and trans-isomers of (4S)-vinyloxypent-2-enes. These reactions have in common that stereoisomeric substrates are transformed to stereoisomeric products. For example, bromination of (Z)-butene gives racemic 2,3-dibromobutane but (E)-butene is converted to the corresponding meso isomer under the same reaction conditions.
1) Stereospecific reactions
trans-addition Br2 (Z)-butene H Br + Br H Br H (Z)-butene

cheletropic syn-addition

CH2 cis-1,2-dimethylcyclopropane

H Br racemic 2,3-dibromobutane Br




+ racemic trans-1,2-dimethylcyclopropane


Br H meso 2,3-dibromobutane


electrocyclic reaction

sigmatropic Claisen rearrangement O (S) O

ring closure (disrotatory) trans,cis,trans-2,4,6octatriene


cis-dimethylcyclohexadiene trans-(4S)-vinyloxypent-2-ene




O (S) O

ring closure (disrotatory) trans,cis,cis-2,4,6octatriene

+ racemic trans-dimethylcyclohexadiene





trans-(3R)-3-methylhex-4-enal cis-(4S)-vinyloxypent-2-ene

2) Stereoselective reactions
nucleophilic 1,2-addition O t-Bu 4-tert-butylcyclohexanone LiAlH4 + t-Bu

H OH electrophilic addition HCO2H O H norbornene O racemic exo-2-norbornyl formate

trans-4-tert-butylcyclohexanol OH

H t-Bu cis-4-tert-butylcyclohexanol Ph OH Et OH

CHO Bu2N Et2Zn benzaldehyde


Scheme 5.2

Examples of stereospecific and stereoselective reactions.

Principles of Asymmetric Synthesis


In a stereoselective reaction, a single reactant may be transformed to several stereoisomers but one is obtained predominantly or even exclusively. This is observed during stereoselective addition of formic acid to norbornene, which yields diastereomerically pure exo-2-norbornyl formate; diastereoselective reduction of 4-tert-butylcyclohexanone with lithium aluminum hydride, providing trans-4-tert-butylcyclohexanol in 80% de; and enantioselective alkylation of benzaldehyde with organozinc reagents in the presence of catalytic amounts of (1R,2S)-N,N-dibutylnorephedrine. Reactions that proceed with perfect stereoselectivity are often inaccurately described in the literature as stereospecific. Electrophilic addition of formic acid to norbornene yields exclusively the racemic exo-ester and no endo-product is formed. However, this does not constitute a stereospecific process but is an example of a highly diastereoselective reaction.

A basic concept of asymmetric synthesis is to effectively embed a substrate into the chiral environment of a catalyst, auxiliary or reagent. In all cases, chiral induction is accomplished either under kinetic or thermodynamic reaction control. In a thermodynamically controlled reaction, product formation is reversible and the stereochemical outcome is governed by the relative stability of the diastereomeric products, Figure 5.1. For example, asymmetric transformation of compound X to diastereomers Y and Z produces a mixture with the more stable species Y as the major isomer. When products and starting materials are in equilibrium, the product ratio is solely determined by the difference in the free energy, DG, of the diastereomers Y and Z at a given temperature, as defined by Equation 5.1. The energies of the transition states leading to the formation of Y and Z are irrelevant and do not affect the diastereoselectivity of the reaction. Enantioselective synthesis under thermodynamic control is not possible because enantiomers are isoenergetic and a racemate must be obtained at equilibrium unless a chiral solvent or resolving agent is used.i ½YŠ ¼ Keq ¼ eÀDG=RT ½ZŠ where DG ¼ GY À GZ ð5:1Þ







free energy G


-∆G = GZ - GY
GY Y X = chiral starting material Y, Z = diastereomeric products

Figure 5.1

Energy profile for a thermodynamically controlled asymmetric reaction.

In fact, this constitutes a diastereoselective process. The presence of a chiral additive or solvent generates diastereomeric adducts that can have different thermodynamic stability and may therefore be formed in unequal amounts.


Chapter 5




kZ kY

Z -∆∆G


free energy G

∆G≠Z ∆G ≠ Y

≠ ≠

-∆∆G = ∆G Z - ∆ G Y Y X = achiral or chiral starting material Y, Z = enantiomeric or diastereomeric products


Figure 5.2

Energy profile for a kinetically controlled asymmetric reaction.

When a reaction is carried out under kinetic control the products can not equilibrate and the stereoselective outcome solely depends on the rates of product formation, rY and rZ, Figure 5.2. In this case, X is converted to enantiomeric or diastereomeric products Y and Z under irreversible conditions, and the product ratio is determined by the difference in the free energy of the corresponding transition states of Y and Z, DDGa, at a given temperature as defined in Equation 5.4. Because conversion of X to Y has a lower free energy of activation, DGaY, than the competing formation of Z, Y will be the predominant product. Under kinetic control, the relative stability of the products Y and Z is irrelevant and does not affect the stereoselectivity of the reaction. Enantioselective synthesis is feasible when nonequienergetic diastereomeric transition states can be established under irreversible conditions. rY ¼ ½XŠkY where kY ¼
¼ 6 k kB T eÀDG Y =RT h


rZ ¼ ½XŠkZ where kZ ¼
¼ 6 k kB T eÀDG Z =RT h


rY ½YŠ kY ¼ 6 ¼ ¼ ¼ eÀDDG =RT rZ ½ZŠ kZ where DDGa ¼ DGaY À DGaZ


Equations 5.1 and 5.4 describe the exponential dependence of the product ratio Y/Z on the difference in the free energy of the products, DG, or of the corresponding transition states, DDGa, at a given temperature. The stereoselectivity of an asymmetric reaction improves as the difference in the relative stability of the products or transition states increases. This is illustrated in Figure 5.3 and Table 5.1. At 0 1C, a product ratio of 9 : 1 (80% ee or de) can be achieved when DG or DDGa is about 5 kJ/mol. A further increase in DG or DDGa to approximately 6.7 kJ/mol enhances the enantiomeric or diastereomeric excess to 90%. The same stereoselectivity can be obtained with energy differences of 4.8 and 7.3 kJ/mol at À78 1C and 25 1C, respectively. It is important to realize that these values are fairly small and similar to the energy of a weak hydrogen bond or the energetic differences of conformational isomers.ii Because of the exponential relationship between stereoselectivity and the difference in the free energy or free activation energy, the curves shown in Figure 5.3 start with a

For example, the energetic difference between the axial and equatorial conformation of methylcyclohexane is approximately 7 kJ/mol.

Principles of Asymmetric Synthesis
12000 10000 25.0 οC 0.0 οC


∆G or 6000 ∆∆G ≠


(J/mol) 4000
2000 0 0 10 20 30 40 50 60 K or kY /kZ 70 80 90 100

Figure 5.3

Dependence of stereoselectivity on the difference in the free energy of the products, DG, or of the corresponding transition states, DDGa, at frequently used temperatures.

Table 5.1

Dependence of the product ratio of Y and Z and the corresponding ee or de on the difference in the free energy of the products, DG, and of the corresponding transition states, DDGa.
ee or de (%) À78.0 1C 50 75 80 90 92 96 98 1782 3157 3565 4777 5156 6314 7455 DG or DDGa [J/mol]a 0.0 1C 2495 4419 4990 6687 7217 8838 10435 25.0 1C 2723 4824 5447 7299 7878 9647 11390

K or kY/kZ 3 7 9 19 24 49 99

1.0 J/mol ¼ 0.239 cal/mol

steep slope that gradually decreases until an essentially straight line is obtained at Y/Z ratios above 20. A change in stereoselectivity from 3 : 1 to 9 : 1 requires doubling of DG (thermodynamic control) or DDGa (kinetic control) from 2.5 to 5 kJ/mol at 0 1C, Table 5.1. In contrast, small energetic changes have a profound effect on stereoselectivity in the flat part of the curve. A further increase of DG or DDGa by another 50% to 7.5 kJ/mol drastically improves selectivity to more than 27 : 1, which is close to 93% ee or de. Since the flat part of the curve is wider at À78 1C than it is at 0 1C or 25 1C, small energetic differences generally have a stronger impact on stereoselectivity at lower temperatures. In general, stereoselectivity increases at lower temperatures as described above. But this is not necessarily the case because both DG and DDGa depend on the absolute temperature according to the Gibbs–Helmholtz equation: DG ¼ DH À TDS Combination of the Gibbs–Helmholtz relationship and Equation 5.1 gives: ½YŠ ¼ Keq ¼ ðeÀDH=RT ÞðeDS=R Þ ½ZŠ where DH ¼ HY À HZ and DS ¼ SY À SZ ð5:6Þ ð5:5Þ

Chiral catalysts are usually employed in enantiopure form but this is not always necessary. In this case. a decrease in temperature will be detrimental to asymmetric induction.186 Chapter 5 Equation 5.7 outweighs the temperature-dependent enthalpic term which in this case has a relatively small effect on the product ratio. As a result.6 and 5. This often implies the use of a chiral catalyst or auxiliary that is designed to control the number of possible orientations and conformations of a substrate in the activated complex. The success of these approaches and the usefulness of an asymmetric reaction can be evaluated based on the following criteria:14 1. the second term of Equations 5. An important example is the enantioselective iii Since the reactions are entropy controlled. In many cases.6 describes enthalpic and entropic contributions in a thermodynamically controlled reaction. the stereoselectivity of an asymmetric reaction is determined by (a) the relative rate of competing reaction pathways if it is conducted under kinetic control. The reaction must be highly stereoselective and provide high yields. The chiral catalyst or auxiliary must be inexpensive and readily available in both enantiopure forms. Much effort has been devoted to the development of synthetic strategies that generate a single or at least a predominant welldefined transition state in order to achieve effective and predictable asymmetric induction. These requirements can not be generally applied to assess the usefulness of every asymmetric reaction and have to be carefully evaluated case by case. combination of Equations 5. a decrease in temperature will improve selectivity although the effect is diminished since only the relatively small enthalpic term increases. more than two reaction courses exhibiting individual transition states and different asymmetric induction are operative.8–13 If both enthalpic and entropic changes are in favor of formation of the same stereoisomer. the difference in DG or DDGa and therefore the stereoselectivity of such an entropically controlled reaction must decrease.6 and 5. ð5:7Þ 5. 4. however. When the entropic term predominates. 3. This does not affect the stereochemical outcome of thermodynamically controlled reactions if the individual pathways afford the same products.5 gives: ½YŠ kY 6¼ 6¼ ¼ ¼ ðeÀDDH =RT ÞðeÀDDS =R Þ ½ZŠ kZ where DDHa ¼ DHa À DHa and DDSa ¼ DSa À DSa Y Z Y Z A closer look at Equations 5. In the case of a kinetically controlled reaction. the reaction is entropy controlled and one can imagine two scenarios. 2. the enthalpic contribution favoring the minor stereoisomer will increase relative to the entropic term favoring the major isomer.3 ASYMMETRIC INDUCTION As discussed above. or (b) the relative stability of diastereoisomeric products if the reaction is thermodynamically controlled. But the stereoselectivity of kinetically controlled reactions can be significantly compromised because the success of asymmetric induction under irreversible reaction conditions depends on both the relative stability and the number of coexisting diastereomeric transition states. The chiral catalyst or auxiliary must be recoverable without racemization.4 and 5. The reaction must be applicable to a wide range of substrates.iii If enthalpy and entropy favor formation of opposite stereoisomers.7 reveals that a negative enthalpy term favors formation of Y over Z and stereoselectivity should therefore increase at lower temperatures. The preceding discussion of thermodynamically and kinetically controlled asymmetric reactions is based on the comparison of just two competing reaction pathways leading either to enantiomeric or diastereomeric products. . This is true for the majority of reactions which are enthalpy controlled because the enthalpic term outweighs entropic contributions.

the ease of operation. (À)-DAIB. this process can afford homochiral syn-dimers bearing both alkyl groups on the same side. Figure 5. alkylation of aldehydes with dialkylzinc reagents which is catalyzed by a wide range of readily available b-amino alcohols. 95% ee NMe2 OH (-)-DAIB lin ea r negative NLE eecatalyst Figure 5.54–63 Such a process is the enantioselective alkylation of heteroaryl carbaldehydes with dialkylzinc reagents. and possible relationships between enantioselectivity and ee of a catalyst. affords (S)-1-phenylpropanol in 92% yield and 95% ee even when the enantiopurity of the catalyst is very low.50 The equilibrium between the monomeric and dimeric species therefore strongly favors formation of the heterochiral complex which serves as a trap for the minor enantiomer.49.51–53 Even more impressive results are observed when positive nonlinear effects occur in autocatalytic asymmetric reactions. which means that the structure of the catalyst and the product is the same. The term reservoir effect has been coined to illustrate that the minor enantiomer of the catalyst is trapped while the excess of the major enantiomer remains catalytically active. In asymmetric autocatalysis the chiral product accelerates its own stereoselective formation. The reaction shows a positive deviation from the usually observed linear relationship between enantioselectivity and enantiomeric purity of the catalyst. In the presence of both enantiomers of DAIB. Consequently.4.44–48 The origin of the (þ)-NLE in the DAIBcatalyzed enantioselective alkylation of aldehydes has been attributed to the formation of homochiral and heterochiral complexes with different thermodynamic stability. When (À)-DAIB exhibiting 15% ee is employed in the reaction between benzaldehyde and diethylzinc.4 Asymmetric alkylation of benzaldehyde catalyzed by (À)-DAIB (15% ee).Principles of Asymmetric Synthesis 187 O H (-)-DAIB (8 mol%. the anti-dimer is approximately 12 kJ/mol more stable than the syn-isomers. Because of this positive nonlinear effect (NLE) a highly enantioenriched or enantiopure catalyst is not required to produce the alcohol in excellent yield and ee. Initial reaction between DAIB (which is actually a precatalyst) and one equivalent of the organozinc reagent generates a catalytically active tricoordinate alkylzinc complex that undergoes reversible dimerization to inactive species consisting of a four-membered m-oxo ring. the minor (þ)-enantiomer is almost quantitatively consumed in the catalytically inactive dimeric (À)-(þ)-DAIB complex. and the observation of intriguing nonlinear relationships between the ee of the product and the enantiopurity of the catalyst used. the reaction is mainly catalyzed by highly enantioenriched (À)-DAIB which is easily generated from the less stable homochiral (À)-(À)-DAIB complex. Scheme 5.15–24 Because of the significance of chiral secondary alcohols in asymmetric synthesis.3. this reaction has become one of the most intensively studied asymmetric C–C bond formations. or a heterochiral anti-dimer with both alkyl groups on opposite sides of the four-membered ring. Soai and coworkers demonstrated that the reaction between a 2-alkynylpyrimidine5-carbaldehyde and diisopropylzinc in the presence of catalytic amounts of the corresponding . Due to less steric repulsion between the alkyl moieties. Both positive and negative nonlinear effects have been encountered in a variety of asymmetric reactions30–43 and used as powerful mechanistic probes.25–29 Noyori et al. 15% ee) Et2Zn 0 οC OH positive NLE eeproduct 92%. observed that alkylation of benzaldehyde with diethylzinc in the presence of (À)-3-exo-(dimethylamino)isoborneol.

4.5% ee O H Scheme 5. (S)-1(-2-alkynyl-5-pyrimidyl)-2-methylpropanol exhibiting only 5 Á 10À5% ee generates the (S)-pyrimidyl alcohol in 57% ee.64 The active catalyst is initially formed by reaction of the alcohol and the organozinc reagent. 57% ee 2nd run: 96%. Scheme 5. (S) (S) N i-Pr2Zn 0 οC N N ≥2 mol% OH OZn H3O N N OH N chiral autocatalyst 1st run: 0.00005% ee 2nd run: 57% ee 3rd run: 99% ee i-Pr2Zn N N 1st run: 96%.4 Autocatalytic asymmetric alkylation of a pyrimidyl carbaldehyde. 99% ee 3rd run: 90%. > 99.188 Chapter 5 N Zn O R Zn R O N R Zn O Zn N N O R homochiral (-)-(-)-DAIB complex homochiral (+)-(+)-DAIB complex N Zn O catalytically active (-)-DAIB zinc complex N R R Zn O catalytically active (+)-DAIB zinc complex N Zn O Zn R R O N heterochiral (-)-(+)-DAIB complex (reservoir) Scheme 5.and heterochiral dimers. The resulting zinc alkoxide then catalyzes the asymmetric alkylation of the aldehyde. resulting in remarkably stereoselective replication which is a .3 Equilibrium between monomeric DAIB-derived alkylzinc complexes and homo.

5. the rotational freedom of the substrate is further reduced by A1.65-68 Reiteration of this process using the (S)-enantiomer with 57% ee as the catalyst provides another batch with 99% ee.iv Mechanistic studies and prediction of the sense of asymmetric induction are generally simplified because fewer structures of coexisting transition states have to be considered. Scheme 5.3 strain between the enone moiety and the oxazolidinone ring which forces the molecule into an s-cis conformation.S)-bisoxazoline ligand.5.95 cyclopropanations. this can be illustrated with a chiral Lewis acid-catalyzed Diels–Alder reaction using Evans’ N-acryloyl oxazolidinone or other bidentate substrates. 5. chiral catalysts derived from rigid C2symmetric ligands including binaphthols such as BINOL and BINAP. the Si-face of the dienophile is shielded while the Re-face is accessible independent of the substrate orientation in the activated complex. Both chelation and steric repulsion lock the activated dienophile into a single geometry which gives rise to a highly stereoselective Diels– Alder reaction with cyclopentadiene.104–106 As discussed above. For example.83. The inherent fluxionality of acyclic compounds can often be controlled through chelation of activated intermediates.69 Competing reaction pathways are therefore eliminated and.85 and TADDOL86 have proved to be exceptionally versatile and useful in a wide range of asymmetric reactions.87–93 Mukaiyama aldol reactions. The enantiomeric excess of the (S)-pyrimidyl alcohol can be further enhanced to above 99.82 salen. The introduction of the C2symmetric ligand DIOP to asymmetric catalysis by Kagan in 1971 has prompted the development of other equally successful ligand designs.101–103 Coordination of a prochiral bidentate substrate to the metal center of a square-planar bisoxazolinederived copper(II) complex can occur with two different orientations. In order to establish a well-defined reaction course one has to control the relative orientation of the reactants in the transition state.96–100 and aziridinations. This effectively limits the number of possible transition states and therefore enhances enantiofacial control. coordination of an N-acryloyl oxazolidinone to a bisoxazoline-derived Lewis acid generates a well-defined arrangement of the activated dienophile within the C2-symmetric environment of the catalyst. bisoxazoline-derived chiral Lewis acids (CLAs) have been very successfully applied in catalytic asymmetric Diels–Alder and ene reactions. Importantly.71 In particular. Scheme 5. the C2-symmetry of the catalyst renders the two possible CLA-dienophile arrangements identical. This example demonstrates that a small imbalance of enantiomers can be effectively transformed to a highly enantioenriched mixture after just a few consecutive runs without an additional source of chirality.70. . This so-called amplification of chirality can be observed in asymmetric autocatalytic processes that involve a positive nonlinear effect and may explain the origin of biological homochirality such as the dominance of (S)-amino acids in nature.84 DUPHOS. The endo-approach of the diene to the well-defined copper coordination complex provides the (S)-cycloadduct.72–75 bisoxazolines. Formation of a complex between the Lewis acid and the N-acryloyl oxazolidinone substrate reduces the energy of the LUMO of the dienophile and activates it for Diels–Alder reaction with cyclopentadiene. when compared with a chiral catalyst devoid of a C2-axis.5% in a third run.Principles of Asymmetric Synthesis 189 consequence of a positive nonlinear effect based on the principles of Kagan’s reservoir model. Coordination of the bidentate substrate also impedes rotation about the acryloyl imide bond.94.76–81 semicorrins. Again.3. Figure 5. However. and particularly in the case of acyclic substrates the equilibrium between conformational isomers.6. Due to the C2-symmetry of the (S.1 Control of Molecular Orientation and Conformation A common feature of successful chiral catalysts is a rigid C2-symmetric structure which reduces the number of possible catalyst–substrate arrangements and isomeric transition states. superior stereoselectivities and yields are often obtained. thus providing the corresponding bicyclic adduct in 86% yield iv The presence of a symmetry axis (C2 or C3) is a common feature of many powerful chiral catalysts but this is by no means a strict requirement for effective asymmetric induction.

or b-position to the carbonyl function is often rationalized using Cram’s chelation model.5 Enantiofacial control with a C2-symmetric catalyst. The stereochemical outcome of Grignard additions to chiral substrates that possess a stereocenter bearing a heteroatom in a.107–118 Another example is the CLA-catalyzed hetero-Diels–Alder reaction between a-keto esters and Danishefsky’s diene.119–124 Coordination of methyl pyruvate to an (S. Chelation also plays an important role in diastereoselective reactions.190 CN Chapter 5 O O DIOP O PPh2 PPh2 OH OH PPh 2 PPh 2 R BINOL BINAP R P N R R OH N HO R R R salen DUPHOS P R R O O N BOX N O R R N N R semicorrins R R OH OH R R TADDOL Figure 5.7. The restricted conformational freedom results in a highly diastereoselective transition state in which the .5 Structures of C2-symmetric ligands. This concept is not limited to oxazolidinones and has been applied to a number of other reactions including nucleophilic Michael additions and radical reactions.125 Cram and others realized that a-alkoxy ketones and Grignard reagents form a cyclic structure with the alkoxy group synperiplanar to the carbonyl function.S)-bisoxazoline-derived copper(II) complex effectively reduces the conformational freedom of the activated dienophile which then undergoes cycloaddition with the diene to give the corresponding (S)-dihydropyranone in 83% yield and 91% ee. Scheme 5. The two possible catalyst-substrate arrangements are identical and lead to the same transition state and product. and more than 98% ee. O N R Si-face is blocked O O N R N Cu2+ R O N Cu O N 2+ O R H (S) O endo-selective approach from the rear N O O O O N O O Re-face is accessible different substrate orientation affords the same TS R O N Cu2+ O O N O N O endo-selective approach from the front H O R O Si-face is blocked Re-face is accessible O N (S) Scheme 5.

126. Attack from the opposite face is disfavored due to steric repulsion by the larger ligand L. 91% ee O Scheme 5. ketones and their derivatives is further complicated by Schlenk equilibria. nucleophile is delivered from the less sterically hindered side displaying the smaller ligand S. However. Me Mg O OMe (S) OMe Me2Mg Me H Ph OMgMe Me Ph (R) H Me Ph OMgMe (S) OMe Me Si-face attack O OMe Ph 99% de favored transition state Scheme 5. formation of an intermediate dimethylmagnesium complex of (S)-2-methoxy-1-phenylpropanone locks the substrate into a single conformer and thus restricts the number of possible transition states.3S)-3-methoxy-2-phenylbutan-2-ol in excellent diastereoselective excess. restriction of the conformational flexibility of a-hydroxy ketones during complexation to zinc v The mechanism of the Grignard addition to a.or b-alkoxy aldehydes. 96% de OMe OMe TMSO O + O OEt OMe O O TMSO CO2Et OMe CLA O TMSO chelation impedes free rotation O OEt CLA O O OEt CLA = N t-Bu Cu2+ N t-Bu O 5 mol% CLA 25 oC TMSO O (S) CO2Et H (S) O CO2Et 83%. competition between acyclic and cyclic reaction pathways. producing (2R.6 Examples of catalytic enantioselective Diels–Alder reactions using a chiral Lewis acid derived from copper(II) triflate and a bisoxazoline ligand. For example. >98% ee. Cram’s model correctly predicts the stereochemical outcome of many p-facial diastereoselective nucleophilic additions.v Similarly. Comparison of the diastereotopic faces of the five-membered chelate explains why the nucleophilic attack on the carbonyl group occurs predominantly from the Si-face. .Principles of Asymmetric Synthesis 191 O N t-Bu + O N O O A1. and stereoelectronic and solvation effects.2.7 Rationalization of the Grignard reaction of (S)-2-methoxy-1-phenylpropanone using Cram’s chelation model.3 strain 10 mol% CLA -78 oC s-trans N H H N O O N t-Bu t-Bu Si-face approach is blocked N O Cu2+ O O O Cu2+ O O N O t-Bu N O endo-attack s-cis Re-face approach is favored chelation impedes free rotation O O 86%. see Chapter 2.

192 H H B H H (S) C H 2 5 Si-face attack H Zn O OH C2H5 C3H7 H H B H H Chapter 5 O C3H7 (S) C H 2 5 OH Zn(BH4)2 OH C3H7 (R) >98% de OH Scheme 5. . O S Si-face attack O RMgCl S R (S)-3-alkylcyclopentanone R Al/Hg O MeO Br Br Zn O S O RMgCl MeO O S O O O O Al/Hg R R (R)-3-alkylcyclopentanone MeO MeO Re-face attack RMgCl conformational control due to stereoelectronic effects S conformational control due to chelation RMgCl ZnBr2 Br S RMgCl Zn Br Si-face attack is favored Re-face attack is favored Scheme 5.10 Chelation-controlled diastereoselective Michael addition of Grignard reagents to (S)-2-(4-methoxyphenylsulfinyl)-2-cyclopentenone.8 Stereoselective reduction of (S)-4-hydroxyheptan-3-one with zinc borohydride. O S O S O O MeO MeO Scheme 5.9 Conformational isomers of (S)-2-(4-methoxyphenylsulfinyl)-2-cyclopentenone.

if stereoelectronic effects are operative in addition to chelation and steric interactions. Scheme 5.129 Chelation with a Lewis acid such as zinc dibromide has two important affects on the Grignard reaction: it increases the reactivity of the Michael acceptor for an electrophilic attack and it generates a rigid conformationally stable coordination complex exhibiting parallel ketone and sulfoxide groups. favoring nucleophilic attack from the Si-face and formation of (S)-3-alkylcyclopentanone derivatives.128 In the absence of a chelating metal ion. the chiral auxiliary blocks the Si-face and the Grignard addition occurs from the Re-face.8. Scheme 5.127 Asymmetric reactions may become more versatile. Stepwise Zn(II)-promoted Michael addition and reductive cleavage of the chiral auxiliary therefore furnishes 3-substituted R favored TS R′′ O M H ≠ O fast R R′ R′′ R′ syn (favored) OH O R′′ OM + R′ (Z)-enolate R H O H O H H R R′′ M O slow R R′ OH O R′ anti R′′ disfavored TS favored TS H O M R′′ ≠ O OH O R fast R R′ R′′ R′ H OM O anti (favored) + R′′ R′ R H O H R R′′ H M O OH O (E)-enolate slow R R′ R′′ R′ syn disfavored TS Scheme 5.10. Posner et al.9. 2-(arylsulfinyl)-2-cycloalkenones prefer a conformation with the ketone and the sulfoxide groups pointing in opposite directions to minimize destabilizing dipole–dipole interactions. Scheme 5. Formation of a zinc complex locks (S)-4-hydroxyheptan-3-one into a single conformation that undergoes selective intramolecular reduction at the less sterically hindered Si-face of the carbonyl group.Principles of Asymmetric Synthesis 193 borohydride affords diols with high diastereoselectivity due to chelation.11 Zimmerman–Traxler transition states. but also more complicated. utilized chelation control to switch the asymmetric induction in the diastereofacial Michael addition of Grignard reagents to chiral 2-(4-anisylsulfinyl)-2-cycloalkenones. producing the (SS. . As a result. yielding the erythro diol in more than 98% de.R)-diastereoisomer. Because of this stereoelectronic effect the bulky aryl group in (SS)-2-(4-methoxyphenylsulfinyl)2-cyclopentenone preferentially occupies the Re-face of the Michael acceptor.

e. Scheme 5. ZnBr2-mediated Michael addition of neopentylmagnesium bromide to (SS)-2-(4-methoxyphenylsulfinyl)-2-cyclopentenone and subsequent reductive removal of the arylsulfinyl auxiliary gives (R)-3-neopentylcyclopentanone in 69% yield and 87% ee. .160. aldol reaction between the lithium (E)-enolate derived from 2.6-dimethylphenyl propionate and 2-methylpropanal favors formation of the anti-b-hydroxy ester. thus generating aldol products with two chiral centers. Accordingly. coordination of both the (Z)-enolate and the aldehyde to a metal center leads to two diastereomeric chairlike transition states with different substrate orientations. Scheme 5. According to the Zimmerman–Traxler model. Both reactants are prochiral and have two heterotopic faces that can be attacked from either the Si. in particular when chiral substrates130–146 or chiral Lewis acids147–158 are employed.12 Diastereoselective aldol reactions.12.161 They observed that the lithium (Z)-enolate prepared from tert-butyl ethyl ketone and benzaldehyde affords the syn-product in more than 96% de..11.3-diaxial repulsion between these substituents only occurs in the transition state that leads to the anti-aldol product.194 OH OLi + t-Bu Ph H syn/anti > 98:2 OLi O O + i-Pr H anti/syn > 98:2 i-Pr OH O O Ph t-Bu O Chapter 5 Scheme 5. For example.or the Re-face. A closer look at a diastereoselective aldol reaction between an achiral aldehyde and an achiral enolate reveals how the relative orientation of the substrates is controlled by metal coordination.11 and 5.vi In these cases.3.159 This simple but powerful model is applicable to kinetically controlled aldol-type reactions and assumes that the relative stability of the two possible transition states is determined by repulsive steric interactions between the aldehyde substituent R and the a-substituent R 0 in the (Z)-enolate. Because of its important role in polyketide synthesis the stereochemical course of the aldol reaction has been studied extensively. Destabilizing 1. In contrast. (R)-cyclopentanones.12. reaction via the more stable transition state with the aldehyde substituent in equatorial position proceeds more rapidly and preferential formation of the syn-aldol product can be expected. i. the stereochemical course and the sense of asymmetric induction vi This is not the case in the crossed aldol reactions shown in Schemes 5. 5. The Zimmerman–Traxler model has been confirmed experimentally by Heathcock and coworkers. selective formation of one stereoisomer over another is a consequence of so-called single asymmetric induction or single stereodifferentiation.2 Single and Double Stereodifferentiation The stereochemical outcome of the majority of the enantioselective and diastereoselective reactions described above is controlled by a single chiral element present in either the substrate or the catalyst. The selectivity of crossed aldol reactions is governed by chelation as well as by steric and stereoelectronic effects. The same considerations explain why the (E)-enolate predominantly reacts to the antialdol product. Many asymmetric reactions of chiral substrates with achiral or chiral reagents are highly diastereoselective due to effective substrate-based stereocontrol.

13. It is known that copper(II) complexes often accommodate four to six ligands forming various coordination geometries which ultimately affects the sense of asymmetric induction.14. auxiliary or reagent C is employed. A more complicated scenario arises when two or more elements of chirality influence stereoselectivity. The results demonstrate that the concept of double stereodifferentiation is well suited to obtaining mechanistic insights into asymmetric reactions. the reaction of the (S)-aldehyde with the (R)-(Z)-enolate constitutes a double stereodifferentiation with a mismatched pair and ultimately affords low diastereoselectivity. Consequently. Comparison of the individual heterofacial preferences of the chiral (S)-(Z)-enolate and (S)-2-cyclohexylpropanal suggests that a combination of these will result in a synergistic effect and improved diastereoselectivity. for example in a kinetically controlled aldol reaction between a chiral aldehyde and a chiral (Z)-enolate.and the Si-face is sterically hindered. In contrast. as shown in Scheme 5. respectively. Crystallographic analysis and the results of double stereodifferentiation described above are in agreement with the assumption that the Diels–Alder reaction is catalyzed by a square planar copper complex. a diastereoselective reaction of a chiral substrate X and an achiral reagent favors formation of Y over Z if the pathway leading to the former has a lower transition state energy.175 Diastereoselective cycloaddition of cyclopentadiene and (4R)-3-acryloyl-4-benzyl-oxazolidin-2-one in the presence of an (S. and their proximity and relative arrangement in the diastereomeric transition states. In the case of a mismatched pair the . Figure 5. In the case of a matched pair. Such a single asymmetric induction becomes more complicated when a chiral catalyst. In contrast. Double stereodifferentiation plays a fundamental role in dynamic kinetic resolution. and the reaction proceeds much more slowly and low yields of the cycloadduct are obtained because the approach of the diene from both the Re. Inspection of the single asymmetric induction of both lithium (2S)-(Z)-2-phenyl-2-trimethylsiloxypent-3-en-3-olate and (S)-2-cyclohexylpropanal in the reaction with an achiral reactant reveals moderate stereofacial selectivity and ineffective substrate-based stereocontrol. the sense and efficiency of asymmetric induction depend on the absolute configuration of the two chiral centers.6. This combination is an example of a double stereodifferentiation involving a so-called matched pair. In fact. Apparently.162 In such a double stereodifferentiation. The reaction is controlled by the stereoselective bias of the substrate.Principles of Asymmetric Synthesis 195 is overwhelmingly determined by the chiral element in the substrate. the individual stereogenic elements of X and C favor formation of the same stereoisomer by further lowering the activation energy for the path towards Y and increasing the activation energy for the reaction towards Z. aldol reaction between the two produces the syn-isomer in 78% de. The effect of double stereodifferentiation on both reactivity and selectivity can be understood from the energy profiles of kinetically controlled reactions involving a matched and a mismatched pair. Under irreversible conditions.14. In the reaction of a matched pair the stereochemical biases of the chiral reactants are alike and both prefer formation of the same stereoisomer. the (S)-benzyloxazolidinone-derived template shields the Re-face of the substrate. The chiral lithium enolate favors attack at the Re-face of benzaldehyde and generates the corresponding syn-diastereomer in 56% de. This has important consequences: the diastereoselectivity decreases to only 36%. the difference in the transition state energies is higher and double stereodifferentiation increases selectivity and reaction rate. the (S.S)-bisoxazoline-derived copper(II) catalyst gives the endo-product in excellent yield and de. dynamic kinetic asymmetric transformation and other synthetic strategies and has been applied as a mechanistic probe in a range of asymmetric reactions.163–174 The effect of double stereodifferentiation on the CLA-catalyzed Diels–Alder reaction introduced above becomes evident when both a chiral bisoxazoline-derived copper(II) complex and an acryloyl imide template bearing a chiral auxiliary are employed.S)-catalyst and the (R)-configured chiral auxiliary constitute a matched pair because both shield the Si-face at the a-carbon of the dienophile. The outcome of the reaction between an achiral lithium enolate and (S)-2-cyclohexylpropanal proves that the latter prefers attack at the Re-face because the syn-aldol product is formed in 46% de. Scheme 5. Scheme 5.

Chapter 5 .196 Single stereodifferentiation O Ph (S) OTMS + 56% de OH O syn OTMS OH 2.7:1 O + OH O (S) OTMS + 46% de H Re-face attack at aldehyde is favored syn OTMS O 3.5 OH O OTMS + 8:1 O (S) syn Ph OTMS OH O (S) (S) OTMS + O Ph syn Ph OTMS OLi Ph (R) OTMS + OLi Scheme 5.13 Single and double stereodifferentiation in the aldol reaction of (Z)-enolates and aldehydes.5:1 OH O OTMS + Re-face attack at H aldehyde is favored syn syn Ph Ph OTMS OLi OLi Double stereodifferentiation Ph syn matched pair H 78% de OH syn mismatched pair H 20% de OH O O Ph OTMS + 1: 1.

>99% de Mismatched pair O N t-Bu O + 10 mol% CLA -78 οC N N O O N Bn O Cu2+ O O O t-Bu O O N O Bn steric bulk on opposite sides Bn 20%. Solid lines refer to single asymmetric induction and dashed lines to double stereodifferentiation. a useful asymmetric reaction must afford excellent yields and stereoselectivities for a wide range of substrates.Principles of Asymmetric Synthesis 197 Matched pair O N t-Bu O + 10 mol% CLA -78 οC N N O O N Bn O Cu2+ O O O t-Bu O O N O endo-attack Bn steric bulk on the same side Bn >99%.S)-bisoxazoline copper(II) complex and an acryloyl imide template bearing a chiral auxiliary. The Sharpless asymmetric epoxidation is a very good example of this concept which is often referred to .14 Double stereodifferentiation in a Diels–Alder reaction using an (S. 36% de Scheme 5. Ideally. the sense of asymmetric induction is predictable and independent of any stereogenic element present in the substrate and is solely determined by the catalyst or reagent used. Matched pair ∆∆G ≠ free energy G Mismatched pair ∆∆G ≠ X+C Z Y X+C Z Y X = chiral starting material C = chiral catalyst. In the case of diastereoselective reactions of chiral compounds showing insufficient substrate-based stereocontrol.6 Energy diagram for matched and mismatched pairs. As has been pointed out above. stereoselective biases of X and C are opposite and the difference in the free energy of the transition states is reduced. auxiliary Y. reagent. Z = diastereomeric products Figure 5. This combination therefore results in a less stereoselective reaction. it is advantageous if the stereochemical outcome of a reaction can be overwhelmingly controlled by a chiral catalyst or reagent.

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Once molecular chirality is established it might be necessary to further manipulate it. interconversion of stereoisomers can also be advantageous. Examples include asymmetric catalysis with chiral relays or stereolabile chiral ligands. Nevertheless.CHAPTER 6 Asymmetric Synthesis with Stereodynamic Compounds: Introduction. The formation of chiral carbanionic species. for instance Grignard reagents prepared from nonracemic alkyl halides. i The term conservation of chirality refers to a process in which the original enantiomeric and diastereomeric purity of a chiral compound is not compromised. dynamic kinetic asymmetric transformation (DYKAT) and dynamic thermodynamic resolution (DTR). The control of the stereodynamics of axially chiral compounds plays a key role in atroposelective biaryl synthesis. is often accompanied by rapid inversion of configuration and loss of stereochemical purity. The challenge here is to implement both axial chirality and sufficient conformational stability to avoid atropisomerization of the product. Methods that allow selective translocation of a chiral element along a carbon framework or change of a chiral center to a chiral axis with complete conservation of chirality provide invaluable access to complex structures. It is crucial to identify and to carefully select reaction conditions that rule out undesirable racemization or diastereomerization because these processes can significantly compromise the efficacy of asymmetric synthesis. generally entails incorporation of several chiral elements in addition to strategic carbon–carbon bond formation. reagent or product is the first step to stereodynamic control and successful multiple-step synthesis.i A profound understanding of the stability of a chiral target compound and starting materials to racemization and diastereomerization is indispensable for planning an efficient synthetic route. for example by intramolecular chirality transfer or interconversion of elements of chirality. and many synthetic methods exploit conformationally or configurationally unstable compounds. in particular natural products. Configurationally and conformationally unstable chiral compounds constitute both a challenge and an opportunity at the same time. as well as dynamic kinetic resolution (DKR). However. 204 . Conversion and Transfer of Chirality Asymmetric synthesis of complex chiral molecules. The determination of the energy barrier to isomerization of a stereolabile substrate. Coupling of racemization or diastereomerization with stereoselective reactions has become a powerful strategy. a variety of powerful asymmetric methods using chiral organolithium compounds that are configurationally stable under cryogenic conditions has been developed.

. Nonracemic organolithium compounds can be prepared by deprotonation of carbamates and esters derived from a chiral alcohol.6. and (c) the usefulness of organolithium reagents for carbon–carbon bond formation. titanium or copper reagents prior to asymmetric carbon–carbon bond formation. tin. iii Nonfunctionalized aliphatic organolithium compounds are generally of limited use due to their inherently low configurational stability which decreases even further in the presence of polar organic solvents.1 He observed that lithiation of (–)-2-iodooctane followed by trapping of the 2-octyllithium intermediate with carbon dioxide at –70 1C yields nonracemic (–)-2-methyloctanoic acid.2. thiol or amine.1 ASYMMETRIC SYNTHESIS WITH CHIRAL ORGANOLITHIUM REAGENTS Probably the first asymmetric reaction involving an enantiomerically enriched chiral organolithium compound was reported by Letsinger in 1950. Chiral organolithium compounds are usually generated under cryogenic conditions and are instantly trapped by transmetalation or carbon–carbon bond formation.36° (>95% ee) −70 °C C6H13 Li CO2 C6H13 [ ]D = − 1. aluminum. Scheme 6.iii Nonracemic organolithium intermediates are frequently subjected to metal exchange with borane.4 Powerful methods such as dynamic thermodynamic resolution (DTR) utilize configurationally unstable organolithium compounds.2. see also Chapter 3.1 First asymmetric synthesis with a chiral organolithium reagent. lithiated chiral carbanions are generally stabilized by incorporation of proximate heteroatoms that coordinate to the lithium cation and thus significantly reduce the rate of inversion. several (þ)-sparteine surrogates have been developed to provide additional means for the synthesis of chiral carbamoyl-stabilized carbanions.2.ii (b) the availability of a range of functional groups that stabilize the absolute configuration at the lithiated carbon atom. Since sparteine is only available in one enantiomeric form.Asymmetric Synthesis with Stereodynamic Compounds 205 6. that the configurational stability of chiral organolithium compounds is not necessarily a prerequisite for asymmetric synthesis. Scheme 6. however.3 Since then. stannylation has become a routine procedure for the generation of isolable derivatives which allows one to study the stereochemical integrity of chiral organolithium compounds. thus effectively preventing racemization or diastereomerization.17–21 Conversion of organolithium intermediates to other organometallic compounds has several advantages. It should be noted.18° (~20% ee) CO2H Scheme 6.1. Formation of isolable organostannanes also opens a venue for enantioselective HPLC purification in cases of unsatisfactory I sec-BuLi C6H13 [ ]D = − 44. the metal/halogen exchange generates a chiral organolithium species exhibiting remarkable configurational stability under cryogenic conditions.9–16 In the context of asymmetric synthesis. chiral organolithium reagents have found numerous applications in asymmetric synthesis. a chiral organometallic species is considered configurationally stable if inversion of configuration is relatively slow compared to reaction with an electrophile. In particular.6. see Chapter 7. Although the reaction is accompanied by considerable racemization. To prevent inversion of configuration even at very low temperatures.5 transmetalation with isolable chiral stannanes.7 and enantiotopic deprotonation of prochiral carbamates with organolithium reagents in the presence of an enantiopure amine such as (–)-sparteine.12. ii Common methods for asymmetric synthesis of chiral organolithium compounds are based on lithiation of readily available carbamates derived from enantiopure chiral secondary alcohols or (–)-sparteine-assisted enantiotopic deprotonation of prochiral carbamates and esters. This is a consequence of (a) the ease of preparation of nonracemic chiral organolithium compounds.8 The naturally occurring alkaloid (–)-sparteine is certainly the most popular choice for enantiotopic lithiation. but they can not be isolated or stored at room temperature.

N-diisopropyl-2-ethylbenzamide (bottom). chiral stannanes are often more suitable for asymmetric reactions that require temperatures at which organolithium compounds undergo racemization or diastereomerization as a result of uncontrolled inversion of configuration. 68% ee i-Pr2N O R sec-BuLi conformationally and configurationally unstable ROTs R=n-Bu: 52%.3 Asymmetric alkylation of laterally lithiated N. >96% de RX=MeI: 84%. 80% ee R=BnCl: 52%. 78% de O SnBu3 SnBu3 95%.206 Deprotonation of chiral carbamates NHi-Pr O O Ph H Ni-Pr2 O sec-BuLi O Ph Li sec-BuLi Ni-Pr2 S O S i-PrHN O Li Chapter 6 Enantiotopic deprotonation H H O O N O N N H (−)-sparteine sec-BuLi Li (−)-sparteine O O N Transmetalation OBn H O SnBu3 BuLi Li H O O Bn O Scheme 6.2 Generation of nonracemic organolithium compounds. >96% de i-Pr2N 65 °C 2d 97% 78%. Inversion of configuration of chiral benzylic organolithium compounds is usually fast. 96% de i-Pr2N i-Pr2N O N N O R i-Pr2N O Li (−)-sparteine RCl R=n-Bu: 95%. enantiopurity of organolithium precursors. i-Pr2N O R i-Pr2N O sec-BuLi i-Pr2N slow at −40 °C O Li RX i-Pr2N Bu3SnCl O RX=Me3SiCl: 88%.N-diisopropyl-2-ethylnaphthamide (top) and N. 97% ee R=BnCl: 26%. Beak and Clayden have shown that this process can be controlled through intramolecular .22 Finally.23–25 Hoppe. 77% ee Scheme 6.

configurational stability is not an inherent property of the compound but is dependent on reaction conditions. Heating of a solution of the stannylated anti-product to 65 1C for two days results in almost complete atropisomerization to the thermodynamically more stable syn-diastereoisomer that has the tributylstannyl moiety and the two isopropyl groups of the tertiary amide on opposite sides.28–32 Since naphthamides such as N.N-diisopropyl-2-ethylnaphthamide exist in the form of two atropisomers due to restricted rotation about the aryl–amide bond. v Examples of asymmetric reactions with chiral Grignard reagents are given in Chapter 3.27 or arylamide groups present in anilides or naphthamides. alkylation and silylation occur with retention of configuration while stannylation gives inversion of configuration.1 a-Alkoxy.and anti-diastereoisomers. see Chapter 7. With organolithium compounds this situation is often realized under cryogenic conditions while racemization would be relatively fast at room temperature.iv Chiral a-alkoxy-substituted carbanions are usually derived from ethers.35 Diastereoselective addition of a-lithiated ethers or Grignard analogs to aldehydes at –65 1C provides diols with remarkable syn-selectivity. which constitutes a dynamic kinetic asymmetric transformation. lateral lithiation with sec-butyllithium affords a mixture of syn. In fact. Scheme 6. Interestingly. But not all laterally lithiated aryl amides are configurationally stable under cryogenic conditions. .4.4 Lithiation of an a-alkoxy stannane followed by methylation with retention of configuration (top) and diastereoselective alkylation of benzaldehyde using configurationally stable organolithium and Grignard reagents (bottom).3. In 1980. Scheme 6. >95% ee H O H O OBn Me 2SO4 Scheme 6.33 Lithiation of N. Interestingly. Still and Sreekumar discovered that lithiation of an enantiopure a-alkoxy stannane through metal exchange with butyllithium under cryogenic conditions and subsequent methylation with dimethyl sulfate proceeds with no sign of racemization. 6.v The configurational stability of the organolithium intermediate is a consequence of both a-heteroatom substitution and intramolecular H O SnBu3 OBn n-BuLi −78 °C Li O H O OBn M OH M=Li: 65%.and a-Amino-substituted Organolithium Compounds The vast majority of configurationally stable organolithium compounds possess a-alkoxy or a-amino substituents.34.5. the sense of chiral induction is reversed when alkyl halides and tosylates are used. iv For convenience.36. Clayden’s group found that formation of the syn-diastereoisomer is favored and proved that it is configurationally stable up to –40 1C.N-diisopropyl-2-ethylbenzamide in the presence of (–)-sparteine at –78 1C gives rapidly interconverting diastereomers that nevertheless undergo stereoselective alkylation. Mechanistic studies including Hoffmann’s test revealed that the selectivity is not due to diastereotopic deprotonation and formation of nonequilibrating diastereomeric (–)-sparteine-organolithium adducts.12. a chiral organolithium compound is considered configurationally stable if racemization is relatively slow compared to reaction with an electrophile. >99% de + H −65 °C O OBn OBn >95%. carbamates and esters. 84% de M=MgBr: 65%. In this regard.2.1.Asymmetric Synthesis with Stereodynamic Compounds 207 lithium coordination with proximate carbamoyl26. stereoselectivity is established in the second step and is a consequence of diastereomeric transition states of two competing alkylation pathways.

65 In this case.6. 69% ee Scheme 6.45 Enantiotopic deprotonation of an achiral 13-membered cyclic propargylic allyl ether with lithio bis[(S )-1-phenylethyl]amide generates a configurationally stable chiral a-alkoxy lithium intermediate that spontaneously rearranges to a 10-membered propargylic alcohol. chelation stabilizes the position of lithium and thus impedes racemization.5 Enantiotopic deprotonation of a macrocyclic propargylic allyl ether and subsequent [2.4. Trapping of the chiral lithium carbanion pair can involve both inversion and retention of configuration. allyl and alkynyl alcohols for enantiotopic deprotonation in the presence of (–)-sparteine or another chiral base and subsequent reaction with an electrophile. Lithiation of achiral ethers can initiate sigmatropic [2.67–69 vi The stereochemical course of sigmatropic [2. Hoppe’s group has extended this methodology to 1-alkenyl carbamates.3]-Wittig rearrangements is discussed in greater detail in Chapter 6. Scheme 6.66 This provides a convenient synthetic entry to tertiary alcohols because chiral secondary alcohols are readily available in enantiopure form.2.64.5. Enantioselective (–)-sparteine-assisted lithiation of meso epoxides and aziridines constitutes an important desymmetrization strategy.vi Rearrangements of deprotonated epoxides and aziridines are also known. Hoppe and others have exploited a range of sterically hindered carbamates derived from primary alkyl.3]-Wittig rearrangements of configurationally stable carbanions. which is a characteristic of asymmetric synthesis with organolithium compounds. as indicated in Scheme 6. chelation.3]-Wittig ring contraction of allylic ethers. Scheme 6.37–43 An intriguing example is the enantioselective synthesis of macrocyclic alcohols based on [2. amino alcohols and amines. in the absence of the latter.7. Lithiation of Cb-protected (R)-1-phenylethanol at –78 1C produces a configurationally stable carbanion that undergoes electrophile-dependent stereodivergent substitution. enantiotopic abstraction of a g-proton generates an enantiomerically enriched allylic lithium intermediate that favors stereospecific anti-SE 0 reaction with silyl and stannyl chlorides but shows syn-SE 0 displacement with a range of carbonyl electrophiles. While incorporation of a heteroatom is known to increase pyramidal inversion barriers of carbanions.44. The latter reaction often proceeds with retention of configuration.2. Reactions of chiral organolithium compounds do not necessarily proceed with retention of configuration and the stereochemical outcome often depends on the nature of the electrophile used. and deprotonation of primary alkyl carbamates with sec-butyllithium/ (–)-sparteine generally favors abstraction of the pro-S proton. . The resulting chiral oxiranyl or aziridinyl anions can either be trapped by electrophiles or. rearrange to acyclic unsaturated diols.208 Li Ph N Ph Chapter 6 ≠ 5 4 1 2 OH Ha 5 Hb 1 Ha −78 °C 4 1 5 4 3 O 2 O 3 2 3 82%. for example (R)-pantolactone.50–63 The (–)-sparteinecontrolled lithiation/substitution reaction sequence with achiral carbamates is quite versatile and has also been used for the synthesis of natural products.46–49 Carbamates derived from primary or secondary alcohols are of great synthetic value. Scheme 6. Lithiation of carbamates derived from nonracemic chiral secondary alcohols generates organolithium intermediates that often have remarkable configurational stability due to dipole stabilization and intramolecular chelation of the lithium counterion by the carbamoyl group.3]Wittig ring contraction. for example by asymmetric alkylation of aldehydes with organozinc reagents in the presence of catalytic amounts of a chiral amino alcohol.

≥95% ee OCb SiMe3 OCb 92%. R=SiMe3: 86%. >95% ee N N CbyO Li OCby CbyO OCby sec-BuLi −78 °C CO2 CbyO OCby CO2Li HCl O OH O 80%. 80% ee H CbO (R) Ph CO2Me 85%. 90% ee OCb (S) Ph CO2Me 90%. R=CO2Me: 73%. 92% ee E=Bu3Sn: 61%.Asymmetric Synthesis with Stereodynamic Compounds pro-R pro-S N N 209 H Li OCby (−)-sparteine EX H R OCby Cby = O N O H H OCby sec-BuLi EX=MeOCOCl. >95% ee OCby sec-BuLi −78 °C Ph Ph SiMe3 OCb N N Ph n-BuLi −78 °C SiMe3 E=Me3Si: 18%.6 Examples of (–)-sparteine-controlled enantiotopic deprotonation of achiral carbamates and reaction with various electrophiles. 85% ee Ph Me2N Ph Scheme 6. 95% ee (R)-pantolactone (−)-sparteine OMe OMe N N OMe PhCOCl OCby OCby Li SiMe3 Li (−)-sparteine OCb ECl anti-SE' E Ph O Ph 85%. ≥95% ee SiMe3 OCb 72%. Ni-Pr2 CbO Ph (R) H sec-BuLi TMEDA −78 °C O (R) Li (MeO)2CO O NMe2 ClCO2Me MeOH 80%. ≥95% ee Ph SiMe3 Li OCb (−)-sparteine O O Cb = Ni-Pr2 syn-SE' O OH Ph MeO OMe MeO O Scheme 6. .7 Stereodivergent electrophilic substitution of a TMEDA-stabilized organolithium species. ≥95% ee E=Ph3Sn: 96%. >95% ee EX=Me3SiCl. 80% ee AcOH OCb (S) 75%.

The bridging holds the lithium more strongly on one side of the heterocycle which ultimately impedes inversion of configuration. 70% ee i-Pr i-Pr i-Pr O H O O i-Pr sec-BuLi TMEDA −78 °C 98%. and inversion of configuration i-Pr i-Pr i-Pr O H O O i-Pr sec-BuLi TMEDA −78 °C Li O i-Pr i-Pr O D CD3OD O Ar 95%.8.6-triisopropylbenzoate derivatives of indanol and tetralol and immediate trapping with deuterated methanol gives the corresponding deuterated esters in high yields but in only 70–78% ee. whereas methanol regenerates the original (R)-carbamate.4. The stereochemical outcome of reactions of a-lithiated esters is often difficult to predict and can be reversed by subtle changes in the substrate structure..4. The propensity for racemization and the unpredictable stereoselectivity limit the synthetic value of a-lithiated esters. reaction with dimethyl carbonate and methyl chloroformate gives opposite enantiomers of the a-carbamoyl methyl ester in high yields and up to 90% ee. The preparation of a-lithio amines often entails tin/lithium exchange or (–)-sparteinecontrolled enantiotopic deprotonation of carbamates. and trapping of the intermediate lithium adducts with carbon dioxide or dimethyl carbonate. Scheme 6. a-amino organolithium compounds have become invaluable reagents for asymmetric synthesis. benzyllithium derivatives often racemize considerably prior to reaction with an electrophile. Similarly. In contrast. This configurational stability has been attributed to bridging of lithium across the carbon–nitrogen bond. Scheme 6.6-triisopropylbenzoyl-derived indanol ester proceeds with net retention but the corresponding tetralol ester gives net inversion of configuration. Cyclic a-lithio amines are versatile nucleophiles for stereoselective carbon–carbon bond formation.73–78 Gawley and Zhang discovered the remarkable configurational integrity of cyclic a-lithio amines. . a-lithiated carbamates display higher configurational stability than esters. In general. which is in agreement with the observation of 15N–6Li coupling in the NMR spectrum.210 Chapter 6 Protonation of the TMEDA-stabilized organolithium species proceeds with inversion of configuration yielding Cb-protected (S)-1-phenylethanol when acetic acid is used. Usually.4.70–72 In particular. e. lithiation and subsequent stannylation of the 2. 78% ee Li O i-Pr CD3OD D O Ar O i-Pr Scheme 6.8 Lithiation and deuteration of 2. produces the corresponding amino acid and amino ester with excellent enantioselectivity. Lithiation of chiral 2. reaction with carbonyl electrophiles and stannanes proceeds with retention of configuration. Transmetalation of N-methyl-2-(tributylstannyl)piperidine or its pyrrolidine analog with n-butyllithium at –80 1C.79–81 2-Lithio-N-methylpiperidine and pyrrolidine are stable to racemization for up to 45 minutes at –40 1C in the presence of TMEDA.6-triisopropylbenzoyl derivatives of indanol and tetralol.9.g.

99% ee Ph O 85%. MeOTf -78 oC 1. n-BuLi -78 oC 2. >94% ee. 96% ee Ph N N Ph Li (-)-sparteine R NO2 R O 2N N Ar t-Boc R=Ph: 90%. 99% ee MeN Ph(CH2 )3Br MeN SnBu3 81%. 99% ee MeN Li Bu3SnCl n-BuLi NMe TMEDA SnBu3 −80 °C Li NMe (MeO)2CO NMe CO2Me 84%. 96% de Ph N Ar t-Boc n-BuLi -78 oC N Ar t-Boc Scheme 6. 94% ee 1. 98% ee N N N O O Li N t-Boc sec-BuLi -78 oC ECl N t-Boc E=Me: 76%. 92% ee. allyl triflate 3. n-BuLi 2. Ph N t-Boc Ph N N Ph N Ph t-Boc 87%.Asymmetric Synthesis with Stereodynamic Compounds 211 MeN n-BuLi NMe TMEDA −80 °C SnBu3 Li CO2H 83%.9 Asymmetric synthesis with 2-lithio-N-methyl derivatives of pyrrolidine and piperidine and configurational stabilization due to lithium bridging across the carbon–nitrogen bond. 94% ee MeN NMe CO2 NMe HO 70%. CO2 CO2H Ph N Ph t-Boc 81%. 88% de R=i-Bu: 73%.10 Enantioselective deprotonation of acyclic and cyclic carbamates followed by substitution or conjugate addition. CAN Ph N Ph t-Boc 96%. . 96% ee 1. n-BuLi -78 oC 2. 99% ee N Li lithium bridging N Li Scheme 6. 99% ee MeN 76%. 95% ee E E=TMS: 76%. 95% ee O Cl O CO2 CO2H 76%.

lithiation of t-Boc-protected (S)-N-phenyl-a-methylbenzylamine and subsequent reaction with allyl triflate results in net retention of configuration but net inversion of configuration is observed when carbon dioxide is used as electrophile. Stereolabile a-lithio sulfides have been employed in dynamic kinetic and dynamic thermodynamic resolution.N-diisopropyl-2-ethylbenzamide at –78 1C produces stereolabile (–)-sparteine adducts that undergo dynamic kinetic asymmetric transformation.104 At –78 1C.98.2 Sulfur-. both dynamic kinetic and dynamic thermodynamic resolution pathways may be operative at higher temperatures or when configurationally less stable a-lithio carbamates are used. intramolecular substitution of the configurationally stable organolithium intermediate occurs significantly more quickly than racemization and a range of 2-arylsubstituted pyrrolidines is obtained in up to 96% ee.106–109 Similarly. Scheme 6.99 As has been mentioned above for a-alkoxy and a-amino organolithium derivatives.115–118 A noteworthy example is Hoffmann’s retrocarbolithiation of a chiral (E)-1-arylthio-2-(methylthiopropenyl)cyclopropane derivative. a-sulfonyl carbanions110–112 and a-lithiated selenides113. For example. Many diastereoselective reactions of sulfur-stabilized organolithium intermediates such as chiral a-lithio sulfoxides are known.82 Enantiotopic deprotonation of achiral carbamates with organolithium reagents in the presence of (–)-sparteine and subsequent trapping of the dipolestabilized a-lithium intermediate gives access to a range of chiral amines. In other words. Lithiation of N. Many examples exploiting both cyclic and acyclic carbamates have been reported by Beak and others. predominates when akyl halides are used.1. Scheme 6.212 Ar O N O sec-BuLi −78 °C Cl N Chapter 6 Ar=Ph: 72%.10. see Scheme 6. Alternatively. selenides and halides exhibit lower configurational stability than the a-amino and a-alkoxy analogs discussed in the preceding chapter. albeit few enantioselective variations with configurationally stable a-lithiated sulfides have been reported.83–97 Mechanistic studies revealed that when reactions are carried out under cryogenic conditions asymmetric induction takes place during the (–)-sparteine-controlled deprotonation step rather than during the following substitution step.105 Because of the practicality of the concept of Umpolung (German. Lithiation of the enantiomerically enriched methyl selenoether generates a sulfur-stabilized lithium species with a vii This is not always the case. Phosphorus. .vii However.100–103 An enantioselective synthetic route to substituted pyrrolidines based on asymmetric deprotonation of acyclic t-Boc-protected benzylic 3-chloropropylamines has been described.and Halogen-stabilized Organolithium Compounds In general. configurationally stable organolithium nucleophiles can be employed in stereoselective conjugate additions to nitroalkenes or other suitable Michael acceptors. a-lithio sulfides.3. 93% ee N Ar Scheme 6.114 are prone to racemization but at very low temperatures these compounds can be sufficiently configurationally stable for stereocontrolled substitution. lithiated carbamates can react with electrophiles through both inversion and retention of configuration. the reaction sequence involves enantioselective formation of a configurationally stable organolithium species when temperatures as low as –78 1C are applied. 93% ee Ar=3-thienyl: 51%. 96% ee Ar=4-ClC6H4: 62%. reversal of polarity) which involves transformation of electrophilic aldehydes to dithianes or dithiolanes and subsequent deprotonation with organolithium reagents to generate nucleophilic species for carbon–carbon bond formation.11 Asymmetric lithiation and cyclization of t-Boc-protected benzylic 3-chloropropylamines. a-lithiated compounds have received considerable attention. 84% ee N t-Boc Ar=1-naphthyl: 68%. 6. 84% ee Ar=4-CH3C6H4: 75%.11.

Scheme 6. 99% ee N sec-BuLi SiMe3 R2 N S O PhCOCl Ph Ph 82%. which corresponds to an inversion barrier of 55.13. Scheme 6. . R2 N S O 93%. 99% ee O O Li Ph Ac2O NR2 S O 75%. With the exception of anhydrides and protic reagents such as methanol and acetic acid. Both the intramolecular ring opening and the methylation step proceed with retention of configuration.12.119 The a-lithio sulfide is configurationally stable at –108 1C and can be trapped with methyl iodide. reaction with typical electrophiles occurs with inversion of configuration. S t-BuLi −108 °C S Li S MeI S 90% ee SeMe Li 85%. gives a TMEDA-stabilized a-lithio sulfide species that shows no sign of racemization at 0 1C for up to 10 minutes and proves to be configurationally stable at –78 1C. Hoppe and coworkers explored the usefulness of chiral thiocarbamates. which is readily prepared by Mitsunobu reaction from (R)-1-phenylethanol and thioacetic acid.12 Asymmetric formation of an a-lithio sulfide through cyclopropane ring opening and subsequent methylation. >97% ee Ph O Me3SiCl O O N S H Ph AcOH 98%. 99% ee R2 N MeOCOCl O S O S CO2Me Ph 98%.120–123 Deprotonation of a sterically hindered (S)-1-phenylethanethiol-derived carbamate.13 Asymmetric synthesis of tertiary thiols via configurationally stable a-lithio thiocarbamates. 84% ee Scheme 6.Asymmetric Synthesis with Stereodynamic Compounds 213 racemization half-life time of 90 minutes at –78 1C. Following the successful examples reported for a-lithiated chiral carbamates. (E)/(Z)=87:13. >99% ee −78 °C Ph Scheme 6. 57% ee O CO2 R2N S CO2H Ph 90%.7 kJ/mol.

14 Asymmetric transformation of the second kind and enantioselective reactions of an a-carbamoylthio-substituted propargyllithium-(–)-sparteine complex.127 .14. 90% ee SCb H Scheme 6.126 The excellent conservation of chirality indicates considerable configurational stability of the intermediate lithium ion pair at À78 1C. 96% ee. Phosphorus. Enantiotopic lithiation of prochiral carbamates does not always proceed with high stereoselectivity.15. 98% ee.124 As a result of simultaneous isomerization and diastereoselective crystallization. ≥95% ee t-Bu H t-Bu R O SCb Ti(Oi-Pr)3 ≠ (i-PrO)3Ti RCHO −78 °C t-Bu ClTi(Oi-Pr)3 inversion -78 oC H (R) S O AcOH Ni-Pr2 − 78 °C t-Bu H O O H SCb Ti(Oi-Pr)3 ≠ t-Bu (P) • H R (R) OH R=Ph: 82%. Investigating the lithiation of a prochiral alkynyl thiocarbamate.214 i-Pr2N S H H S t-Bu O N N Chapter 6 O Li (-)-sparteine (R) H crystallization O (−)-sparteine Li Ni-Pr2 S (S) H TMSOTf inversion −78 °C t-Bu TMS H (S) S O Ni-Pr2 Ni-Pr2 n-BuLi − 30 °C t-Bu 83%. ≥96% de R=2-naphthyl: 79%. ≥96% de SCb R=i-Pr: 66%. stereochemically pure (–)-sparteine-derived organolithium complexes can be obtained by asymmetric transformation of the second kind. Scheme 6. 97% ee.and halogen-stabilized chiral organolithium compounds have rarely been employed in asymmetric synthesis. Hoppe’s group observed that the propargyl/lithium ion pair undergoes rapid pyramidal inversion at –30 1C and subsequent precipitation of one diastereomer from solution in pentane. The synthetic utility of the stereochemically pure (S)-a-carbamoylthio-substituted propargyllithium-(–)-sparteine complex is quite remarkable. Configurationally stable a-bromo organolithium intermediates have been prepared from chiral stannanes by transmetalation with butyllithium at À110 1C. The propargyltitanium intermediate can also be transformed to axially chiral 1-thio-substituted allenes with acetic acid or aldehydes. The lithiated alkyl halides can be trapped with acetone prior to racemization and the corresponding alkoxide intermediates readily form epoxides via SNi replacement of the adjacent bromide. Trapping with trimethylsilyl triflate and transmetalation with titanium(IV) chlorotriisopropoxide occurs with inversion of configuration. In some cases. the mixture can be quantitatively converted to a single stereoisomer. Deprotonation of diethyl phosphates derived from chiral secondary benzylic alcohols with butyllithium or LDA affords dipole-stabilized chiral carbanions that rearrange to a-hydroxyphosphonates having up to 98% ee.125. however. ≥96% de t-Bu (M) • H 95%. Scheme 6.

Asymmetric Synthesis with Stereodynamic Compounds H (S) Et Ph O O P sec-BuLi Et Ph OEt −78 °C OEt Li (S) O O P OEt OEt Et O 215 Li Ph O O P OEt OEt OTMS EtO EtO O P (R) Et OH Ph 71%.178. 75% de O OTMS O Scheme 6.133 and murrastifoline-F. as one must achieve both effective asymmetric induction and control of atropisomerization of multi-functional intermediates and products. 5. BINOL.4. Intramolecular aryl–aryl coupling Intermolecular aryl–aryl coupling Atroposelective ring construction Desymmetrization of conformationally stable achiral biaryls Stereodynamic methods such as atroposelective cleavage of conformationally fluxional biaryl lactones 6. 3.177 The unique dynamic stereochemistry of biaryls has been exploited in a number of ways to gain synthetic access to this class of compounds.138–141 BINAP. see Chapter 7. 4.128.160–163 and 2.5 .132 which has been found in varying and highly characteristic enantiomeric compositions in nature. A prominent example is the preparation of the axially chiral aglycon of vancomycin via diastereoselective C–C bond formation and atroposelective equilibration. Figure 6.173–175 Atroposelective synthesis of axially chiral biaryls has attracted considerable attention due to the increasingly recognized importance of this class of compounds.142–146 their derivatives.147–154 binaphthyl-based quaternary ammonium phase-transfer catalysts. 6.20 -bipyridine N.N0 -dioxides164–172 afford excellent enantioselectivity in a wide range of asymmetric reactions.129 the cytotoxic tubulin-binding lignan steganacin.8-diquinolyl. Figure 6.135 Some of these natural products possess other chiral elements in addition to the chiral axis but the latter is usually crucial to their biological activity.155–159 2.130 the anti-HIV agent michellamine B.176 The total synthesis of complex chiral biaryls such as streptonigrin and other antibiotic natural products constitutes a remarkable challenge. 98% ee O OTMS Br n-BuLi 97% de OTMS Br n-BuLi 85% de SnBu3 −110 °C SnBu3 −110 °C OTMS Br Li 79%.20 -bipyridine N-monoxides.15 Phosphate/phosphonate rearrangement via diethoxyphosphoryloxy-derived benzylic carbanions (top) and asymmetric epoxide formation with a-halo organolithium intermediates (bottom). 99% de OTMS Br Li 39%.131 knipholone. Many powerful asymmetric catalysts and auxiliaries possess a chiral axis.134. Important examples are the antibiotic glycopeptide vancomycin. 2. Highly congested atropisomeric 1. neurotrophic mastigophorene A.2 ATROPOSELECTIVE SYNTHESIS OF AXIALLY CHIRAL BIARYLS Axially chiral biaryls display a unique stereochemical motif that is present in a variety of natural compounds and pharmaceutical drugs.2. Interconversion of central to axial chirality which is discussed separately in Chapter 6.179 The most popular asymmetric strategies towards axially chiral biaryls can be classified as follows: 1.137 In particular. which exhibits an axially chiral C–N bond.8-diacridylnaphthalene-derived fluorosensors providing a C2-symmetric cleft for enantioselective recognition of chiral carboxylic acids and amino acids have also been reported.

.8-diquinolylnaphthalene N.N′-dioxides Ar N O O BINOL BINAP BINAL (M ) N Br (M ) (P) (P) (M) (M) Ar binaphthyl-derived ammonium phase-transfer catalyst i-Pr N N i-Pr N N O O 1.N′-dioxide 1.1 Structures of axially chiral natural products.2 Structures of axially chiral catalysts. t-Bu Ot-Bu N (M) OH OH (M) PPh2 PPh2 O (M) O Al OEt H (P) N O O (P) N Ot-Bu t-Bu 2. reagents and sensors.8-diacridylnaphthalene Figure 6.216 HO HO O O O O HO H N O NH HO2C HO (P) OH OH NH2 vancomycin OH O OH OH OH N OMe O O Cl H N O O N H O Cl OH H N O O NH NHMe MeO MeO OMe steganacin HO (M) O O OMe OH O OH O O OAc (M) OH HN OH Chapter 6 HO H2N OH OMe (P) NH OH michellamine B O HO (M) OH HO HO (P) (M) OMe murrastifoline-F N H OMe O knipholone mastigophorene A Figure 6.2-bipyridine N.

while avoiding concomitant rotation about the chiral axis which would ultimately diminish atroposelectivity. >99% de R=5. copper cyanide.6-benzo. >99% de R=5. Scheme 6.or cross-coupling step must occur at temperatures at which the biaryl is stable to rotation about the incipient chiral axis. Lipshutz et al. utilized oxidative coupling of intermediate diarylcyanocuprates for template-mediated diastereoselective biaryl synthesis.2. and metasubstituents further enhance steric hindrance to rotation through the so-called buttressing effect.17. and exposure to oxygen allows mild formation of the (P)-binaphthyl atropisomer. Removal of the tether is accomplished by double benzylic oxidation with NBS and basic hydrolysis. Scheme 6. Exploiting Miyano’s pioneering work. electronic effects of para-substituents on the rotational energy barrier of biaryls play a minor role. highly congested 2. As is discussed in Chapter 3.6-benzo.16 Atroposelective intramolecular Ullmann coupling of aryl halides using a rigid (M)-BINOL template. In other words. Basic hydrolysis of the diesters gives the free (M)-diphenic acids without loss of enantiomeric purity and the BINOL template can be recovered. DMF. the sense of axial chirality in the C2-symmetric BINOL template determines the relative orientation of the two aryl halides and thus governs the chiral induction during Ullmann reaction.Asymmetric Synthesis with Stereodynamic Compounds 217 6. In this approach.16. R′=6-Cl: 33%.1 0 -bi(2-naphthol)-bridged diesters of 2-halobenzoic acid derivatives were prepared and employed in Cu-mediated homocoupling to atropisomeric diphenic acids.180. 85% de R=R′=5. It is therefore difficult to find reaction conditions that allow formation of conformationally stable biaryls in reasonable yield. The (M)BINOL-directed asymmetric coupling produces (M)-diphenic acid-derived 12-membered ring structures in excellent de.6-benzo: 39%.3.1 Intramolecular Atroposelective Biaryl Synthesis Atroposelective aryl–aryl bond formation requires construction of a chiral axis under conditions that do not compromise the stereochemical purity of the target compound. albeit several steps are required to attach and cleave the chiral O O (M) O X X R O Cu.R)-diol bridge followed by treatment with butyllithium.6 0 -tetra-ortho-substituted biaryls bearing fused benzene rings are obtained in only moderate yields. The advantage of this procedure is that it avoids harsh Ullmann reaction conditions.181 Incorporation of ortho-substituents into the coupling components is necessary to avoid atropisomerization of the biaryl product but this causes significant steric repulsion during C–C bond formation. R′=6-NO2: 44%. In contrast to these predominant steric interactions. the stereoselective homo.182–184 Enantiopure 1. . I O (M) O O R′ (M) R KOH > 90% HO2C HO2C R′ (M) R O R′ R=6-Cl.185. >99% de Scheme 6. This challenge is evident in Miyano’s asymmetric biaryl synthesis based on intramolecular Ullmann coupling of (M)-BINOL-tethered aryl halides.1. >99% de R=R′=6-NO2: 70%. ∆ X = Br. the conformational stability of biaryls mainly depends on the presence of bulky ortho-substituents.186 Anchoring of two 1-bromo-2-naphthol units on a C2-symmetric tartaric acid-derived (R. However. R′=6-NO2: 80%.6.2 0 .

202 Genet and Chan have utilized the ˆ same strategy as a convenient entry to axially chiral diphosphine ligands. DEAD. t-BuLi 2. t-BuLi OBn 2. which were originally introduced by Noyori191 and Kocovsky.R)-pentanediol via Mitsunobu reaction with diisopropyl azodicarboxylate is followed by oxidative cross-coupling using Lipshutz’ procedure.17 Atroposelective biaryl synthesis based on oxidative coupling of intermediate arylcyanocuprates. n-BuN4 F 2.5-trimethoxyphenol to the diol tether via two sequential Mitsunobu reactions and intermediate protection of one alcohol group with tert-butyldimethylsilyl chloride has been used to extend this method to asymmetric biaryls consisting of differently substituted aryl moieties. DEAD.R)-pentanediol-assisted C–C bond formation yields a diastereomerically pure (M)-biaryl which can be converted to the corresponding (M)-diphosphine in three steps. template. KOH OBn Chapter 6 O CuCN O OBn OBn O2 0 oC O (P) O (P) OH OH 78%.218 2O (R) Br Br O (R) 1. Stepwise introduction of 1-bromo-2-naphthol and 2-bromo-3. The atroposelective biaryl synthesis of 7. aq.b-unsaturated ketones. Scheme 6.193 Atroposelective intramolecular aryl–aryl coupling mediated by chiral tethers has been adapted by other groups194–198 and applied to the synthesis of complex natural products199 including O-permethyltellimagrandin II.4.viii viii This diphosphine is a useful ligand for asymmetric catalysis and affords excellent results in rhodium-catalyzed hydrogenation of b-keto esters and 1.200 kotanin201 and rhazilinam. Scheme 6.189 and cyclo-NOBIN190 derivatives.5-trimethylphenol to (R. CuCN 3. >99% ee HO (R) OBn OBn 1. The diastereoselective formation of the (P)-biaryl atropisomer can be attributed to preferential population of a diequatorial gauche conformation of the intermediate diarylcyanocuprate. CuCN OBn 1.203–205 In this approach. >99% de BINOL 86%.18. NBS OBn 2. >99% de Scheme 6. PPh3 Br MeO MeO OMe OH O Br Br MeO MeO OMe (R) OBn OBn HO (R) O (R) 62% H O (P) O CH2OBn CH2OBn (M) O O CH2OBn H H 1.192 is noteworthy because it facilitates immobilization of these chiral ligands on polystyrene and other polymers for heterogeneous asymmetric catalysis. O2.4-addition of boronic acids to a. PPh3 Br OH O (R) Br TBDMSO 93% (S) OBn OBn 1.19.187 Bridging of 2-naphthols and 2-naphthylamines by a chiral tether and oxidative coupling with Mn(VI) or Cu(II) salts provides access to cyclo-BINOL188. The (R. TBDMSCl 2. 0 oC O H diequatorial conformation MeO MeO OMe (P) O CH2OBn diaxial conformation OBn OBn 68%. . sequential attachment of 1-iodo-2-naphthol and 2-bromo-3.4.7 0 -tethered BINOL and NOBIN.

can be prepared in diastereomerically pure form by oxidative coupling of glucopyranose-bridged 3. 95% de OH R=i-Pr. HO O O O O Ph O (P) Pb(OAc)4 Ph O O 73% O O O O GO OBn HO GO G = per-O-benzyl galloyl ester H2/Pd 82% O OBn OH HO HO (P) HO O HO HO O O O O O O OH OH OH O O OH OH OH Ph Ph O HO O Ph Ph O O OH Ph Ph GO O O GO HO Scheme 6. OH I O + OH OH DIAD PPh3 85% I OH DIAD. Some natural products including ellagitannins possess axially chiral biaryl units that are bridged by a glucose core. O2 O O 1. >95% de R=SiEt3. R′=H: 71%. an ellagitannin exhibiting a (P)-hexahydroxydiphenic acid core.5-trihydroxybenzoate esters. 99% ee Scheme 6. 91% de R′ H (R) (R) O O (M) OH NH2 79%. HPPh2. NiCl2 PPh2 PPh2 70%. CuCN 3. 86% de H cyclo-NOBIN Scheme 6.Asymmetric Synthesis with Stereodynamic Compounds R H O O H R′ H O O H (R) (R) O O OBn NH2 CuCl2 0 °C O O (R) (R) O O OH OH Mn(acac)3 50−82 °C O O H (R) (R) O O (M) R 219 H cyclo-BINOL R=Ph. R′=H: 73%. 97% de OH R=R′=Ph: 72%.4. It has therefore been postulated that the carbohydrate tether could be the source of asymmetric induction during atroposelective biosynthesis of ellagitannins. R′=H: 69%.19 Atroposelective synthesis of an axially chiral diphosphine ligand. Tf2O. PPh3 Br OH I Br O O 90% 1.18 Diastereoselective synthesis of cyclo-BINOL and cyclo-NOBIN derivatives. py 3. This hypothesis inspired the development of powerful biomimetic methods. 93% de R=Ph.206–208 Feldman’s group showed that tellimagrandin I. R′=i-Pr: 72%. sec-BuLi 2. This confirmed that the glucose tether does indeed provide effective stereocontrol during atropisomer formation. Scheme 6.209 Biomimetic oxidative biaryl coupling . so-called galloyl esters.20 Synthesis of tellimagrandin I by biomimetic atroposelective intramolecular coupling of glucose-bridged galloyl esters. BBr3 2.20. 99% de 72%.

because only one aromatic ring has to be modified with a chiral auxiliary and incorporation of a chiral bridge is not necessary. which is generated in situ. can approach the (S)-valinol-derived aryl oxazoline from two sides to form a magnesium chelation complex. .21. In particular.213–215 6. Although the aryl ring can rotate about the new bond.MeOMgBr OMe O N MeO MeO Mg Br favored aza-enolate i-Pr MeO MeO Mg Br O N i-Pr Scheme 6.3-dimethoxybenzoic acid. aryl Grignard reagents with a methoxy group in ortho-position yield axially chiral biaryls in remarkable diastereomeric excess. Removal of the chiral auxiliary by acidic hydrolysis and subsequent modification of the carboxylic acid function proceeds without concomitant racemization if the biphenyl OMe Br OMe OMe Mg. 80% de MeO i-Pr .220 Chapter 6 has also been utilized in the total synthesis of vancomycin. complexation of the ortho-methoxy group to the magnesium ion favors an arrangement that affords the (P)-biaryl after elimination of methoxymagnesium bromide.21 Meyers’ atropodiastereoselective biaryl formation with chiral aryl oxazolines. and activation of the arene for nucleophilic attack by resonance stabilization of the intermediate negative charge. the aryl Grignard undergoes nucleophilic attack at the ortho-methoxy group of the aryl oxazoline from this side to form an azaenolate intermediate. THF 65 C o Br O N MeO MeO Mg i-Pr OMe MeO MeO Mg O N OMe + O N i-Pr i-Pr Br favored chelation complex O N MeO (P) MeO 79%. Since the face opposite the bulky isopropyl group is more accessible.2. The oxazoline auxiliary apparently fulfills two functions: control of the stereochemical course during carbon–carbon bond formation. One of the most successful strategies for diastereoselective biaryl synthesis has been introduced by Meyers and coworkers. Diastereoselective intermolecular coupling is applicable to a broader variety of biaryl precursors.210.211 diazonamide A212 and stegane lignans. Scheme 6. The aryl Grignard.2 Intermolecular Atroposelective Biaryl Synthesis Synthetic strategies that are based on intermolecular atroposelective biaryl formation are generally more attractive than the intramolecular methods discussed above. They observed that the presence of an oxazoline group promotes nucleophilic aromatic substitution of adjacent methoxy and fluoro substituents by alkyl and aryl Grignard reagents.217–220 The reaction course and sense of asymmetric induction is governed by magnesium chelation and metal coordination of methoxy substituents from both the aryl oxazoline and the Grignard reagent.216 They extended the scope of this nucleophilic displacement reaction to atropodiastereoselective biaryl formation simply by using chiral aryl oxazolines which can be prepared from (S)-valinol or (S)-tert-leucinol and 2.

In both cases. Scheme 6. DMF t-Bu MeO Br O N t-Bu i-Pr OMe MeO OMe 80%. DMSO. Ac2O 3.234–237 Planar chiral tricarbonyl(arene)chromium complexes provide an elegant solution to this problem. Employment of the (S)-tetrahydroisoquinoline-derived aryl iodide in the palladium-catalyzed cross-coupling reaction furnishes the desired diastereomerically pure (P)-atropisomer. However. Lipshutz and others further investigated the scope of atroposelective synthesis with biaryl precursors bearing chiral auxiliaries. BBr3 3. The remote chiral center of the latter thus controls the relative orientation of the coupling partners prior to generation of the chiral axis during reductive elimination. A remaining shortcoming of atropodiastereoselective synthesis with chiral aryl precursors is that the covalently attached auxiliary often has to undergo extensive modification after the homoor cross-coupling step in order to establish the desired biaryl substitution pattern.229 The asymmetric coupling step gives the sterically crowded C2symmetric biaryl in 80% yield and 94% de. the electron-withdrawing (Z6-arene)chromium core fulfills two functions: it is the source of chiral induction during atroposelective C–C . has been prepared by Suzuki coupling of a selectively substituted 1-naphthylboronate ester and a chiral iodotetrahydroisoquinoline carrying a chelating diphenylphosphanyl moiety. A drawback of Meyers’ approach is that it requires the presence of methoxy groups in the ortho-positions of both coupling reagents.230–233 The korupensamine A skeleton. Following Meyers’ seminal work. (COCl)2 OH HO (P) OH OMe MeO OMe O HO OH 221 i-Pr Scheme 6.23. has four ortho-substituents. H2 Pd/C 2. Aryl oxazolines have also been employed in Ullmann coupling reactions. an important component of the antiviral alkaloid michellamine B. unless the chiral auxiliary is directly incorporated into the leaving group and is thus removed during nucleophilic aromatic substitution.228. and a variety of natural products including (–)-steganone. Scheme 6. 94% de MeO 72% OMe i-Pr OMe HO 68% OH i-Pr O ∆ N O (P) O OMe N OMe MeO i-Pr 1.221 (–)-O-methylancistrocladine222 and (–)-schizandrin223 has been prepared using this method.Asymmetric Synthesis with Stereodynamic Compounds MeO MeO MeO i-Pr MeO Cu. The stereochemical outcome has been attributed to an intermediate Pd(II) species. LiAlH4 t-Bu OMe HO (P) MeO i-Pr MeO 1. oxazoline-mediated cross-coupling provides convenient access to axially chiral biaryls consisting of two different aryl rings.224–227 The first total synthesis of (þ)-gossypol was accomplished by diastereoselective copper-mediated coupling of (S)-tert-leucinol-derived bromo(oxazolinyl)arenes. Scheme 6.24. Hydrolysis of the chiral auxiliary and reduction converts the oxazoline groups to methyl substituents and (P)-(þ)-gossypol is finally obtained after Lewis acid-catalyzed ether cleavage and Swern oxidation. The usefulness of (Z6-arene)chromium complexes for atroposelective synthesis of a range of biaryl compounds including natural products has been demonstrated by Uemura.238–241 Aryl chromium complexes are suitable for biaryl synthesis via palladium-catalyzed Suzuki cross-coupling and nucleophilic aromatic substitution.22 Total synthesis of (þ)-gossypol. because the chiral auxiliary can easily be removed by oxidative photocleavage. in which the chiral auxiliary and the dppf ligand coordinate to the transition metal in such a way that the bulky 1-naphthyl moiety is forced above the plane of the aromatic portion of the tetrahydroisoquinoline ring.22. TFA 2.

23 Atroposelective synthesis of the (P)-korupensamine A skeleton. (P)/(M)=92:8 OMe MesO2C MesO2C mesitylene. . R′=CHO: 95%. (P)/(M)<1:99 R=CHO. R′ =Me: 89%.24 Atroposelective biaryl synthesis with (Z6-arene)chromium complexes. ∆ (M) (P) + Cr(CO)3 MgBr + (CO)3Cr CO2Mes (CO)3Cr 76%. and it activates one of the reaction partners. Br MeO R B(OH)2 R′ Pd(PPh3)4 Na2CO3 MeOH/H2O. >99% de Scheme 6.242–246 Alternatively. BHT DMF. (P)/(M)>99:1 R=Me. 117 °C TIPSO dppf OMe Pd Ph MeO − Pd(0) P N Ph O Chapter 6 + O MeO NTs OMe t-Bu O Ts reductive elimination BHT = OH t-Bu OBn OMe OTIPS (P) MeO NTs O OMe Ph2P O 81%. bond formation.247 Unfortunately.222 OMe OBn OBn OMe Ph2P OTIPS O B I O O Pd(dppf)Cl2 (20 mol%) K3PO4. (M)/(P)>99:1 Scheme 6. formation of an electron-deficient (ortho-methoxybenzoate)chromium complex accelerates the nucleophilic displacement of the methoxy group by an aryl Grignard reagent. Coordination of an aryl halide to the tricarbonylchromium fragment facilitates the rate-limiting oxidative addition to Pd(0) which is followed by transmetalation with an aryl boronic acid and subsequent reductive elimination to complete the catalytic cycle. ∆ R R′ MeO R′ (P) + Cr(CO)3 (M) + (CO)3Cr R (CO)3 Cr OMe R=R ′ =Me: 96%. both yield and diastereoselectivity decrease when bulky substituents are present and preparation of sterically crowded tetra-ortho-substituted biaryls is usually not feasible.

the (M)-atropisomer is produced in high enantiopurity.S)-1.1 0 -binaphthyls in up to 95% ee. Scheme 6. Scheme 6. 89% ee R=p-Me2NC6H4CO.26.253 salen. A range of selectively substituted BINOLs has been prepared by enantioselective transition metal-catalyzed oxidative homocoupling of naphthols in the presence of (–)-sparteine.252. 83% ee R=CO2Bn.271 . Intermolecular biaryl synthesis has also been realized by coupling of achiral aryl units with enantioselective catalysts. in the presence of a chiral nickel catalyst formed in situ from (S)-1-[(R)2-(diphenylphosphino)ferrocenyl]ethylmethyl ether and nickel bromide. 40 °C R′ accessible top face MeO H N O Cu(I) O N H MeO O H N Cu (I) O N H H O O CO2Me blocked bottom face OMe (M) OH OH R R=CO2Me.255–257 Atropoenantioselective cross-coupling has been achieved with aryl Grignard reagents258. the chelating (S. R′=Br: 60%. Scheme 6.26.251 Accordingly.261. 93% ee R=CO2Me.262 Suzuki coupling with chiral catalysts prepared from palladium and ferrocenylphosphines263–265 or BINAP266–268 tolerates a wide range of functional groups and is probably the most widely used method. 90% ee R=PhCO. R′=H: 85%.Asymmetric Synthesis with Stereodynamic Compounds H N R′ R′ R OH NH CuI (10 mol%) O2. Impressive results were obtained by Buchwald and coworkers who discovered that 1-bromo-2-naphthylphosphonates and ortho-alkylated phenylboronic acids can be coupled with excellent enantioselectivity when minute amounts of palladium and an axially chiral electron-rich aminophosphine ligand are employed. For example.269 Transition metal-free atropoenantioselective coupling of aryl lead compounds and ortho-lithiated phenols in the presence of brucine has also been reported. Hayashi and Ito showed that cross-coupling of (2-alkyl-1-naphthyl)magnesium bromides and 1-bromonapthalenes.25. oxidative dimerization of 3-substituted 2-naphthols using an (S. R′=H: 82%. R′=H: 88%. provides practical access to 1.3 0 -disubstituted BINOL derivatives in up to 94% ee. R′=H: 93%.S)-diamine blocks the bottom face of the bidentate naphthol derivative while the second substrate can easily approach from the top face.5-diazadecalin-derived copper catalyst in the presence of oxygen has been reported by Kozlowski’s group. A catalytic cycle involving formation of an intermediate tetrahedral copper(I) complex exhibiting a carbon-centered radical has been proposed.25 Enantioselective synthesis of 3.3 0 -disubstituted BINOL derivatives via oxidative coupling of naphthols in the presence of an (S.259 (Kumada coupling) and arylboronic acids260 (Suzuki coupling) but examples with organozinc compounds (Negishi coupling).270. Dimerization is then followed by tautomerization and concomitant clockwise rotation about the incipient chiral axis. silanes (Hiyama coupling) and stannanes (Stille coupling) are still elusive. R′=H: 79%.254 and prolineor binaphthyl-derived diamines.248–250 The procedure allows preparation of 3.5-diazadecalin-derived copper catalyst. Since rotation past the chelating carbonyl moieties rather than the peri-hydrogens is favored.S)-1. 90% ee 223 R CO2Me OH OH (M) H H Scheme 6. The development of atroposelective access to BINOL derivatives is important because of the outstanding results obtained with this class of catalysts. 94% ee R=p-MeOC6H4CO.

83% ee R′ R=Me: R′=Me: 69%. 88% ee OMe R=Ph: 86%. The use of a photochemically activated chiral Co(I)-complex in the cycloaddition of 2-methoxy-1-(1. . 3 °C.o-binaphthyldiynes and 1. 60-80 °C R O P OEt OEt P OEt OEt R=Me: 98%.8-tetrahydroisoquinolines by Co(I)-catalyzed atroposelective [2þ2þ2]cycloaddition. 87% ee R=Et: 96%. Scheme 6. thus providing a highly effective alternative to aryl– aryl coupling methods. demonstrated that cycloaddition of a.27 Synthesis of 1-aryl-5. Transition metal-catalyzed cyclotrimerization has been applied in the synthesis of other biaryls including polyaryls with more than one chiral axis. 6. 92% ee R=i-Pr: 89%.3 Atroposelective Ring Construction Atroposelective [2þ2þ2]cycloaddition of alkynes and nitriles can accomplish both arene construction and incorporation of a chiral axis in a single step. 95% ee R=Et: R′=Me: 85%. Shibata et al. Ring construction and incorporation of two chiral axes occur with excellent stereoselectivity and formation of the meso isomer is not observed. 3 d) R OMe + C N (1 mol%) THF. R′=H: 92%. 93% ee (−20 °C.27.7-octadiynyl)naphthalene and nitriles allows asymmetric synthesis of 1-aryl5. 85% ee R=Ph: 74%.S)-MeDUPHOS-derived iridium catalyst affords axially chiral teraryls. Co R N R=Me: 88%.272 This cyclotrimerization proceeds with excellent regioselectivity and formation of constitutional isomers is not observed. 1 d (hν = 420 nm) (M) Scheme 6.4dimethoxy-but-2-yne or other symmetric alkynes in the presence of an (S.26 Atropoenantioselective Kumada (top) and Suzuki coupling (bottom). Cobalt(I)-catalyzed asymmetric ring construction is fairly slow when the temperature is decreased to À20 1C but the enantioselectivity improves under cryogenic conditions. 88% ee R=t-Bu: 74%.273.5−2 mol%) K3PO4. 77% ee (P) NMe2 PCy2 R B(OH)2 + Br O Pd2(dba)3 (0.224 H MeO Chapter 6 Fe R MgBr + Br R′ NiBr2 (2−5 mol%) < 10 °C (M) R R=Me. 89% ee R=Ph: 86%. 74% ee (+)-enantiomer Scheme 6.8-tetrahydroisoquinolines.

and both procedures can be optimized independently.276–278 >99.3S)-1. Intermediate protection of one alcohol group of 1. >99.5% ee X=C(CO2Et)2: 77%.6 0 -biphenyltetrol during acetalization with menthone279. and Negishi cross-coupling can be used for preparation of an achiral biaryl framework in high yields prior to desymmetrization. Scheme 6.275 Diastereoselective biaryl synthesis based on benzannulation of chiral chromium carbene complexes and 1.28 Atroposelective formation of teraryls using an (S. PPh3 HO HO O O OBn (P) HO HO OH OH DEAD PPh3 OBn 94% NH 90%. Stille. Desymmetrization of a prochiral biaryl by enantiotopos.6.4-di-O-benzyl-L-threitol with tert-butyldimethylsilyl chloride furnishes a monosilyl ether that undergoes Mitsunobu reaction with the achiral tetrol in the presence of diethyl azodicarboxylate.or diastereotopos-selective transformation of one of two identical aryl substituents allows asymmetric introduction of axial chirality.29.5% ee OMe X + [IrCl(cod)2] (10 mol%) OMe xylene.3-butadiynes has also been accomplished.6 0 -biphenyltetrol with (2S. 99% ee X=CH2: 96%.280 and etherification with either (2S.2 0 . 99% ee X=NTs: 92%. Harada’s group proved the feasibility of diastereotopos-differentiation of the ortho-substituents in 2.4 Desymmetrization of Conformationally Stable Prochiral Biaryls Topos-selective modification of conformationally stable achiral biaryls is an attractive alternative to atroposelective aryl–aryl bond formation.2-propanediol. >99% de ≠ ≠ H OBn OBn HO HO OBn BnO HO HO (M) O O OBn H OPPh3 H disfavored TS HO HO O (P) O H OPPh3 OBn favored TS Scheme 6. Deprotection of the silyl ether .3S)-1. An intrinsic advantage of this strategy is that a wide range of effective methods including Suzuki.2 0 . 1 h X Scheme 6. Hiyama.S)-MeDUPHOS-derived iridium catalyst. Kumada.282 Scheme 6. OBn HO + TBDMSO 77% OBn TBDMSCl N OBn HO HO O OH OBn OTBDMS 1) Bu4N F 2) DMAD.4-di-O-benzyl-L-threitol281 or the bis(mesylate) of (S)-1.4-di-O-benzyl-L-threitol.Asymmetric Synthesis with Stereodynamic Compounds 225 P OMe P (20 mol%) OMe X=O: 83%. 100 °C.29 Desymmetrization of 2.

and incorporation of two ortho-substituents of a stereolabile biaryl into such a chiral linkage has been successfully exploited for atropodiastereoselective synthesis.2 0 -di-ortho-substituted biaryl precursor was reported by Levacher et al.7-fused bicyclic lactam from a stereolabile 2.O-ketal sterically hinders cyclization via clockwise rotation and thus controls the stereochemical outcome of the biaryl bridging. A similar ix This is often accomplished under kinetic reaction control. It is assumed that the stereochemical outcome of the desymmetrization is determined during the Mitsunobu cyclization step.289 A remarkable example of diastereoselective construction of a conformationally stable 5. The SN2-type transition state generating the (M)-atropisomer is disfavored due to destabilizing steric interactions between one phenyl ring and one benzyloxymethyl group of the chiral auxiliary. 94% ee R=m-MeC6H4-: 90%. The rotational energy barrier of biaryls can be increased by introduction of a rigid nonplanar bridge. followed by a second intramolecular Mitsunobu coupling using dimethyl azodicarboxylate then yields the diastereomerically pure C2-symmetric (P)-biphenyl-2.5 Asymmetric Transformation of Stereodynamic Biaryls The challenges encountered with atroposelective biaryl synthesis have led to the development of alternative strategies that disconnect the aryl–aryl coupling step from the actual incorporation of axially chiral bias. The remaining triflate group can be further derivatized by another cross-coupling reaction.288. 88% ee R=PhC≡C-: 84%. Scheme 6. 86% ee Ph (5 mol%) Scheme 6.290 The nonisolable enantiomers of ethyl 2-acetylbiphenyl-2 0 -carboxylate undergo stereoselective oxazolidine formation with (R)-phenylglycinol.. Few other atropoenantiotopos-differentiating procedures have been reported to date and the synthetic potential of this approach remains to be fully explored. The rigid (M)-atropisomer is obtained in 95% yield and more than 95% de after refluxing ethyl 2-acetylbiphenyl-2 0 -carboxylate and the chiral auxiliary in toluene for six days. Scheme 6. the methyl group of the N.2.2 0 -diol. 95% ee R=Ph3SiC≡C-: 91%. the ratio of atropodiastereoisomers that are susceptible to rotation about the chiral axis at elevated temperatures can be manipulated according to the principles of asymmetric transformation of the first kind (thermodynamic control).286. An enantiotopos-selective monoarylation and alkynylation process with prochiral biaryl ditriflates and Grignard reagents has been developed by Hayashi.287 6.30. Apparently. the stereoselective conversion of a fluxional biaryl to a conformationally stable atropisomer can be optimized separately.226 Chapter 6 TfO RMgBr. Lactamization of the rapidly interconverting diastereomers then occurs preferentially from the side opposite to the phenyl and methyl groups of the oxazolidine unit via counterclockwise rotation of the aryl ester moiety about the chiral axis. Alternatively. In addition. which underscores the usefulness of this method.31. This can be accomplished if a stereolabile biaryl scaffold is prepared first and then stereoselectively transformed to a conformationally stable atropisomer in a separate step.30 Enantiotopos-selective transformation of a prochiral biaryl ditriflate. LiI OTf N PdCl2 P Ph TfO (P) R R=Ph: 92%. .ix One advantage of this approach is that the synthesis of stereolabile biaryls possessing less steric hindrance than conformationally stable analogs usually proceeds with better yields.283–285 The palladium-catalyzed desymmetrization proceeds with excellent enantioselectivity in the presence of an (S)-b-(dimethylamino)alkyldiphenylphosphine ligand.

S)-N.N 0 -dioxides. Noyori.N 0 -dioxides which have been successfully employed as chiral Lewis base catalysts in the asymmetric allylation of aldehydes with allyltrichlorosilanes. ∆. generating the thermodynamically favored homochiral (M. Gagne and others for deracemation of axially chiral 2.xi By analogy with the stabilization of interconverting axially chiral ligands by incorporation of a rigid bridge. This concept has been used by Mikami.2 0 -bipyridines with (M)-2.291 An intriguing asymmetric route towards conformationally stable 2.2 0 -bis(diarylphosphino)biphenyl-derived transition metal complexes in order to generate new enantioselective hydrogenation catalysts.M)diester in diastereomerically pure form. Subsequent oxidation with m-chloroperbenzoic acid and saponification yields enantiopure (P)-2.31 Atropodiastereoselective formation of a bridged biaryl using a chiral oxazolidine auxiliary.32.P)-macrocycles in toluene for two days or treatment with trifluoroacetic acid results in asymmetric transformation of the first kind. .2-diamino-1.293 According to NMR studies.P)-ruthenium complex is obtained by atrop´ isomerization at 50 1C within one hour. xi More examples of thermodynamically controlled atropodiastereoselective biaryl synthesis are given in Chapter 7. 6d OEt O O EtO HN O (S) Ph (R) O O (M) N (S) O OEt Ph (R) Ph (R) O NH (S) O 95%.2-diphenylethane (DM-DPEN) results in equilibration towards the thermodynamically favored (P)-atropisomer. the diastereomerically pure (S.and (M)-2.6. x This method provides enantiodivergent access to enantiopure (P). >95% de lactamization via counterclockwise rotation of the aryl ester ring Scheme 6.2 0 -bipyridine N. see Chapter 6.1 0 -binaphthalene affords the heterochiral diesters in good yield and up to 92% de. Scheme 6.292 Dynamic kinetic resolution of 3.N 0 -dimethyl-1. The addition of enantiopure diamines to ruthenium and rhodium complexes of BIPHEP and DMBIPHEP has been reported to give atropodiastereoisomers that are stable to isomerization at room temperature. Scheme 6.3 0 -bis(hydroxymethyl)-6.2 0 -bipyridine N.2 0 -bipyridine N.2 0 -bipyridine precursors has been developed by Hayashi.33.Asymmetric Synthesis with Stereodynamic Compounds 227 EtO O O Ph NH2 (R) OH toluene.S. Alternatively. refluxing of the (M.2.6 0 -disubstituted-2. The bridged macrocycles are stable to diastereomerization at room temperature (activation energies range from 102 to 104 kJ/mol) which permits chromatographic isolation of homo. For example. atropodiastereoselective condensation of 2-formylbiphenyl-2 0 -carboxylic acid and (S)-valinol has been reported by Wallace. coordination of a bidentate biaryl to a metal center can significantly enhance the rotational energy barrier. 2.and heterochiral products.2.x. the conformational stability of these diphosphines increases upon transition metal complexation.N 0 -dioxides from fluxional 2. Heating of an initially equimolar mixture of diastereomeric ruthenium complexes of DM-BIPHEP and (S. However.2 0 bis(chlorocarbonyl)-1.2 0 -bis(diarylphosphino)biphenyls such as BIPHEP and DM-BIPHEP undergo rapid rotation about the chiral axis at room temperature.

>99% ee R N (P) N O O R R HO N (M) HO N R O O O COCl Et3N COCl 25 oC 1. >99 de R HO 35-100%. chromatography 2. m-CPBA (M) 2. Scheme 6. 90% de R=Me: 66%. 33 oC R O N (M) O N R=H: 87%. The planar lactone bridge fulfills two purposes: it promotes intramolecular C–C coupling. >99 de R=t-Bu: 59%.228 HO OH Chapter 6 30-87%.N'-dioxide thermodynamically favored homochiral macrocycle Scheme 6. >99 de R=Me: 83%.2 0 -bridged biaryls depends strongly on the ring size and bulkiness of the ortho-substituents.N 0 -dioxides from racemic stereolabile bipyridine precursors. The majority of six-membered lactone-bridged biaryls shows rapid enantiomerization at room temperature. In the first step. m-CPBA 3. 89% de HO N R ∆. esterification of a 2-bromobenzoic acid and a phenol derivative establishes a rigid scaffold that preorganizes the two aryl rings.2 0 -bipyridine N. Bringmann et al. recognized the unique stereodynamics of these compounds and their general susceptibility to nucleophilic ring opening. >99% ee HO N (M) N O O 1. >99 de R=Ph: 75%. and more . The conformational stability of 2. 92% de R=t-Bu: 52%.32 Synthesis of enantiopure (M)-2. NaOH R O N (P) N R R O (M) O O O N (M) N R ∆G ≠ = 102-104 kJ/mol (103 C) R o + R HO N (M) + kinetically controlled esterification favors formation of the heterochiral macrocycle R=H: 59%. Nonstereoselective cross-coupling with a palladium(0) complex then generates a stereolabile racemic biaryl lactone. NaOH O O R conformationally stable N. They developed a broadly applicable atroposelective synthetic strategy based on dynamic kinetic resolution (DKR) of stereolabile lactone-bridged biaryls. this so-called lactone concept disconnects the aryl–aryl coupling step from the actual incorporation of chiral bias which is accomplished separately by stereoselective transformation of interconverting biaryl enantiomers to a conformationally stable atropisomer.34. 48 h or TFA. toluene. 66% de R=Ph: 67%.294–296 In accordance with some of the methods discussed above.

In the final step.33 Atropodiastereomerization of 2.Asymmetric Synthesis with Stereodynamic Compounds Ar Ar P RuCl2 P Ar Ar 50 °C Ar Ar P RuCl2 P Ar Ar Ph NHMe (S.34 Atroposelective biaryl synthesis based on the lactone concept (top) and axial attack of a chiral nucleophile at the lactone-bridged (M)-biaryl (bottom). importantly it dramatically reduces the rotational barrier of the biaryl axis. R CO2H atroposelective R biaryl formation OH R′ Nu* (M) O OH conformationally stable atropisomer Br + R′ esterification Nu* atroposelective lactone cleavage R O Pd(0) Br R′ O nonstereoselective biaryl coupling R O (M) O R′ fast R O (P) O R′ stereolabile enantiomers equatorial attack R O O axial attack Nu* O Nu* *Nu Nu* R′ R O R′ R O O R R′ H3O *Nu R′ HO O Scheme 6.2 0 -bis(diarylphosphino)biphenyl-derived ruthenium complexes in the presence of DM-DPEN.P) >99% de BIPHEP: Ar = phenyl DM-BIPHEP: Ar = 3.S)-DM-DPEN (P) i-PrOH Ar2 Cl H2 P N Ru N P Ar2 Cl H2 (S. atroposelective lactone cleavage with a chiral nucleophile or with an achiral reagent in the presence of a chiral catalyst results in DKR and preferential formation of one conformationally stable biaryl atropisomer. According to quantum mechanical calculations. an axial approach of the nucleophile .S.5-dimethylphenyl Ph (S) (S) Ph 229 Ph NHMe Scheme 6.

treatment of the lactone with a lithium sulfinyl carbanion generated from methyl 4-tolyl sulfoxide provides equal amounts of both diastereomers of the b-keto sulfoxide-derived biaryl. >99% de -30 C o O (M) O 85%. In the example shown in Scheme 6.230 Chapter 6 H N (P) O OH HO O Ph S O HO 73%. to the lactone unit is favored over an equatorial attack. Unfortunately.306 Atroposelective lactone opening with potassium (S)-1-phenylethylamide gives the (P)-biaryl amide in 85% yield and 90% de.34 the chiral nucleophile reacts more rapidly with the bridged (M)-biaryl.2 0 -bridged biaryl lactones.35. 90% de 0 → 25 C o KHN LiH2C S O 0 oC Ph NaO O Pd(OAc)2. PPh3 (10 mol%) R Br O NaOAc. 86% de R R R H Ph O O Al OEt Li H Ph −35 oC BH3. Employment of (R)-menthoxide and (R)-8-phenylmenthyloxide in the same enantiomer-differentiating reaction favors formation of (M)-biaryls. 78% ee (M) HO 94%.305. 88% ee Scheme 6.xii It is crucial that the nucleophilic ring opening proceeds with high stereoselectivity and incorporates sufficient steric bulk into the ortho-positions to establish conformational stability.5-dimethylphenol or other phenols affords stereolabile 2. Enantioselective reduction with either stoichiometric amounts xii The stereochemical outcome is controlled by the chiral nucleophile or catalyst used. 30 oC N B O (10 mol%) OH 94%. The scope of the lactone concept is demonstrated in Scheme 6. 0% de 95%.298 Selective addition of the nucleophile to the (M)-biaryl lactone produces a tetrahedral intermediate that forms the open (M)-biaryl phenoxide and the corresponding phenol after aqueous work-up.35 Atroposelective ring opening of a lactone-bridged biaryl. 130 oC R O (M) O R=Me: 75% R=H: 80% R=i-Pr: 72% R (P) O O i-Pr NaO i-Pr O 0 oC HO (M) O 95%. This has been attributed to fast equilibration of the 2-keto-2 0 -hydroxy-6 0 -methylbiaryl product rather than to lack of atroposelectivity during lactone cleavage. .297.299–304 Palladium-catalyzed intramolecular cross-coupling of esters prepared from 1-bromo-2-napthoic acid and 3.

I2 (P) 1. EtMgBr 2. introduced atropoenantioselective DKR of dinaphthothiophene and related dibenzothiophenes using Grignard reagents in the presence of a chiral nickel catalyst. EtMgBr 2. It has been applied in the synthesis of complex axially chiral biaryls including (–)-steganone. m-CPBA R=Ph Ph (P) S(O)Me 1.317 Shortening the length of a biaryl bridge considerably decreases conformational stability. EtMgBr (P) 2.36 Dynamic kinetic resolution of dinaphthothiophene with aryl Grignard reagents using a chiral oxazolidinylphenylphosphine-derived nickel catalyst.358–363 Uemura’s group discovered that atroposelective synthesis of nonbiaryls is . 95% ee R=Ph: 92%. Because of the synthetic versatility and the mild conditions required for the atroposelective ring opening step.344–347 Atropisomeric nonbiaryls have also been incorporated into molecular gears348–350 and used as stereochemical relays. H3O (M) S R SH 1.Asymmetric Synthesis with Stereodynamic Compounds 231 (P) Ni(cod)2 (3. Importantly.3. RMgBr. boronates and phosphines.320 In particular.351–357 Some of the synthetic strategies described in the preceding sections have been applied to axially chiral nonbiaryls.311 dioncophylline C.36. Variable-temperature NMR analysis revealed that the rotational energy barrier of dinaphthothiophenes is less than 50 kJ/mol.0 mol%) (P) S O PPh2 N i-Pr Ph 67% I 1. MeI.308 mastigophorene A and B.3 NONBIARYL ATROPISOMERS Biaryls such as BINOL and BINAP are certainly the most widely recognized atropisomers but other axially chiral compounds that do not possess a biaryl framework have received increasing attention. 95% ee R=4-MeOC6H4: 96%. This procedure affords conformationally stable biaryl thiophenols in excellent yield and ee. Ph2PCl (P) Ph 62% PPh2 Scheme 6. B(OMe)3 then pinacol Ph O B O 48% R=4-MeC6H4: 97%. Hayashi et al. and axially chiral biaryls having a five-membered bridge rapidly racemize at room temperature.310 korupensamine A. the mercapto group can easily be converted to the corresponding sulfoxide and then to a range of other synthetically versatile functionalities such as aryl iodides.316. 93% ee 91% 1. the lactone concept has found numerous applications.318 Applying the lactone concept to sulfur-bridged biaryls. imides and anilides have emerged as versatile chiral auxiliaries321–343 and ligands for asymmetric catalysis.313–315 Atropodiastereoselective synthesis exploiting the chiral plane of (Z6-arene)ruthenium complexes of biaryl lactones for intramolecular stereocontrol during nucleophilic ring cleavage is a useful alternative.312 and other targets. K2CO3 2.319 6. 20 °C 2. Scheme 6. aromatic amides. Figure 6.307 (þ)-isoschizandrin. of (P)-BINAL or borane in the presence of catalytic amounts of an (S)-2-methyl-CBS-oxazaborolidine produces the (M)-2-hydroxy-2 0 -hydroxymethylbiaryl in 94% yield and 78–88% ee.309 knipholone.

368 Walsh et al. The chromium moiety can be removed by mild oxidative photocleavage without concomitant racemization.4. developed a catalytic asymmetric N-arylation procedure for the synthesis of atropisomeric anilides. described in detail in Chapter 7. PhMe2SiCl (i-Pr)2N PhMe2Si 84%. 96% ee 2. 95% ee EX=BnBr: 90%. feasible with planar chiral (Z6-arene)chromium complexes.369 . 94% de N(i-Pr)2 O t-Bu >94% de O O N(i-Pr)2 1.6-dimethylaniline)chromium with a chiral lithium amide and subsequent electrophilic trapping yields axially chiral anilides. Taguchi et al. O N O Cr(CO)3 t-Bu 1. -78 °C CH2E Scheme 6. This dynamic kinetic resolution is applicable to inter.364. Scheme 6.37 Desymmetrization of a prochiral anilide chromium complex. catalyst ligands and relays.367 For example.232 Chapter 6 PPh2 MeO O N(i-Pr)2 O MeO2C Ph CO2Me N(i-Pr)2 O H PhMgBr O N(i-Pr)2 OH OAc Ph [PdCl(η3-C3H5)]2 Ph MeO C CO2Me 2 LiOAc O N t-Bu t-Bu O O (i-Pr)2N PhCNO Ph N O Ph 97%.38. 93% ee O N t-Bu 1. >96% de N(i-Pr)2 SiMe2Ph 77%.3 Examples of asymmetric synthesis utilizing nonbiaryl atropisomers as auxiliaries. Scheme 6.366. EX. MeI N(i-Pr)2 O 71%.37. N MeN Li N Ph t-Bu O (M) N O2. exploited a proline-catalyzed asymmetric aldol reaction for DKR of axially 2-formylbenzamides and 2-formylnaphthamides. A palladium-catalyzed nitrogen–carbon coupling step converts a stereolabile axially chiral 2-tert-butylanilide into the corresponding N-aryl atropisomer which apparently does not racemize under the reaction conditions. enantiotopic deprotonation of tricarbonyl(N-methyl-N-pivaloyl-2.365 Selective desymmetrization of prochiral chromium complexes of aryl amides and anilides is also possible. s-BuLi SiMe2Ph 2. >99% de Figure 6. s-BuLi 2.2.and intramolecular asymmetric C–N bond formation. 97% ee EX=PhC≡CCH2Br: 84%. hν 0 °C 95-98% t-Bu (M) N CH2E Cr(CO)3 EX=MeI: 90%.

The presence of a chiral center in close proximity to the stereolabile chiral axis favors the syn-conformer which readily crystallizes from solution. −78 oC fast 2. >98% ee slow N(i-Pr)2 (P) N(i-Pr)2 SiMe3 (P) (S) racemization diastereomerization Scheme 6. O N(i-Pr)2 SiMe3 (M) (S) O N(i-Pr)2 O N(i-Pr)2 SiMe3 (M) (S) O N(i-Pr)2 (M) 1. s-BuLi. Chapter 7. the TMS group can be removed with TBAF.6. 96% ee t-Bu N t-Bu 84%.M)-trimethylsilyl atropisomer through asymmetric transformation of the second kind. 97% de after crystallization 1. TMSCl O N(i-Pr)2 93%.39. 6−22 h t-Bu N O 95%. resolution of N. If desirable. 93% ee O (M)-DTBM-SEGPHOS NO2 O O O PAr2 PAr2 233 I Ar = OMe Scheme 6. (−)-sparteine fast 2.Asymmetric Synthesis with Stereodynamic Compounds O NH t-Bu + O Pd(OAc)2 (M)-DTBM-SEGPHOS t-BuOK 80 °C.N-diisopropyl-2-ethylbenzamide is achieved under thermodynamical control.Ndiisopropyl-2-ethylbenzamide in the presence of (–)-sparteine followed by silylation produces the corresponding stereolabile (S. Clayden’s group applied the principles of dynamic thermodynamic resolution (DTR) to atropisomeric synthesis of aryl amides. MeI O N(i-Pr)2 SiMe3 (P) (S) O 98% slow TBAF 0 oC O 99%. 2−6 h NO2 O NH t-Bu I Pd(OAc)2 (P)-BINAP Cs 2CO3 t-Bu 80 °C.371 6. in particular when nonracemic starting materials from .39 Atropisomeric synthesis based on DTR of a stereolabile benzamide.4 CHIRALITY TRANSFER AND INTERCONVERSION OF CHIRAL ELEMENTS The synthesis of chiral target molecules typically involves introduction of new stereogenic elements and manipulation of existing chirality. s-BuLi. This atropisomer is then trapped by ortho-lithiation and reaction with methyl iodide. Overall.370 Asymmetric lithiation of rapidly racemizing N. Scheme 6.38 Catalytic asymmetric N-arylation of anilides.

or external control with chiral agents or catalysts. Representative examples include conversion of central to axial chirality in asymmetric allene or atroposelective biaryl synthesis.40. a-hydroxy carboxylic acids.xiii The term transfer of chirality has been coined for reactions in which at least one element of chirality is translocated from one site to another. Wittig and Claisen rearrangements.i]-chirality transfer the stereogenic element is moved to a new site that is (i–1) atoms away from its original position. interconversion of chirality elements is slightly different from chirality transfer. The displacement of a substituent attached to a chiral center of an enantiopure compound without concomitant racemization and diastereomerization is a key task in many asymmetric syntheses. but the chirality of the whole molecule is maintained at all times. preferably without compromising the stereochemical purity of the substrate.. 6. The following chapters focus on reactions in which conservation of chirality is an inherent feature of chirality transfer or chiral element conversion rather than a result of stereocontrol due to the presence of other stereogenic elements within the substrate. the chiral element of a catalyst. This is routinely accomplished by bimolecular nucleophilic substitution when complete inversion of configuration is required. for example enantioselective catalysis or diastereoselective synthesis.e. Methods that enable chemists to relocate a chiral element or to transform a chiral element into another one have become powerful tools in asymmetric synthesis. This SN2 0 pathway prevails when a xiii xiv Since the original element of chirality is destroyed in these reactions. i. transfer of chirality requires destruction of the original chiral element while it is formed somewhere else.1 Chirality Transfer in SN2 0 and SE2 0 Reactions A bimolecular nucleophilic substitution at an allylic substrate involves either an SN2 or an SN2 0 mechanism. It is important to emphasize that only an element of chirality is destroyed at a specific site and simultaneously regenerated at another location. Scheme 6.xiv This can often be achieved by stereospecific reactions such as SN2 0 and SE2 0 displacements or sigmatropic Cope.372 An SN2 reaction entails a nucleophilic displacement at the tetrahedral carbon without participation of the adjacent double bond. they are sometimes referred to as self-immolative processes. amino acids. the nucleophile can approach the more distant sp2-hybridized carbon atom in the alkene moiety and replace the leaving group through a simultaneous allylic rearrangement.e. The term transfer of chirality is often inaccurately used to describe asymmetric induction during the course of a stereoselective reaction. The stereochemical outcome of a stepwise replacement of a substituent attached to an asymmetric atom via an elimination-addition pathway.. . terpenes) are available.5. for instance an SN1 reaction. Typically. In these cases. Conceptually. is less predictable and partial racemization or diastereomerization is usually observed.234 Chapter 6 nature’s chiral pool (carbohydrates. this is an intramolecular process but the chiral element may also be exchanged between two molecules in an intermolecular reaction. By definition. In an intramolecular [1. Alternatively. vide infra. but remains intact while it is exploited for preferential formation of one stereoisomer over others. Synthetic strategies based on chirality interconversion often provide access to nonracemic molecules that are difficult to obtain otherwise. It should be noted that both concepts place emphasis on overall conservation of chirality. i. reagent or substrate is not simultaneously destroyed and translocated. Several strategies that allow manipulation of the absolute configuration at an asymmetric center including Seebach’s concept of self-regeneration of stereocenters (SRS) are discussed in Chapter 6. the sterochemical purity of the product should not be compromised by simultaneous racemization or diastereomerization.4. Nucleophilic substitutions may result in complete inversion or retention of the absolute configuration at an asymmetric carbon center but SN1 and SN2 reactions do not permit translocation of a stereocenter or conversion of central chirality to a chiral axis or another chiral element. the original chiral element is destroyed while a different type of chiral element is formed without loss of the stereochemical integrity of the molecule.

i. Organocuprates. particularly when cyanocuprates are used. thus producing the (R)-(E )-isomer by anti-SN2 0 reaction with almost quantitative [1.41. In addition to regioselective assistance of a g-attack.40 Nucleophilic displacements at allylic substrates via SN2 and SN2 0 pathways. were among the first to realize the potential of allylic substitutions for efficient generation of chiral quaternary carbon centers.3]-chirality transfer. The syn/anti-selectivity of SN2 0 reactions that fulfill the criteria of true chirality transfer.. The cuprates can be generated in situ from Grignard. which are commonly used as nucleophiles in both SN2 and SN2 0 reactions. This can give rise to leaving group-directed SN2 0 displacement even in the presence of steric hindrance at the g-position.391–401 Major advantages of this transformation are excellent regio. SN2 0 reactions proceeding with high or even complete conservation of chirality have found widespread use in natural product synthesis. Employing organocuprates in the reaction with enantiopure (R)-(E )-a-alkyl-g-mesyloxy-a. the stereochemical outcome is not controlled by a chiral catalyst or auxiliary. Since the latter approach offers excellent regio. is mostly determined by . carbamate leaving groups affect the stereochemical outcome of the SN2 0 reaction. anti-SN2 0 reactions between cuprates and readily available nonracemic allylic alcohol derivatives provide a powerful means for asymmetric carbon–carbon bond formation. halides and sulfonates are usually replaced by an anti-SN2 0 mechanism in which the nucleophile attacks the double bond at the side opposite to the leaving group. Other leaving groups such as carboxylates.and stereocontrol.3]-chirality transfer. It is assumed that the nucleophilic attack preferentially occurs at the major conformational isomer.and stereoselectivity and predictability of the stereochemical outcome of the [1. The presence of bulky groups at the g-terminus impedes SN2 0 attack and therefore favors SN2 reaction whereas steric hindrance at the a-carbon favors the SN2 0 pathway. Asymmetric allylic substitutions commonly include the use of chiral catalysts.b-enoates under cryogenic conditions they obtained (R)-(E )-a. thus promoting synselectivity.g-enoates in excellent yield and ee.e.3]-chirality transfer.373–383 chiral auxiliaries. Scheme 6.402.390 The ratio of the competing SN2 and SN2 0 pathways is generally determined by the structures of the substrate. Comparison of the most likely conformations suggests that allylic A1.403 Yamamoto et al. Complexation of the cuprate generally directs the nucleophile to the same side of the leaving group. the leaving group and the nucleophile.389. direct attack at the tetrahedral center is sterically hindered and in transition metal-mediated allylic displacements. As mentioned above.384–388 or nonracemic allylic electrophiles that undergo SN2 0 reaction and simultaneous [1. organolithium and organozinc reagents by transmetalation with copper salts.Asymmetric Synthesis with Stereodynamic Compounds X R Y Nu γ β α O Nu SN2 (α-attack) SN2′ (γ-attack) O LiCuMe2 84% LiCuMe2 67% Nu O α β γ Nu O R′ Y R R′ R Y X R′ Y R R′ 235 SN2 SN2′ Scheme 6. are known to coordinate strongly to the nitrogen in carbamoyl groups.3 strain disfavors an arrangement that would lead to (S )-(Z )-isomers.a-dialkyl-b.

42 Leaving group-directed alkylation of an allylic carbamate. 94% ee (C5H11)2Zn CuCN•2LiCl -10 C o Scheme 6. 88% ee Ph Si directed syn-SN2′ Scheme 6. and when syn-substitution is desirable. >96% ee [LnRCu] (R) CO2Me H (R) TBDMSO OSO2Me (E) CO2Me RCu(CN)Li•BF3 -78 C OSO2Me EtO2C H o OTBDMS (Z) R TBDMSO (S) CO2Me H A1.405–409 Introduction of directing ortho-diarylphosphanylbenzoate leaving groups to copper-mediated SN2 0 reactions offers excellent stereocontrol. the presence of bulky groups at the g-terminus can significantly reduce the stereoselectivity of nucleophilic displacements. 93% ee R=C6H11: 79%.3 strain (not observed) OTBDMS C6F5 C6F5 O O n-Bu R2Zn CuCN•2LiCl -10 oC R n-Bu Ph C6F5 Ph (Z) O O O (E) R=C5H11: 97%.404 To overcome this limitation. The directing effect of these leaving groups is based on the affinity of organocopper species to the carbamoyl nitrogen or other heteroatoms. The allylic substitution then proceeds with high stereoselectivity and regioselectivity (SN2 0 /SN2499:1). 95% ee O (C5H11)2Zn CuCN•2LiCl -10 C o Ph (S) C5H11 84%.42. the substrate structure. 95% ee R=AcO(CH2)4: 71%. nucleophile-directing leaving groups such as carbamates and benzothiazoles are used. 95%ee R=Bn: 83%. (Z)/(E)=94:6.41 Examples of anti-SN2 0 reactions. Formation of an intermediate complex between the cuprate and the allylic carbamate prior to the SN2 0 displacement governs the stereofacial attack of the nucleophile which approaches the g-carbon atom from the side of the leaving group. Scheme 6. Although anti-attack is quite common. Coordination of the cuprate to the carbamoyl nitrogen therefore leads to highly stereo. 95% ee R=EtO2C(CH2)3: 68%. The stereochemical outcome of the .and regioselective syn-SN2 0 displacements. >98% ee R=n-Bu: 97%. Scheme 6.410 Coordination of the phosphine ligand to a cuprate prepared from a Grignard reagent and copper(I) bromide directs the nucleophlic attack to the syn-position with respect to the leaving group. Ph NH O O H PhMe2Si >94% ee PhMe2Si Me n-BuLi CuI•2LiCl i-BuMgCl i-BuCu N O O H H 90%.43.236 OSO2Me H CO2Et Chapter 6 (E) TBDMSO R R=Et: 92%. 94% ee Ph (R) C5H11 92%.

25 °C R P TBDPSO O CO2Et O H H OTBDPS R=Et: SN2′/SN2>99:1. Scheme 6. xv The syn-elimination occurs spontaneously but full conversion is observed upon addition of a base. 84%. cuprates generated from organozinc reagents preferentially approach the alkene from the side opposite to the leaving benzoyl unit to minimize steric repulsion.414. In the absence of a coordinating phosphine ligand. allylic disilanyl ethers undergo palladium-catalyzed intramolecular disilylation followed by Peterson-type syn-elimination in the presence of a strong base.43 Stereodivergent syn. −30 °C R P O O O H H OTBDPS anti-SN2′ TBDPSO CO2Et R=Et: SN2′/SN2>99:1. (E)/(Z)>99:1.Asymmetric Synthesis with Stereodynamic Compounds directed syn-SN2′ 237 Ph Ph PPh2 O TBDPSO CO2Et H2O2 O CuBr•SMe2 RMgX. .xv This reaction sequence involves formation of an intermediate four-membered trans-siloxane ring and yields chiral allylsilanes with almost perfect [1. 84%. 97% ee R=i-Pr: SN2′/SN2>99:1. see Chapter 7. Palladium-catalyzed allylic substitution is an important alternative to leaving group-directed synSN2 0 reactions if racemization can be ruled out.416 Relatively few examples of efficient asymmetric SN2 0 reactions with heteroatom nucleophiles are known.and anti-allylic substitution using either a directing or a nondirecting leaving group. (E)/(Z)>99:1.413 For example. 87%. kinetic measurements and the well-known oxophilicity of zirconium imido complexes. (E)/(Z)>95:5. 84%. (E)/(Z)>99:1.418 A noteworthy exception is the regioselective and stereospecific formation of Cbzprotected allylic amines by zirconium-mediated syn-SN2 0 displacement of electron-rich allylic (trimethylsilyl)methyl ethers.45.412.3]-chirality transfer. >99% ee EtO2C [LnRCu] Scheme 6.417. [1. (E)/(Z)>98:2.44.3]-chirality transfer can be reversed through oxidation of the directing group to a noncoordinating phosphine oxide.419 The stereochemical outcome of this transformation has been explained by a chairlike transition state that accounts for the observed syn-selectivity. 87%. This anti-SN2 0 pathway therefore produces the opposite enantiomer.415 Asymmetric alkylation of stereolabile allyl palladium complexes showing facile Z3-Z1-Z3-migration from one heterotopic face of the coordinating p-system to the other can be accomplished through dynamic kinetic asymmetric transformation. 99% ee R=n-Bu: SN2′/SN2>98:2. 99% ee R=i-Pr: SN2′/SN2>95:5.5. 85%. (E)/(Z)>99:1. Scheme 6. 98% ee R=n-Bu: SN2′/SN2>99:1.411 Initial formation of a cationic p-allyl palladium complex from a nonracemic allyl acetate and subsequent nucleophilic attack can proceed via a double-inversion mechanism with overall retention of configuration. 97% ee [LnRCu] EtO2C Ph Ph PPh2 O O TBDPSO CO2Et O CuCN•2LiCl R2Zn. The results demonstrate how incorporation of a switchable directing/nondirecting leaving group affords stereodivergent access to multi-functionalized compounds with a quaternary chiral center.

96% ee Scheme 6.1 mol%) inversion TBDMS PdL2 HO (R ) R′ R (S) R′ CO 2Me CH 2(CO2Me) 2 NaH inversion TBDMS CH(CO 2Me)2 (R) 84%.238 MeO2C OAc TBDMS (R) 90% ee Pd(PPh3)4 (0. The corresponding cationic . Cp2Zr=NTBDMS 90 °C 2. R′=C6H13: 87%.46. 95% ee n-BuLi syn-elimination + O SiPh2 H Ph2Si O R′ R SiMe2Ph Scheme 6. Stereochemical analysis of the products obtained from (R)-(E )-2-trimethylsilyl-3-pentene showed that (S)-(Z)-2-adamantyl3-pentene is formed in 60% yield while the remaining 40% consist of a nonracemic mixture of the (E )-alkene. Coordination of the (trimethylsilyl)methoxy functionality to the Lewis acidic zirconium complex generates a more effective leaving group and guides the nucleophilic imido moiety to the g-position of the allylic system. 96% ee R=CH2OTBDMS: 85%. 97% ee R=C6H11. Since electrophilic substitutions often involve cationic intermediates. Scheme 6.44 Palladium-catalyzed alkylation of an allyl acetate with complete [1. R′=C6H13: 96%. OCH2TMS R 96% ee 1.and trans-isomers of (R)-2-trimethylsilyl-3-pentene. Chirality transfer is a common feature of electrophilic substitutions such as SE2 0 displacement of allylsilanes.45 Zirconium-mediated SN2 0 displacement of allylic ethers.420 An interesting case is the Lewis acid-promoted electrophilic attack of an adamantyl cation at the cis. CbCl TMSCH2O H Cp Zr Cp H N TBDMS R NHCbz R R=Me: 91%.3]-chirality transfer (top) and formation of allylsilanes through intramolecular disilylation of allyl alcohol derivatives (bottom). Addition to the former conformation gives a cationic intermediate that undergoes elimination to the major (S )-(Z )-diastereomer. R′=Ph: 85%.421 Electrophilic displacement at the (Z )-allylsilane gives (S )-(E )-2-adamantyl-3-pentene as the major product. but reaction of the (E )-isomer affords a mixture of three stereoisomers. Rotation about the single bond connecting the cationic carbon and the trimethylsilyl-derived group apparently occurs on the same time scale and produces the minor (S )-enantiomer of the trans-product after elimination. Electrophilic anti-addition to the other major conformer of the starting material displaying the allylic hydrogen in the plane of the double bond leads to the (R)-enantiomer of (E )-2-adamantyl-3-pentene. this has been attributed to anti-attack of the adamantyl cation at two preferentially populated conformations having either the allylic methyl or the hydrogen in the plane of the double bond. 90% ee Chapter 6 R Ph2ClSiSiMe 2Ph SiMe2Ph Pd(acac)2 R′ SiMe2Ph R R O Ph2 Si H R′ Ph2Si O SiMe2Ph R=Me. 98% ee R=Me. Formation and cleavage of the two carbon–heteroatom bonds occur simultaneously at the same side of the allylic system.

99. (R)/(S)=90:10 −TMSCl H H Ad Cl electrophilic attack anti to TMS group Me3Si H Ad major conformers H H rotation H Ad H SiMe3 Ad electrophilic attack anti to TMS group H Me3Si H Cl SiMe3 H H −TMSCl Ad Cl Me3Si H SiMe3 (R) Cl (S) 99%.46 Electrophilic anti-substitution of allylsilanes using adamantyl chloride and titanium tetrachloride.9% (Z). The cationic intermediate resides in the favored conformation during elimination and (S )-(E )-2-adamantyl-3-pentene is obtained almost exclusively. 90% ee −TMSCl Ad H SiMe3 H Cl electrophilic attack anti to TMS group H TiCl4 Ad H Me3Si H Me3Si H preferentially populated conformer H H A 1. In contrast. In this case.8% (E). A1. . >98% ee −TMSCl + (S) + (R) TiCl4 40%. 99.9% (E).3 strain between the two methyl groups disfavors one conformer and electrophilic attack occurs preferentially at the major species bearing the hydrogen in the allylic plane. intermediate occupies a relatively stable conformation with the bulky groups on opposite sides and is therefore less prone to rotation prior to elimination.Asymmetric Synthesis with Stereodynamic Compounds 239 SiMe3 (R) Cl (S) 60%.3 Scheme 6. anti-SE2 0 displacement of (R)-(Z)-2-trimethylsilyl-3-pentene furnishes only one major product. 99.

4. 92% de SiMe2Ph OTMS R=n-Bu: 88%. chiral crotylsilanes show anti-SE 0 displacement and simultaneous [1.4. 6.6.3]-Cope.240 OTMS O CO2Me + R TMSOTf H H O H R CO2Me ≠ O CO2Me + SiMe2Ph R H TMSOTf H O MeO2C SiMe2Ph R H MeO2C O R MeO2C O R ≠ SiMe2Ph Chapter 6 R=i-Pr: 86%.436 the C1-C13 fragment of bistramide A. In particular.j ]-rearrangement involves a shift of a s-bond (carrying a substituent) across a system of conjugated double bonds to another site whose termini are (i–1) and ( j–1) atoms away from the original location. 80% de R=n-Bu: 88%.6-disubstituted dihydropyrans and dihydropyridines from chiral (E)-crotylsilanes. such as methyl (2S.3]-Wittig. [3.432 The formal [4 þ 2]-annulation of chiral crotylsilanes and electrophilic oxonium derivatives has been exploited by Panek’s group for the total synthesis of a range of natural products including (þ)-discodermolide.3]-chirality transfer with thionium ions.422–428 The asymmetric synthesis of 2. 88% de R=Ph: 85%.3S)-(4E)-3-(dimethylphenylsilyl)-2-(trimethylsiloxy)-4-hexenoate or its 2-amino derivative. Lewis acid-catalyzed electrophilic substitutions at allylsilanes or allylstannanes with aldehydes are more complicated but usually follow an anti-SE 0 mechanism.438 methyl L-callipeltose. By analogy with reactions with oxonium ions. [2. These transformations are discussed in Chapters 6.434 the C1-C22 fragment of leucascandrolide A. thus forming homoallylic thioethers.2 Rearrangements Rearrangement reactions resulting in transfer of chirality with predictable stereochemical outcome are extremely useful for the construction of complex chiral frameworks. On the other hand.6.4. and aldehydes formally constitutes a [4 þ 2]-annulation but in fact involves an anti-SE 0 pathway. An intramolecular anti-SE 0 process then yields the cis-2.48. Diastereomeric trans-2.47 Asymmetric synthesis of cis-2.6-dihydropyrans are obtained when (2R.and trans-2.442.440 In some cases. sigmatropic rearrangements are pericyclic reactions which have been defined as processes ‘‘in which all first-order changes in bonding relationships take place in concert on a closed curve.433 the C19-C28 fragment of phorboxazoles. which can be generated from dithioacteals in the presence of a Lewis acid. SN2 0 and SE2 0 reactions proceed with simultaneous interconversion of chirality elements.47. promotes the formation of an intermediate oxocarbenium ion that undergoes cyclization through a boatlike transition state having the dimethylphenylsilyl group in pseudoaxial orientation. >94% de Scheme 6. nonracemic propargylic compounds can be obtained by allylic displacements from axially chiral allenes.437 the C1a-C10 fragment of kendomycin.3]-Claisen and other stereospecific sigmatropic migrations with a highly ordered transition state have found numerous applications.429–431 It is generally assumed that trimethylsilyl triflate.3S)-hexenoates are applied to the formal [4 þ 2]-annulation.435. 83% de R=Ph: 87%. a strong O-silylating agent.443 . Scheme 6. [3.’’441 A sigmatropic [i.6-dihydropyrans via intramolecular anti-SE 0 reaction. Similarly to cycloadditions and electrocyclic reactions. Conversion of central to axial chirality via SN2 0 reaction of substituted allyl and alkynyl substrates provides a unique entry to chiral allenes.439 and (–)-apicularen A.5 and 6.6-dihydropyran as the major diastereoisomer. Scheme 6.

From the perspective of the migrating group.2]-shifts to a carbanionic center such as the [1.3]-migration (oxy-Cope) [3.j]-rearrangements.48 Examples of sigmatropic [i.5]-migration HO HO [3.49 Wagner–Meerwein rearrangement and [1. thermal sigmatropic rearrangements involving (4N þ 2) electrons are symmetry-allowed if both components react in a suprafacial fashion.2]-chirality transfer play an important role in terpene chemistry.2]-Wittig rearrangement are symmetry-forbidden and entail a stepwise mechanism.3]-migration (Wittig) R O H 1 1 4 3 2 H1 1O 1 1 2 R 3 3 O [1.2.448–450 Martinez described a highly enantiospecific electrophile-promoted Wagner–Meerwein rearrangement of a methylenenorbornanol derivative to enantiopure camphor Br OH X 1 OH 2 OH X X O X X=Cl: 83% X=Br: 85% X=I: 80% O X Br 1 2 Br OH Br X Br Br X Br O (not observed) Scheme 6. With regard to the p-system.3]-migration (Claisen) O [3.2]-chirality transfer. 6. In general. It is antarafacial if the bonds are made and cleaved on opposite sides. Both geometric and orbital symmetry constraints have stringent implications for reactivity and stereochemical outcome of sigmatropic rearrangements which often proceed with excellent conservation of chirality.444 The Wagner–Meerwein rearrangement has been identified as a synthetically useful stereospecific [1.2-Chirality Transfer. a rearrangement is considered suprafacial if the migrating group remains at the same side of the conjugated system. Frontier molecular orbitals and Woodward–Hoffmann rules have to be considered to determine whether a thermally or photochemically initiated rearrangement with (4q þ 2) suprafacial and 4r antarafacial components is symmetry-allowed.4. the process is suprafacial (antarafacial) if it moves with retention (inversion) of configuration.Asymmetric Synthesis with Stereodynamic Compounds 5 4 3 2 5 2 241 R R O [3.2]-shifts of an alkyl group to an adjacent carbocation are symmetry-allowed and show retention of configuration at the migrating atom.445–447 Various examples exhibiting [1. Suprafacial [1. and processes involving 4N electrons are less frequently observed because they require one antarafacial component.2]-shift with predictable stereochemical outcome. but suprafacial [1.1 1.3]-migration (aza-Cope) Scheme 6. .3]-migration (Cope) R N N R [2.

and aza-Cope reactions. Palladium-catalyzed arylation of chiral allyl alcohols and subsequent [1.3-Chirality Transfer. the socalled Nametkin rearrangement.454 Problems associated with the reversibility of Cope rearrangements can be overcome through introduction of a well-defined driving force that shifts the equilibrium to the desired product. 6. albeit in low ee. the Claisen rearrangement is more synthetically useful than the Cope equivalent which is reversible and requires higher reaction temperatures. However.1.2.2]-rearrangements of chiral a-hydroxy imines produce tertiary a-amino ketones.50. The stereochemical outcome of sigmatropic rearrangements is usually highly stereospecific and predictable. exo-migration of the neighbouring methyl group. ion stabilization in oxy. and is often independent of remote chiral elements located outside the pericyclic system of the substrate. Scheme 6. for example in aza-Cope/Mannich tandem reactions.50 [1. To predict the sense of chirality transfer one has to compare the relative stability of coexisting transition states.4. Thermal [1. This requires consideration of the absolute configuration at chiral centers residing within the pericyclic system and the double bond geometry. Scheme 6. see Chapter 6.242 SiMe3 Chapter 6 O N H 89% ee MeO OMe MeO 110 °C 3h HN O O 89% ee OMe N H >96% ee Ph Ph 110 °C 3h O HN >96% ee SiMe3 Scheme 6. antibonding orbital interactions are not possible in the energetically favored chairlike transition state. Electrophilic and nucleophilic allylic substitutions are powerful reactions because they combine synthetically useful carbon–carbon or carbon–heteroatom bond formation with [1. Among [3.2]-chirality transfer proceeds with complete conservation of chirality. analogs. see Chapter 6. the (E )-allyl vinyl .4. As a result of the strong preference for a chairlike transition state with equatorial substituents.4. Because of the different geometry.452 This reaction includes migration of an allyl or propargyl group from an asymmetric a-carbon center to the sp2-hybridized carbon of an adjacent imine function. the [1.2]-shifts.4.451 Interestingly. both reaction pathways are allowed by the Woodward–Hoffmann rules and can lead to the formation of diastereoisomeric mixtures. The high stereospecificity inherent to asymmetric Cope and Claisen rearrangements is generally explained by a chairlike transition state that is more stable than the corresponding boatlike conformation exhibiting destabilizing secondary orbital interactions. In many cases. This has been accomplished by incorporation of ring strain that is released upon rearrangement.49. was not observed. and coupling of the Cope process with other reactions. For example.2]-Chirality transfer with a-hydroxy imines.3]-sigmatropic processes.2]-chirality transfer has been reported to yield a-substituted ketones. Figure 6. Claisen rearrangement of cis.453 Nitrogen-to-carbon chirality transfer can be achieved by Stevens rearrangements and other [1. Sigmatropic rearrangements provide an equally viable alternative for stereospecific translocation of a chiral element across an allylic system.and trans-isomers of (4S )-allyl vinyl ethers comprises destruction of the chiral center at C-4 and simultaneous formation of an asymmetric carbon in position 6.3]-chirality transfer.4.2 1.

The principles of the Claisen rearrangement have also been extended to aza.and boatlike transition states of [3. and even [3. ether typically forms the (S )-(E )-product and the (Z )-allyl vinyl ether rearranges to the corresponding (R)-(E )-isomer. Heathcock et al.3]-chirality transfer can be achieved with chiral nonracemic allylic alcohols and different enol trapping reagents. For example.Asymmetric Synthesis with Stereodynamic Compounds 243 antibonding orbital interaction (E) (E) ∆G≠ chairlike transition state fast rearrangement ∆G≠ boatlike transition state slow rearrangement (E) (Z) Figure 6.475–477 and trimethylsilyl chloride (Ireland variation)478–480 are frequently used for generation of reactive ketene acetal intermediates.3]-chirality transfer have been incorporated into total syntheses of challenging natural products including lentiginosine.481 The sigmatropic .and thia-variations. Scheme 6.51. Scheme 6. These and other Claisen modifications have been incorporated into many natural product syntheses.456 blasticidin S. Scheme 6.458–468 The preparation of the allyl vinyl ether framework necessary for Claisen rearrangement and concurrent [1.52.3]-sigmatropic rearrangements.469–474 N.3S )-(E )-2-methyl1-(triphenylmethoxy)-4-hexen-3-ol to the corresponding (3S. utilized both Eschenmoser’s and Johnson’s variation to convert (2S. Orthoesters (Johnson variation).3]-sigmatropic allyl cyanate-to-isocyanate transformations have been reported. Asymmetric Claisen rearrangements with [1.455 latifoline.6R)-(E )-2-heptenoate amide and ester via in situ formation of ketene acetal derivatives at 135–140 1C.457 and others.51 Chairlike transition state geometries in Claisen rearrangements.53. R (S) (E) O ∆ R O ring inversion O ≠ R (E ) O H (S ) O (minor) (Z ) (R) H (major) R R (S) (Z) O ∆ O O ring inversion ≠ R R R (E ) O (major) (R) H O (Z) H (minor) (S) R R Scheme 6.4 Chair.N-dimethylacetamide dimethyl acetal (Eschenmoser variation).

CBr4 Et3N -20 oC O O NH2 O O 2 3 2 1 1 O O O TBSO 3 3 2 1 2 N TBSO TBSO 3 C C 1 N O Cl3CCH2OH O O HN TBSO O OCH2CCl3 82% Scheme 6.3]-Chirality transfer in Eschenmoser and Johnson Claisen rearrangements. Eschenmoser-Claisen rearrangement MeO OTr O NMe2 −MeOH OTr O NMe2 O TrO H MeO OMe N ≠ OTr O NMe2 82%.244 3 2 Chapter 6 O O 2 3 1 1 3 2 2 3 1 1 H HO H HO H2O/MeOH 80 oC HO H HO 85% H O O PPh3.53 [1.52 [1. 80% de NMe2 chair transition state 140 °C ≠ NMe2 TrO H O boat transition state 135 °C EtO OTr O EtO OEt OEt OTr OH Johnson-Claisen rearrangement OEt ≠ OTr O OEt H OEt 61%. 80% de chair transition state O TrO OEt −EtOH OTr O Scheme 6. .3]-Chirality transfer in Claisen rearrangements.

which is the driving force for the retro Claisen rearrangement. but few asymmetric versions with allyl aryl ethers are known. Scheme 6. xvi The syn-SN2 0 cyclization of the diethyl malonate derivative constitutes another case of [1. 93% ee ≠ O Eu(III) chair H O Eu(III) (1 mol%) 50 °C O Eu(III) boat H OH H OH + 97%. shifts proceed with good yield and stereospecificity.482 Aromatic Claisen rearrangements are often sluggish and of limited synthetic value due to substantial racemization.54 Lewis acid-catalyzed aromatic Claisen rearrangement.484. Claisen rearrangements are not restricted to aliphatic allyl ethers.54.3]-chirality transfer was reported by Trost and Toste. The formation of the chiral eight-membered ring is thermodynamically favored due to release of ring strain in the cyclobutane precursor.3]-chirality transfer. and other side reactions.55. Boeckman’s group gained access to a stereochemically pure vinyl cyclobutane diester that was produced in 85% yield. although a boatlike geometry that would produce the same stereoisomer is also feasible. The latter result has been attributed to two coexisting transition states possessing either a chairlike or a less favorable boatlike conformation.483 They found that europium-catalyzed migration in both cyclic and acyclic substrates proceeds with excellent enantioselectivity at ambient temperatures. although mixtures of (E ).and para-migration.and stereoselectivity. Scheme 6. (E)/(Z) = 6:1. . competing ortho.Asymmetric Synthesis with Stereodynamic Compounds 3 2 1 1O 3 2 3 1 245 Eu(III) H (1 mol%) 50 °C O 2 H 3 2 O 1 H OH O O O O O 91%.and (Z )-alkenes are obtained with acyclic allyl aryl ethers. 91% ee Scheme 6. generation of intermediate allylic cations that migrate with low regio.485 Having developed a procedure for highly diastereoselective intramolecular syn-SN2 0 displacement of an allylic carbonate group by a diethyl malonate-derived enolate.3]-chirality transfer is a key step in the total synthesis of the marine natural product (þ)-laurenyne.xvi Reduction with lithium aluminum hydride followed by oxidation with Dess–Martin periodinane gave a vinyl cyclobutane dicarboxaldehyde that readily rearranged to the desired dihydrooxocene. This has been explained by a favorable chair transition state having both alkyl substituents in equatorial positions. The first aromatic Claisen rearrangement with effective [1. A remarkable example of a retro Claisen rearrangement with [1.

Hydrolysis then generates the desired (S.3]-Wittig rearrangement of chiral allyl ethers is another powerful sigmatropic reaction exhibiting stereospecific transfer of chirality. a thermally initiated sigmatropic rearrangement involving 4N electrons must include one antarafacial component.and aspidospermatan-type alkaloids from a tryptophan derivative.or sp3-hybridized orbital and can therefore react in an antarafacial fashion.2]octane derivatives.503 Similarly to Cope and Claisen reactions.486.59. Although the [1.3]-Wittig migration of deprotonated allylic ethers proceeds via a highly ordered cyclic transition state and the stereochemical outcome can often be predicted from the double bond geometry and absolute configuration of the substrate. Dess-Martin periodinane 92% OPMB CHO CHO CHO 45 °C O PMBO >99% de Chapter 6 Cl CO2Et O retro [3.501 The [2.2]-Wittig shift.2. Aza.0]-2-hepten-6-yl acetate at 300 1C.2. >99% de CO2Et OPMB OPMB OTBS CO2Et CO2Et 1.498 The irreversible rearrangement of a benzofuran-derived norbornenyl system proceeds under relatively mild conditions and yields an important precursor of coronafacic acid.and oxy-Cope rearrangements afford synthetic entries to cyclooctanoids. For example.3]-shift involving 4N electrons is symmetry-allowed because it has one antarafacial component.60. Scheme 6. the [2. Tautomerization of the intermediate enol to the corresponding ketone shifts the equilibrium to the desired product. an atom of higher atomic number such as carbon can utilize both lobes of a p. . although highly stereospecific construction of complex carbon frameworks is feasible whenever a single transition state prevails.3]-sigmatropic rearrangement and a Mannich cyclization.58.246 TBSO TBSO TBSO O NaH O O SN2′ 85%.3]-chirality transfer and inversion of configuration at the migrating carbon atom has been accomplished with deuterated bicyclo[3.499 Upon heating to 140 1C a double Overman rearrangement occurs with quantitative chirality transfer and the corresponding diamide is obtained in literally enantiopure form. According to the Woodward–Hoffmann rules. Knochel and coworkers developed a practical procedure for the synthesis of trans-1. Scheme 6. terpenes and other natural products.55 Retro Claisen rearrangement of a strained vinyl cyclobutane dicarboxaldehyde. Impressive examples demonstrating the versatility and synthetic usefulness of Cope rerrangements include the synthesis of cis-decalins from unsaturated endo-bicyclo[2.3]-sigmatropic rearrangements. Scheme 6.500 A [2ps þ 2sa]-process with concomitant [1.491–497 An intriguing case of an anionic oxy-Cope reaction with double [1.3] (+)-laurenyne Scheme 6.S )-diaminocyclohexene.504–507 The [2. This is not observed. a thermal [1.3]-Wittig rearrangement is sometimes accompanied by the nonpericyclic [1.xvii The five-membered transition state is more flexible than the well-defined six-membered chairlike geometry of [3. Cope rearrangements are not as frequently employed in asymmetric synthesis as the Claisen variants.56. The latter exploits a reaction cascade including a [3.57. LiAlH 4 93% 2. In this reaction both asymmetric centers at C-1 and C-1 0 are destroyed while new chiral elements are generated at carbons 3 and 3 0 . Scheme 6.487 and the diastereoselective synthesis of strychnan.3]chirality transfer was observed by Jung and Hudspeth. in particular when allylic benzyl and propargylic ethers are present. In this case a thermal [1.3]sigmatropic shift of hydrogen across an allylic system is symmetry-allowed if the process is antarafacial. which somewhat reduces stereocontrol and the synthetic value of the [2.502. which means that the hydrogen must migrate from one side of the conjugated system to the other.3]-migration. since it is not feasible for geometric reasons.2]-rearrangement xvii The Wittig rearrangement can be considered an orbital symmetry-allowed [2ps þ 2sa þ 2sa]-process.3]-rearrangements of an allylic diimidate.2diamino-3-cyclohexene based on two consecutive sigmatropic [3.488–490 Scheme 6. However.

.57 Anionic oxy-Cope rearrangement with double [1.Asymmetric Synthesis with Stereodynamic Compounds OMe OMe 2 3 1 1 2 2 3 1 247 H >95% MeO H H 250 °C 2 3 3 1 H H 150 °C endo H CO2Bn NHBn R CHO >95% exo no reaction CO2Bn NBn −H CO2Bn NBn R N H CO2Bn CO2Me PhCO2H 70 °C BnO2C N H CO2Me R BnO2C N CO2Me NBn 1 2 1 3 NBn 1 NBn 2 Cope R 1 2 3 R 3 +H R N H CO2Bn NBn −H N H 2 3 CO2Me CO2Bn NBn N H CO2Me CO2Me R N MeO2C N H R CO2Me R=Me: 51% R=4-MeOC6H4: 74% Scheme 6.3]-chirality transfer.56 Sigmatropic Cope rearrangements with [1. MeO HO OMe MeO O 1 OMe 1′ 2′ MeO O 1 2 OMe H 1′ 2′ 3′ 3 O H 2O H O H H OMe OMe NaH O 65 °C O 2 3′ 3 O 88% Scheme 6.3]-chirality transfer.

3] 2 1 2 3 O chirality transfer to positions 3 and 4 R′ 3 H R R′ ≠ H [2. R′=benzyl. R 1 1 2 3 2 R base O R′ ≠ H R [2.2.60 Stereochemical outcome of the [2.3] R 1 1 HO 2 R 1 2 3 2 base O H R′ O 1 2 1 R= alkyl.2] O 2 1 HO R′ 2 R′ R′ Scheme 6.3]-rearrangement of deuterated bicyclo[3.3]-shifts.2]-Wittig shift (bottom). Orbital symmetry-allowed hydrogen and carbon [1.3]-Wittig rearrangement (top) and the [1. . 3 2 1 H AcO H [1.248 CCl3 O (S) OH CCl3CN NaH (S) OH HN O CCl3 HN O CCl3 O NH Cl3C O CCl3 140 °C (S) NH NH CCl3 (S) N H O NaOH Chapter 6 (S) (S) NH2 NH2 65% 56%. and participating frontier molecular orbitals (bottom).0]-2-hepten-6-yl acetate with inversion of configuration at the migrating carbon atom (top).3]-shift 300 oC D D C-inversion AcO H >95% H ≠ H AcO H (symmetry allowed but not observed) D D = bonding orbital overlap H H OAc H D H AcO H Scheme 6.59 Suprafacial sigmatropic [1.58 Double Overman rearrangement. propargyl R′ R′ 1R 1 1R HO 1R base O 2 1 [1. >99% ee Scheme 6.

Asymmetric Synthesis with Stereodynamic Compounds ≠ H O n-BuLi −85 °C 98% ee SiMe3 Me3Si H C6H13 N N LDA −78 °C CO2t-Bu C6H13 Me2Si 98% ee O 0 °C O H Ot-Bu C6H13 n-BuLi Me2Si Li ≠ Bn2N CO2Et O m-CPBA −50 °C R R = Me. >99% de H C6H13 ≠ O H 249 HO SiMe3 64%. involves a transient radical pair it can be highly stereoselective. TBDMSOCH2 R ONBn2 70−80%.62 Palladium(II)-catalyzed migration of an acetyl group across an allylic system. Me2CHCH2.2]-shift when low temperatures are applied. >99% (E). an impressive range of [2.514 sila-. TBSO CO2Et Pd(MeCN)2Cl2 C5H11 O H OAc +Pd(II) PdL2 C5H11 O O O TBSO CO2Et 1.3]-Wittig rearrangements of allyl ethers has been reported. >98% ee SnMe3 Scheme 6.511–513 phosphorus-. Bn.509.510 To date.515 and aza-variants516–518 are also known. >99% de.61 Examples of [2. >95% ee Bn2N CO2Et R CO2Et O Me2Si OH 88%. O H OAc −Pd(II) PdL2 C5H11 O O PdL2 C5H11 O O TBSO CO2Et C5H11 THPO H 69% OAc Scheme 6. but it is not as synthetically useful as the pericyclic [2.508 The latter usually prevails over the [1. and sulfur-. 97% ee C6H13 C6H13 N CO2t-Bu H 98%.3]-variant. .3]-Wittig and Meisenheimer rearrangements. NaBH4 C5H11 2.

2 LDA.564 Dihydropyrans are known to rearrange through a boatlike transition state because a chairlike geometry would yield conformationally strained (E )-cyclohexenes.562 The (E )-silyl ketene acetal undergoes stereospecific Ireland–Claisen rearrangement with [1. the latter is sterically less favored and the corresponding (R)-(Z )-isomer is formed in only syn-1.4-Chirality Transfer.546–549 The usefulness of transition metal-catalyzed allylic [1. Scheme 6.6.5-diene in 87% yield and more than 94% ee.4S.64.565–567 Accordingly.550 The palladium-catalyzed allylic transposition of the acetyl group across the allylic system shown in Scheme 6.2-syn-stereochemistry to a 1. Paterson’s group utilized trimethylsilyl chloride to trap the kinetically favored ester enolate of (3S.542–545 Mercury(II).3]-rearrangements with a chairlike transition state.4]-chirality transfer in Cope rearrangements of cyclic and acyclic systems are known. and offer an additional entry to [1. unless this is not feasible due to steric or geometric constraints.3]-migrations for the total synthesis of prostaglandin congeners has been demonstrated by Danishefsky’s group. Sigmatropic Claisen rearrangements with simultaneous [1.4]chirality transfer are quite common and have been implemented in the total synthesis of many natural products. Some examples of [1.3]-chirality transfer based on a nonpericyclic mechanism with an intermediate p-allyl transition metal complex.8-trimethyl-7-(propanoyloxy)-1. By analogy with more flexible acyclic compounds.62 is irreversible and strictly suprafacial.8-nonadien5-one. involves a sigmatropic [2.5 60 °C O 83%.2.4]chirality transfer and conversion of the original 1. As expected.3]-shift and offers stereospecific access to chiral hydroxylamines. the stereochemical outcome of pericyclic rearrangements is generally controlled by the relative stability of competing chair. 92% de OTBDMS O O OTMS chairlike transition state OTBDMS Scheme 6.551–561 In an elegant approach to b-lactone enzyme inhibitors (–)-ebelactone A and B. As mentioned above. This reaction can occur via two chairlike transition states with the phenyl group either in equatorial or axial position.3 1.519–532 The intrinsic stereospecificity of Wittig rearrangements of both allylic ethers and vinylaziridines has been exploited for the synthesis of N-heterocyclic alkaloids533–535 and other natural products. Diastereoselective reduction of the cyclopentanone moiety and protection of the corresponding alcohol furnishes the desired tetrahydropyranyl ether in 69% overall yield.5-diene at 250 1C gives (S )-(E )-3-methyl-6-phenylhepta-1. . Scheme 6.568 Thermal rearrangement of (R)-(E )-3-methyl-3-phenylhepta-1. 6. TMSCl O O O OTBDMS −78 °C TMSO O (E) ≠ O OTBDMS HO O syn-1.61.4]-chirality transfer.4.63 Stereospecific Ireland–Claisen rearrangement and [1.63. the thermal rearrangement of lactonic silyl enolates derived from dihydropyrans and seven-membered analogs produces (Z )-cycloalkenes. which are readily prepared by oxidation of amines with m-chloroperbenzoic acid.and boatlike transition states. ring systems favor sigmatropic [3.6R.and palladium(II)-mediated allylic rearrangements are somewhat reminiscent of sigmatropic shifts.5-syn-relationship.7R)-3-[(tert-butyldimethylsilyl)oxy]-2-ethyl-4.536–541 The Meisenheimer rearrangement of allylic tertiary amine oxides.563.250 Chapter 6 Scheme 6.

66.3]-Wittig rearrangements often proceed with [1. As a result. the chiral information can be transferred one atom further across the newly formed s-bond.571 The oxyvariation occurs under considerably milder conditions than the Cope reaction and with excellent conservation of chirality.65 Cope rearrangement of (R)-(E)-3-methyl-3-phenylhepta-1. the intermediate oxyanion group favors an equatorial position and exo-bond formation.3]-chirality transfer along the allylic system. The diastereoselectivity of the rearrangement decreases if an exoattack involving a conformer with an equatorial oxyanion is not feasible. The rearrangement of (R)-4-(2-norbornenyl)-but-3-en-2-ol generates 59% of the exo-product in over 98% de. ≠ Ph 250 °C Ph Ph Ph Ph Ph (E) (S) 87%. Alternatively. the oxy-Cope rearrangement of the (S)-diastereoisomer affords a similar yield but only 82% de. ≥94% ee Scheme 6.64 Ireland–Claisen rearrangements with simultaneous [1.4]-chirality transfer in oxy-Cope shifts of cyclic molecules including norbornenyl derivatives.5-diene. Scheme 6.67.3].570.and [1. uncovered that sigmatropic [2.576–578 .3]-rearrangements of propargylic ethers generate chiral allenes based on [1. As shown above.4]-chirality transfer and conversion of central to axial chirality. ≥94% ee (Z) Ph (R) 13%.Asymmetric Synthesis with Stereodynamic Compounds ≠ H O 4 3 1 2 251 105 °C H OTBDMS HO2C R boatlike TS ≠ R=H: 63% R=Me: 75% R=Ph: 77% R (Z)-cyclohexene TBDMSO O R O R OTBDMS (E)-cyclohexene H chairlike TS (not observed) TBDMSCl O O CO2H 105 °C O TBDMSO 73% Scheme 6.569 Paquette et al. Scheme 6. [2.65.572–575 Marshall et al. studied the stereochemical course and [1.4]-chirality transfer. Scheme 6. 13% yield. Apparently.

252 ≠ KH (R) OH 50 °C Chapter 6 H O equatorial oxyanion exo-bond formation H O axial oxyanion endo-bond formation 59%. 98% (E).2.4. 59% ee ≠ HO2C O t-Bu LDA −78 °C t-Bu O2C O HO • t-Bu 85%. Accordingly.4Z)-2-deuterio-6-methyl-2. partly due to lack of reaction control.4 1.66 Oxy-Cope rearrangement of diastereomeric norbornenyl derivatives. 82% de. 98% (E). ≠ 3 4 2 1 n-BuLi O −85 °C O HO 90%.4]-chirality transfer. hydrogen migration from an asymmetric carbon center across two double bonds of the s-cis-diene framework of (S)-(2E. a carbon substituent migrates with retention of configuration in order to comply with Woodward–Hoffmann rules. 6.5]-hydrogen shifts are highly stereospecific they have found few synthetic applications.67 [2.5]-migration involving (4Nþ2) electrons can have either two suprafacial or two antarafacial components. 84% ee O n-BuLi (CH2)10 −85 °C (CH2)10 51%.3]-Wittig rearrangements resulting in [1. >98% de CHO CHO 57%.580 For example.579.xviii Although [1. 93% ee CO2H OH Scheme 6.4-octadiene xviii A thermal suprafacial [1.5-Chirality Transfer. . A symmetry-allowed thermal [1. 82% de ≠ KH (S) OH 50 °C O H axial oxyanion exo-bond formation O H equatorial oxyanion endo-bond formation Scheme 6.5]-shift of hydrogen and carbon constitutes a symmetry-allowed [4psþ2ss]-process.

69 Regioselective suprafacial hydrogen shift with [1.4.E)/(S.582.5:1 4 3 Me (not observed) Ph T D (S) Me D (S) Me 5 Et D (S) 1 2 250 °C Me D (S) Et H (Z) Me T 200 °C t-Bu H H Me Me >99% (E) endo-conformer H exo-conformer t-Bu H Scheme 6.581 The presence of a sterically demanding tert-butyl group destabilizes the endo-conformation and exclusive sigmatropic rearrangement of the prevailing exo-isomer is observed. The competing suprafacial hydrogen migrations form a mixture of diastereoisomers despite complete conservation of chirality during each [1.69.5-trimethoxyphenyl)-3H-2-benzopyran-3-one derivative is followed by carbon dioxide extrusion and subsequent migration of hydrogen from C-3 to the carbon bearing the phenyl ring. Diels–Alder reaction of dimethyl maleate and a 1-(3. Interestingly. O O O O O CO2Me O CO2Me 140 °C MeO O O CO2Me −CO2 CO2Me O O 4 H H 3 1 2 O O H 71% CO2Me H CO2Me CO2Me CO2Me MeO MeO OMe MeO H H OMe MeO OMe OMe MeO OMe OMe O 4 H H 3 1 2 O CO2Me O H CO2Me CO2Me O O O O O CO2Me MeO MeO OMe MeO OMe (not observed) OMe MeO OMe OMe 4-deoxypodophyllotoxin Scheme 6. showed that interconversion of endo.Z )=1.5]-hydrogen shifts along s-cis-diene frameworks. Scheme 6. an important precursor of 4-deoxypodophyllotoxin and other chiral lignans.583 This stereospecific hydrogen shift produces a cis-dihydronaphthalene.5]sigmatropic shift. Scheme 6.5]-chirality transfer. Mulzer et al.5]-hydrogen shift has been realized with an o-quinodimethane intermediate carrying cis-oriented methoxycarbonyl groups.68 Stereospecific suprafacial [1. (R. .and exo-isomers can be avoided by incorporation of steric bulk into the asymmetric carbon center. A regioselective suprafacial [1.68.Asymmetric Synthesis with Stereodynamic Compounds 4 3 253 Ph Ph H H (S) H 2 Me 5 H 1 250 °C (R) T Me (E) 200 °C T (R) t-Bu D (Z) D (S) exo-conformer Me Me D Et Et D t-Bu endo-conformer Ph Me 73%. engages two rapidly equilibrating conformers.

but overall chirality is perfectly conserved in the newly formed a-hydroxy ester. the chirality of (S)-N-benzyl-3-(hydroxymethyl)-4-methyl-1.585 6.595. Scheme 6.586. 95% ee Scheme 6.4. Similar asymmetric [1.5]-migration of the hydrogen at C-2 to C-4 is also symmetry-allowed but is not observed. 54% ee R=2-naphthyl: 58%. In one of the more successful approaches.4-dihydropyridines. Intermolecular chirality transfer has been accomplished in asymmetric Meerwein–Ponndorf– Verley reactions588–594 and reductions of ketones with chiral metal hydrides. Scheme 6. 70% ee R=2-bromophenyl: 51%.597 The stereochemical outcome can be explained by the formation of a cyclic six-membered transition state in which the carbonyl substrate and the secondary alkoxide coordinate to the metal center. .4-dihydropyridine is transferred to the prochiral ester which is reduced to (S)-methyl mandelate.584. 82% ee Ph Cl O 0 °C O Ph R O Cl Scheme 6. A quite intriguing case arises during asymmetric reduction of methyl benzoylformate with chiral 4-methyl-1.70.596 but moderate enantioselectivities are usually observed. As a result of the hydride transfer the central chirality of the reducing agent is destroyed as the achiral pyridinium salt is formed. xix Dihydropyridines are frequently used as NADH analogs in biomimetic transformations.xix In this reaction.5]-hydride shifts have been reported for intramolecular Meerwein–Ponndorf–Verley/ Oppenauer reactions of hydroxyketones.598 The aluminate complex enhances the nucleophilicity of the chiral hydride donor while coordination H OH + N Ph 95% ee Ph O CO2Me Ph Mg(ClO4)2 N OH HO H + Ph CO2Me 94%.71.587.3 Intermolecular Chirality Transfer Most examples of chirality transfer are intramolecular processes. but chiral elements can also be relocated in intermolecular reactions.71 Intermolecular chirality transfer in a Meerwein–Ponndorf–Verley reduction.70 Intermolecular chirality transfer with a chiral NADH mimic. R (R) OH (PhMeHCO)2Al O O Al(OCHMePh)2 L 5 mol% L Al O H R Ph (S) Cl OH R=Ph: 82%.254 Chapter 6 [1. Maruoka’s group utilized stoichiometric amounts of (R)-1-phenylethanol and other chiral secondary alcohols in the presence of an aluminum catalyst for reduction of 2-chloroacetophenone.

and [2. 6. allylic N-oxides undergo Meisenheimer rearrangements with concomitant transfer of stereogenicity from the configurationally stable nitrogen to a remote carbon atom.3]-migrations.3]-sigmatropic Meisenheimer rearrangement of a chiral N-oxide.3]-migrations.2]. This arrangement favors Re-facial attack at 2-chloroacetophenone and formation of (S)-2-chloro-1-phenylethanol. Important alkaloids consisting of bicyclic pyrrolizidine.605. Scheme 6. Nitrogen-to-carbon chirality transfer has been achieved by [1. Comparison of two orbital symmetry-allowed doubly suprafacial five-membered transition states suggests that the absence of a nonbonding interaction between the 4-tolyl moiety and the allylic methyl group favors the pathway to the (S)-enantiomer. copper carbenoids generated from vinylpyrrolidine-derived a-diazo ketones form spirofused ylides that generate bicyclic amines through [2.0]undecene.72. Scheme 6.3]-rearrangements of chiral N-oxides and nitrogen ylides or via Stevens rearrangement of quaternary ammonium salts. This takes place through an endo-transition state having the vinyl group in equatorial position and pointing to the incipient eight-membered ring.and [2.599–604 In accordance with the stereochemical course of sigmatropic [2.4. Chirality transfer based on destruction of stereogenicity at a sulfur atom and simultaneous generation of an asymmetric carbon center has been achieved with allylic and benzylic sulfonium ylides. the two rapidly interconverting diastereomeric pyrrolidine-derived copper carbenoids afford an intermediate that further reacts to the corresponding (R)-(Z)azabicyclo[6.3]-rearrangement to a chiral ≠ H N O N (R) O ≠ H N O H O (S) N 87% H O (R) N 13% Scheme 6.606 The thermally initiated concerted rearrangement of (R)-trans-crotyl-N-methyl-4-toluidine N-oxide gives (S)-O-methylvinylcarbinylN-methyl-4-tolylhydroxylamine in 87% yield.2]. indolizidine and quinolizidine cores can be prepared from chiral ammonium ylides by stereospecific [1. To minimize steric repulsion. The translocation of stereogenicity is often accomplished with sigmatropic rearrangements exhibiting complete conservation of chirality.612 Since ylide formation preferentially occurs at the pyrrolidine side bearing the vinyl group.613–616 The formation of a reactive sulfur ylide from (S)-1-adamantylallylethylsulfonium tetrafluoroborate with potassium tert-butoxide entails sigmatropic [2. . the largest groups of the two reagents preferentially reside on opposite sides of the cyclic transition state.607–611 For example.3.4 Transfer of Stereogenicity Between Carbon and Heteroatoms The transfer of chiral information between carbon and heteroatoms provides unique access to a range of chiral compounds.72 Transfer of stereogenicity from nitrogen to carbon during [2.73.3]-migration with complete nitrogen-to-carbon chirality transfer.Asymmetric Synthesis with Stereodynamic Compounds 255 of the ketone to the Lewis-acidic metal ion increases the electrophilicity of the hydride acceptor.

The presence of the chiral carbon center in the propargylic silyl ether has no influence on the stereochemical outcome since employment of the (S.75. Scheme 6. The introduction of the new chiral carbon center to the rearranged carbon skeleton can therefore be attributed to net silicon-to-carbon chirality transfer. Et S Ad (S) BF4 : t-BuOK Ad : S S Ad 94% ee (R) H Scheme 6. the scope of asymmetric synthesis with chiral sulfonium salts is limited because of the inherently low energy barrier to racemization. Scheme 6. However.SSi)-diastereomer in the same reaction sequence gives the (S.5anti-diol. sulfide.3]-rearrangement of a spiro ammonium ylide.74 Transfer of chirality from sulfur to carbon via a folded envelope conformation of an intermediate sulfonium ylide. The reaction is solely controlled by the asymmetric silicon atom and proceeds without loss of stereochemical integrity.5-syn-diol and tert-butyltrifluorosilane upon addition of TBAF.xx Virtually complete chirality transfer from silicon to carbon is obtained with a strained allylic silacycle that can be prepared by rhodium(I)-catalyzed silylformylation of a propargylic (S.73 Synthesis of an (R)-(Z)-azabicyclo[6.618 The five-membered silacycle is prone to spontaneous intramolecular allylation and forms a bicyclic siloxane that is readily cleaved to the (S. However.xxi xx xxi Sulfonium salts undergo facile pyramidal S-inversion in solution at ambient temperatures. the destruction of silicon stereogenicity and the generation of a new chiral carbon center do not occur simultaneously but in consecutive steps. .RSi)-silyl ether precursor.0]undecene via [2.S)-1.3.617.256 Chapter 6 O N : H O N Cu(acac)2 (2 mol%) N2 : O N − δ + δ CuLn N H O (S) H O δ CuLn δ+ O − 56% N endo H N (R) H O N H favored cyclization route H exo N O N (R) H O possible ylide intermediates Scheme 6.R)-1.74.

The two elements of central chirality in the (S.621 Addition of 1-naphthyllithium to an enantiomerically pure 3-quinolyl oxazoline and subsequent removal of the chiral auxiliary establishes a chiral center at C-4 in .4.2 and 6. dr = 90:10 Ph OH Ph TBAF O Si O O t-Bu Si O t-BuSiF3 OH 43%. elimination of HCl produces the corresponding (M)-1-phenylnaphthalenes in good to high yields and without any sign of racemization. The reaction course is reminiscent of the concept of regeneration of stereogenicity via stereolabile chiral intermediates discussed in Chapter 6. As a result. In most cases this requires three steps: covalent attachment of the chiral auxiliary. see Chapters 6.2-dichlorocyclopropylmethanol are destroyed as the chiral information is stored in the incipient biaryl axis.Asymmetric Synthesis with Stereodynamic Compounds 257 t-Bu Si (R) O H Ph (S) dr = 90:10 Rh(I) (10 mol%) CO Ph t-Bu t-Bu O Si O Ph Ph TBAF OH 38%. and removal of the auxiliary under carefully selected conditions to avoid concomitant racemization.2-dichlorocyclopropylmethanols. Scheme 6.S)-diaryl-2. Subsequent elimination of the hydroxyl group then generates a cationic intermediate that undergoes benzannulation to an axially chiral 1-phenyl-3.S)-diaryl-2.S)-dichlorocyclopropyl alcohol moiety initiates rotation of the adjacent phenyl ring to reduce steric interactions with the Lewis acid.3. atroposelective transformation.75 Formation of 1. A direct conversion of central chirality to an atropisomeric framework within a single reaction is a much more efficient synthetic alternative. 6. Interconversion of central to axial chirality in a single step without loss of stereochemical integrity has also been observed during mild oxidation of enantiomerically enriched (S)-4-(1naphthyl)dihydroquinolines.5 Conversion of Central Chirality to Other Chiral Elements Atroposelective synthesis often relies on translation of central to axial chirality based on asymmetric induction with a temporary chiral template or asymmetric transformation of the first and second kind.619 This has been accomplished through Lewis acid-promoted benzannulation of enantiopure (S. the ortho-substituent R 0 preferentially occupies the opposite side of the chelation complex.5.76.4-dihydronaphthalene.3.620 Regioselective coordination of titanium tetrachloride to the (S. dr = 88:12 OH t-BuSiF3 t-Bu t-Bu Si (S) O H Ph (S) dr = 88:12 Rh(I) (10 mol%) CO Ph t-Bu t-Bu O Si O Ph Ph O Si O O Si O Scheme 6.5-diols from strained allylic silacycles. A general drawback of these methodologies is the necessity of an auxiliary for introduction of axially chiral bias. Finally.

Because the naphthyl ring attached to the chiral center can freely rotate about the naphthyl–dihydroquinolyl bond the sense of axial chirality is not established prior to oxidation and this reaction constitutes a true example of chirality interconversion.2. Another viable approach to axially chiral biaryls entails dehydration of an enantiopure 1-naphthyl-1. Dehydrogenation of the sample having 95% ee with DDQ at elevated temperature affords (M)-2 0 -methoxy-2-methyl1.624 Since axially chiral allenes have been identified as versatile building blocks for asymmetric synthesis. 4-(1-naphthyl)-1. >99% ee R=Cl. Scheme 6. R′=Cl: 65%.258 Cl Cl Cl (S) (S) R OH TiCl4 R′ −78 oC R Cl Cl TiCl4 OH R′ −OH R R′ −H R R′ −HCl R Cl Cl Cl Chapter 6 Cl (M) R′ >99% ee R=Cl. Despite the attractive features of this strategy. R′=Me: 71%.78.4-dihydroquinoline-3-carboxaldehyde. R′=Cl: 70%. trifluoroacetic anhydride-mediated elimination of water in these solvents gives (M)-3. Scheme 6. corresponding to 86% and 34% de.3 in dichloromethane and 1:1. Oxidation of the dihydroquinoline with DDQ under cryogenic conditions then results in stereoselective transformation of the asymmetric center to a chiral axis. few examples of natural product synthesis based on one-step interconversion of central to axial chirality have been reported to date. >99% ee Scheme 6. indicating that chirality interconversion coincides with dynamic kinetic asymmetric transformation. respectively. NaBH4 (S) N H H DDQ CHO −78 °C −78 °C Ph 76% de MeO (P) CHO N H 76% ee N 80% ee Scheme 6.4-tetrahydronaphthalene-1-ol that is readily available through ytterbium triflatecontrolled diastereoselective addition of 2-methoxy-1-naphthylmagnesium bromide to 2-methyl1-tetralone. MeOSO2F 2.2-dichlorocyclopropylmethanols. the development of stereoselective methods providing access to this class of compounds . >99% ee R=Me. respectively. >99% ee R=MeO.76 Conversion of central to axial chirality via Lewis acid-promoted benzannulation of enantiopure (S.622 The tertiary alcohol exists as a mixture of two interconverting conformers in a ratio of 1:6.4-dihydro-2 0 methoxy-2-methyl-1. Ph N O N Li H O N OMe 1.623.77.9 in benzene. >99% ee R=MeO.77 Generation of axial chirality by oxidation of 4-(1-naphthyl)-1.1 0 -binaphthalene in 95% or 82% ee.3.4-dihydroquinoline-3-carboxaldehyde. R′=Cl: 47%. R′=H: 97%.1 0 -binaphthalene in 83% ee due to partial racemization. Although axial chirality is already present prior to the dehydration step. and because of the abundance of allenic pharmacophores and subunits in natural products.S)-diaryl-2.

79. however. It should be noted. The final step produces an axially chiral allene while the catalytically active Pd(0) species is regenerated. Chapter 6.Asymmetric Synthesis with Stereodynamic Compounds MeO O (R) 259 (R) Yb(OTf)3 (R) OH 1:6. MsO C6H13 R R • Pd(PPh3)4 (5 mol%) 96% ee C6H13 Ph PhZnCl R • C6H13 Ph MsO R=CF3: 77%.625–638 However.3 (CH2Cl2) (CF3CO)2O 1:1. 96% ee H C6H13 Pd(0) R oxidative addition C6H13 • H reductive elimination R C6H13 • R H PdPh H PdOMs MsOZnCl PhZnCl transmetalation Scheme 6.9 (C6H6) −H2O 25 °C 95% ee (CH2Cl2) 82% ee (C6H6) (R) (R) + MgBr OMe (M) OMe DDQ 80 °C (M) OMe 83% ee OH OMe Scheme 6. chirality conversion not only plays an important role in the synthesis of allenes.4.79 Palladium-catalyzed synthesis of axially chiral allenes from propargylic mesylates.639 Copper. has received considerable attention.640 An important example is the palladium-catalyzed reaction between propargylic mesylates bearing perfluorinated alkyl groups and phenylzinc chloride shown in Scheme 6. that Pd-catalyzed SN2 0 reactions of chiral propargylic or allylic alcohol .642 Oxidative addition of the palladium catalyst initially forms an allenylpalladium species that undergoes transmetalation with the organozinc reagent and subsequent reductive elimination with retention of configuration.1 0 -binaphthalene.641 The reaction course and interconversion of chirality elements can be explained by anti-SN2 0 -type removal of the mesylate group. the chiral axis of allenic starting materials is also often utilized to gain access to compounds exhibiting central chirality.and palladium-mediated SN2 0 attack of suitable nucleophiles at nonracemic chiral propargylic substrates provides axially chiral allenes.78 Atroposelective formation of (M)-2 0 -methoxy-2-methyl-1.6. 96% ee R=C2F5: 70%.

. A conceptually different approach to axially chiral allenes involves tetrabutylammonium fluoride-promoted anti-elimination of tributyltin acetate from allylic esters.2. SN2 0 reactions of propargylic alcohol derivatives with organometallic reagents644–647 or hydrides648 and SN 0 0 -type substitutions of enyne acetates649.1.xxii To date. 94% ee C6H13 Scheme 6. 92% ee R=s-Bu: 94%.2-diols provide convenient access to nonracemic helical (E)-cycloalkenes. For example.4.643. In some cases.2. but trapping of the lithium salt with various electrophiles usually yields products in low enantiomeric purity. xxiii An SN 0 0 reaction is similar to an SN 0 displacement but occurs with simultaneous rearrangement of two double bonds.260 O (S) RMgBr CuBr or CuCN•2LiBr (10 mol%) −78 °C BnO OH H Me 94% ee SnBu3 F 0 Chapter 6 R • OBn R=Me: 92%.2]oct-5-ene-2-one.1.81. Transmetalation of such a diastereomerically pure (–)-sparteine complex with titanium chlorotriisopropoxide has been reported to proceed with inversion of configuration.6-hexamethyl-1-sila-4-cycloheptene through xxii Racemization during Pd-catalyzed SN2 0 reactions is almost negligible when perfluorinated alkyl groups are present in the propargylic substrate.3]-Wittig rearrangement of propargylic ethers. The corresponding fused ring framework already displays a helical structure and after four further steps (P)-2-acetoxy-11. Conversion of central to helical chirality has been realized through aromatic oxy-Cope rearrangement of (1R. preparative HPLC enantioseparation of 1. 93% ee R=CH2CN: 79%. Cyclic trans-1.6.5-cycloheptanediol.3. 93% ee R=i-Pr: 92%. asymmetric transformation of the second kind furnishes a pure lithiated propargylic stereoisomer. This is probably due to the low configurational stability of (–)-sparteine-derived propargylic complexes.6-hexamethyl-1-sila-trans-4. and treatment of the corresponding titanate with aldehydes affords a range of 4-hydroxyallenyl carbamates.8-dimethyl-3-phenanthryl)-2-ol which can be prepared in 60% yield by addition of a phenanthryl Grignard complex to (1R.4S)-1-methoxybicyclo[2. Scheme 6.3.6. 90% ee O (M) HO2C OAc H Me SnBu3 (R) C6H13 Bu4N F (R) C6H13 Ac2O.651 Deprotonation of alkynyl carbamates may occur with high enantiotopic selectivity.S )-enantiomer to the corresponding thionocarbonate. Scheme 6. see Chapter 6.xxiii are the most common methods for the synthesis of allenes based on central to axial chirality conversion.3.80 Copper-catalyzed SN2 -type ring opening of alkynyl-substituted b-lactones with Grignard reagents (top) and chirality conversion during stereoselective deoxystannylation of (R)-(Z)-3tributylstannyl-3-decene-2-ol (bottom).2S.2]oct-5-ene-2-(5. Enantioselective lithiation of prochiral Cb-protected propargylic alcohols with butyllithium in the presence of (–)-sparteine followed by transmetalation and treatment with aldehydes or acetic acid offers another route to chiral allenes. and conversion of the levorotatory (S.3. paved the way to (–)-(R)-(E )- DMAP 81% H Me H • (P) 42%.14dimethyl[5]helicene is obtained in literally enantiopure form. derivatives are frequently accompanied by partial or even complete racemization.4S )1-methoxybicyclo[2.652 The rearrangement is initiated by potassium bis(trimethylsilyl)amide in the presence of 18-crown-6 at 0 1C. Scheme 6.650 Allenylcarbinols can be prepared via stereospecific [2.

crystallization O O 1.3.Asymmetric Synthesis with Stereodynamic Compounds i-Pr2N H H 2. 6. Corey–Winter elimination using 1.4.653 Stereospecific syn-elimination of the intermediate carbene gave the helical (R)-cycloalkene in 98% yield and 97% ee. R′=Me: 70%. R′=Ph: 86%. R′=Me: 73%.3. >98% ee (P) + O (S) MeO (R) >98% ee MgBr HO (S) (S) 60% ∆ MeO (R) Scheme 6. 18-crown-6 oxy-Cope 47% (S) H OMe H (R) OAc 24%.83.84. BuLi.2-diol by the same procedure. 2d Si (R)-(E)-1-sila-4-cycloheptene 98%. Matsumoto et al. >95% ee R=t-Bu. 97% ee Scheme 6.82 Conversion of central to helical chirality via oxy-Cope rearrangement.6-hexamethyl-1-sila-4-cycloheptene.2-diazaphospholidine for abstraction of sulfur. (−)-sparteine (i-PrO)3Ti N H Li O R R N O R Ni-Pr2 R • 261 H R′CHO OCb AcOH OCb R′ R • OCb H OH ClTi(Oi-Pr)3 H H R=Me3Si: 86%. 88% ee R=t-Bu: 80%.3.6 Conversion of Axial Chirality to Other Chiral Elements The advance of atroposelective methods described in Chapters 6. O KHMDS.6. erythrinan alkaloids exhibiting a quaternary chiral center. 93% ee R=t-Bu.83 Enantioselective synthesis of (R)-(E)-1.655–661 Following a multiple step synthetic route based on Suzuki cross-coupling and HPLC enantioseparation. The development of reactions that allow one to transform axial chirality into other chiral elements has provided a powerful means for the total synthesis of natural products. prepared an enantiopure polysubstituted biphenyl bearing a t-Boc-protected amino function. 84% ee R=Me3Si.1.81 Asymmetric synthesis of 4-hydroxyallenyl carbamates. e. R′=i-Pr: 76%.2 and 6..654 The opposite enantiomer was obtained from the dextrorotatory trans-1. R′=Ph: 86%. Ph P OH Si (S) (S) OH CSCl2 DMAP Si O S O 69% N N O Si O −CO 2 40 °C. 93% ee R=Me3Si. Selective . >95% ee Scheme 6.3 has led to a pool of readily available axially chiral compounds that serve as versatile synthetic building blocks.g. Scheme 6. Scheme 6.3-dimethyl-2-phenyl-1. >95% ee R=Me3Si.

666. comparison of the structure with N-alkyl-N-acyl-2-methylanilides. The usefulness of allenes as synthetic building blocks stems from the exceptional combination of axial chirality and reactivity in regioselective and stereospecific cycloadditions.668–684 The potential of this approach.667 A wide range of chiral carbocyclic and heterocyclic compounds has been prepared by [2 þ 2]-. sigmatropic rearrangements and electrocyclic reactions. the chiral axis of a tri-ortho-substituted biphenyl is destroyed during ring formation and a chiral spiro center is established without any sign of racemization. suggests that racemization should occur rapidly at room temperature. which possess rotational energy barriers of approximately 80 kJ/mol.662–665 They determined the energy barrier to racemization of atropisomeric N-methyl-N-(2-iodo-4. was recognized by Kanematsu and coworkers. and [2 þ 2 þ 2]cycloadditions.9 kJ/mol. The desired spirotetrahydroisoquinoline was isolated in enantiopure form and transformed to O-methylerysodienone. In this reaction sequence. and ene reactions. [4 þ 2]-.84 Spirocyclization of an axially chiral quinone acetal.85. Scheme 6.262 OMe MeO MeO CHO Br 1) Pd(PPh3)4 2) Ph3P=CH2 3) (sia)2BH H2O2. and employed enantiomerically enriched samples in Et3B/O2-initiated radical cyclizations using Bu3SnH for chain propagation at room temperature. Nevertheless. [2 þ 2 þ 1]-. [4 þ 3]-. intramolecular trapping and lactam formation of the axially chiral N-aryl acrylamide radical appears to be considerably faster than rotation about the stereolabile chiral axis and radical cyclization of various ortho-iodoacrylanilides yields chiral oxindoles in high enantiomeric excess. Although the conformational stability of the intermediate radical is not known. This group found that the Lewis acid-promoted Diels–Alder reaction between a (–)-menthyl-derived . oxidation in methanol gave an atropisomeric quinone acetal that was subjected to Lewis acidcatalyzed spirocyclization via intramolecular Michael-type addition. the conversion of the axial chirality of allenes to other chiral elements. Curran and coworkers discovered that control of the stereodynamic properties of intermediate radicals prepared from axially chiral ortho-iodoacrylanilides is feasible and allows asymmetric cyclization coinciding with chirality conversion.6-dimethylphenyl)acrylamide as 128. NaOH MOMO MOMO OBn OBn (rac) OH OTIPS 95% (3 steps) TMS OMe MeO OMe Chapter 6 + B(OH)2 OTIPS NHt-Boc OTIPS 46% (12 steps including HPLC enantioseparation) OH (AcO)2IPh MeOH 99% MeO MeO N MeO MeO MeO Nt-Boc MeO TMS 90% MeO MeO O MeO MeO TMS OTIPS BF3•OEt2 OMe NHt-Boc OTIPS O O-methylerysodienone O Scheme 6.

86 Cycloaddition of allene-1.685–687. R″=Ph: 75%. R′=R″=H: 65%.xxiv The corresponding endoadduct was obtained in almost enantiopure form and used for the synthesis of (–)-cyclosarkomycin. although menthyl esters are known to be effective chiral auxiliaries in cycloadditions. R′=H. R′=H. 89% ee R=Me. For instance. 90% ee O R R′ (M) N R N (P) O R″ H N fast R′ O R R′ R″ H O NR (R) 263 ∆G = 128. R″=Me: 73%.85 Chirality conversion in radical cyclizations of ortho-iodoacrylanilides and racemization of N-alkyl-N-acyl-2-methylanilides. introduction of a diene motif to an axially chiral allene sets the stage for fast Rh(I)-catalyzed intramolecular cycloaddition. R′=H. R″=Me: 93%. 5 h RO2C H • CO2R H CO2R O H + H RO2C H • H CO2R CO2R 96%. Scheme 6. This reaction furnishes diastereomerically pure bicyclic products xxiv The high p-diastereofacial selectivity of this reaction is probably due to the axial chirality of the allene. 94% ee R=R′=R″=Me: 91%. R′=R″=H) R′ R″ I O R N (P) R″ R′ O ≠ slow R N R′ ∆G≠ ≈ 80 kJ/mol Scheme 6. 49% ee R=Et.3-dicarboxylate and cyclopentadiene produces a synthetically challenging bicyclo[2.86. 87% ee R=Me.1]hept-2-ene derivative with an exocyclic (Z)-alkene moiety. 96% ee R=(−)-menthyl O O (−)-cyclosarkomycin π-diastereofacial selectivity and endo-approach Scheme 6. H RO2C • CO2R H AlCl3 −78 °C.2.Asymmetric Synthesis with Stereodynamic Compounds R′ R″ (M) O R N I Bu3SnH Et3B/O2 25 °C R=Me.9 kJ/mol (R=Me. .3-dicarboxylates and cyclopentadiene. The availability of chiral allenes has generated increasing interest in the use of these versatile building blocks for the asymmetric synthesis of complex target compounds. (M)-allene-1.

and animals.90.3. xxvi In a reaction with substrate-based stereocontrol. see the concept of double stereodifferentiation described in Chapter 5. Scheme 6. This arrangement avoids 1.688 Irradiation of chiral allenediynes in the presence of CpCo(CO)2 produces tricyclic adducts through a sequence of intramolecular cycloadditions showing excellent regio-. Substituted allenes are excellent substrates for Claisen rearrangements resulting in [1.3-diaxial repulsion with the dimethylamino group but it requires the vinyl moiety to approach the allene from the more sterically crowded face bearing the carbamate protecting group. 30 min H CO2Me CO2Me H R=n-Bu: 93%.689 It is assumed that initial [2 þ 2]cycloaddition generates a cobaltcyclopentadiene-derived intermediate that participates in a Diels–Alder reaction with the internal double bond of the allenic unit. unsaturated silyl analogs react with electrophiles through an SE 0 mechanism. Ito.6. the stereochemical outcome is completely controlled by the chirality of the substrate and is independent of the reagent structure.2. On the other hand.and stereoselectivity. >99% de. allenyl. . Substrates with a propargylic chiral center are often employed in the synthesis of axially chiral allenes. fungi. Scheme 6.xxvi xxv Multifunctional stereotriads are invaluable precursors for the synthesis of polyketides which are important secondary metabolites of bacteria. The cyclization is controlled by steric interactions between the diene and the dienophilic allene which is preferentially approached at the readily accessible Re-face. Overall. Marshall and others demonstrated that electrophilic displacements of allenylsilanes with aldehydes yield chiral homopropargylic alcohols possessing two new chiral centers.691 Hoppe found that treatment of an enantiopure a-hydroxy allene with a ketene N. formation of the corresponding (Z)-alkene via Si-face attack is not observed. Organocopper reagents are particularly useful for stereoselective anti-SN2 0 displacements of 1. the direction of chirality conversion can be reversed by stereoselective allylic substitutions at haloallenes with organometallic nucleophiles. 91% ee R=n-Bu: 87% ee R=BnO(CH3)2CH: 91% ee Scheme 6.693–696 Reaction of matched and mismatched pairs of chiral allenylsilanes and aldehydes in the presence of titanium tetrachloride produces diastereomeric stereotriadsxxv with perfect substrate-based stereocontrol.O-acetal gives a (Z)-vinyl ether that spontaneously forms an (E.or (allenylmethyl)silanes. exhibiting three stereocenters.5]tricyclic Z4-cobalt complex with an (E)-exocyclic double bond. plants. allenylic and propargylic structures that are susceptible to nucleophilic displacements.88.E )-diene via [3. see Chapter 6. Scheme 6.264 R R • Chapter 6 CO2Me CO2Me [(C10H8)Rh(cod)]SbF6 (2-3 mol%) 25 °C.690.87 Intramolecular Diels–Alder reaction of allenes. >99% de. 87% ee R=BnO(CH3)2CH: 89%. These transformations proceed with efficient chirality conversion and afford synthetically useful chiral building blocks from allyl-.3-disubstituted 1-bromoallenes.692 By analogy with SN2 0 reactions of allylic.3]-sigmatropic rearrangement. Scheme 6. The unstable cobalt-bridged cycloadduct then undergoes reductive elimination to a [6. The stereochemical outcome of this reaction suggests that the favored transition state has a chairlike conformation with the benzyloxy-derived substituent in pseudoequatorial position. Scheme 6. Interestingly. chemo. For comparison. this reaction sequence constitutes a [2 þ 2 þ 2]cycloaddition.87.4]-chirality transfer and simultaneous translation of axial to central chirality.

Ph H H (E) P Ph Ph H [4+2] Ph • Re-face approach O Ph Ph • Co P P CpCo Ph Ph O Ph Ph Cp Cp O Ph P Ph H Si-face approach • O Co CpCo(CO)2 66 °C.5%. >99.88 Transformation of axial to central chirality in a cobalt-mediated [2 þ 2 þ 2]cycloaddition of allene diynes.5% ee CpCo H Ph Co P Cp O Ph Ph Ph not observed P H (Z) O Ph Ph Asymmetric Synthesis with Stereodynamic Compounds [4+2] Ph O Co P Ph Ph Cp Scheme 6. hν >99. 265 .

>99% de OH OBn PhMe2Si • H Et TiCl4 0 70%.3-disubstituted 1-bromoallenes with organocopper reagents. R(CN)CuLi t-Bu • R R(CN)CuLi 0 °C Br H t-Bu (S) (M) R=Me: 92%.90 Allylic anti-substitution of 1.89 Claisen rearrangement of a vinylic a-alkoxy allene. 94% ee Scheme 6.and (allenylmethyl)silanes (top). allenyl. R3Si E E E E R3Si R3Si • E E • SiMe2Ph • OH CHO C6H13 C6H13 TiCl4 Cy 76%.91 Classification of SE reactions with allyl-. >90% de Me2N O H H • H OCb NMe2 OBn 1. >98% ee R=n-Bu: 92%. and asymmetric transformation of allenylsilanes to propargylic alcohols (bottom). .3-diaxial repulsion Scheme 6. >99% de Scheme 6. 93% ee O Et OBn OH OBn PhMe2Si • H Et O TiCl4 Et OBn 70%. 90% de (syn/anti).266 OBn • Chapter 6 OBn OCb • pseudoequatorial position OBn 50 °C OCb 2h H Me2N H OCb OBn OCb OH MeO + Me2N O O • H O NMe2 79%. >98% ee R=Ph: 96%.

PhSeCl.3-allenoic acids via copper(II)-. The intermediate five-membered metallacycle reacts with the silane to give an Z3-allyl nickel complex that undergoes reductive elimination with retention of configuration at the isotope-labeled carbon. which has prompted mechanistic studies including deuterium labeling with Et3SiD. The electrophile therefore approaches the allene with its Re-face to form an (S)-configured secondary ether. Interconversion of axial to central chirality occurs through an SE 0 pathway having a synclinal-like transition state in which the most sterically demanding tert-butyl group of the electrophile is placed in the least crowded location.and enantioselectivity. 5-8 h Me3Si H • R Me3Si + H (M) t-Bu H MeO H R=CMe(CO2Me)2: 79% ee R=C(NHAc)(CO2Et)2: 87% ee R Me3Si (S) t-Bu MeO H t-Bu MeO (S) H Me3Si R H t-Bu • R H O Me H R=MeC(CO2Me)2: 87%. xxvii Multi-component coupling reactions of allenes usually occur at the more reactive sp2-hybridized carbons.92.705–709 In particular.and enantioselective Ni-catalyzed three-component coupling procedure that utilizes nonracemic allenes. Few tandem and multi-component reactions of axially chiral allenes are known. Ogasawara’s and Hayashi’s groups successfully employed axially chiral (allenylmethyl)silanes in asymmetric SE 0 reactions. Scheme 6. 74% ee synclinal-like transition state Scheme 6. This reaction includes addition of an electrophilic aldehyde to the central sp-hybridized carbon and affords allylic silyl ethers in good yields and with high diastereo.698–703 Jamison discovered a highly regio.Asymmetric Synthesis with Stereodynamic Compounds ≠ H • 267 R MeO OMe TiCl4 −78 °C.93. These and other heterocycles are often prepared from chiral a-amino and a-hydroxy allenes or 2. and spontaneous cleavage of the silyl group establishes a 1. silver(I)-. Scheme 6.or NBS-mediated cyclization with concomitant conversion of chirality. butenolides and dihydrofurans are abundant components of natural products and are important building blocks for asymmetric synthesis.xxvii Results obtained with (P)-1-cyclohexyl-3-methylallene and benzaldehyde are in accordance with an initial approach of the nickel complex to the less substituted double bond from the more accessible face opposite to the cyclohexyl ring. Oxidative addition is followed by coordination of the prochiral aldehyde from the less sterically encumbered face opposite to the axial methyl group. . 70% ee R=C(NHAc)(CO2Et)2: 90%.704 A remarkable feature is the unusual addition to the least nucleophilic sp-carbon in the allenic substrate and the surprising stereochemical outcome.697 Treatment of pivalaldehyde dimethyl acetal with stoichiometric amounts of titanium tetrachloride generates an electrophile that preferentially approaches the central carbon of (allenylmethyl)silanes from the less sterically hindered side.92 Chirality interconversion in SE 0 reactions between (allenylmethyl)silanes and pivalaldehyde dimethyl acetal in the presence of a Lewis acid. aromatic aldehydes and silanes. Chiral pyrrolines.3-diene unit.

TFA O H2N CO2H H 76% (+)-furanomycin >95% >95% Scheme 6.716 The introduction of carbophilic gold(III)-derived Lewis acids to catalytic cyclization of chiral allenes has led to additional synthetic entries towards dihydrofurans. R′=Me. pyrrolines and dihydrothiophenes. NaClO2 3.5-dihydrofurans. A mechanism that is in agreement with the stereochemical outcome of the reaction between (þ)-camphor-derived (M.5-dihydrofuran ring that is easily derivatized to (þ)-furanomycin. has found many synthetic applications.95. have been obtained by NMR analysis and ab initio calculations.718 Cycloisomerization of a-hydroxy allenes in the presence of catalytic amounts of AuCl3 at room temperature furnishes tri. 95% ee R=R′=n-Pr. Ar=4-MeOC6H4: 75%. Ar=4-CH3C6H4: 74%. 95% ee R=R′=n-Pr. (Z)/(E)>95:5. Ar=Ph: 76%. R′=Me. Ar=Ph: 40%. (Z)/(E)>95:5. (Z)/(E)>95:5. 98% ee H Me H H Me (R) H Ph OSiEt3 Me L O Ph NiL O Et SiD Cy 3 H H NiL2 Cy H H Ni Cy H H H Ph Cy H (R) Ni Ph OSiEt 3 D H D L Scheme 6.SS)-allenyl sulfoxide and iodine in the presence of water is given in Scheme 6.93 Multi-component coupling of nonracemic allenes. Ar=4-ClC6H4: 66%. which can also be applied to a-amino allenes and a-thio allenes.and tetrasubstituted 2. 95% ee R=R′=n-Pr.94. 95% ee R=R′=n-Pr.94 Total synthesis of (þ)-furanomycin. Scheme 6. (Z)/(E)>95:5. 95% ee R=R′=n-Pr. (Z)/(E)>95:5. (Z)/(E)>95:5. Stereoselective cyclization and demetalation of the intermediate aurate complex then destroy the chiral axis and generate a new chiral center.268 H R • (P) Chapter 6 H Ni(cod)2 (20 mol%) i-Pr N N i-Pr OSiEt3 R (R) Ar R′ R′ + O Ar H + i-Pr i-Pr Et3SiH Me Me NiL2 Cy H • R=R′=n-Pr.719 Mechanistic insights into this reaction. This . (Z)/(E)>95:5. Ar=2-CH3C6H4: 70%.720 The mild reaction produces (E )-2-halo-1-phenylsulfinyl-1-alkene-3-ols in excellent yield and enantiopurity. The soft Lewis acid first enhances the electrophilicity of one of the two allenic double bonds upon coordination. a natural amino acid found in Streptomyces. Scheme 6. aryl aldehydes and silanes using an N-heterocyclic carbene-derived nickel catalyst. 95% ee R=Cy.717. electrophilic addition of iodine forms a threemembered iodonium ring that is opened by intramolecular attack of the sulfinyl oxygen. the Ag(I)-catalyzed cyclization of a-allenic alcohols. t-BocN HO O AgNO3 O • t-BocN H O H t-BocHN O H OH 1. Regio. Ar=Ph: 80%. Accordingly.96. Dess-Martin 2.710–715 Standaert utilized this stereospecific reaction for construction of a trans-2. (Z)/(E)>95:5. Ar=4-MeO2CC6H4: 56%.and stereoselective halohydroxylation of allenic sulfoxides transforms axial to central chirality. 98% ee R=t-Bu. which has been intensively investigated by Marshall and coworkers.

721–725.97. R′=R′′=Me. Scheme 6. X=I: 98%. SNi reaction furnishes a heterocyclic five-membered ring exhibiting a vinyl iodide unit. R′=C8H17. 97% ee R=H. R′=t-Bu. R′′′=CH2OMe: 90%. ring opening through SN2 attack of water at the positively charged chiral sulfur atom completes the halohydroxylation with concurrent inversion of configuration. R′′=Me.4 0 -biphenanthryl-3.3 0 -ylene dinonaflate and aniline in the presence of catalytic amounts of Pd2(dba)3 and Xantphos gives 94% of the corresponding (P)-aza[7]helicene in more than 99% ee. R′=t-Bu. >98% de H R=t-Bu. R′=Me. Finally. NHMs. 95% ee R=n-Bu. R′=H. X=Br: 96%. NHTs Scheme 6. >98% de Cl3Au R′′′ R′ R X H R′′ H R′′′ -H R′ R X R′′ H R′′′ H R R′ XH XH = OH. R′′′=CO2Et: >99%. Several readily available axially chiral compounds have been employed in the synthesis of nonracemic helical compounds. R′′′=CO2Et: 78%. X=Br: 99%. >99% ee R Ph O S • X2 or CuX2 R R′ LiOAc H2O/ACN 25 oC O S Ph OH X I2 -I • + H2O I I O S O Ph H2O O I S Ph (R) S O Ph -H I (R) OH (M) Ph Ph S (S) S O Scheme 6. R′=H. R′=n-Bu. R′′′=CO2Et: 94%. cyclization via double N-arylation of enantiopure (P)-4.95 Gold(III)-catalyzed asymmetric cyclization of allenes. R′′=H. R′′′=CO2Et: 74%. R=n-Bu.4 0 biphenanthryl-3.731 The key step of this approach is an xxviii Helicenes are nonplanar ortho-annulated aromatic frameworks with a helical structure. . 96% ee R′ R=H.3 0 -diol derivatives.96 Asymmetric halohydroxylation of chiral allenyl phenyl sulfoxides. SH. X=I: 88%.727–730 A synthetic route to thiahelicenes based on transition metal-mediated reductive cyclization of sterically crowded biaryl dialdehyde precursors has been described by Tanaka’s group.Asymmetric Synthesis with Stereodynamic Compounds R′′ H R R′ • 269 R′′ AuCl3 R′′′ (5−10 mol%) 25 oC R′ R O R′′ H R′′′ AuCl3 XH Cl3Au R R′ • OH R′′ • R=t-Bu. R′=H.or O-arylation and concomitant ring fusion of 4. X=Br: 85%.xxviii Nozaki and coworkers developed a synthetic route towards hetero[7]helicenes that is based on conversion of axial to helical chirality during palladium-catalyzed N. R′′=H. The stereospecific helicene formation requires long reaction times but proceeds with excellent yield and conservation of chirality.726 For example. NH2. >98% de R=t-Bu. >98% de R=t-Bu. >98% de R′′′ R=t-Bu. Helicenes have become popular synthetic targets due to the inherent chirality and intriguing optical and electronic properties of this class of compounds. >99% ee R=H. R′=R′′=Me.

3-b 0 ]dithiophene gives a C2-symmetric (P)-tetrathia[7]helicene in literally enantiopure form.and stereoselective ring opening of isopropyl (R)-1. Cyclization of enantiopure (P)-2.99 Regio.3 0 -ylene dinonaflate. 6.7 0 -dimethyl-1.12-dioxa[12](1. >99% ee Scheme 6.270 Pd2(dba)3 (10 mol%) 100 °C Chapter 6 ONf (P) NfO + (P) NPh NH2 O PPh2 PPh2 Xantphos 94%. Chelation of the aryl Grignard by both the ester and ortho-methoxy group of the ansa compound initiates the regioselective nucleophilic displacement of the tether.7 Conversion of Planar Chirality to Other Chiral Elements Few examples of conversion of a chiral plane to other elements of chirality have been reported to date.99.97 Asymmetric synthesis of an aza[7]helicene via double N-arylation of enantiopure (P)-4.733 The stereochemical outcome can be explained by preferential Grignard attack from the less sterically hindered side opposite to the naphthalenophane bridge.2-b:4. Scheme 6.14) naphthalenophane-14-carboxylate with 2-methoxy-1-naphthylmagnesium bromide provides an atropisomeric (P)-1.4 0 biphenanthryl-3. >99% ee Scheme 6.1 0 -bi[benzo[1.2 0 -diformyl-7. Scheme 6. S S TiCl3 Zn/Cu (P) S (P) S S S OHC CHO S S 52%. >99% ee Scheme Regio.1 0 -binaphthyl derivative.98 Thia[7]helicene formation based on intramolecular McMurry coupling.and stereoselective opening of an ansa compound. intramolecular McMurry coupling step that accomplishes ring closure and aromatization. Additional coordination of the 2methoxy group of the introduced naphthyl moiety to magnesium then governs the generation of axial chirality during opening of the naphthalenophane bridge. . O (R) (CH2)10 Oi-Pr O O (CH2)10 Oi-Pr Br O Mg OMe O (CH2)10 Br O Mg O HO(CH2)10O Oi-Pr CO2i-Pr OMe (P) O + MgBr MeO O OMe 82%.

734 Treatment of a chiral diallylic cyclic ether with tert-butyllithium under cryogenic conditions generates a reactive organolithium species that undergoes transannular [2.5.3]-Wittig rearrangement.100 Conversion of planar chirality of a cyclic ether to central chirality by [2. which is discussed in detail in Chapter 6. chirality interconversion proceeds without measurable racemization.1 Stereocontrolled Substitution at a Chiral Center The synthesis of chiral compounds often requires modifications at an asymmetric carbon center.100. one would obtain either achiral products or a racemate.5. provide an elegant entry to asymmetric synthesis of complex target compounds. >98% de.5 SELF-REGENERATION OF STEREOGENICITY AND CHIRAL RELAYS The advance of stereoselective synthesis has been fueled by the discovery of powerful asymmetric reactions and imaginative strategies. Seebach’s concept of self-regeneration of stereocenters (SRS).Asymmetric Synthesis with Stereodynamic Compounds 271 t-BuLi −78 to 25 °C O 93% ee (R) O Li H Wittig rearrangement (R) Cope rearrangement PdCl2(PhCN)2 25 oC (R) (S) 82%. This can often be accomplished by a concerted reaction with predictable stereochemical outcome and without racemization or diastereomerization of precious starting materials. 93% ee HO (R) 78%. The SRS approach allows manipulation of a chiral center without concomitant racemization by a four-step reaction sequence that involves formation of isolable chiral intermediates.735 In such a case. A closer look at reactions that supposedly show a ‘‘chiral memory’’ reveals that chirality is in fact conserved throughout the whole reaction.3]-Wittig and palladium-catalyzed Cope-type rearrangements. As a result. the planar chirality of the nine-membered ether ring is translated to two asymmetric carbon atoms. see Chapter 6. the use of this stereochemical metaphor should be discouraged because it implies that the chirality of the molecule is temporarily lost and then somehow ‘‘remembered’’ later in the reaction. Bimolecular nucleophilic substitution allows stereocontrolled replacement of a substituent attached to an . Asymmetric synthesis with relays may be considered the diastereoselective variant of enantioselective catalysis with conformationally flexible achiral ligands. Scheme 6. Alternatively. 6. Diastereoselective synthesis with so-called chiral relays relies on fluxional auxiliaries that enhance the stereochemical information of an existing chiral element and allow effective transmission of chirality to a remote reaction site. In particular. and other methods that exploit temporary or transient chiral intermediates. Tomooka’s group realized that macrocyclic unsaturated ethers are useful synthetic precursors of complex tetrahydrofurans and cyclohexenols. a trisubstituted tetrahydrofuran can be obtained from the same ether by Pd(II)-catalyzed Cope-type rearrangement. >98% de.6. As Siegel and Cozzi have pointed out. 93% ee O Scheme 6. In both cases. 6.3. The term ‘‘memory of chirality’’ has been coined for transformations of enantiopure compounds via transient and stereolabile chiral intermediates that can not be isolated.

the Mitsunobu reaction provides a venue for stereospecific SN2 reactions of compounds that do not bear a good leaving group or when weak nucleophiles are used. Alternatively. Scheme 6. A classic example is the transformation of a chiral alcohol to the tosylate and subsequent nucleophilic replacement by a hydroxide ion. Of course. Alternatively. PPh3 O CO2Et N N + PPh3 EtO2C N N PPh3 CO2Et RCO2H EtO2C H N N PPh3 + RCO2 CO2Et R′ R″ RCO2 + R′ H N N H CO2Et OPPh3 R″ R R′ O R″ CO2Et Ph3P=O EtO2C Scheme 6.737 Treatment of a carboxylic acid and an alcohol with diethyl azodicarboxylate and triphenylphosphine generates a nucleophilic carboxylate and an intermediate alkoxyphosphonium salt susceptible to SN2 attack. interconversion of enantiomers can also be accomplished by other SN2 displacements.272 Chapter 6 asymmetric carbon atom. O H (S) OH TsCl Et3N H (S) O S O NaOH HO H (R) (+)-2-isopropylmalonamic acid CONH2 CO2H CH2N2 CONH2 CO2Me HNO2 CO2H CO2Me N 2H 4 (−)-2-isopropylmalonamic acid CO2H CONH2 NH3 CO2H CON3 HNO2 CO2H CONHNH2 Scheme 6.736.102 Strategies for controlled interconversion of enantiomers. .101 Stereocontrolled transformations at a chiral center: nucleophilic substitution of a tosylate (top) and Mitsunobu reaction (bottom).101. a reversal of the O H (S) O S O NaN3 N3 H (R) (R) CO2Me O2N OH CO2H (S) CO2Me O OH O NO2 DEAD. nucleophilic attack of an azide at a chiral secondary tosylate follows an SN2 mechanism with inversion of configuration. The Mitsunobu reaction conveniently transforms a chiral secondary alcohol to the corresponding acylate with inversion of configuration.102. Scheme 6. For example.

Systematic xxix Fischer and Brauns carefully chose a route that (a) avoids achiral intermediates such as malonic acid and (b) allows chemical differentiation of the two peripheral carbon atoms of the chiral substrate during each step.104 Asymmetric Pinacol-type rearrangement.xxix In the first step.. After hydrolysis of the primary amide function. the free carboxylic acid group was protected as the methyl ester. 99% ee Scheme 6. absolute configuration at an asymmetric carbon atom with complete conservation of chirality is feasible through stepwise exchange of peripheral functionalities. i. Scheme 6. .102.738 They were able to transform dextrorotatory 2-isopropylmalonamic acid to the levorotatory enantiomer by stepwise interconversion of the primary amide and carboxylic acid functions. This has been demonstrated in a historic experiment conducted by Fischer and Brauns. without direct involvement of any bonds at the asymmetric carbon atom. Bn OH R OH Bn CH3SO2Cl Et3N OMs R O OH Bn Et3Al O S O O AlEt2 R ≠ O R Bn R=Ph: 92%. treatment with ammonia completed the conversion of the originally free acid group to a primary amide.e.9·10−7 s−1 (100 °C) OAc AcO OAc O achiral acetoxonium ion OAc + OAc AcO (rac) 273 O OTs OAc OAc CH3CO2H OTs OAc CH3CO2H + OTs OAc AcO (rac) Scheme 6.Asymmetric Synthesis with Stereodynamic Compounds OTs O O CH3CO2 CH3CO2H k = 1.103 Neighboring effects in nucleophilic displacements. >98% ee R=vinyl: 89%. >98% ee R=2-thiofuryl: 93%.9·10−4 s−1 (100 °C) CH3CO2 CH3CO2H k = 2. the ester group was converted to an acyl azide using hydrazine and nitrous acid. Finally. All reactions were performed under mild conditions to exclude enolization and racemization. >98% ee R=3-benzofuran: 96%.

functional group transformations thus allowed conversion of (þ)-2-isopropylmalonamic acid to the levorotatory enantiomer without manipulation of the bonds attached to the asymmetric carbon center.105 Possible racemization courses of substitution reactions at asymmetric carbons involving either achiral or stereolabile chiral intermediates. Nucleophilic ring opening by an acetate anion occurs at either carbon atom with inversion of configuration and gives the racemic trans-diacetate. Solvolysis of the trans-isomer is approximately 700 times faster than the reaction of the cis-isomer. The stereochemistry and reaction rate of nucleophilic substitutions are susceptible to anchimeric effects originating from participation of neighboring groups. Conversion of enantiopure trans-2-acetoxycyclohexyl 4-toluenesulfonate to the corresponding acetoxonium ion generates a symmetry plane and therefore results in the loss of chirality.103.274 a) Formation of racemic products due to achiral trigonal-planar intermediates X −X R R′ R″ R′ R R′ +B R R′ Ph −BH R R′ +E R R′ Ph R″ R +Y R R′ − Chapter 6 Y + R″ R″ Y R R′ H E + Ph E R R′ b) Formation of racemic products due to fast racemization of trigonal-pyramidal intermediates − H +B R R′ R″ −BH R R′ R″ E +E R R′ R″ + R″ R″ R′ E R R′ R Scheme 6.739–741 For example. This is generally attributed to participation of the neighboring acetoxy group in the reaction of the trans-isomer. By contrast.and trans-2-acetoxycyclohexyl 4-toluenesulfonate by acetate requires considerably different reaction times. The adjacent acetoxy group not only facilitates replacement of the tosylate group but also affects the stereochemical outcome of the reaction. Such intramolecular assistance is geometrically impossible in the cis-isomer which explains its different reactivity in nucleophilic substitutions. nucleophilic displacement of the tosylate group of cis. Similar effects have been observed with 3-phenyl-2-butyl tosylates that . Scheme 6. the enantiopure cisisomer undergoes SN2 reaction with inversion of configuration to the trans-isomer without any loss of stereochemical integrity. The nucleophilic displacement in this isomer includes formation of an intermediate acetoxonium ion by intramolecular SN2 attack.

2]-migration is not affected by the configuration at the tertiary alcohol group. The rearrangement proceeds with inversion of configuration at the mesylated carbon center and yields enantiopure a-substituted ketones. Importantly.742.743 Nucleophilic displacements that occur during concerted rearrangements generally provide excellent stereocontrol. Pinacol-type [1.2]-migrations allow stereospecific conversion of chiral diols to a-substituted ketones with complete conservation of chirality.4. aryl and heteroaryl groups undergo enantiospecific [1.Asymmetric Synthesis with Stereodynamic Compounds Nucleophilic substitution of a chiral alcohol with retention of configuration due to synfacial chloride delivery O OH SOCl2 R R′ H −HCl (gas) R R′ O H S Cl R O O S Cl H −SO2 S Ni R R′ Cl H 275 R′ solvent cage O Nucleophilic substitution of a chiral alcohol with inversion of configuration due to SN2 attack OH SOCl2. In contrast to stereospecific bimolecular nucleophilic displacements and rearrangements. the [1. resulting in . B R R′ H −BH R R′ O H Cl S Cl Cl R′ R H −SO2. For instance. probably due to the flexibility of the seven-membered transition state. twostep substitution pathways based on heterolytic or homolytic elimination of one substituent prior to incorporation of a new one often proceed via trigonalization of the reaction center. −Cl SN 2 Isotope exchange at the benzylic position of a fluorene derivative with retention of configuration H D +NH3 Me Me2N D H Me N H −DNH2 H Me Me2N O solvent cage O Me2N O Scheme 6.2]-migration from the carbon carrying the tertiary alcohol to the secondary sulfonate moiety.748 Reaction of methansulfonyl chloride with chiral diols bearing adjacent tertiary and secondary alcohol groups proceeds faster at the latter position. thus setting the stage for an aluminumcatalyzed rearrangement. methanesulfonylation of chiral diols and Lewis acid-catalyzed Pinacol rearrangement have been combined in a convenient one-pot procedure. see also Chapter 6.744–747 This has been demonstrated with regioselectively mesylated diols.106 Concerted and dissociative displacements with trigonal-planar cationic and anionic intermediates. A variety of substituents with inherently high migratory aptitude such as vinyl. show participation of the adjacent phenyl ring and SNi replacement of the tosylate prior to solvolysis. In fact.104. Scheme 6.

Gawley. and others.N-acetal unit. enantiopure (R)-Nt-Boc-alanine is converted to a diastereomerically pure trans-imidazolidinone with a pivalaldehydederived N. 6. Some noteworthy exceptions to the scenarios outlined above have been developed into practical synthetic strategies.2 Self-regeneration of Stereocenters The stereoselective replacement of a substituent attached to an asymmetric atom via an elimination/addition pathway represents a major synthetic challenge. Protection of the imidazolidinone using trifluoroacetic anhydride is followed by trigonalization of the asymmetric carbon in the amino acid unit in the presence of a strong base and stereoselective alkylation of the intermediate enolate with 4-bromobenzyl bromide.276 Chapter 6 loss of stereochemical purity. In particular. For example. Seebach coined the term selfregeneration of stereocenters (SRS) to describe the stepwise manipulation of a chiral center via intermediate trigonalization and subsequent diastereoselective regeneration in the presence of a second chiral element. The same reaction proceeds with inversion of configuration in the presence of pyridine or another base that forms a salt and thus retains nucleophilic chloride in solution. unimolecular nucleophilic substitutions usually involve an achiral carbocation while deprotonation at a chiral center generates a stereolabile carbanionic intermediate. The synthesis of BIRT-377 is finally completed by removal of the temporary chiral center and conversion of the imidazolidinone to the desired . Beak. The change in the stereochemical outcome upon base addition is a consequence of an SN2 attack by the free chloride anion on the chlorosulfinate ester.107. Similarly.105. the chiral information is not lost and remains stored in the temporarily incorporated asymmetric center that controls diastereoselective introduction of a new substituent to regenerate the original chiral center in the third step. Racemic products are ultimately obtained in both cases. or (b) chiral unconjugated radical and anionic trigonal-pyramidal species that are prone to rapid racemization. chiral organolithium intermediates have been utilized for asymmetric synthesis by Hoppe. Seebach et al. The principles and usefulness of Seebach’s SRS method are evident in the synthesis of the cell adhesion inhibitor BIRT-377 exhibiting an N-aryl substituted hydantoin structure and a quaternary chiral center. Scheme 6.749 Treatment of an alcohol with thionyl chloride in the absence of a base generates a reactive chlorosulfinate ester while hydrogen chloride is released.750 Although one would expect the intermediate carbanion to display an achiral trigonalplanar geometry to maximize p-conjugation. the protonated product is obtained with high enantioselectivity. The two reactive species are trapped within a solvent cage that effectively limits rotational and translational movements. developed a general strategy that utilizes a four-step sequence for stereoselective manipulation of a chiral center without concomitant racemization. The interconversion of chiral alcohols to alkyl chlorides with thionyl chloride is known to follow an SNi-type mechanism with retention of configuration. isotope exchange of a deuterated chiral fluorene derivative in the presence of ammonia proceeds with considerable retention of configuration.5. see Chapter 6. to realize the second and third steps of the SRS sequence. Importantly. Subsequent chlorination of the intermediate carbocation occurs with retention of configuration. Still. Dissociation of this ester generates a short-lived ion pair consisting of a trigonal-planar cation and a chlorosulfite anion. The temporary chiral element is finally removed in the fourth step.751 The first step involves diastereoselective introduction of a temporary chiral center to the enantiopure starting material. Scheme 6.1. Scheme 6. The alkylation occurs predominantly at the face of the enolate opposite to the shielding tert-butyl group of the chiral N. Then.N-acetal unit. the rate of D/H exchange is much faster than competing tumbling movements that would lead to the formation of racemic products.752–754 In this example.106. Apparently. This is generally attributed to formation of (a) achiral trigonal-planar cationic or p-conjugated radical and carbanionic intermediates. Diastereoselective formation of a rigid heterocyclic structure with a second chiral center thus accomplishes the first of the four steps required for SRS. the original chiral center of the substrate is trigonalized upon removal of one substituent.

TFA t-Bu 2. Alternatively.755.and trans-isomers of imidazolidinones.a-disubstituted amino acid moiety.761 .4.107 Synthesis of (R)-N-arylsubstituted hydantoin BIRT-377 from (R)-N-t-Boc-alanine. >99% ee Cl Scheme 6. In particular. The higher thermodynamic stability of cis-isomers compared to trans-isomers of oxazolidinones and imidazolidinones has been attributed to a combination of ring strain and A1. Et3N 2. and was successfully employed in the production of BIRT-377 on a multi-kilogram scale. Acetalizations with pivalaldehyde are often quantitative and unreacted excess of the volatile aldehyde can easily be removed from the product. but not exclusively. LHMDS.Asymmetric Synthesis with Stereodynamic Compounds temporary chiral center NHt-Boc i-BuOCOCl N-methylmorpholine Cl NH2 Cl 277 original chiral center O N LHMDS Br Br original chiral center NHt-Boc CO2H CF3 CF3 E N t-Bu N OLi E O 1. see Chapter 6. In many cases. respectively. ClCO2Me. prochiral ketones such as pinacolone and acetophenone can be used to generate a temporary chiral ketal center. t-BuCHO 3. The overall success of SRS depends on the selectivity of two asymmetric reactions: introduction of the temporary chiral element and regeneration of the original chiral center. oxazolidinones and dioxolanones from enantiopure a-amino and a-hydroxy acids. protecting N-acyl groups are frequently not just passive spectators but serve as chiral relays. BnMe3N OH 50% NaOH 2. This route was found to be robust and cost-effective. oxazolidinones and dioxolanones is feasible by careful selection of reaction conditions.757–759 Allylic strain can also have a significant impact on the stereochemical outcome of alkylation reactions of heterocyclic enolates. TFAA Cl Cl Cl O HN N O −30 to 0 °C Cl Cl diastereomerically pure trans-imidazolidinone Br Br Cl trigonalizization of the chiral carbon atom (enolization) Br CF3 O N t-Bu N O 1.760.5. MeI O O N N O BIRT-377 Cl Cl Cl Cl Cl 43% overall.756 Selective formation of cis. The preparation of diastereomerically pure imidazolidinones. The enantiopurity of the product is determined by the individual diastereoselectivity of these steps.3 strain involving the exocyclic amide or carbamate group. cis-substituted heterocycles are obtained by thermodynamically controlled acetalization of a-heterosubstituted carboxylic acid derivatives and trans-isomers are favored under kinetic control. Incorporation of the second chiral center into these heterocycles is usually accomplished with pivalaldehyde rather than benzaldehyde because the bulky tert-butyl group affords superior diastereoselectivity during both acetalization and regeneration of the original chiral center. hydantoin bearing an a. is a common feature of many SRS routes because enolization of these species generates rigid intermediates that undergo highly stereoselective alkylations with predictable asymmetric induction. HCl regenerated chiral center H 2N HN 1.

>98% de 76%. By analogy with stereoselective transformation of readily available amino acids using imidazolidinones or oxazolidinones as key intermediates.763 Acid-catalyzed acetalization of (R)-malic acid with pivalaldehyde furnished the corresponding cis-dioxolanone.and (R)a-ethyl-a-phenylglycine.2S. respectively. The general availability of inexpensive naturally occurring chiral building blocks. MeMgBrpromoted cyclization of the (1 0 S. 95% de Ph (S) O O 75%. which is thermodynamically favored over the trans-isomer.110.and trans-oxazolidinones with ethyl iodide under catalytic phase-transfer conditions followed by hydrogenolysis furnishes (S).5S)-cis-dioxolanone in 94% de. the chiral center of the malic acid moiety was re-established with high diastereoselectivity. which gives rise to a convenient switch for selection of the stereochemical course of the SRS sequence. for example tartaric. isovaleric.4-disubstituted b-lactams which are important subunits in many antiobiotics. Because alkylation occurred predominantly at the face of the enolate opposite to the shielding tert-butyl group of the chiral O.5. CH2Cl2 BnO N (S) Ph O Ph H2 Et Pd(OH)2 H2N (S) CO2H 80−90% cis-oxazolidinone 66%.109.a-disubstituted a-heterocarboxylic acids. provides another entry to SRS. KOH/K2CO3 Bu4N I . 92% de O BnO N (R) Ph O Et (S)-N-Cbz-Phg Ph (R) O EtI. O’Donnell et al.2S. lactic. formation of cis. citramalic.764–766 Treatment of (S)-lactic acid with pivalaldehyde gives the thermodynamically favored (2S.O-acetal unit.5R)heterocycle in moderate yield but with remarkable diastereofacial control. has certainly contributed to the popularity of the SRS method for the synthesis of a. Addition of this dioxolanone-derived enolate to a solution of N-trimethylsilylphenyl aldimine generates the corresponding (1 0 S. CH2Cl2 BnO N (R) Ph O Et H2 Ph Pd(OH)2 H2N (R) CO2H 80−90% trans-oxazolidinone 89%.762 Apparently the absolute configuration of the temporary chiral N. whereas the corresponding trans-isomer is obtained when the reaction is carried out in diethyl ether. Scheme 6. and malic acids. Enolization with lithium bis(trimethylsilyl)amide and subsequent alkylation with dimethylallyl bromide was found to proceed with excellent stereocontrol. KOH/K2CO3 Bu4N I .a-disubstituted malic acid in enantiopure form. found that treatment of N-Cbz-protected (S)-phenylglycine with benzaldehyde dimethyl acetal in the presence of a Lewis acid in dichloromethane yields a cis-oxazolidinone.108 Stereodivergent conversion of N-Cbz-protected (S)-phenylglycine to (S). Subsequent hydrolysis and hydrogenation gave the desired a. The principles of SRS have also been applied to the synthesis of 3. mandelic.108. Alkylation of the diastereomeric cis. Scheme 6.4S)-lactam in 68% yield and 86% ee.and (R)-a-ethyl-aphenylglycine. in particular enantiopure a-amino acids and a-hydroxy acids. in high yield. Scheme 6. 95% de Scheme 6.or trans-dioxolanones from enantiopure a-hydroxy acids. Figure 6. Finally.278 O Ph (S) N (S) Ph O O O Ph Et (S) O Chapter 6 PhCH(OMe)2 BF3·Et2O CH2Cl2 O BnO N H CO2H PhCH(OMe)2 BF3·Et2O Et2O BnO EtI.767–781 Of .5R)-amino lactone produces a (3R. Battaglia and coworkers discovered that (S)-lactic acid-derived dioxolanones are invaluable precursors of chiral b-lactams. Tietze’s group employed (R)-malic acid in the synthesis of enantiopure a-alkyl malates. Chiral a-alkyl malates are important building blocks in biologically active natural compounds such as Orchidaceae alkaloids and Orchidaceae glycosides.O-acetal center is controlled during ring closure simply by the choice of solvent.

MeO2C NHCO2Me CO2H NH2 HO Bn N H (from hydroxyproline) CO2H N H Ph OH CONH2 BnO (from 4-hydroxyphenylglycine) Ph CO2H HO2C (from 4-hydroxyphenylglycine) OH CO2H H2N H2N CO2H (from norleucine) N H (from proline) CO2H CO2H HO2C HO CO2H (from malic acid) NH (from azetidine carboxylic acid) Figure 6.785 and oxazolopyrrolidine phosphonates.787 configurationally stable aziridines. PtO2 2.110 Synthesis of a 3. HCl 3.109 Formation of an enantiopure a-alkyl malate.) O HO2C 92% Br LiO2C E OLi trigonalization of the chiral carbon atom (enolization) OH 82%. 86% ee HO Ph 2. H2.Asymmetric Synthesis with Stereodynamic Compounds temporary chiral center controls diastereoselective alkylation E LHMDS (2 equiv.5R)-dioxolanone 37%. 99% ee CO2H HO2C O cis-dioxolanone −78 °C O O t-Bu 279 temporary chiral center CO2H O OH HO2C (R)-malic acid t-Bu O O 82% HO2C O regenerated chiral center 1.5S)-dioxolanone 99%.4S)-β-lactam 68%. t-Bu HO t-BuCHO HO2C (S)-lactic acid H O cis-(2S. . course. 94% de O (3R. LHMDS.a-disubstituted a-heterocarboxylic acids synthesized from enantiopure a-amino acids and a-hydroxy acids.788 boron-amine adducts.4-disubstituted b-lactam from (S)-lactic acid.792–794 have also been explored.789–791 and oxazaborolidinones. H2O t-BuCHO.784 azetidine carboxylic acid. this methodology is not limited to intermediate formation of imidazolidinones. −90 °C Ph N SiMe3 t-Bu O Ph O MeMgBr NH NH2 O (1'S. oxazolidinones and dioxolanones.782. Heterobicyclic analogs derived from cyclic amino acids such as proline.2S. K2CO3 Scheme 6.783 hydroxyproline. H .786 C2-symmetric pyrrolidinyl nitrones.5 Selected examples of a. 94% de O O 1. H t-Bu Scheme 6.

The use of chiral heterocycles with endo.or g-position of enoates via Michael additions. −78 °C 2. >98% de R=n-Bu: 78%.801 The dioxin-4-one was subjected to O O H O O O OH O O RX R O O O O O O O O 1.or exocyclic double bonds extends the SRS concept.795 Deprotonation of the diastereomerically pure dispirane obtained after recrystallization results in trigonalization of the originally asymmetric carbon atom in the lactic acid unit while the chiral information is stored in the two ketal moieties. to stereoselective incorporation of substituents into the b. 92% de Scheme 6.3-dioxin-4-one exhibiting an endocyclic double bond.280 Chapter 6 Dispiroketals derived from a-hydroxy acids provide another interesting opportunity for diastereoselective a-substitution.1 0 -bis(dihydropyran) form a dispiroketal in high de due to anomeric stabilization. bromination and amidine-promoted elimination. 96% ee + O 85%.111 Self-regeneration of stereocenters using dispiroketals. H HO OH R HO OH HO2C + O H LDA.a-disubstituted a-hydroxy carboxylic acids can be isolated by transketalization with an excess of ethylene glycol. cycloadditions or radical reactions. found that (S)-lactic acid and 1. Subsequent regeneration of the chiral center by treatment of the intermediate dispiro enolate with alkyl halides or aldehydes is highly diastereoselective and the a. t-Bu OH F3C CO2H t-BuCHO. 92% de R=Ph: 96%. . t-BuLi.111. MeOH O O Scheme 6. >99% ee R2CuLi t-Bu F3C R OH CO2Me >95%.112 Synthesis of b-substituted carboxylic acids using a 1. BuLi O O O O −78 °C LiO O O RCHO R=Me: 93%. Br2 O F3C O t-Bu O DBU O 98% Br F3C O t-Bu O O F3C 76% dioxin-4-one 62%. >98% de R=Ph: 58%. MeOH R=Bn: 86%. by acetalization. Scheme 6. >99% de R CO2Me O O R=Bn: 80%.796–800 Seebach’s group converted (S)-trifluorohydroxybutanoic acid into enantiopure (R)-2-tert-butyl6-trifluoromethyl-1.3-dioxin-4-one intermediate. >98% de F3C H . H O O 1. described above for a-substitution of enolates. >98% ee O R R=Me: 85%. Ley et al. Scheme 6.112. 96% de R=allyl: 94%. 84% de (>99% de after recrystallization) 2.

802–804 In this reaction sequence. i-PrI Cr(CO)3 OMe OMe 75%. Protection of the aryl position adjacent to the methoxy groups is necessary to ensure selective alkylation in both benzylic positions. TBAF 2.6.4S)-7.5.8-dihydroxyclamenene shown in Scheme 6.4-tetrahydro-5.821 didehydromirabazole A. the scope and efficiency of the SRS concept is hampered by the inevitability xxx The concept of transition metal-mediated allylic substitution has been further developed to powerful catalytic processes based on dynamic kinetic asymmetric transformation.8-dihydroxyclamenene is obtained in 75% yield and without loss of enantiopurity after replacement of the trimethylsilyl group by a methyl substituent and oxidative decomplexation with iodine. Nevertheless. see Chapter 7. >99% ee OMe TMS 84% TMS 99% OMe Scheme 6. I2 Cr(CO)3 OMe 1. 85% de (>99% de after chromatography) OMe 92%.xxx The principle of self-regeneration of stereocenters has found widespread use in the synthesis of an impressive range of natural products including 10-methyltridecan-2-one. BuLi. Enders and others used chiral Z3-allyl-derived transition metal complexes prepared from unsaturated substrates such as (E )-(S )-4-benzyloxypent-2-enoic methyl ester for asymmetric allylic substitution.3.811. >99% ee BuLi.2. Temporary metal complexation enhances the acidity at the benzylic positions for mild deprotonation/alkylation and implements a bulky group shielding one p-face of the tetrahydronaphthalene ring for diastereoselective regeneration of the original central chirality.824 Figure 6. a benzylic (S)-alcohol is first prepared by enantioselective oxazaborolidine-catalyzed borane reduction of 1.812 amathaspiramides. As a result.114. The intermediate chiral Z6-arene tricarbonylchromium complex fulfills two functions.815 myoporone. HSiEt3 OMe 74%.816 eremantholide A. . Nucleophilic addition of amines and subsequent oxidative cleavage of the iron complex with CAN regenerates the chiral center.8-dihydroxyclamenene via an Z6-arene Cr(CO)3 complex.4S)-7. the chirality at the asymmetric allylic carbon atom of the ligand is transferred to the chiral plane of the cationic metal complex. Michael addition with organocuprates and then hydrolyzed to (S)-3-hydroxy-3-trifluoromethyl alkanoates. 99% ee OMe BH3 OMe 1.822 and lactacystin.805–810 Reaction of the chiral alkene with stoichiometric amounts of Fe2(CO)9 gives a neutral Z2-olefin tetracarbonyliron complex that is converted to an isolable Z3-allyl tetracarbonyliron tetrafluoroborate salt via acid-promoted removal of the benzyloxy group.113 Synthesis of (1S.817 indicine N-oxide.813 rhodomycinones. BuLi.823. BuLi. Scheme 6.818 mevalolactone. The diastereoselective synthesis of the anti-infective sesquiterpene (1S. TMSCl Cr(CO)3 OMe OMe O N B O n-Bu Ph Ph OMe HO Cr(CO)6 OMe 93%. Benzylic alkylations occur at the face opposite to the tricarbonyl chromium unit and (1S.Asymmetric Synthesis with Stereodynamic Compounds H 281 Cr(CO)3 OMe HO TFA. MeI 3.and stereoselectivity.6-dimethoxy-1-naphthone.814 frontalin.4S)-7.819 brevianamide B.820 desferrithiocin. Complexation with chromium hexacarbonyl then gives the syn-adduct and the chiral alcohol group is reductively removed to generate an enantiopure Z6-aryl Cr(CO)3 complex.113 involves formation of a temporary chiral plane. MeI 2. providing (E )-(S )-4-amino2-enoates with high regio.

Fuji and coworkers explored the feasibility of asymmetric a-alkylation of chiral alkyl aryl ketones possessing an enolizable chiral center adjacent to the carbonyl function.282 O OMe OBn Fe2(CO)9 Bn O Fe(CO)4 O OMe HBF4 O OMe Fe(CO)4 BF4 83%. oxazolidinones and dioxolanones in more than 90% de is common.3 Self-regeneration of Chiral Elements with Stereolabile Intermediates In 1991. The enolate was trapped with various electrophiles at À78 1C in the absence of any additional chiral source. 97% de R=(R)-PhCH(CH3)-. Scheme 6. >95% ee 1. 96% de Chapter 6 OMe NRR′ Scheme 6. time-consuming purification by crystallization or chromatography is often necessary to obtain SRS products in high enantiopurity. 3 Br MeO O OH O H H O O O S OH N O NH N H NH O N eremantholide A (from lactic acid) i-Pr N S didehydromirabazole A (from cysteine) N S O frontalin (from lactic acid) S O O mevalolactone (from lactic acid) O O Br H OH N H NMe O amathaspiramide F (from proline) brevianamide B (from proline) Figure 6. of multiple laborious reaction and purification steps. R′=H: 72%.825 Although enolization generates a trigonalized carbon atom. 6. alkylation did not afford racemic products. Although formation of imidazolidinones. CAN O R=R′=Et: 55%. Consequently.6 Structures of natural products prepared via self-regeneration of stereocenters. 97% ee R=R′=Bn: 91%.5. faster and more convenient alternatives based on one-step regeneration of stereogenicity with nonisolable chiral intermediates and chiral relays have been developed. An enantiomerically enriched 1-naphthyl ketone was prepared from the Weinreb amide of (S)-mandelic acid and 2. 97% ee R=(S)-PhCH(CH3)-.115. vide infra.3-diethoxy-1-naphthyllithium and then subjected to deprotonation with potassium hydride in the presence of 18-crown-6.114 Iron-mediated allylic substitution via a cationic Z -allyl tetracarbonyliron complex. R′=H: 71%. RR′NH 2. These findings were explained by an intermediate enolate that stores the central chirality of the starting material in the form of transient axial chirality. Fuji coined the term ‘‘memory of chirality’’ to emphasize that .

X=Br: 31%. X=I: 27%.115 Deprotonation of chiral aryl ketones and alkylation of a transient axially chiral enolate. 65% ee R=Bn. 0% ee Scheme 6.6 kJ/mol 21.0 °C OEt Ph OMe fast MeI −78 °C to −20 °C EtO stereolabile axially chiral enolate MeO Me O OEt Ph O OEt −78 °C KH. X=I: 48%. Asymmetric regeneration of the stereocenter due to conformational stability of the intermediate naphthyl enolate (top) and racemization of the corresponding phenyl enolate (bottom). 66% ee R=Et. 18-crown-6 EtO RX OEt R=Me. 283 . 18-crown-6 EtO KO OEt MeO OMe Ph −78 °C to −20 °C OEt 54%.Ph O Ph (S) O OEt O OEt −78 °C EtO nonisolable but sufficiently stable transient axially chiral enolate Ph MeO OMe EtO ∆G ≠ = 94. 67% ee OMe slow KO MeO N OMe + Li Ph MeO R Ph (R) MeO Me Asymmetric Synthesis with Stereodynamic Compounds EtO Ph (S) MeO 96% ee OEt OEt 51%. 93% ee OEt OEt KH.

81% ee R=4-MOMOC6H4CH2: 94%. It is therefore reasonable to assume that the intermediate axially chiral enolate shown in Scheme 6.xxxi When the corresponding phenyl ketone is employed in the same reaction. −78 °C R (S) CO2Et Me t-Boc N O EtO EtO R * R * EtO t-Boc R * MOM t-Boc O K N MOM O N KO N MOM K central chirality t-BuO O O N Ph axial chirality EtO O Ot-Bu planar chirality O KHMDS Ph OMe MOM N OK MeI MeI t-Boc Bn Me t-Boc CO2Et N O transient axially chiral enolate Figure 6. possible transient enolate structures (middle). 87% ee R=Me2CHCH2: 78%.6 kJ/mol at 21. Unfortunately. xxxii Chirality is a molecular property whereas stereogenicity refers to an atom or group within a molecule. Since the molecule remains chiral at all times and does not undergo substantial racemization.115 is sufficiently stable to racemization under cryogenic conditions and therefore affords C-alkylation products in 65–67% ee. 93% ee N t-Boc R (S) CO2Et N t-Boc O 1.7. deprotonation of the (S)-mandelic acid-derived naphthyl ketone under cryogenic conditions and immediate addition of methyl iodide gives the (R)-enantiomer in 48% yield and 66% ee. a racemic product is obtained because enantioconversion of the stereolabile axially chiral enolate intermediate is faster than the trapping reaction.826 Fuji’s group then applied the concept of self-regeneration of stereocenters with nonisolable chiral intermediates to the asymmetric synthesis of a-alkylated amino acids.xxxii It has been pointed out by Carlier that this scenario involves transient storage of the chiral information at another site of a nonisolable intermediate. KHMDS 2. the stereochemical information is temporarily stored at a different site in the intermediate. the term ‘‘memory of chirality’’ has led to the false impression that chiral information is lost and somehow regenerated later in the reaction. For example. self-regeneration of a stereocenter is feasible within a single reaction if the transient chiral species does not undergo spontaneous racemization. . This is conceptually different from Seebach’s SRS strategy which requires introduction of a temporary chiral element for control of a separate diastereoselective reaction. The results clearly demonstrate the usefulness of this methodology. Apparently. Figure 6. One can assume formation of three different transient enolates exhibiting xxxi The formation of an intermediate atropisomeric enolate was confirmed by isolation of small amounts of the O-methylated side product. In fact.827–830 They found that N-MOM-N-t-Boc-protected amino esters undergo enolization and subsequent methylation under cryogenic conditions with excellent selectivity. and postulated reaction course (bottom).284 Chapter 6 R=Bn: 96%. Kinetic studies revealed that this O-methyl enolate has a rotational energy barrier of 94. the original chiral element can be regenerated with considerable selectivity upon reaction with an alkyl halide.0 1C. MeI. molecular chirality is conserved throughout the reaction while only a stereogenic element is temporarily lost. 79% ee R=i-Pr: 81%.7 Methylation of N-MOM-N-t-Boc-protected amino esters (top). 78% ee R= N : 83%.

n=5: 61%. . 97% ee Me N t-Boc CO2Et CO2t-Bu KHMDS −78 °C t-Boc EtO2C Me N CO2t-Bu 94%. Fuji and others have successfully utilized this concept for asymmetric alkylation of chiral amides. MeOH CO2Me N2 O O Scheme 6. axial or planar chirality.831 Kawabata.836–843 Clayden’s group developed a multi–step route for stereoselective functionalization of aryl amides combining features of Fuji’s and Seebach’s SRS methodologies. n=3: 78%.832 enantioselective formation of azacyclic amino acids833 and for intramolecular conjugate addition of enolates. n=2: 61%. 97% ee (CH2)n R=Bn. producing pyrrolidine-. −78 °C MeO Ph Me N 28%. while the central chirality at the b-carbon has only a minor effect on the stereochemical outcome of the reaction.834. n=4: 84%.117. 95% ee R=Bn. Computational analysis favors a transient axially chiral enolate that is formed by deprotonation of the most populated amino ester conformation. 56% ee Bn CO2t-Bu Et3N. piperidine. MeI. Stoodley’s and ´ Gonzalez-Muniz’ groups discovered that complex thiazolidines and 4-alkyl-4-carboxy-2-azetidin˜ ones can be prepared by ring closure of transient axially chiral enolates generated from amino esters under basic conditions.Asymmetric Synthesis with Stereodynamic Compounds 285 either central.and tetrahydroisoquinoline-derived chiral heterocycles.844 In the first two of OMe N Ph O R N t-Boc (CH2)n CO2Et 1. Scheme 6. n=3: 94%. Scheme 6. 95% ee O S N O O O S N O reflux O Bn CO2Me NH N 86%. LTMP. 98% ee R=Bn. Alkylation then occurs from the less sterically hindered side and affords the quaternary carbon center with retention of configuration.116. n=3: 91%. employed b-branched a-amino acids in similar enolization/alkylation sequences and observed that the stereoselectivity of the transformation is decisively controlled by the transient chiral C–N axis of the intermediate enolate. 94% ee R=Me. 95% ee EtO2C Bn CO2t-Bu Bn N t-Boc CO2Et KHMDS CO2t-Bu −78 °C t-Boc N 66%. 72% ee R=i-Pr. Kawabata et al. t-BuOMe 2.116 Synthesis of amino esters and amides via transient axially chiral enolates.835 In closely related studies. >99% ee Cl O N PMB CO2t-Bu Cs2CO3 ACN O N PMB 53%. 41% ee O KHMDS Br −60 °C EtO2C R N t-Boc R=Bn.

syn: >95% ee Scheme 6.4benzodiazepin-2-ones with a quaternary chiral center. four steps. The diastereomeric ratio is controlled by the absolute configuration at the asymmetric carbon atom: a substituent at C-3 preferentially occupies the pseudoequatorial position and (3S)-benzodiazepines adopt (M)-helicity. Due to facile rotation about the axially chiral aryl amide bond at room temperature.SS)(–)-menthyl toluenesulfinate gives rise to amido sulfoxides. >95% ee tert-BuLi −90 °C O OH R′ + syn-conformer anti-conformer NR2 O OH R′ R′CHO.4-benzodiazepin-2-ones lacking a chiral center exist in the form of axially chiral enantiomers that usually show rapid interconversion due to facile ring flipping at room temperature. −90 °C fast NR2 (P) Li −90 °C slow O syn-conformer O NR2 NR2 (M) Li R=i-Pr.xxxiii The unique dynamic stereochemistry of chiral benzodiazepines offers another opportunity for self-regeneration of stereogenicity. the previously induced axial chirality is maintained because rotation about the aryl amide axis is very slow under cryogenic conditions. exploited Fuji’s concept for the synthesis of 1. The sense of helicity can be described based on the R(amide)-N(1)-C(7)-C(8) dihederal angle. The (S)-sulfoxide group thus induces formation of the (P)-atropisomer.P)-isomer is then subjected to sulfoxide/lithium exchange at À90 1C and stereoselective reaction with an aldehyde.849. syn: 88% ee R=i-Pr. The presence of a tert-butyl group gives rise to isolable enantiomers whereas N-methyl and N-isopropyl analogs afford energy barriers to racemization of only 75. 88% ee R=i-Pr: 74%.117 Stereoselective ortho-functionalization of 1-naphthamides.5R. syn/anti = 95:5. Diazepam and other glycine-derived 1. incorporation of the p-tolyl sulfoxide group into the ortho-position of aromatic amides favors formation of a single diastereomeric conformer.3 and 88. According to NMR analysis. regioselective lithiation of tertiary aryl amides and treatment with (1R. syn/anti = 90:10. only one intermediate (the naphthalic amido sulfoxide) of this four-step reaction sequence has to be isolated. syn: 93% ee R=i-Pr. syn/anti = 93:7.848. The synthesis of 1.851 Deprotonation of an (S)-alaninederived 1. The stereochemical information of the replaced chiral sulfoxide group is thus temporarily stored in the axially chiral aryl amide moiety which governs the diastereoselective addition to aldehydes.3 kJ/mol. . The (S.845–847 The stability to racemization of these seven-membered ring systems depends on the bulkiness of the substituent attached to the amide nitrogen. R′=Et: 94%. Scheme 6.4-benzodiazepin-2-ones from chiral amino acids introduces a chiral center which renders the diazepine conformations diastereomeric.286 O NR2 O NR2 O Chapter 6 O S O p-Tol i-Pr NR2 (P) (S) S p-Tol O 25 °C fast O NR2 (M) (S) S p-Tol O sec-BuLi −78 °C Li favored anti-conformer stereoselective ortho-functionalization R=Et: 60%. R′=Ph: 88%. R′=i-Pr: 79%.850. Although the chiral sulfoxide group is removed upon lithiation.xxxiv Carlier et al.2S.118. respectively. the amide group readily adopts an anti-orientation relative to the sulfoxide unit in order to minimize dipole–dipole interactions.4-benzodiazepin-2-one and trapping of the enolate intermediate with an electrophile xxxiii xxxiv In contrast to Seebach’s SRS.

EX=BnBr: 72%.852 Few examples of self-regeneration of a stereocenter via chiral radical intermediates are known. 94% ee R R=i-Pr.4-benzodiazepin-2-ones at À109 1C if the enolate intermediate is trapped within a few seconds in the presence of benzyl bromide.5 kJ/mol R=Me (diazepam): ∆G ≠ = 75. Scheme 6. proceeds with retention of the original stereochemistry and gives 3. This can be avoided when enolization of 1. 0% ee R=i-Pr. BuLi.3 kJ/mol which corresponds to a half-life of approximately one minute at À78 1C.3-dialkylated products in up to 99% ee. EX=BnBr: 72%. Nevertheless.4-benzodiazepin-2-ones affords a trigonal-planar carbon atom which has been confirmed by DFT calculations. The diastereofacial alkylation of the enolate is therefore controlled by the transient axial chirality and the asymmetric center is regenerated with high selectivity. careful reduction of an (R)-1-phenylethanol-derived chromium complex with two xxxv Enolization of 1.3 kJ/mol R=t-Bu: ∆G≠ > 100 kJ/mol Scheme 6. Although the stereogenic center is essentially lost due to enolization. Based on computational calculations. EX Ph N E Me N O R=Me. EX=allyl bromide: 76%.118 Interconversion barriers of enantiomeric conformations of glycine-derived 1.119. EX=2-PhC6H4CH2Br: 70%.853 They rationalized that enantioselective reduction of readily available 1-arylalkanol-derived tricarbonylchromium complexes would generate an intermediate radical exhibiting a chiral plane.Asymmetric Synthesis with Stereodynamic Compounds Cl Cl Cl Cl Me 3 7 1 N N 2 Ph R O (M)-conformer 8 8 7 1 N N 2 Ph R O (P)-conformer 3 Me 3S 7 1 N N 2 Ph R O (M)-conformer 8 8 7 1 N N 2 Ph R O (P)-conformer 3S 287 R=H: ∆G≠ = 51. Since the corresponding methyl derivative is prone to fast equilibration at À78 1C. EX=4-MeC6H4CH2Br: 68%.4-benzodiazepin-2-ones carrying an isopropyl group at the amide nitrogen is carried out under cryogenic conditions.119 Enantioselective alkylation of 1. 95% ee R=i-Pr. −78 °C N Me N O R 2. or by instantaneous deuteration using deuterated methanol as solvent. stereogenicity can be selectively regenerated even with conformationally labile N-methyl 1. the energy barrier to racemization of such a radical chromium complex was estimated as 55.4-benzodiazepin-2-ones. Schmalz and coworkers found that benzylic radicals derived from arene tricarbonylchromium complexes are best described as a 17-valence electron species bearing an exocyclic double bond. . LDA.4-benzodiazepin-2-ones (left) and diastereomerization of (S)-alanine derivatives (right).3 kJ/mol R=i-Pr: ∆G≠ = 88. 99% ee Scheme 6. 97% ee R=i-Pr. one observes formation of racemic products. Central chirality could thus be temporarily stored in the chiral plane and regenerated through rapid formation of the corresponding anion and treatment with an electrophile. Cl Cl Ph 1. Indeed.xxxv chirality is conserved in the diazepine ring. It is crucial that the axially chiral benzodiazepine enolate does not racemize via ring flipping during the reaction.

288 OEt LiDBB + e . reaction cavities control tumbling and translational movements of short-lived radical intermediates. -EtO Cr(CO)3 91% ee racemization Cr(CO)3 ∆H ≠ = 55.121.e.862 and in-cage recombinations of radical pairs obtained by photolytic cleavage of aryl ethers and esters in n-alkanes and polyethylene films. In many cases racemization can be avoided at low temperatures. the evaluation of the configurational and conformational stability of a chiral intermediate requires consideration of reaction conditions and time scale. Decarboxylation or reductive decyanation of enantiopure tetrahyropyranyl-derived carboxylic acids or nitriles produce an anomeric-stabilized chiral radical that can be trapped at À78 1C.120.1.0]decanes.860 cyclizations of photochemically generated diradicals. This method has been used for the synthesis of the sesquiterpene (þ)-a-curcumene. While acyclic chiral radicals undergo rapid racemization due to inversion barriers below 4 kJ/mol.857.863.xxxvi For example.859 Similar concepts have been employed in stereoselective transannular cyclizations of intermediate cyclodecenyl radicals to bicyclo[5. Scheme 6. 87% ee RX=MeOCOCl: 67%. see Chapter 6.864 The stereoselectivity observed in the latter case is a consequence of templating effects.855 The stereoselective displacement of a substituent attached to a chiral center via an elimination/ addition sequence does not necessarily require transient or temporary storage of stereochemical information in the form of another chiral element.3.861. equivalents of lithium 4.865–867 xxxvi In the context of asymmetric synthesis. Scheme 6. . stabilization of the absolute configuration of chiral organolithium compounds by a proximate carbamoyl group has been used extensively for racemizationfree synthesis under cryogenic conditions.120 Stereoselective radical reaction of a tricarbonylchromium complex derived from (R)-1-phenylethanol. Regeneration of a chiral center through formation of a planar chiral intermediate in a stereospecific tandem oxy-Cope/ene reaction has also been reported. Rychnovsky’s group recognized the remarkable stereochemical stability of tetrahydropyranyl radicals. 87% ee RX=BnBr: 37%. generation of the radical intermediate.4 0 -di-tert-butylbiphenyl (LiDBB) at À78 1C and subsequent treatment with various electrophiles gave the desired products with high stereoselectivity.3 kJ/mol LiDBB +e Cr(CO)3 Cr(CO)3 Chapter 6 RX R RX=TMSCl: 72%.856 cyclic analogs show significantly enhanced half-lives.. reduction to the benzylic anion and alkylation or acylation are considerably faster than competing racemization pathways. 84% ee Cr(CO)3 (17 VE) (+)-α-curcumene Scheme 6.854 Apparently. as the knowledge of the relative rate of isomerization and trapping reactions is sufficient. 86% ee RX=Me2NCOCl: 57%.858 Racemization of tetrahydropyranyl radicals requires ring inversion which is likely to have an energy barrier between 20 and 40 kJ/mol. i.

2 F/mol NaOMe/MeOH. proceeds with retention of configuration.4 Chiral Relays The success of asymmetric synthesis is determined by the difference in the free energy of the reaction products (thermodynamic control) or by the difference in the free activation energy of competing reaction pathways (kinetic control). Several groups have recognized the usefulness of fluxional auxiliaries that convey stereochemical information of an existing chiral element to a remote reaction site.869 Oxidative decarboxylation of N-2-phenylbenzoyl serine. and subsequent addition of methoxide to the intermediate iminium ion. threonine or allo-threonine N.870 Electrochemical oxidation of the N-2-phenylbenzoyl serine N. 87% ee Bn 289 Bn O Scheme 6. The underlying principle of this strategy is to utilize intramolecular or interligand-mediated relays for chiral amplification and enhanced stereochemical . 6.O-ketals.5. −30 °C O N MeO Re-face attack O O Si-face attack MeO 40%. 80% ee N OMe O Scheme 6. Computational studies of the serine-derived N.O-ketal suggest that the N-2-phenylbenzoyl unit resides preferentially beneath the carboxylic acid group.122 Regeneration of a stereogenic center involving an electrochemically generated acyliminium ion. Few examples of regeneration of chiral centers with carbocation intermediates have been reported.868.O-ketal in the presence of sodium methoxide gives the corresponding a-methoxylated product in 40% yield and 80% ee. Nucleophilic methoxide addition therefore occurs at the freely accessible Re-face resulting in the observed retention of configuration.Asymmetric Synthesis with Stereodynamic Compounds Bn O O S O N O Bn Bn Li/NH3 −78 °C CN Bn O O 80%. enantiofacial shielding of the Si-face of the iminium ion by the 2-phenylbenzoyl group has been proposed. Oxidative decarboxylation of the most stable conformer forms a chiral iminium ion species that slowly racemizes due to hindered rotation about the amide bond.121 Photolytic and reductive generation of a chiral tetrahydropyranyl radical and enantioselective trapping under cryogenic conditions. N O CO2H O −2 e . 90% ee Bn hν −78 °C racemization ring inversion O PhSH −78 °C O 92%.122. To account for the stereochemical outcome of this reaction. Scheme 6. The extent of asymmetric induction depends on how effectively chirality can be expressed in close proximity to the reaction center.

and with opposite absolute configuration.872 ¨ Davies et al.2 0 -biphenol into the diphosphite ligand gave a rhodium catalyst that produced the diester in 97% ee. were among the first to systematically design chiral relays for diastereofacial reaction control. Indeed. .xxxvii Exploiting Schollkopf’s bislactimether method for the synthesis of enantiopure amino acids. Davies’ chiral relay approach provides a useful tool for the synthesis of (R)-a-amino acids (or (S)-a-amino acids if the dibenzylated diketopiperazine is derived from (R)-valine) and the auxiliary can be recovered after completion of the reaction by hydrolysis of the diketopiperazone. xxxvii The assumption of a single prevalent catalytic species seems reasonable but this is not necessarily the case.5-dione would produce a planar enolate structure that preferentially populates a conformation with the proximal benzyl moiety in anti-position relative to the isopropyl group at the chiral center.123. The principal idea is that the chiral information of the (S)-valine-derived auxiliary is amplified by both benzyl groups and effectively relayed to the reaction center to impede alkylation at the Si-face of the enolate. reaction of the enolate with various electrophiles gives trans-alkylation products with excellent diastereoselectivity. Using the diastereomeric (P). respectively. Scheme 6.873–876 They concluded from molecular modeling studies that deprotonation of (3S)-N. intraligand chiral amplification conveys asymmetric induction from the bicyclic sugar backbone via the biphenyl phosphite motif to the reaction site and thus forms a powerful asymmetric catalyst. Scheme 6.124.N 0 -bis(4 0 -methoxybenzyl)-3-isopropylpiperazine-2. They attached diphosphite ligands carrying either two conformationally stable BINOL units or two stereolabile biphenyl moieties to a rigid sugar-derived template. The high enantioselectivity can also be a consequence of coexisting (and rapidly interconverting) diastereomeric rhodium complexes.2 0 -biphenol groups decreased the ee to 39% but incorporation of 3.and (M)-BINOL-derived diphosphites they obtained the chiral ester in 88% and 95% ee.290 Chapter 6 CO2Me CO2Me R [Rh(cod)2]BF4 H2 O P O O O O H O P O R H O CO2Me CO2Me R O O O O = 88% ee O O O O 39% ee O O O O O O diphosphite ligand 95% ee 97% ee Scheme 6.3 0 -dimethyl-2. The excellent selectivity is probably due to stabilization of one distinct chiral conformation of the biphenyl moiety.871 The chiral ligands were then used for rhodium-catalyzed asymmetric hydrogenation of dimethyl itaconate. Replacement of the BINOL portions by stereolabile 2. The advantage of stereodynamic auxiliaries has been demonstrated by Reetz and coworkers. control of an asymmetric reaction. To reduce steric interactions. the proximal and distal benzyl groups reside on opposite sides of the ring plane. Comparison of the results obtained with Schollkopf’s (S)-valine¨ derived diketopiperazine auxiliary uncovers the significant enhancement in diastereoselectivity which is transmitted by the communicating benzyl groups.123 Asymmetric hydrogenation of dimethyl itaconate using conformationally stable and stereolabile chiral diphosphite ligands. one of which affords excellent stereoselectivity and considerably higher catalytic activity. These findings imply that the stereochemical outcome of this reaction is overwhelmingly controlled by the axially chiral components of the catalyst and not by the chiral sugar backbone. Accordingly.

R′ R O O Ph Me N N i-Pr Ph O TiCl . Et N 4 3 O Cl3 Ti O N N i-Pr Me chiral relay chelated (Z)-enolate Ph Me O R R′CHO O O Cl3 Ti O N N i-Pr O R H R′ Ph O R O N N i-Pr Me R=Me. X=I: 54%.881 The configuration at the rapidly interconverting tertiary amino group in the pyrazolidinone ring is effectively controlled by the chiral bisoxazoline . R′=t-Bu: 96%.126. 98% de Schöllkopf's bislactimether strategy H N i-Pr O 1. 59% de E=Bn.Asymmetric Synthesis with Stereodynamic Compounds Davis' chiral relay strategy OMe OMe proximal benzyl group (anti to i-Pr) OMe 291 i-Pr N O LHMDS O N −78 °C H i-Pr O N N OLi EX EX Re-face attack O N E N O 1.2S)-norephedrine-derived N3-acyl-N4-isopropyloxadiazinone with aldehydes.125. n-BuLi − 78 oC H i-Pr MeO N N OMe EX EX Re-face attack MeO N E N OMe 1. 93% de E=Bn. X=Br: 88%. 93% de O OH Re-face attack at (Z)-enolate Si-face attack at aldehyde Scheme 6. 98% de R=Me.124 Synthesis of a-amino acids using Davies’ chiral relay. Sibi’s group used a configurationally labile auxiliary to amplify the chiral induction of a C2symmetric bisoxazoline-copper(II) complex in the Diels–Alder reaction of butenoyl-pyrazolidinones with cyclopentadiene. Schollkopf’s bislactimether strategy is ¨ shown for comparison.880. The Lewis acidic titanium(IV) chloride provides chelation control and enhances the electrophilicity of the coordinating aldehyde. Hitchcock applied a conceptually similar approach in diastereoselective titanium(IV)-mediated aldol reactions of a (1R. Me3O BF4 O N H 2.125 Diastereoselective aldol reaction with an intramolecular chiral relay. CAN 2. R′=4-ClC6H4: 73%. 91% de Scheme 6. HCl E NH2 CO2H + NH2 CO2H MeO OMe distal benzyl group (syn to i-Pr) MeO trans-diketopiperazone E=Me. X=I: 72%.877–879 The chirality of the (1R. R′=Ph: 78%. Scheme 6. 98% de R=Me.2S)-norephedrine portion is relayed to the N3-enolate via the stereogenic N4-nitrogen atom carrying an isopropyl group that selectively shields the Si-face of the titanium (Z)-enolate. X=Br: 81%. HCl E CO2H NH2 + NH2 CO2H E=Me. Scheme 6. The stereoselective outcome of the aldol reaction is in agreement with a chairlike Zimmermann–Traxler transition state in which the Re-face of the enolate undergoes carbon–carbon bond formation with the Si-face of the prochiral aldehyde.

however. catalytic activity and asymmetric induction of a chiral catalyst need to be fine-tuned to achieve high turnover numbers in addition . In many cases. as well as computational and iterative optimization methods.886 and Michael additions. ligand of the chiral Lewis acid.887 The principles of configurational dynamics of nitrogen-based relays outlined above have been exploited for azasugar synthesis and the first preparation of adenophorine. have produced a plethora of chiral catalysts that can be applied in numerous asymmetric reactions.1.126 Template-mediated chiral amplification using a configurationally labile pyrazolidinone auxiliary.889–894 6. BnOLi O N N R O O N Cu(OTf)2 O N N R O N i-Pr N i-Pr O 2+ O N Cu i-Pr O N N R O i-Pr i-Pr O N N R O N Cu O i-Pr N O 2+ O Scheme 6.883 Other auxiliaries that possess stereolabile units suited to chiral amplification and relay of asymmetric induction have been employed in enantioselective alkylations of aldehydes with diethylzinc. The direct impact of the steric demand of the amino group on the stereoselectivity is in agreement with the proposed templatemediated chiral amplification. Cu(OTf)2 O N N R O Chapter 6 + O N i-Pr N O i-Pr R=H: 8% ee.6 ASYMMETRIC CATALYSIS WITH STEREOLABILE LIGANDS Combinatorial synthesis and high-throughput screening assays. The selectivity of the reaction is independent of the size of the residues attached to the bisoxazoline ligand and the ee of the cycloadduct improves to 92% with increasing bulkiness of the amino substituent.292 1. endo/exo = 90:10 O OBn 2.882. It is therefore assumed that the amino function in the pyrazolidinone adopts a single chiral configuration in the presence of the chiral Lewis acid and relays the chiral information to the adjacent dienophile. endo/exo = 96:4 R=Bn: 71% ee. Pyrazolidinone templates have also been used as effective chirality relays in conjugate additions of hydroxylamines and tributyltin-propagated isopropyl radical reactions.888 Clayden’s group used the relay concept for transmission of chiral information across an array of conformationally interlocked axially chiral aromatic amide moieties to afford impressive asymmetric induction at a remote reaction center. an a-glycosidase-specific inhibitor. Replacement of the nitrogen substituent with hydrogen results in almost complete loss of stereoselectivity. indicating that the p-facial selectivity is not directly induced by the chiral bisoxazoline ligand.884 Diels–Alder reactions885. endo/exo = 93:7 R= : 92% ee. see Chapter 8. endo/exo = 95:5 R=Et: 56% ee.

conformationally labile axially chiral ligands and fluxional achiral additives that can populate chiral conformations have been reported to increase both the enantioselectivity and efficiency of chiral catalysts. a fast release of the product facilitates regeneration of the catalyst and ultimately increases turnover frequency. This is routinely accomplished by optimization of temperature and solvent effects.901 As has been discussed in Chapter 2. the structure of a fluxional metal complex comprising rapidly interconverting enantiomeric species can be controlled by coordination of a nonracemizing enantiopure ligand. % ee) asymmetric catalysis diastereomerization (S)-catalyst (S)-activator (S)-catalyst (S)-activator racemization (b) Asymmetric activation via selective formation of a single diastereomer and concomitant interconversion of the remaining enantiomer (S)-catalyst (S)-activator substrate (R)-catalyst (R)-catalyst product (% yield. For example. . This concept of asymmetric activation was introduced by Mikami. The prospect of increasing both enantioselectivity and efficiency of a catalyst with inexpensive and readily available additives is attractive. At the same time. compared with laborious fine-tuning of the chiral ligand structure. The presence of an enantiopure compound can therefore induce a conformational bias in an achiral ligand resulting in amplification of chirality.8 Asymmetric activation of a stereolabile racemic catalyst with a nonracemic activator. and has been successfully applied to catalysts derived from conformationally unstable chiral ligands such as BIPHEP. product formation and dissociation of the product-catalyst complex.Asymmetric Synthesis with Stereodynamic Compounds 293 to satisfactory enantioselectivity and product yield. This concept has been exploited for asymmetric catalysis.895–900 In particular. accommodation of the stereodynamic ligand by the chiral metal complex changes the coordination sphere of the metal which can affect the rate of individual catalytic steps including substrate coordination. achiral ligands can exist as a fluxional mixture of achiral and enantiomeric conformers. Interactions with another chiral compound can render the equienergetic and equally populated chiral conformations diastereomeric. the ligand is likely to preferentially occupy one chiral conformation.902. Since diastereomers differ in energy.8. % ee) asymmetric catalysis (R)→(S)-enantioconversion (S)-catalyst (S)-activator (S)-catalyst (S)-activator racemization Figure 6. This can further improve catalytic properties.904 (a) Asymmetric activation via nonselective formation of equilibrating diastereomers (S)-catalyst (S)-activator substrate (R)-catalyst (R)-catalyst (S)-activator product (% yield. The striking sensitivity of many catalytic processes to small amounts of additives has culminated in the development of asymmetric activation and chiral poisoning strategies. and extensive screening of other reaction parameters. The chirality of the metal complex is then amplified and this may increase asymmetric induction during catalysis. One can imagine that a stereodynamic achiral ligand populates a distinctive chiral conformation upon coordination to a chiral catalyst consisting of a metal ion and an enantiopure ligand. Figure 6.903 Alternatively.2.

insect toxins. Although formation of a single diastereomer through asymmetric activation of a racemic stereolabile catalyst is desirable. and conformational changes in the catalyst structure and geometry resulting in increased activity.910 6. 92% ee Cu(SbF6)2: 22%. This important reaction was discovered by Jacobsen and Katsuki who independently developed chiral (salen)manganese catalysts for asymmetric epoxidation of nonfunctionalized alkenes. or selective poisoning of an undesired catalytic species that favors an alternative reaction pathway with lower stereoselectivity. The presence of additives can completely alter the mechanistic pathway and outcome of an asymmetric reaction. faster release of the product from the catalyst in the presence of an achiral additive.127 Counteranion effects on the enantioselectivity and yield of the chiral Lewis acid-catalyzed hetero-Diels–Alder reaction of Danishefsky’s diene and ethyl pyruvate. Scheme 6. One of the first successful examples was reported by Katsuki and coworkers who employed chiral N-oxides and manganese complexes bearing flexible achiral salen ligands in the asymmetric epoxidation of olefins. preferential formation of one well-defined nonfluxional catalyst structure. . 80% ee Scheme 6.912 Katsuki recognized that pyridine N-oxide increases the enantioselectivity and life time of chiral (salen)Mn catalysts which are believed to form reactive intermediate xxxviii Dihydropyranones are important building blocks for natural product synthesis of carbohydrates. Both anions are generally considered noncoordinating counterions. An impressive example is the poorly understood counterion effect of triflate and hexafluoroantimonate anions on the hetero-Diels– Alder reaction of a-keto esters and activated dienes.909.905–908. Enhanced turnover frequency is often explained by facilitated dissociation of inactive or less reactive oligomeric complexes to a catalytically active monomeric species. The interactions between a stereolabile racemic catalyst and a nonracemic chiral activator can be classified into two ultimate scenarios: (a) nonselective formation of an equimolar mixture of diastereomeric species that equilibrate towards a single catalytically active diastereomer. and (b) selective coordination of the chiral activator to one enantiomer of the metal complex and concomitant conversion of the remaining enantiomer to the same diastereomerically pure catalyst. antibiotics. pheromones. 25 °C Cu(OTf)2: 85%.294 OMe Cu(II)X2 (10 mol%) O O N t-Bu N t-Bu Chapter 6 OMe O H TMSO (S) CO2Et O (S) CO2Et O TMSO O + O OEt CH2Cl2.xxxviii Jørgensen and coworkers found that bisoxazoline-derived copper(II) triflates provide dihydropyranones in significantly higher yield and ee than their hexafluoroantimonate analogs. but these findings confirm that the impact of triflate and hexafluoroantimonate ions on chiral Lewis acid catalysis is by no means negligible. antitumor agents.1 Stereodynamic Achiral Ligands Several stereodynamic bidentate ligands that effectively amplify chirality at a metal center have been reported to improve both selectivity and efficiency of asymmetric catalysis. The introduction of achiral additives to asymmetric catalysis can have multi-faceted mechanistic implications leading to increased stereoselectivity and faster turnover. a mixture of diastereomeric catalytic species with individual enantioselectivity and turnover frequency is obtained in many cases.127.6. and anti-inflammatory sesterterpenoids.911. Increased selectivity is usually attributed to amplification of the chiral environment of the catalyst.

They systematically examined the influence of achiral additives on the asymmetric induction in titanium. The dramatic effect on enantioselectivity can be attributed to amplification of the chiral environment of the (P)-BINOLderived zinc catalyst upon coordination of the diamine or diimine. 77% ee O O O N O N 60%. (S)-1-phenylpropanol was obtained in only 44% ee.and zincmediated alkylations of aromatic aldehydes.3 0 -dimethyl-2. In the absence of a stereodynamic additive. However.3 0 -diphenyl BINOLcatalyzed alkylation of benzaldehyde with diethylzinc.Asymmetric Synthesis with Stereodynamic Compounds H t-Bu t-Bu H N O O Mn H N O t-Bu t-Bu t-Bu H H N O t-Bu H O H N Mn O H t-Bu t-Bu 295 PF6 PF6 O N Mn t-Bu O t-Bu O t-Bu t-Bu N O2N O O2N O NC 59%.3 0 -dimethyl2. 78% ee O O AcHN N O O N AcHN PhIO 90%.128 Enantiomeric stepped conformations of interconverting (salen)oxomanganese(V) complexes (top) and asymmetric epoxidation of a 2. oxomanganese(V) complexes possessing a nonplanar stepped conformation. Katsuki hypothesized that achiral (salen)Mn catalysts may exist in the form of rapidly interconverting enantiomeric stepped conformations that can be rendered diastereomeric in the presence of a chiral Lewis base.2-dimethylchromenes proceeds with remarkable enantioselectivity when catalytic amounts of enantiopure 3. The preferential population of one chiral conformation of the cis-diaminocyclohexane ligand therefore .2-dimethylchromene using an achiral (salen)Mn catalyst in the presence of axially chiral 3.2 0 -bipyridine N.N 0 -dioxide (bottom). Coordination of such a ligand to a (P)-3.2-dimethyl-7-nitrochromene gives the corresponding epoxide in 83% ee in the presence of the N. This interligand chiral amplification ultimately leads to high asymmetric induction during olefin epoxidation.922–924 The employment of achiral diamine or diimine activators significantly altered the stereochemical outcome of the (P)-3.918.N 0 -dioxide are added.919 In contrast.N 0 -dioxide.3 0 -diphenyl BINOLzinc complex gives rise to diastereomeric conformations that exist in nonequimolar amounts.N 0 -dioxide to the metal center and selective stabilization of one chiral salen conformation. Scheme 6. the alcohol was produced in ee’s ranging from 96% (R) to 75% (S) when an activator was added.921 Walsh and coworkers realized the advantage of screening inexpensive and readily available stereodynamic achiral ligands for optimization of asymmetric catalysis. Achiral ligands such as cisdiaminocyclohexane derivatives can access equienergetic enantiomeric chair conformations that easily interconvert via ring inversion. Nguyen and coworkers applied the same concept to asymmetric olefin cyclopropanation using an achiral (salen)ruthenium(II) complex in the presence of catalytic amounts of chiral sulfoxides.128.2 0 -bipyridine N. This has been explained by coordination of the atropisomeric N. alcohols or amines such as (–)-sparteine were used. 83% ee Scheme 6.913–917 It is generally assumed that the stepped conformation of the salen ligand plays a crucial role in the stereochemical course of this reaction. the asymmetric epoxidation of 2.920 The (salen)manganese-catalyzed reaction of 6-acetamido-2. Screening of a range of achiral (salen)Mn(III) complexes and chiral Lewis bases gave only moderate results when amino alcohols.

The selectivity of the (biphenoxide)Ti(TADDOLate)-catalyzed alkylation of 3. In addition.6. The absolute configuration and enantiomeric excess of 1-phenylpropanol obtained in the presence of a diamine or diimine additive is given under the structure of the activator.2 0 -di-tert-butylbiphenyl is stable to racemization and the enantiomers can be isolated.129 (P)-3. This approach is conceptually different from Mikami’s asymmetric activation methodology depicted in Figure 6.5-bis(trifluoromethyl)benzaldehyde with methyltitanium triisopropoxide depends strongly on the xxxix Biphenyl has a dihedral angle of 421 in the gas phase and 20–301 in solution. the presence of some diamines or diimines gives rise to ligand-accelerated catalysis. amplifies the asymmetric environment of the catalyst and enhances asymmetric induction.925. upon coordination (bottom). In contrast. .8.3 0 -Diphenyl BINOL-catalyzed alkylation of benzaldehyde and structures of achiral activators (top). Walsh’s approach utilizes stereolabile achiral activators to optimize the performance of a chiral enantiopure catalyst that is inherently stable to racemization.2 0 -disubstituted biaryls that undergo facile rotation about the chiral axis and rapid enantioconversion at room temperature.3. The angle between the aryl rings generally increases with the size of the ortho-substituents when intramolecular interactions such as hydrogen bonding are negligible.926 Incorporation of smaller groups gives rise to 2. Scheme 6.1. Mikami’s concept is based on rapidly interconverting chiral catalysts. This reaction proceeds much more slowly when it is conducted without the achiral ligand. see Chapter 3.2 0 -disubstituted biphenyls are inherently chiral but the enantiomers can not be isolated at 25 1C. For example.296 Ph Ph OH OH Ph Chapter 6 Ph N N N N 75% ee (R) O OH 73% ee (R) + ZnEt2 (10 mol%) N N achiral activator 0 °C 83% ee (R) 5 min t-BuHN NHt-Bu 73% ee (S) Me2N NMe2 64% ee (S) NHR NHR ring inversion RHN enantiomerization NHR RHN ZnL2* NHR ring inversion *L2Zn RHN NHR diastereomerization Scheme 6. ethylation of benzaldehyde with diethylzinc using (P)-3.129.927 Stereolabile 2. for example racemic BIPHEP-derived transition metal complexes. Mikami’s group recognized the usefulness of conformationally unstable biphenol-derived ligands in asymmetric catalysis. ZnL2*.2 Stereolabile Axially Chiral Ligands Axially chiral biaryls exist in the form of enantiomeric ground state conformations with dihedral angles typically above 301. Because of severe steric hindrance to rotation. that are converted to a diastereomerically enriched or pure catalytic species through addition of an enantiopure activator. Enantiomeric and diastereomeric conformations of a diaminocyclohexane-derived ligand and chiral amplification of a BINOL-derived zinc catalyst. 2.xxxix The energy barrier to rotation about the chiral axis of biaryls mainly depends on the number and size of ortho-substituents. 6.3 0 -diphenyl BINOL combined with a meso diamine carrying flexible pendant biphenyl groups is completed within 5 minutes at 0 1C.

933 xl Alternatively. 97% ee Scheme 6.130 Enantiomerization of biphenols and (biphenoxide)Ti(TADDOLate)-catalyzed methylation of 3. L2 O R HN O CO2R′ [Rh(cod)L L ]BF4 1 2 R HN H2 (60 bar) O O O POMe fast O MeOP R=R′=Me: 100%. .5 0 -bis(trifluoromethyl)phenyl]ethanol is produced in 60% yield and 73% ee in the presence of 2. R′=Et: 90%. R′ =H: 36%. 69% ee R=2-MeOC6H4-.928 While 1-[3 0 .R)-TADDOLate] complex is 15 kJ/mol more stable than the (P)-biphenoxide-Ti[(R. enantioselectivity increases dramatically to more than 99% when 3. R′ =H: 40%. the high enantioselectivity of the methylation can be attributed to two coexisting diastereomeric (biphenoxide)Ti(TADDOLate) complexes that have considerably different catalytic activity. CO2R′ O Pt-Bu O Biphenol phosphite.2 0 -biphenoxideTi[(R. 65% ee R=Me. 96% ee R=Et. Mechanistic studies proved the coexistence of two rapidly interconverting diastereomers. It has been hypothesized that this impressive increase in enantioselectivity is due to formation of a highly effective Ti(TADDOLate)-derived catalytic species exhibiting the coordinating biphenol ligand in one exclusively populated chiral conformation.3 0 -dimethoxy-5.131. This assumption is supported by molecular mechanics suggesting that the (M)-3.930 Reetz and Li examined a series of rhodium complexes consisting of monodentate BINOLand fluxional biphenol-derived ligands to uncover an effective catalyst for hydrogenation of b-acylamino acrylates. >99% ee CF3 F3C CF3 MeTi(Oi-Pr)3 -78 to -35 oC F3C Scheme 6.5-bis(trifluoromethyl)benzaldehyde with MeTi(Oi-Pr)3. L1 (M)-BINOL phosphonite. of which the homochiral (M.xl Other groups have utilized stereolabile axially chiral biphenols to improve the efficacy of asymmetric ene reactions929 and Baeyer–Villiger oxidations. R′=Me: 60%.R)TADDOLate] diastereomer.130.931 Extensive screening revealed that combination of an (M)-BINOL phosphonite and a conformationally labile biphenol phosphite provides a rhodium species that allows reduction of b-acylamino acrylates to the corresponding b-amino acids with excellent enantioselectivity. Scheme 6.932.Asymmetric Synthesis with Stereodynamic Compounds R 297 R OH OH R OH OH R fast R′ R′ R Ph Ph O O R′ R′ R′ CHO R′ O O Ti O O Ph Ph R (10 mol%) Me H OH R=R′ = H: 60%.M)-form is assumed to afford higher enantioselectivity and catalytic activity. R′ =H: 56%. 73% ee R=Ph.2 0 -biphenol. substitution pattern of the biphenol additive. Scheme 6. 95% ee R=n-Pr.131 Hydrogenation of b-acylamino acrylates with an (M)-BINOL-derived Rh catalyst bearing a conformationally flexible biphenol phosphite ligand. R′=Et: 94%.3 0 -dimethoxy-5. R′=Me: 90%. 98% ee R=Me.5 0 -dimethyl-2.2 0 biphenol is used. 88% ee R=OMe.5 0 -dimethyl-2.

S.S.S):(M. Apparently. Noyori.S) Ph (S) (S) Ph diastereomeric 3:1 mixture at equilibrium BIPHEP: Ar=phenyl DM-BIPHEP: Ar=3. It is important to remember that enantioselective synthesis requires kinetic reaction control and that the stereochemical outcome is determined by the individual stereoselectivity and turnover frequency of each catalytic species present. were able to employ different diastereomeric catalyst mixtures in the hydrogenation of 1-acetylnaphthalene.S.4 mol% of a 1:1 diastereomeric ruthenium catalyst mixture gave (R)-1-(1 0 -naphthyl)ethanol in more than 99% yield and 63% ee.S)=2:1: >99%. They found that the enantiomeric excess of the (R)-alcohol product steadily improves with increasing diastereomeric purity of the catalyst.S):(M.132 Formation of interconverting diastereomeric catalysts through addition of (S. Treatment of these species with base and hydrogen generates catalytically active ruthenium(0) complexes that were applied in the reduction of ketones. Mikami’s studies show that the thermodynamically favored ruthenium complex bearing (S.132.5-dimethylphenyl O (DM-BIPHEP)RuCl2 (S. 63% ee (P.934–937 NMR spectroscopic studies revealed that addition of (S.S)-DPEN to (DM-BIPHEP)RuCl2 results in deracemization of the diphosphine ligand and effectively amplifies the chiral environment of the ruthenium complex.S. Because of the slow equilibration process.S)-DPEN to a racemic mixture of (DM-BIPHEP)RuCl2(DMF)n (top) and enantioselective hydrogenation of 1-acetylnaphthalene using different catalyst ratios (bottom).S)=1:1: >99%.8 mol%) H2 (40 bar) OH (P.S)-diphenylethylenediamine (DPEN) to racemic (DM-BIPHEP)RuCl2(DMF)n initially produces a 1:1 mixture of diastereomeric ruthenium(II) precatalysts.2 0 -bis(diarylphosphino)biphenyls such as BIPHEP and DM-BIPHEP.S)-DPEN and Ar Ar P RuCl2(DMF)n Ph P NH2 (P) enantiomerization Ar Ar NH2 Ph (S.S):(M.S. Mikami and others introduced these chelating diphosphines as conformationally flexible analogs of BINAP. which slowly changes within three hours to a 3:1 ratio in favor of the (P)-DM-BIPHEP-derived complex. Hydrogenation of 1-acetylnaphthalene using 0.S) Ph (S) (S) Ph diastereomerization Ar Ar P RuCl2(DMF)n P Ar Ar 1:1 mixture of enantiomers (M) Ar2 Cl H2 P N Ru N P Ar2 Cl H2 (M.298 Chapter 6 Another class of flexible ligands that is known to improve the performance of chiral catalysts comprises 2. 73% ee (P.S.S)=3:1: >99%. Mikami et al. 84% ee Scheme 6.S)-DPEN (0. coordination of (S. .4 mol%) KOH (0. Scheme 6. The enantiomeric excess increased to 84% when a 3:1 catalyst mixture was used under the same conditions.S.S)-DPEN Ar2 Cl H2 P N Ru N P Ar2 Cl H2 (P.S.

Scheme 6. Asymmetric activation of racemic (DM-BIPHEP)Rh(I) with (M)-DABN generates diastereomerically pure [(M)-DM-BIPHEP-(M)-DABN]Rh(I) which has been successfully employed in enantioselective cyclization of 1.6-enynes.944 The high enantiopurity and considerable stability to racemization of [(M)-BIPHEP]platinum(II) complexes at room temperature for at least eight hours was confirmed by 31P NMR measurements using (S. as well as electronic and steric properties of ancillary ligands. endo/exo > 99:1 (2 mol%) Scheme 6.and endo-selectivity in the Diels–Alder . that coordination of BIPHEP to a metal center can significantly enhance the stability to rotation about the chiral axis.S)-DPEN-derived ruthenium complexes. Scheme 6. and one can expect that this di-ortho-substituted biphenyl undergoes rapid racemization at room temperature. subsequent rotation and recoordination to the metal center.940 It is important to realize. ´ Gagne exploited the conformational stability of platinum-coordinated BIPHEP to prepare [(M)-BIPHEP]Pt(OTf)2 in 98% enantiomeric excess from racemic [(M)-BIPHEP]PtCl2 via isolation of [(M)-BIPHEP]Pt[(P)-Binolate] and ligand exchange with triflic acid. The chiral catalyst shows high enantio.133 [(M)-BIPHEP-(M)-DABN]Pd(II)-catalyzed hetero-Diels–Alder reaction of ethyl glyoxylate and cyclohexadiene.941 The mechanism and extent of metal-mediated conformational stabilization of coordinating 2. This would explain the slow equilibration towards a thermodynamically favored 3:1 ratio of diastereomeric (S.S)-DPEN as chiral shift reagent.Asymmetric Synthesis with Stereodynamic Compounds 299 H2N 2+ Ph2 P (M)-DABN Pd P Ph2 N H2 H2 N Ph Ph P Pd(OH2)2 P Ph Ph Ph Ph P Pd(OH2)2 P Ph Ph H2N 2+ Ph2 P Pd P Ph2 H2 N N H2 [(M)-BIPHEP-(M)-DABN]Pd(II) O + H O OEt O CO2Et 75%.2 0 -bis(diarylphosphino)biphenyls is difficult to predict.1 0 -binaphthyl (DABN) forms a Lewis-acidic [(M)-BIPHEP-(M)-DABN]Pd(II) catalyst exhibiting both high enantioselectivity and activity in the hetero-Diels–Alder reaction of ethyl glyoxylate and cyclohexadiene. The energy barrier to rotation of BIPHEP is 92 kJ/mol at 125 1C.134. however. (P)-DM-BIPHEP affords higher enantioselectivity and reaction rates than the diastereomeric (M)-DM-BIPHEP-derived catalyst.938. (M)-2.939 For example.942 Mikami’s group discovered that the conformational stability of (BIPHEP)rhodium(I) complexes depends critically on the presence and nature of ancillary diamino ligands.2 0 -bis(diarylphosphino)biphenyl conformers occurs via intermediate dissociation of one phosphine group.2 0 -diamino-1. The concept of asymmetric activation of racemic BIPHEP-derived metal complexes with chiral amines has been extended to other reactions. 94% ee. coordination number and geometry of the metal complex.133. and it depends on a variety of factors including electron configuration. It is assumed that interconversion of metal-coordinated 2. while the corresponding (DABN)rhodium complex and amine-free (BIPHEP)Rh(I) show atropisomerization at room temperature.943 They found that BIPHEP coordinating to (DPEN)rhodium(I) does not rotate about the chiral axis. vide supra.

The Diels–Alder reaction depicted xli The facile P-pyramidal inversion in 1-phenylphospholes is a consequence of a resonance-stabilized planar transition state. 94% ee Scheme 6.4 0 -tetramethyl-2.136. . The enantiopure (BIPHOS)Pd complex catalyzes the asymmetric allylic substitution of 1.1 0 -diphenyl-3. Although preparation of enantiopure transition metal complexes derived from BIPHEP or other stereolabile ligands is feasible. Ph P PtCl2 P Ph Ph HO HO Ph2 P (M) Pt P Ph2 Ph O O HOTf Ph2 P (M) P Ph2 Pt OTf OTf Ph P PtCl2 P Ph Ph [(M)-BIPHEP]Pt[(P)-Binolate] 98% de [(M)-BIPHEP]Pt(OTf)2 98% ee O N O O + Ph2 OTf P Pt P OTf Ph2 (10 mol%) O N O O 94% ee. reaction of cyclopentadiene and 3-acryloyl-oxazolidin-2-one. formation of asymmetric catalysts from inherently stable atropisomeric diphosphines remains a much more attractive strategy. BIPHOS crystallizes as a conglomerate consisting of (M.2 0 -biphosphole (BIPHOS) and other biphospholes exist as a mixture of three pairs of rapidly interconverting enantiomers in solution due to the presence of a stereolabile chiral axis and two chiral phosphorus atoms that undergo facile pyramidal inversion. and enantioselective Diels–Alder reaction of cyclopentadiene and 3-acryloyl-oxazolidin-2-one.135 Preparation of [(M)-BIPHEP]PtCl2. Scheme 6.945–948 Axially chiral 1.RP)-enantiomers that can be isolated under cryogenic conditions.SP).5-dimethylphenyl O 99%.3-diphenyl-prop-2-enyl acetate with sodium dimethyl malonate and the corresponding homoallylic diester is obtained in 93% yield and 80% ee.4.and (P. Scheme 6.6-enynes.RP.3 0 .135. Both Mikami’s and ´ Gagne’s groups have successfully employed isolated [(M)-BIPHEP]palladium and platinum complexes in hetero-Diels–Alder and carbonyl ene reactions.134 Ph [(M)-DM-BIPHEP-(M)-DABN]Rh(I)-catalyzed cyclization of 1. endo/exo = 94:6 Scheme 6.300 + Ar2 P Rh P N Ar2 H2 H2 N Chapter 6 (10 mol%) O Ar = 3.xli Fortunately. and the ligands are stable to isomerization upon coordination to palladium.949.SP.

135 has also been accomplished with readily available [(M)-BINAP]platinum and palladium catalysts.SP)-BIPHOS]Pd catalyst. and asymmetric allylic substitution of 1.SP).SP. 92% ee O Scheme 6.951 Deracemization of a (DPPF)Ni complex with (M)-DABN produces the homochiral diastereomer which catalyzes the glyoxylate-ene reaction of methylenecyclohexane with high enantioselectivity.RP.3-diphenylprop-2-enyl acetate with sodium dimethyl malonate. preparation of the [(M. and equilibration is completed within seconds. . Scheme 6. In contrast to (BIPHEP)platinum and palladium complexes. the chiral conformations of metal-coordinated DPPF can be effectively controlled with enantiopure diamines.136 Structures of enantiomeric (M. providing the cycloadduct in up to 98% ee.Asymmetric Synthesis with Stereodynamic Compounds 301 P Ph (S) (M) Ph P (S) PdCl2(ACN)2 -78 C o P Ph Cl Pd Cl Ph P Ph (R) P (P) P (R) Ph P Ph Pd Cl (1 mol%) P OAc Ph Ph Ph Cl MeO2C CO2Me NaCH(CO2Me)2 25 to 35 oC Ph Ph 93%. 80% ee Scheme 6. in Scheme 6.SP.137. while the slow interconversion rate restricts its use as a perfectly flexible activator for amplification of asymmetric induction of a chiral catalyst. Mikami therefore introduced the conformationally less stable bis(diphenylphosphino)ferrocene (DPPF). a highly flexible diphosphine ligand forming axially chiral staggered conformations upon coordination to a transition metal.and (P.950 The studies conducted by ´ Mikami’s and Gagne’s groups discussed above demonstrate that the stereodynamic properties of BIPHEP limit its use as a conformationally stable diphosphine ligand that has the stereochemical integrity of BINAP.RP)-BIPHOS.137 Formation of a diastereomerically pure [(M)-DPPF-(M)-DABN]Ni complex using (M)-DABN as chirality controller (top) and glyoxylate-ene reaction (bottom). 2+ 2+ PPh2 NCMe Fe Ni PPh2 + NCMe NH2 NH2 Ph2 P Ni P Ph2 H2 N N H2 (M)-DABN Ph2 P Ni P Ph2 H2 N N H2 [(M)-DPPF-(M)-DABN]Ni(II) 2+ O OH OEt + H O OEt (5 mol%) 91%.

988–990 Similarly. order and orientation of organic molecules in crystalline materials give rise to distinguished stereo.and regioselective photodimerizations.138 Stereoselective solid-state synthesis of an anti-head-to-head coumarin dimer using a tartaric acid-derived template. this is often achieved by chelation control and use of C2-symmetric catalysts.964–970 The well-defined regularity.987 Enantiopure ammonium salts have been used to arrange achiral carboxylic acids in an asymmetric solid-state environment for enantioselective photoreactions and topotactic single-crystalto-single-crystal transformation.971–976 Nevertheless. . inclusion complexes of prochiral guest molecules and hosts such as cyclodextrins or tartaric acid derivatives have been used for stereoselective Ph Ph O O Ph Ph O OH Ph Ph HO O O O HO Ph Ph hν O 4h Ph Ph O O Ph Ph O OH Ph Ph HO O O H H H H O HO Ph Ph O 89%. In solution. pre-organizes two coumarin molecules in the chiral environment of the diol template. As discussed in Chapter 5. Irradiation of the coumarin-derived cocrystal with a 400 W high-pressure mercury lamp results in asymmetric single-crystal-to-single-crystal [2 þ 2]cycloaddition providing the enantiopure anti-head-to-head dimer in 89% yield.952–954 Solid-state synthesis is attractive for several reasons: it is interesting from environmental and sustainability standpoints because it eliminates the use of solvents.7 STEREOSELECTIVE SYNTHESIS IN THE SOLID STATE The success of asymmetric synthesis is directly tied to the control of both the stereodynamics and the relative orientation of reactants. and it often affords stereochemically pure products in literally quantitative yield. A well-defined fixation of the three-dimensional structure and relative orientation of organic compounds is often elusive in solution.S)-bis(hydroxydiphenylmethyl)-2.3-dioxacyclopentane.302 Chapter 6 6.961–963 The combination of the principles of molecular recognition and supramolecular self-assembly of bifunctional building blocks has paved the way for powerful template-assisted solid-state reactions. Weak interactions including hydrogen bonding and p-stacking have been exploited to build supramolecular assemblies of unsaturated substrates that participate in stereo.and diastereoselectivities are generally obtained with rigid and cyclic compounds that possess less rotational freedom than acyclic analogs. but this can be achieved in the solid state.977–985 Cocrystallization of coumarin or thiocoumarin and C2-symmetric (S.955 Topochemical polymerization of unsaturated carboxylic acids has been accomplished through photochemical and g-radiationinduced reactions using ammonium carboxylates as solid-state templates for control of polymer tacticity.956–960 Similarly. stereocontrolled solid-state photodimerization of ammonium salts of trans-cinnamic acid or trans-cinnamamide carboxylates allows stereoselective formation of truxinic acids and truxinamides. superior enantio. For the same reason. 100% ee OH O OH O pre-arranged prochiral coumarin molecules anti-head-to-head coumarin dimer Scheme 6. which can be prepared from tartaric acid. few enantioselective solid-state reactions have been reported to date.and regiochemical selectivity and excellent yields.138. molecules exist as a mixture of rapidly interconverting conformational isomers that constantly undergo tumbling motions.986.2-dimethyl-1. A fundamental strategy of asymmetric synthesis is to limit the number of coexisting conformers and competing transition states that ultimately lead to the formation of different stereoisomers and thus compromise selectivity. Scheme 6.

Stereoselective intramolecular reactions of compounds that exist as a mixture of rapidly interconverting chiral conformations in solution have been realized in the solid state.139 Asymmetric solid-state reactions of ‘‘frozen’’ chiral conformations. thus generating the corresponding chiral alcohol in 90% ee at 92% conversion. see Chapter 7.1]hexane-derived keto acid with (R)-1-cyclohexylethylamine affords one conformational diastereomer that undergoes asymmetric Yang photocyclization. synthesis within the chiral cavity.139.xlii Another example of an asymmetric intramolecular reaction using a ‘‘frozen’’ chiral conformation xlii The same ammonium salt forms a racemate when the photocyclization is carried out in solution. 92% ee diastereomerically pure cocrystal CO2H solution O no rotation about the single bond in the solid state ("frozen conformation") H O Ph racemization O Ph O N O enantiopure crystal solid state Ph O solution H Ph O O fast hν O N Ph O solid state O O N N O 95% + O N O 5% Scheme 6. Irradiation of the crystal initiates an asymmetric photoreaction that transforms the ‘‘frozen’’ chiral conformer to a single configurationally stable isomer.Asymmetric Synthesis with Stereodynamic Compounds CO2H 303 O no rotation about the single bond in the solid state ("frozen conformation") NH2 O OH diastereomerization O fast CO2 NH3 1. The conversion of equilibrating stereoisomers to a single chiral conformer is usually achieved by cocrystallization with a chiral template or spontaneous resolution based on crystallization-induced asymmetric transformation. the stereodynamic freedom of a fluxional compound is reduced to a single ‘‘frozen’’ chiral conformation which can be exploited for asymmetric synthesis. and the sense of chiral induction can not be predicted. H CO2H 92%.1.1000–1003. In these cases. For example. crystallization of an endo-bicyclo[2.991–994 The scope of this approach is limited because the chiral recognition mechanism of cyclodextrins and the reactivity and stereoselectivity of organic reactions proceeding within the hydrophobic interior are very difficult to control. hν 2.995–999 Scheffer observed that rapidly interconverting mixtures of enantiomeric keto acids form diastereomerically pure ammonium salts with chiral amines via asymmetric transformation of the second kind. .3. Scheme 6.

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vitamin C. B = achiral compound C.1 Deracemization. this is often confused with desymmetrization.2 The term deracemization has been coined to describe conversion of a racemate to either enantiomer. desymmetrization.1 This dilemma may be alleviated by enantioconvergent synthesis. enantioconvergent synthesis or kinetic resolution. Despite the advance of asymmetric synthesis. menthol. both enantiomers of a racemic starting material are used to prepare a single chiral product which may require several synthetic steps. In a kinetic resolution one enantiomer of a racemate is selectively derivatized. chiral compounds are often obtained as racemates or nonracemic mixtures that need additional purification. and kinetic resolution. nutrients. or only slightly. Deracemization A + A′ A Desymmetrization fast C B slow C′ Kinetic resolution A + slow A′ fast B or C B or C′ Enantioconvergent synthesis A + A′ C A. which has fueled the development of ingenious synthetic strategies and numerous asymmetric reactions. and limonene are chiral. carvone. selective crystallization of diastereomeric salts. vancomycin. Preparative separation of enantiomers can be accomplished by chromatography on a chiral stationary phase. Biomedical and nutritional applications generally require the use of chiral compounds in enantiopure form. while the other one is less reactive and is therefore not.1. aspartame. and fragrances such as naproxen. 331 . kinetic resolution. deracemization or through repetition of a laborious sequence of preparative enantioseparation and external racemization of the undesired enantiomer. In the case of enantioconvergent synthesis. In many cases. A desymmetrization reduces the number of symmetry elements in a molecule. C′ = enantiomeric products Figure 7. A major drawback of these methods is the inherently poor atom economy because the maximum yield is limited to 50%. consumed at 50% conversion.CHAPTER 7 Asymmetric Resolution and Transformation of Chiral Compounds under Thermodynamic and Kinetic Control Many pharmaceuticals. A′ = enantiomers. stereoselective destruction of a symmetry plane or inversion center of a meso compound provides a useful entry to asymmetric synthesis of chiral compounds. Figure 7. flavors. preferential crystallization with seed crystals and chiral additives. and enantioconvergent synthesis. esomeprazole.

23 A renowned example is the asymmetric ring opening of achiral epoxides with trimethylsilyl azide.17 aryl alkanes. 97% ee 90%.11–14 carboxylic acids. >99% ee NH2 CO2Et CO2H 90%. However. Scheme 7.15.19 and transition metal complexes.16 esters.3 Treatment of racemic a-methylbenzylamine with an enantioselective amine oxidase results in selective conversion of the (S)-enantiomer to the corresponding achiral imine which is reduced in situ with ammonia borane.1 Deracemization of a-methylbenzylamine.1. Scheme 7.5–7 amines.24 A representative case of enantioconvergent synthesis involving an enzyme-catalyzed kinetic resolution step of a racemic tricyclic diol has been reported by Yoshida and Ogasawara. . An elegant approach to deracemization of chiral amines has been reported by Turner. 99% ee Figure 7.22 However.3. >99% ee OH 97%. In particular. Deracemization is frequently achieved by formation of achiral intermediates in combination with enantioselective biocatalytic processes that exploit isolated enzymes or even intact cells. incorporation of both reactions into a one-pot procedure allows continuous recycling of the (S)-enantiomer until the entire mixture is deracemized to (R)-a-methylbenzylamine.20 Figure 7. 99% ee 76%.2. In most cases. it has been applied to many classes of chiral compounds including amino acids. Desymmetrization of achiral molecules provides another useful entry to asymmetric synthesis.2 Structures of compounds obtained by deracemization. 97% ee CO2H Cl O 95%.9.2. Jacobsen’s (salen)chromium(III) complex catalyzes ring opening of a series of readily available epoxides with high enantioselectivity and affords azido silyl ethers that can easily be hydrolyzed to azido alcohols.i The nonselective chemical reduction produces equal amounts of the enantiomers of a-methylbenzylamine. 93% ee NH2 Chapter 7 Scheme 7. >99% ee N H CO2H 86%. Scheme 7. 92% ee H N 85%.8 alcohols.4 Since quantitative deracemization eliminates cumbersome preparative enantioseparation and presents an atom-economical solution to asymmetric synthesis with racemic starting materials. an increasing number of desymmetrization procedures applicable to centrosymmetric compounds has emerged.21. OH O OH OH OH OH OH 83%. meso compounds possessing a mirror plane are desymmetrized with a chiral reagent or in the presence of a chiral catalyst or enzyme.25 Lipase-mediated transesterification of the racemic starting material using vinyl acetate as acyl i The enzyme used does not recognize (R)-a-methylbenzylamine and selectively oxidizes the (S)-enantiomer.10 diols.332 NH2 amine oxidase NH NH3 BH3 NH3 BH3 77%.18 biaryls.

88% ee OH 80%.4. 82% ee OH 80%. 94% ee OH 80%.ii In many cases. 98% ee 10 steps CO2H + CO2Me OH (-)-diol HO + O O CO2Me OAc 44%. the enantioconvergent approach shown above requires many synthetic steps. ii The strategy towards (–)-shikimic acid shown in Scheme 7. one could synthesize the final product from the racemate in just nine steps. The two compounds were then separated and employed in individual synthetic routes to prepare (–)-shikimic acid. Important atom-economical synthetic strategies that incorporate interconverting chiral starting materials or intermediates into a one-pot procedure are dynamic kinetic resolution (DKR).1. To limit the total number of reactions. This reaction constitutes a kinetic resolution (KR) which is discussed in more detail in Chapter 7. 98% ee N3 OH 65%. CO2Me OH (+)-diol HO KR Chirazyme L-2 HO CO2Me OH 47%. Although (–)-shikimic acid can be prepared from both enantiomers of the racemic starting material.3 requires a total of 18 steps including kinetic resolution because enantioconvergence is established at the end of each synthetic branch. . (R.R)-(salen)CrCl TMSN3 R 2. coupling of racemization of a stereolabile chiral compound with an enantiomer-differentiating reaction in the presence of a chiral catalyst or reagent allows quantitative transformation of a racemic mixture to an enantiopure compound within a single process. The success and popularity of these broadly applicable methodologies clearly emphasize the usefulness of stereolabile chiral compounds in asymmetric synthesis. If enantioconvergence were achieved in the first step. dynamic kinetic asymmetric transformation (DYKAT) and dynamic thermodynamic resolution (DTR). donor produced a mixture of the remaining dextrorotatory diol and the acetate of the (–)-enantiomer. 95% ee Scheme 7.R)-(salen)CrCl N3 FmocN OH 80%. >99% ee HO HO 7 steps OH (-)-shikimic acid OH Scheme 7.Asymmetric Resolution and Transformation of Chiral Compounds 333 O R N3 1. it is desirable to establish enantioconvergence as early as possible. for example by deracemization to the (–)-diol.2 Desymmetrization of meso epoxides with (salen)Cr(III)Cl.3 Enantioconvergent synthesis of (–)-shikimic acid based on kinetic resolution. H N3 R N3 t-Bu N Cr N t-Bu O Cl O t-Bu t-Bu R OH N3 O (R.

the objective of KR can be to obtain the enantiopure or enantioenriched reaction product. and are used to recover the less reactive enantiomer. 7. The coupling of kinetically controlled enantiomerization or diastereomerization with a stereoisomer-differentiating reaction in a one-pot process constitutes a dynamic kinetic resolution or a dynamic kinetic asymmetric transformation.e.iii Asymmetric transformations of the first and second kind are generally aimed at the recovery of one stereoisomer of the starting materials and are conceptually related to separation techniques such as crystallization and chromatography. In other words. crystallization and extraction.6. with a subsequent synthetic step under conditions that exclude isomerization. In contrast to KR. This method provides the less soluble diastereoisomer which is not necessarily the more thermodynamically stable one.g. and allows quantitative conversion of a stereoisomeric mixture to a single chiral product. Pirkle and Reno discovered base-promoted deracemization of stereolabile enantiomers of N-(3. The term dynamic thermodynamic resolution (DTR) has been coined for the combination of asymmetric transformation of the first or second kind. DKR. e. which is often used for preparative separation of a racemate by consumption of one enantiomer in a stereoselective reaction. catalyst or solvent). As has been mentioned above. and many examples have been incorporated into asymmetric syntheses of natural products. If such a process is not coupled with a separation step. Alternatively. vide infra. and different solubility or partitioning between two immiscible phases in the case of stereolabile diastereomers. This concept comprises deracemization of enantiomers in the presence of a chiral solvating agent and interconversion of diastereomers under thermodynamical control.334 Chapter 7 7. Both strategies involve interconversion of stereolabile chiral compounds under thermodynamic control. the scope of kinetic resolution (KR) is limited due to the inherently low yield of 50% but it can be the most effective method when enantioseparation by chromatography or crystallization is not successful. Asymmetric transformation of the second kind entails physical separation and depends on conglomerate formation of interconverting enantiomers.4 and 7. . Chapter 7.1 SCOPE AND PRINCIPLES OF ASYMMETRIC RESOLUTION AND TRANSFORMATION The equilibration of a stereoisomeric mixture to a single stereoisomer has traditionally been referred to as asymmetric transformation of the first or second kind.5..2 ASYMMETRIC TRANSFORMATION OF THE FIRST KIND Asymmetric transformation of the first kind refers to an equilibration process resulting in the enrichment of one stereoisomer from a racemic or diastereomeric mixture of stereolabile chiral compounds without concomitant separation. kinetic resolutions can be aimed either at purification of enantiomers or at asymmetric synthesis. see Chapters 7.’’ Kinetic resolutions are usually stopped at 50% conversion. whereas the term asymmetric transformation of the second kind is reserved for processes that combine isomerization and concomitant separation.27 The transformation of the racemic starting material to a mixture exhibiting the (R)-leucine thioester in 78% ee is a consequence of iii Isomerization due to diastereoselective crystallization is based on the different stability of the crystal lattices formed by the interconverting isomers. According to the 1996 IUPAC recommendation.26 KR is defined as ‘‘the achievement of partial or complete resolution by virtue of unequal rates of reaction of the enantiomers in a racemate with a chiral agent (reagent. DYKAT and DTR are always aimed at asymmetric synthesis.5-dinitrobenzoyl)leucine butyl thioester in the presence of substoichiometric amounts of (R)-11-undecenyl N-(2-naphthyl)alaninate. i. Asymmetric transformation is often the ultimate method of choice. it is called asymmetric transformation of the first kind. Asymmetric transformation of the first kind is based on the relative thermodynamic stability of interconverting diastereomers or diastereomeric complexes. thermal equilibration of interconverting stereoisomers..

Scheme 7.4..31 Figure 7. Riedner and Vogel applied the same concept to a stereolabile 5-(4-hydroxyphenyl)-5-phenylhydantoin bearing an asymmetric quaternary carbon atom. Asymmetric transformation of the first kind provides a convenient means of enhancing the diastereomeric ratio of axially chiral compounds.1.1.4 Deracemization of N-(3.5-dinitrobenzoyl)leucine butyl thioester through asymmetric transformation of the first kind.3 and 3. 78% Scheme 7. occur during complexation of the (R)-leucine thioester with the (R)-alaninate. 22% more stable complex.5. two hydrogen bonds in addition to p-p-stacking. It has been proposed that three simultaneous interactions. The deracemization processes described above are based on equilibration of noncovalent diastereomeric adducts derived from a stereolabile racemate and an enantiopure resolving agent. i. differential complexation and formation of diastereomeric complexes with different thermodynamic stability. OH O O O OH H N O N H NaOH Ph O O H N N H Ph O Ph HN NH O O O H N N H Ph O NaOH O H N N H Ph O Scheme 7. while the heterochiral complex is less stable because it can only accommodate two of these interactions at the same time.3.5 Base-promoted interconversion of hydantoin enantiomers. Meyers’ group described a remarkable example .Asymmetric Resolution and Transformation of Chiral Compounds 335 O O N N (S) H SBu Et N O N O NO O N H O SBu Et N O N O N (R) H O NO SBu NO O O N N (S) H SBu O O O 9 NO O N O N (R) H SBu O O O 9 NO · H N (R) · H N (R) less stable complex.28 Equilibration of the racemic hydantoin mixture in the presence of sodium hydroxide and brucine as the chiral complexing agent is highly stereoselective and permits isolation of the (S)-enantiomer in excellent enantiopurity.29 oxazinones30 and transition metal complexes. see Chapters 3.e. It is assumed that the enantioconversion involves ring opening of the nonenolizable hydantoin and intramolecular Michael addition of an achiral intermediate.4. Scheme 7. Diastereomerization processes including mutarotation and epimerization are prime examples of asymmetric transformation of the first kind. Interconversion of covalent diastereomers is a practical alternative and has been used to enrich stereoisomers of a variety of chiral compounds including amino acids.

2 and 6. They recognized that the conformation of the actinoidinic acid unit is controlled by the global aglycon structure rather than by proximate chiral elements.32–34 The coupling reaction occurs within one hour generating both biaryl atropisomers with low diastereoselectivity. . DMF reflux. Boger et al. Continuous refluxing of the interconverting isomers in DMF for a further 39 hours increases the initial diastereomeric ratio from 62:38 to 93:7. Indeed.3 Structures of chiral compounds prepared by asymmetric transformation of the first kind. Asymmetric transformation of the first kind has thus become a key feature in the synthesis of vancomycin. 39 h N MeO OMe dr = 93:7 MeO MeO OMe N (P) OMe OMe OMe O Scheme 7. favoring the desired (P)-atropisomer which is a key intermediate for the total synthesis of permethylated tellimagrandin. and that rotation about the central bond between aryl rings A and B proceeds at ambient temperature favoring formation of the (P)-axis. thermal equilibration at 55 1C resulted in atropisomerselective interconversion of the two diastereomeric tetrapeptides providing the desired axial stereochemistry in 90% de.6. teicoplanin and other antibiotics.36.6 Atroposelective biaryl synthesis based on asymmetric transformation of the first kind. Atroposelective synthesis with stereodynamic compounds is discussed in more detail in Chapters 6. developed a different approach to vancomycin. in which the tricyclic aglycon is obtained by thermally controlled stereomutation of the axially chiral biaryl moiety and the two chiral aryl ether planes.37 and for the synthesis of the aglycon of the antibiotic glycopeptide vancomycin. an important ellagitannin.3.7. O N MeO MeO MeO O N Cu.336 Chapter 7 H2N CO2H N O O O Zr O Figure 7. Scheme 7. 1 h MeO MeO + O OMe N (P) N MeO O OMe OMe 62% O (M) OMe N O 38% Cu.35 Asymmetric transformation of the first kind has also been exploited for deracemization of ortho-dihydroxylated biaryl ligands VANOL and VAPOL in the presence of (–)-sparteine-derived copper(II) complexes. DMF MeO MeO Br OMe reflux.38–41 Evans and coworkers prepared a bicyclic tetrapeptide vancomycin precursor exhibiting the unnatural (M)-actinoidinic acid moiety. that is based on oxazoline-mediated asymmetric Ullmann coupling of aryl bromides and subsequent thermodynamically controlled transformation to a diastereomerically enriched biaryl. Scheme 7.

3. extraction or chromatographic separation step.42. which is defined as equilibration of a mixture of stereoisomers towards a stereochemically enriched or pure sample with concomitant separation. Although either enantiomer of a stereolabile compound can be enriched through this procedure. Theoretically. Crystallization-induced asymmetric transformation is sometimes referred to as crystallization-induced dynamic resolution (CIDR) or total spontaneous resolution.43 While deracemization of enantiomers requires conglomerate formation. The stereochemical outcome is controlled by the stereoselective crystallization. The total . Scheme 7.9% of the desired enantiomer. 7.3 ASYMMETRIC TRANSFORMATION OF THE SECOND KIND Deracemization of stereolabile chiral compounds that undergo enantioconversion at elevated temperature can be achieved through repetitive enantioseparation based on chromatography or crystallization and racemization of the undesired enantiomer upon heating. Effective asymmetric transformation of racemic narwedine to either enantiomer based on total spontaneous resolution has been reported by Shieh and Carlson. and several economically viable one-pot procedures are known. 7. In the latter case. the success of crystallization-induced asymmetric transformation of interconverting diastereomers depends solely on the relative thermodynamic stability of the corresponding crystal lattices.7 Structure of vancomycin (left) and asymmetric transformation favoring the formation of the natural (P)-diastereoisomer of the tetrapeptide precursor (right). an important tertiary alkaloid.5% of enantiopure seed crystals to a supersaturated ethanolic solution of racemic narwedine. The remaining 25% of the undesired enantiomer can then be converted to the racemate and subjected to a third separation process. isolation of each enantiomer of a chiral compound by HPLC allows selective off-column racemization of the undesired fraction which is then employed in a second resolution process to yield another 25% of the preferred enantiomer. a series of separation and off-column racemization steps is required.8. and can also be observed with interconverting diastereoisomers. deracemization based on five separation and four racemization steps affords 96. initiates crystallization of a single enantiomer in 84% yield.44 Addition of 2. spontaneous or crystal seed-induced crystallization from solution or from the melt may lead to quantitative deracemization and formation of enantiopure solids. For example.1 Crystallization-induced Asymmetric Transformation Crystallization of a mixture of stereolabile enantiomers in solution produces either a racemic precipitate or a conglomerate. Enantioenrichment of a racemate is more conveniently accomplished through asymmetric transformation of the second kind. and so on. and when enantioconversion occurs on the crystallization time scale. Asymmetric transformation of the second kind eliminates the need for cumbersome separation and recycling of the undesired enantiomer by external racemization.Asymmetric Resolution and Transformation of Chiral Compounds HO HO O O O HO O NH HO2C HO A B OH OH C H N O Cl H N O D O N H O NH2 O O O Cl E H N O O OH NH NHMe HO O O MeHN NH (P) A HO H N 337 HO H 2N OH O C Cl O H N B OH OH O OPiv OMs D 55°C NHTFA HO O O MeHN HO C H N NH (M ) A B HO OH O O Cl H N O OPiv D OMs NHTFA 95 : 5 Scheme 7.

10. The mixture was then converted to a stereochemically pure diastereomer by stirring at room temperature and the chiral auxiliary was recovered by extraction. Hydrogen/deuterium exchange experiments suggest that the enantiomers of narwedine racemize via reversible retro Michael addition and subsequent ring closure of the achiral intermediate. Scheme 7. which increases the diastereomeric ratio from 3. thus driving the equilibrium of the interconverting enantiomers towards the (R)-amino ester which can be isolated in 68% yield and 96% ee.S )-tartaric acid generates an insoluble diastereomeric salt. Scheme 7. the predominant species in solution must not necessarily be the one that precipitates because asymmetric transformation of the second kind is solely driven by crystallization of the stereoisomer that forms the more stable crystal lattice. Subsequent hydolysis and hydrogenolysis of the amino nitrile finally gave (S )-tert-leucine.51 i.52–62 Virtually every amino acid has been employed in deracemication studies by using aldehydes or ketones to generate a stereolabile Schiff base that undergoes crystallization in the presence of a chiral additive. Jochims et al.9.50 It has been suggested that the interconversion proceeds through reversible diastereofacial addition of HCN to an intermediate imine. such as camphersulfonic and tartaric acid. interconversion of solid chiral stereoisomers through an equilibrium process that occurs in solution. Scheme 7.64 Vedejs explored crystallization-induced asymmetric transformation of diastereomeric oxazaborolidinone complexes derived from amino acids or their amidino-protected derivatives. However.4.8 Enantiomerization of narwedine via an achiral intermediate (left) and structure of galanthamine (right).. the more stable diastereoisomer in solution undergoes preferential crystallization. They prepared an ethanolic suspension consisting of equimolar amounts of diastereomeric amygdalates derived from an aliphatic or aromatic racemic a-amino nitrile and (R)-mandelic acid. Figure 7. or enantiopure crystal seeds of the desired enantiomer. accomplished deracemization of a-amino nitriles via asymmetric transformation of the second kind based on Dimroth’s principle.11.65–67 Appropriate substitution at boron affords a stereolabile chiral center showing epimerization due to reversible cleavage of the boron–nitrogen or boron–oxygen bond.45–49 Broxterman and coworkers coupled a diastereoselective Strecker reaction using pivalaldehyde.63 Villani and coworkers observed racemization of the hydrochloride salt of 4-chlorophenylalanine methyl ester in the presence of catalytic amounts of salicylaldehyde in refluxing methanol. sodium cyanide and (R)-phenylglycine amide with crystallizationinduced asymmetric transformation to produce the corresponding a-amino nitrile in 93% yield and 98% de.9. Scheme 7. Oxazaborolidinone complexes derived from boranes with .e. Addition of one equivalent of (S. spontaneous resolution of narwedine can also be induced by addition of enantiopure seed crystals of a structural analog such as galanthamine. In this case. Asymmetric transformation of amino acids based on in situ racemization of N-acylamino derivatives or Schiff base intermediates has become a popular method.338 O O O OH Chapter 7 O NMe HO NMe O NMe O NMe MeO MeO MeO MeO Scheme 7.1:1 in solution to 39:1 in the solid state. Slow evaporation of the solvent from a mixture of stereolabile oxazaborolidinone diastereoisomers derived from (S )-phenylalanine results in crystallization of the anti-diastereoisomer. Asymmetric transformation of the second kind has been incorporated into several synthetic routes to a-amino acids. and the same concept has been used to prepare a-methyl-DOPA.

see Chapter 6.Asymmetric Resolution and Transformation of Chiral Compounds Ph Ph H N + CONH O NaCN H HOAc H CN HCN HN CONH N H Ph CONH HCN H CN HN Ph 339 CONH (R)-phenylglycine amide (R. electron-withdrawing substituents can be exploited for asymmetric synthesis based on the principles of self-regeneration of stereocenters (SRS). 98% ee (S)-tert-leucine CN BnH N H R H HO CO Ph BnH N CN H R BnH N CN R H BnH N CN R H H HO CO Ph EtOH solution solid state CN BnH2N CO2 R=alkyl. aryl BnH N CN CO H H Ph R HO (R. This approach circumvents racemization of (S )-phenylalanine and provides asymmetric access to quaternary amino acids. NH2 CO2H H2N NH2 NH2 CO2H NH2 HO CO2H N H NH2 CO2H HO S CO2H S N H CO2H H N N NH2 NH2 CO2H NH2 CO2H N H CO2H N H CO2H HS CO2H CO2H Figure 7.11.9 Synthesis of (S)-tert-leucine via crystallization-induced asymmetric transformation of an intermediate a-amino nitrile (top) and deracemization of a-amino nitriles using Dimroth’s principle (bottom).R)-α-amino nitrile 73%.S)-α-amino nitrile preferential crystallization Ph HN CONH H H CN 93%.R)-amygdalate Scheme 7.R)-amygdalate R H Ph H HO (S.5% ee.2.4 Structures of amino acids that have been purified by crystallization-induced asymmetric transformation. the sense of chirality at the boron atom is first determined by crystallization-induced asymmetric transformation of diastereomeric borate complexes bearing an a-amidino derivative of an amino acid such as (S)-phenylalanine.69 In this reaction sequence. Scheme 7. hydrolysis of the borate complex releases (R)-2-propylphenylalanine in 81% yield and 99. The chiral center of the amino acid moiety is then destroyed by deprotonation and the chiral borate unit is used to control the stereoselective alkylation of the enolate with propyl bromide to regenerate the asymmetric carbon atom. A similar strategy involving crystallization-induced .5. In the final step.68 Vedejs’ group uncovered that oxazaborolidinones are configurationally stable under cryogenic conditions and allow basepromoted enolization of the amino acid moiety and subsequent asymmetric alkylation. 98% de NH CO H (R.

10 Asymmetric transformation of 4-chlorophenylalanine methyl ester.1:1 H syn-oxazaborolidinone (purification by conventional crystallization gives 70% of the stereochemically pure anti-oxazaborolidinone) Ph B F Me2N O O Ph H KOt-Bu -78 °C Ph C3H7Br B F Me2N O O Bn H2O HO O Bn N Bn H N C3H7 H H2N C3H7 81%.5% ee Scheme 7. NaO O Ph H KPhBF3 B F Me2N O O H F B Ph O O F H B Ph Me2N O O H Bn N Me2N H Bn TMSCl N Bn Me2N N H Bn N H anti-oxazaborolidinone crystallization Ph B F Me2N N O O H Bn H O B F Me2N N Bn H dr = 39:1 OK anti/syn = 3. .11 Asymmetric transformation of borate complexes bearing an amino acid ligand (top) and selfregeneration of the original stereocenter during alkylation of an oxazaborolidinone-derived enolate (bottom).340 (R) CO2Me Cl HN OH Cl HN OH CO2Me Cl Chapter 7 (S) CO2Me HN OH O OH O OH (R) CO2Me Cl NH3 Cl CO2H H OH CO2H (S ) CO2Me Cl NH3 Cl HO H (R) CO2Me Cl NH2 2:1 CO2H · HO H H OH CO2H Scheme 7. 99.

a key intermediate for the synthesis of 2-deoxynucleosides. i.4.12 Chiral phosphines employed in asymmetric transformation of the second kind (top) and iodine-catalyzed interconversion of diastereomeric tertiary phosphines (bottom).79 Komatsu and Awano developed an attractive synthetic route to 2-deoxy-a-D-ribosyl-1-phosphate. Scheme 7. Scheme 7.5-dioxo-1-imidazolidine)butanoic acid occurs upon addition of (1R.2-diphenylethanol and catalytic amounts of tetrabutylammonium bromide.8% anomeric purity.78 Crystallization-induced asymmetric transformation of racemic 2-bromo-4-(3.80 Treatment of readily available 3. secondary phosphines and fluorophosphines exhibiting an energy barrier to pyramidal inversion between 80 and 100 kJ/mol have been described..3-di-Obenzyl-4.2S)-2-amino-1. Asymmetric transformation of several chiral carboxylic acids including mandelic acid and naproxen has been reported. Vedejs and Donde developed a crystallization-induced asymmetric transformation procedure based on iodine-catalyzed equilibration of diastereomeric tertiary phosphines.b-D-glucopyranose unit and concomitant crystallization of the desired b-anomer into a multi-kilogram scale synthesis of the anticancer drug etoposide. Scheme 7. The diastereomer that forms the more stable crystal lattice. the less soluble isomer.71–74 Since tertiary phosphines containing three alkyl or aryl groups have pyramidal inversion barriers exceeding 120 kJ/mol and are therefore configurationally stable at ambient temperature. asymmetric transformation of diastereomeric oxazolidinones derived from (S)-alanine followed by enolization and asymmetric alkylation based on SRS has been reported. discovered that 2-arylpropionic acids show amidine-promoted racemization and stereoselective crystallization from the melt in the presence of enantiopure a-methylbenzylamine.14. incorporated anomerization of a 2. The configurational instability of other a-halogenated carboxylic acids in the presence of a quaternary ammonium salt has been utilized for crystallization-induced epimerization of diastereomeric imidazolidinone analogs.e.6-O-ethylidene-a. was isolated in 83% yield and 95% de.4-trimethyl-2.70 Asymmetric transformations with tertiary acylphosphines. Silverberg et al.Asymmetric Resolution and Transformation of Chiral Compounds MeO PhO O P Ph Ph I I P Ph I2 P Ph I P I Ph I I P Ph I2 P Ph H P BH3 NMe2 Pd 341 Cl P i-Pr F preferential crystallization 83%.77 Kiau and coworkers developed a procedure for deracemization of a-substituted carboxylic acids that interconvert under mild conditions and form diastereomeric ammonium salts.13. The interconversion process presumably involves a pentavalent trigonal bipyramidal adduct. The crystallization-controlled epimerization increases the anomeric ratio to 89:11 and subsequent removal of the 4-chlorobenzoyl residues and crystallization yields 2-deoxy-a-D-ribosyl1-phosphate in 98.76 Zwanenburg et al. Selective crystallization shifts the epimeric equilibrium to the desired a-anomer.5-di-O-(4-chlorobenzoyl)-2-deoxy-a-D-ribosyl-1-chloride with orthophosphoric acid produces an almost equimolar mixture of anomeric sugar 1-phosphates that rapidly interconvert in acetonitrile.12. 95% de Scheme 7.81 Crystallographic .75 Conversion of a 3:1 mixture of a menthyl-derived diastereomeric phosphine to a highly enriched isomer was achieved through slow solvent evaporation over 30 hours.

8:1. and thus overcomes the anomeric effect which favors formation of the latter.7-dihydroxynaphthalene.342 O N O O N N O Br CO2H Br CO2H Chapter 7 N HO Ph NH2 Ph HO NH3 Ph O2C Br Bu4N Br Ph i-PrOAc:MTBE (1:1) οC. 88% ee Scheme 7. 24 h 55 O N N O 90%. with selective formation of an inclusion complex containing the desired stereoisomer in a cocrystal with 2.iv They combined pyridoxal-mediated epimerization of a mixture of cefadroxil and one of its diastereoisomers. Another clathrate-induced asymmetric transformation of stereolabile N-nitrosamines that undergo racemization in solution at room temperature has been accomplished with iv A clathrate is an assembly consisting of a molecule which is trapped in a cage formed by a different molecule. Epimerization in the presence of pyridoxal and concomitant clathrate formation increased the diastereomeric purity of cefadroxil from 63 to 94%.13 Crystallization-induced deracemization of an a-substituted carboxylic acid. Bu N ACN O O O O α/β = 89:11 OH P O O 2-deoxy-α-D-ribosyl-1-phosphate Cl Scheme 7. analysis revealed that the b-isomer of the carbohydrate derivative forms a more stable crystal lattice than the a-anomer.82.2 HO O OH P O O 2) crystallization Cl O 1) NH α-anomer H PO . Scheme 7. Zwanenburg’s group described a process that affords the cephalosporin antibiotic cefadroxil through clathration-induced asymmetric transformation.15. O O O Cl O O Cl Cl H PO O O O O O O OH P O O Cl O O O O O O OH P O O α/β = 49:51 in ACN β-anomer Cl Cl Cl selective crystallization O OH O α/β = 98. . epicefadroxil.14 Synthesis of 2-deoxy-a-D-ribosyl-1-phosphate by crystallization-induced epimerization.

deracemization of a solution of 2-substituted cyclohexanones is achieved by complexation with insoluble chiral host molecules. (R.84.Asymmetric Resolution and Transformation of Chiral Compounds N N OH N H N O HO N HO C O OH 343 N HO C HO C N S N OH HO CO H O H N OH HO2C N S N CO H HO C O OH H N O N O CO H OH S O HO N NH H N O N O NH2 S O H N N S HO cefadroxil HO CO H OH O epi-cefadroxil CO2H HO NH2 H N N O S HO OH O HO CO2H 2 clathrate Scheme 7. O (R) NaOH MeOH/H O O MeOH/H O NaOH solution solid state Ph O (S) O (R) Ph Ph Ph OH (R) O HO (R) O (S) Ph Ph Ph Ph HO (R) (R) O OH O · O · thermodynamically favored inclusion complex Scheme 7.R)-TADDOLs as crystal host.15 Clathration-induced asymmetric transformation of cefadroxil.16 Thermodynamically controlled deracemization of 2-benzylcyclohexanone based on enantioconversion and formation of insoluble diastereomeric TADDOL complexes.83 In a conceptually similar approach that exploits stereoselective partitioning. sodium hydroxide-catalyzed enantioconversion of 2-benzylcyclohexanone in aqueous methanolic solution can be coupled with .85 For example.

16. The possibility of deracemization based on chromatographic enantioseparation coupled to on-column enantioconversion was first mentioned by Pirkle. a.105 allenes.99.97. Scheme 7.120 Wolf and coworkers described a chromatographic procedure that integrates several racemization and enantioseparation steps into one HPLC process.v Formation of the thermodynamically favored homochiral inclusion complex of the chiral host and 2-benzylcyclohexanone causes deracemization.115 and chiral transition metal complexes. This resolution technique provides invaluable access to chiral amines and amino azepinones. high chromatographic enantioselectivity is v TADDOLs generally consist of two adjacent trans-diarylhydroxymethyl groups attached to a 1.3-dioxolane ring.100 N.2 0 -diiodobiphenyl as 96.95 amino alcohols.7.110–112 helicenes.R)TADDOL complexing agent. In addition to the examples given above.5.101 oxazinones.121 They determined the rotational energy barrier of 2. .106.5 Compounds obtained by asymmetric transformation of the second kind. 7.2 Asymmetric Transformation based on Chromatographic Separation Few chromatographic processes that involve asymmetric transformation of the first or second kind to produce enantioenriched or enantiopure compounds have been reported.96 aldehydes and ketones.103 atropisomeric biaryl lactones and diquinazolinones.102 thiazoles. and the (R)-enantiomer is obtained in 74% ee after two days of equilibration. In this case.107 paracyclophanes.108.113 meso silanes.86–94 alcohols. asymmetric transformation of the second kind has been applied to a wide range of chiral compounds.9-dimethylphenanthroline NH2 N F Me Ph Si Si F Me Ph H2 N H2N Figure 7.104. of 5.109 binaphthyls and oligonaphthalenes.6 kJ/mol and observed that the enantiomers can be separated by HPLC on microcrystalline triacetyl cellulose with an enantioselectivity factor.344 Cl NH2 N N NH2 Ph O OH HN Ph MeO CF3 Ph O N Ph S EtO2C N H CO2Et H N S N O N N N NH O RO2C • Chapter 7 O N N O Ot-Bu O Ph N CF3 H N N O O F Ph O O N F O NH2 S N H NMe2 Br O Br OH Br O CO2Me CO2R H H R = (-)-menthyl (CH2)7 N H3COC ACN N NH2 H2 Ru COCH3 N ACN N Co N N O O = 2.3.O-ketals.114.116–119 Figure 7. enantioselective extraction of the (R)-enantiomer into a solid phase consisting of an (R.98 acetals.

6. .4 mg 1. After cooling to 8 1C. Figure 7.2′-diiodobiphenyl column temperature 50 οC 8 οC 2 mL/min 0 mL/min B A 12.6 Structures of stereolabile compounds that have been employed in preparative chromatographic on-column racemization and separation processes (top).75 B 6.1 mg of the (þ)-enantiomer was recovered.55 A h A = chromatographic separation B = stopped-flow racemization Figure 7. Okamoto’s group later described a deracemization process that exploits on-column enantioconversion of a stereolabile chiral spiro compound.Asymmetric Resolution and Transformation of Chiral Compounds I C12H26O O2N O O I HO2C 345 9. After continuation of the chromatographic vi This is an example of asymmetric transformation of the first kind. Once the less retained (–)-enantiomer was eluted from the column. The remarkable chromatographic selectivity and suitable capacity for the dextrorotatory enantiomer. This procedure allows almost quantitative conversion of a racemate to a single enantiomer and eliminates the need for repetitive injection and off-column racemization.5 mg 50 οC 8 C 2 mL/min 0 mL/min A 0 2.2 0 -diiodobiphenyl. A total of 17.4 mg 4.vi The use of two Chiralcel OD columns coupled in series allowed separation of the enantiomers and selective on-column racemization of the less retained enantiomer at 40 1C in the second column at stopped flow. the flow was re-adjusted to 2 mL/min to continue the enantioseparation process until elution of a further 25% of the (–)-enantiomer was completed. On-column racemization and chromatographic isolation of the less strongly retained enantiomer were repeated two more times to afford a total of 90% of the (–)-enantiomer and 10% of the finally eluted (þ)-enantiomer.75 A 8. Chromatographic conditions for the deracemization of 20 mg of 2. combined with a large capacity factor for the more strongly retained (þ)-enantiomer. allowed enantioseparation and enantioenrichment by a series of on-column racemization/elution cycles.9 mg of the (–)-enantiomer was collected in four fractions and 2.6]-ring opening on a Chiralcel OD column at stopped flow occurred at 40 1C and produced an enantiomeric excess of 31% favoring the more retained enantiomer at thermal equilibrium.50 ο isolated (−) -2.1 mg 8 C 2 mL/min ο flow rate 0 mL/min B 17.2′-diiodobiphenyl isolated (+)-2.50 13. combined with the propensity of this atropisomer to rapid rotation about the chiral axis at ambient temperatures. the chromatographic separation process was stopped and the column temperature was increased from 8 to 50 1C for on-column racemization of the remaining (þ)-2.2 0 -diiodobiphenyl using microcrystalline triacetyl cellulose as chiral stationary phase (bottom).122 Reversible [1.55 8 C 2 mL/min ο 50 οC 2.6 mg 2. Formation of diastereomeric complexes between the interconverting enantiomers and the chiral stationary phase apparently results in significant enantioenrichment. while the other enantiomer was still on the first column which was cooled to 0 1C.

or preferably noncovalent. These examples demonstrate that coupling of enantioselective chromatography and thermal on-column deracemization of one enantiomer allows incorporation of enantiomeric enrichment and separation into a single operation.2. 7. either A or B 0 (but not both) can be obtained in sufficient enantiomeric excess if s is less than 100. Since A 0 reacts much more rapidly than A. but this is not always the case.123 7. viii A nonselective reaction has an s-value of 1. When conventional separation attempts are unsuccessful. see Chapter 5. .4 KINETIC RESOLUTION AND DYNAMIC KINETIC RESOLUTION Enantiomers are usually separated by enantioselective chromatography and selective crystallization of covalent. one can recover the latter if the reaction is not allowed to proceed to completion. both KR and DKR are confined to kinetically controlled reactions and are therefore conceptually different from asymmetric transformation of the first and second kind. the separated enantiomers were collected in a ratio of 4:1. the principles of KR are often exploited for asymmetric synthesis (and not for resolution). providing the atropisomers in 14% ee after chromatographic elution. conducted stopped-flow HPLC and CEC experiments to evaluate the stereodynamics of axially chiral 2 0 -dodecyl-6-nitrobiphenyl-2-carboxylic acid. However.4. a racemate consisting of enantiomers A and A 0 can be resolved to a mixture of the remaining enantiomer A and product B 0 in the presence of a suitable chiral catalyst (or reagent) if kA { kA 0 . s¼ kA 0 ln ½ð1 À cÞ ð1 À eeފ 6¼ ¼ eDDG =RT ¼ ln ½ð1 À cÞ ð1 þ eeފ kA ð7:1Þ where ee is the enantiomeric excess of the remaining enantiomer A.1. By definition. the catalyst and A 0 constitute a matched pair whereas A gives rise to a mismatched pair. a common shortcoming of these resolution techniques is that only 50% of one enantiomer can be obtained from a racemate. s.4. processes that have been introduced as KR are presented in this chapter. which is most obvious in the case of parallel kinetic resolution. which in principle allows quantitative conversion of a racemic mixture to a single chiral product. Lindner et al.346 Chapter 7 process through both columns at low temperature. it can be selectively transformed to a new compound if the reaction is conducted under kinetic control.1 Kinetic Resolution Kinetic resolution is based on the different reactivity of enantiomers during derivatization with a chiral reagent. a selectivity factor of 100 or above is required for effective resolution of both A and B 0 . which is defined as the ratio of the rate constants kA 0 and kA. As a rule of thumb.3. The enantiomeric purities of the product and the remaining starting material are necessarily interdependent and it is impossible to optimize the results for both A and B 0 .7. Following Wolf’s and Okamoto’s work. They observed on-column deracemization of the racemate due to asymmetric transformation of the first kind on a quinine-derived chiral stationary phase.3. as indicated in Figure 7. In this scenario. The enantioselectivity of a KR is a function of the conversion c. However. Integration of racemization and KR into one process results in synthetically more attractive dynamic kinetic resolution (DKR). or with an achiral reagent in the presence of an asymmetric catalyst. The ideal vii The term kinetic resolution was originally restricted to separation of enantiomeric substrates aimed at the recovery of one enantiomer while the other is consumed in an enantiomer-differentiating reaction. The two possible products B and B 0 can be enantiomers. kinetic resolution (KR) can be a useful alternative.viii Usually.vii Because one enantiomer of a racemate reacts more rapidly than the other due to formation of diastereomeric transition states. In accordance with the classifications made in the original literature. For example. diastereomeric adducts formed with enantiopure resolving agents. Chapter 7. The effectiveness of KR depends on the selectivity factor.

154 Several lipases. an enantioselectivity factor. and is readily available. s.155 esters. For example. A′ = enantiomers B. E. does not require a cofactor. B′ = products ∆∆G≠ = ∆G≠A . s.159 lactams.148 including hydroxy butenolides.8. amidases.4.149 spiropentane and dispiroheptane methanols.157 diols. For example.151 and fluorohydrins152 have successfully been resolved by lipase-catalyzed transesterification. conversion. Scheme 7. A continuous-flow KR of 1-phenylethanol using immobilized lipase and vinyl acetate in supercritical carbon dioxide has been reported. To maximize the enantiopurity of the reaction product B 0 . and by the choice between optimization of the enantiomeric purity of either A or B 0 . including industrial applications using acylases. oxidoreductases and hydrolases has been reported. of a given KR process is governed by the selectivity. optimization of the ee of the remaining enantiomer A often requires one to exceed 50% conversion. including Candida antarctica lipase (CAL).Asymmetric Resolution and Transformation of Chiral Compounds A + A′ kA Cat kA' Cat Cat A + B′ ∆∆G≠ B B′ B ∆G ≠ A 347 A + A′ A + A′ ∆G≠A′ B′ A. Since Pasteur discovered the first kinetic resolution in 1858 by treating tartaric acid with fermenting yeast. In accordance with the selectivity. hydantoinases.160 amino alcohols. c.124–126 Kinetic resolution of amino acids has received considerable attention due to potential biomedical applications and their usefulness as chiral synthons or auxiliaries in asymmetric synthesis.127–131 In particular. lipases have been exploited for kinetic resolution of alcohols.168 and amines.9.132 Racemic alcohols are frequently resolved by lipase-catalyzed transesterification using vinyl acetate or isopropenyl acetate as acyl donor.2-diaminocyclohexane to the corresponding (R. Figure 7. can be found in the literature.169 Gotor and others reported CALcatalyzed amidation of racemic 1. maintains catalytic activity and selectivity in organic solvents. Many examples. The enantiomers of numerous chiral primary.7 Kinetic resolution of A and A 0 using a chiral catalyst.150 allenes. carboxylic acids and other classes of compounds because this family of enzymes tolerates a wide range of unnatural substrates. a plethora of enzyme-catalyzed processes with transferases.1. have been employed in kinetic resolutions of carboxylic acids. and acetaldehyde. kinetic resolutions are usually stopped before 50% conversion is reached.17. Figure 7. similar amounts of the remaining (R)-propargylic alcohol.163–167 oxaziridines. has been defined for enzymatic kinetic resolutions:     kcat kcat ln ½ð1 À cÞ ð1 À eeފ E¼ ð7:2Þ ¼ KM R KM S ln ½ð1 À cÞ ð1 þ eeފ where KM is the Michaelis–Menten constant.133 The transfer of the acetyl group is followed by spontaneous tautomerization of vinyl alcohol to acetaldehyde.1 Enzyme-catalyzed Kinetic Resolution.153 Enzymatic KR of alcohols with lipases is quite practical but other methods such as sulfatase-catalyzed hydrolysis of sec-alkyl sulfates are viable alternatives. and esterases. which compromises the ee of product B 0 and also the yield of A.134–137 secondary138–146 and tertiary alcohols147.161.∆G ≠A′ kA « kA′ Cat = nonracemic chiral catalyst Figure 7. which provides the driving force for the esterification process. The advantage of these reagents is that thermodynamically stable and easily removable side products (acetaldehyde and acetone) are obtained. 7.162 amino acids and esters.R)-bisamidoester .158.156. Candida antarctica lipase-catalyzed KR of propargylic alcohols in the presence of vinyl acetate yields a mixture of approximately 50% of (S)-propargylic acetate.

a process was developed that affords 43% of essentially enantiopure (S. 82% ee OH O H Chapter 7 Scheme 7. Reetz and others have shown that this .174 and even unnatural substrates including metallocenes exhibiting a chiral plane. while only minute amounts of the intermediate monoamidoester are formed.348 OH + OAc lipase 47%. 93% ee OH + OAc + 53%.9 Chiral compounds resolved by lipase-catalyzed KR.17 Lipase-catalyzed KR of propargylic alcohols with vinyl acetate. respectively.18. Enzymatic and microbial KR has been applied to 2-hydroxy carboxylic acids. OAc CO2H N H CO2H CO2 H N O CO2H Ot-Bu CO2H NH2 NH2 O OEt CO2Me Ph CN OH OH OH NH2 O MeO OMe HO NH NH2 NH2 Figure 7.8 Structures of alcohols resolved by lipase-catalyzed transesterification. with dimethyl malonate as acyl donor.170–172 This KR involves two consecutive amidations with E-values of 45 and 68.S )-1. Through careful optimization of the amount of acyl donor and substrate conversion.175 A general drawback of enzymatic resolution is the inherently high substrate specificity. Scheme 7. S O OH OH O OH OH OH OH OH OH O OH TBSO O OH HO OH OH OH O OH MeO O F OMe O OH O OH OH OH HO O Figure 7.2-diaminocyclohexane and 57% of the (R.R)-bisamidoester in 97% ee.173 amino acids.

which is probably catalyzed . limitation can be overcome by bioengineering of enzymatic properties via site-specific mutagenesis or directed evolution based on random mutagenesis and protein expression in conjunction with high-throughput screening.3-diol in virtually quantitative amounts and 97% ee.192–195 Chadha and Baskar developed a biocatalytic deracemization procedure for a-hydroxy esters such as ethyl 2-hydroxy-4-phenylbutanoate and ethyl mandelate using intact cells of Candida parapsilosis.19 Kinetic resolution of b-hydroxy ketones by Ab38C2-catalyzed retro aldol reaction.19.3S)-epoxide undergoes regioselective hydrolytic ring opening at C-3 to the same (2R. 97% ee OMe O NH2 43%.3R)-diol.176–178 Alternatively.2-diaminocyclohexane with CAL. This concept has been utilized for the synthesis of a variety of chiral vicinal diols from racemic epoxides.188–191 Resolution of racemic cis-2. Scheme 7.3R)-enantiomer to (2R. Ab38C2 should not only be a useful catalyst for asymmetric aldol reactions but also applicable to KR of aldols.3-epoxyheptane by epoxide hydrolase from bacterial Nocardia EH1 results in selective conversion of the (2S. transesterifications and ester hydrolyses. The combination of KR and enantioconvergent hydrolysis of the remaining enantiomer produces (2R. 99% ee N H + O O + OH O Ab38C2 Scheme 7. OH O N H O N H O OH O O O N H + 52%.20. Indeed. KR can be achieved with antibody-catalyzed aldol reactions.3R)-heptane-2.Asymmetric Resolution and Transformation of Chiral Compounds NH2 MeO NH2 + (rac) NH2 MeO O O CAL E1 = 45 O NH NH2 O NH2 + CAL O E2 = 68 OMe O NH NH + O OMe 57%. treatment of racemic b-hydroxy ketones with Ab38C2 furnishes literally enantiopure starting material due to enantioselective retro aldol reaction.18 Enzymatic transesterification of 1.187 Imaginative enantioconvergent processes that overcome the impractical limitation of 50% theoretical yield inherent to traditional KR have been described. According to the principle of microscopic reversibility. Scheme 7.196 It is assumed that the enantioconvergent stereoinversion involves oxidation of the (R)-a-hydroxy ester to the corresponding 2-keto ester. >99% ee NH2 349 Scheme 7. Kinetic studies and labeling experiments with H218O revealed that under basic conditions the remaining (2R.179–186 The antibody Ab38C2 has been known to convert prochiral aldehydes in the presence of acetone to b-hydroxy ketones with excellent enantioselectivity.3-diol. Faber and others coupled biocatalytic KR of racemic epoxides with nonenzymatic hydrolysis exhibiting complementary stereoselectivity to achieve quantitative formation of highly enantioenriched vicinal diols.3R)-heptane-2.

84% ee HO OH OH >99%.21 Biocatalytic deracemization of ethyl 2-hydroxy-4-phenylbutanoate with Candida parapsilosis. by an NAD1-dependent dehydrogenase. 99% ee (R)-enantiospecific dehydrogenase O reductase CO2Et + Scheme 7.350 O (R) (S) Chapter 7 O (R) (S) OH + OH /H2O SN2 (R) (R) O (S) (R) + Nocardia EH1 KR OH (R) (R) OH >99%.3-epoxyheptane (top) and structures of vicinal diols obtained from epoxide precursors based on KR and subsequent hydrolysis (bottom). and so on. OH (S) CO2Et OH (R) CO2Et Candida parapsilosis OH (S) CO2Et 90%. The achiral intermediate is then converted to the (S )-enantiomer in the presence of an NADPH-dependent reductase.21. 90% ee OH 94%. Kinetic resolution OH Racemization CO2H OH CO2H 3 cycles OAc CO2H 80%.20 Kinetic resolution and enantioconvergent in situ hydrolysis of racemic cis-2.197 Strauss and Faber showed that such a laborious approach can be incorporated into a onepot procedure. 98% ee OH CO2H lipase OAc i-Pr2O + OAc racemase H2O + OAc CO2H CO2H Scheme 7. 98% ee OH HO HO 82%. 97% ee OH O OH HO 98%.198 For example. Scheme 7. Deracemization can also be achieved by combination of KR and external racemization of the isolated undesired enantiomer. 92% ee Scheme 7. 96% ee HO 100%.22 Two-step enzymatic KR and racemization of mandelic acid. deracemization of mandelic acid is feasible by lipase-catalyzed . The racemate is then recycled into another KR process.

1.222 which are converted to N-oxides.208 One of the most impressive examples.2S) O OH + O O NEt2 biomimetic enzyme (5 mol%) (i-Pr CO)2O (0.217–219 cyanohydrins220 and amino alcohols221.5 equivalents of isobutyric anhydride in the presence of 5 mol% of the artificial enzyme allowed preferential acylation of the (1R. 90% ee O O O i-Pr NEt i-Pr SO2 NH N i-Pr 351 N OH (1S. The Sharpless KR protocol has been applied to a variety of other alcohols including furyl alcohols. Many enantioselective catalysts and chiral auxiliaries originally developed for asymmetric synthesis are suitable to kinetic resolution.24.224 (þ)-methynolide. based on simultaneous use of lipase and mandelate racemase in one reaction mixture.5 equiv.207. Although the two enzymes require different reaction conditions and have to be removed after each step.223 koromicin. Noyori and coworkers developed a complementary method based on (BINAP)ruthenium-catalyzed ix The development of a more practical dynamic kinetic resolution of mandelic acid. It is noteworthy that Sharpless’ KR has been employed in the total synthesis of (þ)-grandisol. In particular.ix 7. do not have to be separated. and the remaining substrate.22.226 a component of the aggregation pheromone of the male cotton boll weevil. acylase199–204 and hydrolase205 mimics have been employed in the resolution of chiral alcohols and esters. Scheme 7. Ishihara et al. The attractive features of lipase-catalyzed biotransformations have intensified the search for biomimetic catalysts applicable to KR. Employment of racemic mandelic acid in four KR/racemization sequences affords (S )-O-acetyl mandelic acid in 98% ee and 80% yield. Scheme 7. that certainly rivals enzymatic methods. (R)-mandelic acid. 97% ee Ph Si O Ph O 52%.4.) s = 87 i-Pr + O t-Bu OH O 48%. the desired transesterification product. The (1S. is substantially less reactive.2R) Scheme 7.23 Biomimetic KR of cis-1-(4-diethylaminobenzoyl)-2-hydroxyhexane (left) and structure of the artificial enzyme used (right). is not possible because the enzymes require incompatible reaction conditions. i. up to 700 have been observed. In general. whereas the mismatched pair.2 Nonenzymatic Kinetic Resolution.e. L-(þ)-DIPT/Ti(Oi-Pr)4 and the (R)-alcohol.2-disubstituted substrates and selectivities. s. .225 and laulimalide.2-disubstituted allylic alcohols provide better results than (Z)-1. developed a simple (S)-histidine-derived artificial acylase for KR of secondary alcohols.2R)-enantiomer was recovered in 97% ee at 52% conversion which corresponds to a selectivity factor. Scheme 7.206 Treatment of cis-1-(4-diethylaminobenzoyl)-2-hydroxyhexane with 0.23. s. (S )-O-acetyl mandelic acid.2.Asymmetric Resolution and Transformation of Chiral Compounds NEt2 NEt2 O (1R.. acetylation in diisopropyl ether followed by enzymatic racemization of (R)-mandelic acid in aqueous solution. The (R)-alcohol can therefore be recovered in excellent enantiomeric excess at approximately 50% conversion. Since chiral cyclic allylic alcohols are not good candidates for Sharpless’ AE. is the application of Sharpless’ asymmetric epoxidation (AE) of allylic alcohols with tert-butyl hydroperoxide (TBHP) in the presence of catalytic amounts of Ti(Oi-Pr)4 and diisopropyl tartrate (DIPT)209 to KR of chiral substrates.and 2. of 87.2S)-alcohol.210–216 The matched pair consisting of the (S)-allylic alcohol and the L-(þ)-tartrate-derived catalyst generates an epoxy alcohol. (E)-1.

This problem can be avoided with an oxidative Ru-catalyzed KR protocol generating an achiral ketone that is more easily separated from the remaining alcohol. Scheme 7.250–257 A broad variety of functionalized terminal epoxides has been resolved to x In many cases. 79% ee n=2. Other nucleophiles such as indoles are also suitable to (salen)Cr-catalyzed KR of epoxides. however. which complicates isolation of the unreacted enantiomer. >99% ee R Scheme 7. 94% ee 47%. 94% ee 48%.228.x Nonfunctionalized terminal epoxides can be conveniently prepared in racemic form from readily available alkene precursors. >96% ee OH matched 46%.249 Since the corresponding (salen)cobalt(III) complex catalyzes epoxide ring opening with water.231 Fu et al.234–245. R=Me: 46%. s.25 Noyori’s reductive KR of cyclic allylic alcohols. Scheme 7. up to 630. A drawback of this procedure is that it generates a mixture of saturated and unsaturated alcohols. R=H: 48%. but separation of enantiomers by classical crystallization methods or enantioselective chromatography remains a difficult task. chiral secondary alcohols can be prepared with superior atom economy by enantioselective reduction of ketones or alkylation of aldehydes.2 0 -disubstituted epoxides undergo [(R.352 R1 + R1 OH OH OH OH OH R2 R2 Ti(Oi-Pr)4 L-(+)-DIPT t-BuOOH Chapter 7 R O R2 + R R OH mismatched OH O OH 40%. Jacobsen and coworkers therefore employed a (salen)chromium(III) complex.227 Using ruthenium diacetate in the presence of (M)-BINAP.230.28.246 A range of terminal and 2.232. 96% ee n=2. who utilized stoichiometric amounts of chiral acylating reagents for KR of alcohols.27. Scheme 7. propargylic and allylic secondary alcohols.248 This reaction produces chiral 1-azido-2-siloxy derivatives that can be transformed to synthetically versatile amino alcohols.26. which can also be used for desymmetrization of meso epoxides. >98% ee 46%. they recovered unreacted (S )-allylic alcohols in remarkable ee at approximately 50% conversion.25. several catalytic processes that allow kinetic resolution of chiral alcohols have been developed. OH (M)-(BINAP)Ru(OAc)2 (H 2C)n H2 R OH OH Ph Ph O P O Ru P O O Ph Ph (M)-(BINAP)Ru(OAc)2 + (H2C) n (H 2C) n R n=1. enantioselective hydrogenation.233 Since then.229 Following the pioneering work of Evans and Vedejs. . introduced a broadly applicable planar chiral ferrocene-derived DMAP acylation catalyst that affords excellent results with benzylic. 86% ee Scheme 7.R)-(salen)]CrN3-catalyzed ring opening in the presence of TMSN3 with selectivity factors as high as 280. R=H: 50%. Scheme 7.247. in the kinetic resolution of chiral epoxides. Jacobsen refined the method described above to a hydrolytic kinetic resolution (HKR) process exhibiting selectivities.24 Sharpless’ AE of secondary allylic alcohols.

>99% ee.R)-(salen)CrN3 TMSN3 (0. >99% ee.R)-(salen)CrN3 Scheme 7. >99% ee. crystallization of diastereomeric adducts or preferential crystallization is often not feasible. 93% ee R=CH2CN: 40%. Accordingly. 98% ee R′=Me. 99% ee. >99% ee. s=64 = R′=i-Pr. s=130 R=Bn: 46%.R)-(salen)CoOAc H2O (0. s=500 R=c-C6H11: 44%. >99% ee. 97% ee 42%. 96% ee R′=R″=Me. 94% ee. HKR of epoxides. O R (R. s=80 Scheme 7. >99% ee. R′′=H. >99% ee. and Shi epoxidation of nonfunctionalized alkenes with a readily available fructose-derived catalyst.258. s=79 R=Ph: 44%. Since simple epoxides tend to be liquid and do not undergo strong interactions with commonly used chiral resolving agents or chiral stationary phases. has become a viable alternative to traditional resolution methods. 92% ee R=CH2Cl: 47%.259 The usefulness of KR is most apparent when enantiopure compounds can not be obtained by other means. s=120 N Co t-Bu O t-Bu N O OAc t-Bu t-Bu (R. R′′′=Ph: 47%. s=83 R=CH2Cl: 43%.27 Jacobsen’s KR of terminal epoxides with [(R. s=25 R=CH2Cl: 46%.Asymmetric Resolution and Transformation of Chiral Compounds NMe2 Ph OH R″ R′ R′′′ Ph Ph (1-2. 96% ee R=t-Bu: 49%. Chiral epoxides can be prepared through powerful asymmetric reactions such as Sharpless epoxidation of allylic alcohols. s=630 R=t-Bu: 41%. Hydrolytic KR has .28 HKR of terminal epoxides with (R.5 equiv. literally enantiopure materials by this method.) OH + R R O R=Me: 45%. >99% ee.5 mol%) Ac2O Fe N Ph Ph R′′ R′ + OH R′′ R′ OAc OH Ph R 353 R=Me: 46%.R)-(salen)CoOAc Scheme 7. 95% ee (R. 99% ee OH R′′′ R′′′ R=i-Pr: 48%. R′′′=H: 45%.R)-(salen)]Cr(III).26 Enantioselective acylation of allylic and propargylic alcohols.260–262 Despite the broad success of these methods. enantiopure epoxides are usually not obtained without further purification.55 equiv. s=96 R=CH2OBn: 48%. 98% ee. Jacobsen epoxidation of conjugated olefins with a (salen)Mn(II) catalyst. O R OH (R. 99% ee R=Et: 48%. s=190 R=CO2Me: 43%. separation by enantioselective chromatography. which are very useful intermediates in natural product synthesis. 97% ee R=Bn: 47%. R′′=n-Bu. R′′′ Ph: 46%.) O OTMS N3 t-Bu N Cr O t-Bu N3 O t-Bu t-Bu N + R R R=Et: 41%.R)-(salen)cobalt(III).

72% ee NO2 38%.xi AD has successfully been applied to a few substrates.289–292 aldehydes.3. 99% ee O t-Bu CO2t-Bu Ph 47%.282 Other practical protocols involving either a chiral catalyst or a chiral auxiliary have been developed for alkanes.2. 84% ee 49%. Scheme 7.. Some alkenes. 99% ee OAc O2N Ph 45%.280 has also been reported. 90% ee O Ph 44%.29.320–322 and lactones. see Chapter 5. 92% ee S O O 23%. have been resolved by reductive KR based on hydroboration.299 imines and pyrrolines.281.264 fostriecin. e.294–298 aziridines.263 laulimalide.323.284 amines. 99% ee Ph 45%.g. .271 Although cinchona alkaloids are usually sensitive to existing chirality in alkenes.308.305–307 allenes. including chiral fullerenes and axially chiral alkenes.324 Figure 7.270 Sharpless’ renowned cinchona alkaloid-catalyzed asymmetric dihydroxylation (AD) of olefins has been extended to kinetic resolution.269 and (–)-mycalolide.268 ulapalide.309 ketones.300–302 sulfoxides.10 Structures of enantiomers obtained by kinetic resolution. >99% ee N H N 42%.2-dihydronaphthalenes. >98% ee MeSO2NH2 Ph CO2Me + HO HO Et Et Ph t-Bu N N O H OMe N t-Bu Ph N O H MeO N H N (DHQD)2-PHAL Ph Scheme 7.354 Chapter 7 Ph + (DHQD)2-PHAL (1 mol%) K3Fe(CN)6 K2OsO2(OH)4 Ph 47%.272–277 Oxidative KR of alkenes via selective epoxidation with either Shi’s fructose-derived catalyst278 or (salen)manganese complexes279.10.267 bryostatins. 89% ee Figure 7.304 epoxides.265 (–)-pyrenophorin.293 ethers. been incorporated into the total synthesis of epothilone.266 carquinostatin A.29 KR of chiral trisubstituted olefins based on Sharpless AD and structures of recovered enantiomers.313–319 carbamates.283 alkyl halides. 1-substituted 1. 99% ee Ph Ph 32%.303. NH2 H O O O OMe O n-C6H13 43%. xi This is an example of a reaction course with significant reagent-based stereocontrol.310–312 esters. >99% ee Ph 33%. 93% ee O 44%. which are very difficult to resolve by other means. >98% ee 48%.285–288 alcohols. 95% ee OAc O O O 47%.

Vedejs and Chen utilized pseudoenantiomeric DMAP-derived resolving agents for dual kinetic resolution of secondary arylalkyl alcohols. respectively. of 49 gives products B and C in 96% ee at quantitative conversion.11. Horeau found that hydrolysis of the remaining nonracemic reagent and subsequent polarimetric analysis of the carboxylic acid mixture can be used to deduce the absolute configuration of the resolving alcohol. PKR is advantageous when the selectivity factor is below 150 and when dynamic kinetic resolution or KR coupled with enantioconvergent in situ transformation of the less reactive enantiomer is not feasible. A′ = enantiomers B. the corresponding carbonates are produced in 88% and 95% ee at 98% conversion. to optimize the purity of the less reactive enantiomer one must exceed 50% conversion and thus compromise the ee of the product. The outcome of KR is determined by the rate of the two competing reactions and conversion of the starting material. A′ = enantiomers B. Kinetic resolution gives rise to preferential esterification of one anhydride enantiomer while the other one is enantiomerically enriched. Although the individual stereoselectivity factors of the two chiral N-alkoxycarbonylpyridinium salts shown in Scheme 7. one can not maximize both enantiomeric purity and recovery of the substrate.Asymmetric Resolution and Transformation of Chiral Compounds 355 The principles of KR can also be exploited for analytical purposes. To overcome these limitations.328 In contrast to KR. PKR has been classified into chemo-. regioand stereodivergent processes. Horeau employed an excess of racemic 2-phenylbutyric anhydride or the corresponding acyl chloride to convert substoichiometric amounts of a chiral alcohol of unknown configuration to a mixture of diastereomeric esters. B′ = (enantiomeric) products + B′ kA » kA′ A′ B kA kA′ B C A.11 Principles of KR (left) and PKR (right). Figure 7. Since the ee of the remaining enantiomer steadily increases with conversion. Finn and coworkers developed a high-throughput screening method for determination of the enantiomeric composition of amines and alcohols based on kinetic resolution with pseudoenantiomeric mass-tagged chiral acylating agents in conjunction with mass spectrometric analysis.329 Based on the structural relationship of the products. . This method has been applied to a variety of chiral secondary alcohols and primary alcohols that are chiral only by virtue of isotopic substitution (RCHDOH). s. In theory.4. Because of the interdependence of the ee of the product and the remaining starting material. Formation of a mixture containing product B and the remaining starting material A 0 (kA c kA 0 ) in the same enantiomeric excess by traditional KR would require a selectivity factor of 200 at 50% conversion. C = nonenantiomeric products kA ≈ kA′ Figure 7.326 Siuzdak. PKR of enantiomers A and A 0 based on two independent reactions with a complementary selectivity. even in the case of relatively low selectivity factors. when the concentration and consequently the rate of consumption of the more reactive enantiomer is reduced while the relative reaction rate of the less reactive enantiomer increases significantly.330 The PKR of a secondary alcohol with stoichiometric amounts of A + A′ kA kA′ A A. For example. In PKR both enantiomers are consumed simultaneously by two independent reactions that ideally proceed with similar rates. both enantiomers of the starting material are converted to nonenantiomeric products by different reactions with complementary enantiodifferentiation and one can obtain products with substantially improved enantiomeric purity at 100% conversion.327 7.3 Parallel Kinetic Resolution. Vedejs and Chen introduced a strategy called parallel kinetic resolution (PKR).325. A major shortcoming of KR is that the enantiomeric purity of the product decreases at conversion close to 50%.1. For comparison. it is impossible to maximize the enantiomeric purity of both.30 for the enantiomers of 1-(1-naphthyl)ethanol are only 41 and 42. As a rule of thumb. the recovery of 49% of one enantiomer in 95% ee by traditional KR requires a stereoselectivity factor of at least 125.

342 This finding is remarkable because of the surprising effect of the chiral catalyst structure on the reactivity and fate of the enantiomeric alkynals. Regiodivergent resolutions either involve competing reaction pathways that give rise to regioisomers or examples of positional selectivity. 88% ee O O N O 49%. i. each enantiomer of this b-keto ester is recognized by a different enzyme.e.30 Parallel kinetic resolution of a secondary arylalkyl alcohol using stoichiometric amounts of quasienantiomeric resolving agents.0]octane-2-carboxylate with baker’s yeast leads to reduction of one enantiomer to the corresponding syn-hydroxy ester. Scheme 7.343 Apparently. For example. in which one molecule displays similar functional . They also demonstrated the feasibility of dual KR of structurally related 3-alkyl-cyclopentene-1-carboxylates and 2-amino-5-tert-butyl-cyclopentene-1-carboxylates.3.331–335 Davies and coworkers developed a PKR protocol for methyl 5-alkyl-cyclopentene1-carboxylates that is based on conjugate addition of pseudoenantiomeric lithium N-a-methylbenzylamide-derived salts. This procedure yields a chiral cyclopentenone in 93% ee and recovered starting material in 72% ee.7-(ethylenedioxy)bicyclo[3. while the other enantiomer is transformed to an achiral 7.31. Scheme 7. an oxidoreductase and an esterase.7-(ethylenedioxy)bicyclo[3. treatment of a 3-oxo-7. and the simultaneous formation of two synthetically challenging cycloalkanones. Several other catalytic chemodivergent resolutions are known. The practicality of PKR can be improved when stereoselective chemodivergent resolution is combined with derivatizing agents exhibiting quite different chromatographic properties.. two chiral N-alkoxycarbonylpyridinium salts discussed above affords nonisomeric products and thus constitutes a chemodivergent process.339 It must be emphasized that PKR gives rise to a mixture of nonenantiomeric products that still need to be separated.341 Further investigation and catalyst screening revealed that chemodivergent PKR of the same starting material gives rise to a chiral cyclobutanone if a BINAP-derived rhodium complex is used. Chemodivergent PKR can also produce a mixture of a chiral and an achiral product.3.32.336–338 Parallel kinetic resolution of an activated ester of 2-phenylpropionate has been achieved with stoichiometric amounts of pseudoenantiomeric oxazolidinones. 95% ee N O O t-Bu OBn Cl Scheme 7.340 Tanaka and Fu observed that racemic 4-alkynals can be kinetically resolved through enantioselective cyclization with a DUPHOS-derived rhodium complex. which is not necessarily a trivial task.0]octane-3-one by enzymatic hydrolysis and subsequent decarboxylation.356 N Chapter 7 N Cl3C OH O O t-Bu OMe Cl O O O CCl3 49%.

350 in the resolution of a racemic diallyl . 84% ee Scheme 7. The enzyme differentiates between the enantiomeric ketones and favors migration of different carbon– carbon bonds during Baeyer–Villiger oxidation due to a change in the orientation of peroxidic intermediates in the active site of the monooxygenase.346 cinchona alkaloid-catalyzed alcoholysis of chiral succinic anhydrides.347 and zirconocene-catalyzed ring opening of dihydrofurans.0]octane-2carboxylate.344 Sharpless epoxidation.0]hept-2-en-6-one is almost quantitatively converted to two regioisomeric lactones by incubation with Acinetobacter TD63. a useful catalyst originally designed by Doyle for asymmetric cyclopropanation of prochiral alkenes.2.Asymmetric Resolution and Transformation of Chiral Compounds O H OMe (S. 93% ee O O O 357 + OMe 45%.349 For instance.0]hept-2-en-6-one with Acinetobacter TD63.2. O O baker's yeast OMe O O O O O O + OMe OH O 43%. groups that can participate in the same reaction. O O O 46%. racemic bicyclo[3. employed Rh2[(5S)-MEPY]4. 72% ee O H OMe (M)-(TolBINAP)Rh(I) OMe O OMe 41%.33 Regiodivergent PKR of bicyclo[3. >99% ee O 45% Scheme 7.348 Furstoss observed regiodivergent biocatalytic Baeyer–Villiger oxidation of bicyclic ketones with whole cells of Acinetobacter cultures.31 KR (top) and PKR (bottom) of racemic 4-alkynals with chiral rhodium catalysts. >95% ee Scheme 7. >95% ee + Acinetobacter TD63 O + O O 46%.3.S)-(i-Pr-DUPHOS)Rh(I) s = 21 H OMe + 52%.345.33. This resolution strategy has been applied in a variety of reactions including catalytic aerobic Baeyer–Villiger oxidation of cyclobutanones. 88% ee 47%. Martin et al.32 Biocatalytic chemodivergent PKR of 3-oxo-7.7-(ethylenedioxy)bicyclo[3. Scheme 7. It has been hypothesized that both oxidations are catalyzed by the same monooxygenase.

2S )-epoxide forms an (R)-allylic alcohol in 49% and 96% ee based on (M. O (1S.2R) Ph O P N O Ph (S) (R) OH SN2′ product 49%.351 The chiral rhodium complex catalyzes cyclization of each enantiomer and activates a different double bond with excellent endo-.358 O N2 O Rh2[(5S)-MEPY]4 O I I 41%. The (1R.2S) Scheme 7.353 The complex effectively differentiates between the enantiomers of 1.or diethylzinc establishes a KR. Scheme 7. While treatment of 1.35 Regiodivergent PKR of 1.34. diazoacetate possessing two distinct double bonds.R.5 equiv.352. 87% ee 42%. 90% de.R)-phosphoramidite-derived copper complex. 92% ee (1R. Pineschi and coworkers utilized Feringa’s (M. This procedure gives access to multifunctionalized bicyclic compounds.2-epoxy-3-methylenecyclohexane and catalyzes SN2 and SN2 0 reaction with organozinc compounds.2-epoxy-3-methylenecyclohexane with dimethylzinc catalyzed by an (M.R)phosphoramidite copper-catalyzed SN2 0 attack and the (1S. The complete conversion of a racemate to a mixture of diastereoisomeric products by complementary enantiomer-differentiating reactions constitutes a stereodivergent PKR. enantioand diastereoselectivity. 96% ee + + Cu(OTf)2 Me2Zn (1. This has been .35.S )-alcohol having an exocyclic double bond. Scheme 7. 91% ee O H H + O O H H I H Chapter 7 O N O CO2Me CO2Me N MeO2C N O MeO2C Rh Rh Rh2[(5S)-MEPY]4 N O Scheme 7.R)-phosphoramidite-derived copper complex for regiodivergent addition of dialkylzinc reagents to vinyl oxiranes.R.34 Rh2[(5S)-MEPY]4-catalyzed intramolecular cyclopropanation of a racemic diallyl diazoacetate.2-epoxy-3-methylenecyclohexane with 0. 88% de.R.) O (S) OH SN2 product 51%. the use of excess amounts of dialkylzinc results in PKR and provides two constitutional isomers.2R)-enantiomer undergoes SN2 reaction to an (S.5 equivalents of dimethyl.

or at least 10 times higher than kA in cases of very high selectivity. DDGa.2 Dynamic Kinetic Resolution Dynamic kinetic resolution (DKR) is based on rapid racemization of a chiral compound in conjunction with irreversible conversion of one enantiomer to a chiral product. In addition. enzymatic racemization.36. This has been demonstrated with enzymatic reductions of racemic ketones357 and cyanations of chiral aldehydes. realized in Horner–Wadsworth–Emmons reactions354.12.Asymmetric Resolution and Transformation of Chiral Compounds O CN M. see Chapter 5. In contrast to kinetic resolution. one can employ isolated enzymes or whole cells that promote selective biotransformation of enantiomers to diastereomeric products. isabellina 58%. However. the latter takes advantage of different reactivities of stereolabile enantiomers and therefore requires kinetic control. of at least 30. As has been pointed out for kinetic resolutions. In this example. While the former is based on equilibration and thermodynamic reaction control. whereas A gives rise to a mismatched pair.356 Alternatively. Most common DKR processes are based on thermal racemization. should be higher than the rate constant for the faster of the two conversions. E or s. 7.36 Diastereodivergent PKR of 1-methyl-2-oxocyclohexane carbonitrile with fungus Mortierella isabellina NRRL1757. respectively. By analogy with KR. products B and B 0 can be enantiomeric but this is not a prerequisite for DKR. A basic requirement for efficient DKR is a selectivity factor.or acid-catalyzed racemization.3. and formation of stereolabile intermediates such as organolithium or transition metal complexes. Since dynamic kinetic resolutions obey the Curtin–Hammett principle.4. numerous DKR procedures have been developed to date and applied in the synthesis of complex natural products.xii In contrast. Dynamic KR is aimed at complete conversion of a racemate to an enantiopure product and is closely related to asymmetric synthesis. DKR can provide quantitative amounts of enantiopure materials and the ee of the product does not change with conversion. 73% ee OH CN + CN 42%. the original definition is often not strictly followed in the literature. the ratio of the products formed by the enantiomer-differentiating step is determined by the difference in the free activation energies.2. >99% ee OH 359 Scheme 7. Because of the inherently high atom economy and enantioconvergence. . krac. kA 0 .5. base. The energy profile of a typical DKR obeying Curtin–Hammett kinetics is illustrated in Figure 7. asymmetric transformations of the first and second kind are used for resolution of stereoisomers. Scheme 7.359 Incubation of a culture of fungus Mortierella isabellina NRRL1757 gave a mixture of the diastereomeric b-hydroxy nitriles with 99% and 73% ee.355 and in a oxazaborolidine-catalyzed reduction of a steroidal ketone. the xii The term DKR was originally reserved for processes involving interconversion of enantiomers. see Chapter 7. Asymmetric transformation of the first or second kind and DKR are conceptually different methods. vide infra. the catalyst and A 0 constitute a matched pair.358 Dehli and Gotor examined the use of microorganisms for diastereodivergent bioreduction of racemic 1-methyl-2-oxocycloalkane carbonitrile. Since the same principles can be exploited for stereoselective transformation of interconverting diastereomers. Only racemizations proceeding under mild reaction conditions compatible with the consecutive resolution step are suitable for DKR. the rate constant for racemization. racemization via redox reactions. the latter is better described as dynamic kinetic asymmetric transformation.

resolution and cyclization provides a powerful one-pot procedure that furnishes xiii See Chapter 3. and high yields and ee’s are obtained.391 Enzymatic acylation is not restricted to alcohols. Scheme 7. exhibiting E values greater than 360 and 4-chlorophenyl acetate as acyl donor in the presence of a ruthenium complex.392 Kita’s group introduced a lipase-catalyzed domino process that includes DKR of chiral alcohols exhibiting a diene moiety and an acyl donor providing an electrondeficient dienophile for subsequent intramolecular Diels–Alder reaction.385 and g-hydroxy esters and amides. The combination of racemization.360–365 Because lipases accept a broad variety of substrates.38.382 b-hydroxy esters. hydroxy acetals and hydroxy esters. Scheme 7.2.360 A k rac A′ kA′ Cat B B′ kA Cat B ∆G ≠ A A A.388 The lipase differentiates between the enantiomers and transfers the acetyl unit from the (R)-substrate to isopropyl alcohol.2-diols.393 For example. Transition metal-catalyzed racemization and lipase-catalyzed resolution have been combined for DKR of secondary alcohols. Alternatively. Palladium-catalyzed hydrogenation of ketoximes generates amines that undergo transition metal-catalyzed racemization and enantioselective acylation in the presence of Candida antarctica lipase B (CALB). immobilized lipase isolated from Pseudomonas cepacia. Scheme 7.387 In the case of allylic esters.∆G ≠A′ ≠ ∆G rac Chapter 7 ∆∆G ≠ ∆G ≠ A′ A′ B′ kA « kA′ « krac Cat = nonracemic chiral catalyst Figure 7. albeit at the expense of long reaction times. 3-vinylcyclohex-2-en-1-ol undergoes rapid ruthenium-catalyzed racemization and resolution with a functionalized ethoxyvinyl ester in the presence of CALB.39.384 b-hydroxy alkanephosphonates.371 amines.383 b-hydroxy nitriles.373–375 Pamies and Backvall incorporated lipase-catalyzed KR and ruthenium-catalyzed ¨ racemization of d-hydroxy esters into a one-pot process. one can use tetrakis(triphenylphosphine)palladium(0) and lipase from Candida antarctica (CAL) and Pseudomonas cepacia (PCL) to achieve racemization and concomitant resolution based on selective ester cleavage.2.377–379 b-halo alcohols. 7. A′ = enantiomers B. resolution step can involve bioorganic methods or the use of nonenzymatic chiral catalysts or reagents.372 and allylic alcohols or ` acetates.8 for the mechanism of ruthenium-catalyzed racemization of secondary alcohols.1 0 -bis(diphenylphosphino)ferrocene to the palladium catalyst effectively reduces side reactions such as acetate elimination.389 Addition of 1.376 Using lipase PS-C. . reduction of prochiral ketones to rapidly racemizing secondary alcohol intermediates has been combined with enantioselective transesterification to afford chiral acetates.4.e. The racemization probably proceeds via nucleophilic acetyl displacement and formation of an intermediate p-allylpalladium species. they obtained (R)-d-acetoxy esters in up to 92% and 98% ee.380 b-azido alcohols. i.37.390. B′ = products ∆∆G ≠ = ∆G ≠A .1 Enzyme-catalyzed Dynamic Kinetic Resolution.xiii Similar procedures have been developed for a range of secondary alcohols. the use of these readily available enzymes greatly facilitates screening of KR conditions compatible with fast substrate racemization. Many dynamic kinetic resolutions involve transition metal-catalyzed racemization coupled to an enantiomer-differentiating biotransformation.381 a-hydroxy esters.12 Illustration of dynamic kinetic resolution using a chiral catalyst.386. operate in organic solvents and do not require cofactors..366–370 monoprotected 1.

397 zeolite-mediated alcohol racemization. 99% ee OAc N3 69%.Asymmetric Resolution and Transformation of Chiral Compounds Ph OH O Ot-Bu Ru-catalyst Lipase PS-C Cl OAc 361 O H O Ph OAc O Ot-Bu Ph Ph OC Ph Ru H Ph Ru Ph Ph 92%. 98% ee (2. CAL) R=2-furyl: 87%.398 and base-promoted interconversion of chiral oxazolones and oxazolines.402 A large-scale DKR protocol that takes advantage of base-catalyzed racemization of an isoxazoline-derived thioester was reported by Pesti. CAL) Scheme 7. 94% ee OAc OAc OAc Cl MeO 98%. 98% ee (3 d.395 dissociation and recombination of cyanohydrins in the presence of amberlite. 98% ee 85%. 97% ee (3 d. 98% ee CO CO CO Ru-catalyst OAc O OEt OAc N O 93%. Incorporation of the same lipase and acyl donor into DKR of cyclic a-hydroxy nitrones followed by intramolecular 1.3-dipole cycloaddition gives chiral tetrahydrofuro[3. >99% ee OAc OMe O 70%. >99% ee Scheme 7.394 Lipase-catalyzed KR has been coupled to other types of racemization processes including ring opening and subsequent cyclication of N-acyl hemiaminals. 97% ee 86%. 98% ee (3 d. PCL) R=4-ClC6H4: 77%. OAc lipase R Pd(0) PdOAc R Pd(0) OAc R i-PrOH OH O + R Oi-Pr R=Ph: 83%.396.5 d.403 Deprotonation of the adjacent thioester moiety facilitates racemization via a retro . 95% ee OAc CN 74%. 98% ee (1.37 Backvall’s DKR of d-hydroxy esters based on Ru-catalyzed alcohol racemization and lipase¨ controlled resolution. >99% ee (3 d.4-c]isoxazoles.399–401 Chiral thioesters possess fairly acidic a-protons and racemize under mild conditions. CAL) R=Ph: 81%. >99% ee 98%.5 d.38 Pd-catalyzed racemization and enzymatic resolution of allylic acetates. >99% ee OAc OMe 93%. 98% ee OAc O P OEt OEt O 80%. complex tricyclic lactones with four chiral centers. CAL) R=4-MeC6H4: 81%. CAL) R=1-naphthyl: 70%.

95% ee. pH=9. NaOH. resolution and intramolecular cycloaddition. a promising candidate for the treatment of thrombotic diseases. Dynamic KR is accomplished by selective formation of the (S )-a-acetoxy sulfide because the (R)-hemithioacetal is not recognized by the enzyme and racemizes via silicon dioxidepromoted dissociation and subsequent recombination. >99% ee.40 DKR of an isoxazoline thioester. This industial application highlights the efficiency and robustness of DKR. 28.39 Domino DKR of 3-vinylcyclohex-2-en-1-ol involving racemization.09 NC N O O O -H O Amano PS-30 NHCO n-Bu HN S H3N CH CO N O roxifiban O H N CO Me NC N O O S NC N -H S NC N O O O O Scheme 7. Scheme 7. 3 d Cl Ru Cl Cl Ru Cl Chapter 7 CO2Et O O CO2Et H ∗ ∗ ∗ ∗ O O CO2Et OH Scheme 7. Racemization of a-bromo and a-chloro esters via reversible halide displacement has been coupled to enantioselective enzymatic . Acetylation of interconverting hemithioacetals yields a-acetoxy sulfides from aldehydes and thiols.362 O OH EtO O CALB 86%. Michael/Michael addition sequence followed by Amano PS 30 lipase-catalyzed resolution.41.40.404 Racemic hemithioacetals are readily formed in situ and can be resolved with Pseudomonas fluorescens lipase. The isolated isoxazoline is a key intermediate in the synthesis of roxifiban. Scheme 7. S OH NC O N O 80%.4 kg scale S NC N Et3N.

Dynamic kinetic resolution of methyl 2-bromo-2-phenylacetate using Candida rugosa lipase and polymer-linked phosphonium bromide as the halide source generates (S)-2-bromo-2-phenylacetic acid in 79% ee. Important examples are alcohols.406 At neutral pH.420.409 The applicability of intact microorganisms and enzymes other than lipases to DKR further expands the application spectrum of this technique to a wide range of chiral building blocks.407 The phenylglycine ester reacts with pyridoxal to an intermediate Schiff base that racemizes in the presence of ammonia.Asymmetric Resolution and Transformation of Chiral Compounds O O H O SiO2 HO S(CH2)7CH3 O H O O H lipase O O H 85%. Scheme 7. thiazolin-5-ones and hydantoins are readily prepared and susceptible to enantioconversion under basic conditions or in the presence of a racemase. Br H Ph Br fast Br Ph H Br OMe Br O Ph H O Br O O Br lipase H2O:MeOH (5:1) pH 7 OMe O H O Br 78%. hydrolysis. Scheme 7.411.41 Synthesis of a-acetoxy sulfides through lipase-catalyzed acetylation of interconverting hemithioacetals. Dynamic KR of amino acids based on pyridoxal 5-phosphate.408.419 Furstoss’ group utilized base-catalyzed racemization of 2-benzyloxymethylcyclopentanone and resolution due to microbiological Baeyer–Villiger oxidation with recombinant E. coli for the synthesis of (R)-6-benzyloxymethyltetrahydropyran-2-one. 79% ee Ph slow Scheme 7. the enantiopurity decreases over time and the reaction has to be stopped after 4. while the (R)-amide generated by lipase-catalyzed resolution precipitates and is no longer available for imine formation and racemization. >95% ee AcO S(CH2)7CH3 363 + CH3(CH2)7SH + HO S(CH ) CH 2 7 3 OAc Scheme 7.and 4-chlorobenzaldehyde-catalyzed racemization has also been reported. Although the product is considerably more stable to racemization than the racemic starting materials.421 Since racemic oxazol-5(4H)-ones.414–417 2-benzenesulfonyl cycloalkanones.418 and b-hydroxy esters. they have become useful .405.43.410 hydantoins. Scheme 7. amides and lactones. a similar SN2 attack at the corresponding a-halo carboxylate is relatively slow due to electrostatic repulsion between the negatively charged substrate and the halide.42 DKR based on bromide displacement and enzymatic hydrolysis.412 2-oxo-cycloalkanecarbonitriles.42. Pyridoxal-catalyzed racemization of phenylglycine methyl ester via Schiff base formation and enantioselective ammonolysis with Candida antarctica lipase B provides (R)-phenylglycine amide in 88% ee at 85% conversion.413 b-keto esters.44.5 hours at only 78% conversion to maintain an enantiomeric excess of at least 79%.

422 The availability of complementary enzymes such as (R). 88% ee Scheme 7. O E. a combination of a hydrolase and a racemase is used to produce (R)-amino acid derivatives. a procedure providing (S)-1-azido-3-bromo-2-propanol in 94% ee was developed.426 Through careful optimization of pH and concentration of the azide and bromide nucleophiles.and (S)-hydantoinase significantly enhances the practicality of DKR. substrates for asymmetric synthesis of a-amino acids. The enzyme catalyzes both reactions. The suitability of dual enzyme DKR to industrial production has been demonstrated by incorporation of a . Treatment with nitrous acid or addition of a carbamoylase then generates the free amino acid. Several examples of DKR involving enzyme catalysis in both the racemization and the resolution step are known.364 N HO N OMe OH N OMe O NH N OMe O O HN OH OMe HO N O OH Chapter 7 N MeO OH HO HN OH OMe HO O N MeO HO OH HO O OH H2N N H N O O lipase H N NH OH H N O OH N HO NH3 O N 85%.46. Combination of racemization of a 5-substituted hydantoin with hydantoinase-catalyzed hydrolytic ring opening can afford either enantiomer of the corresponding N-carbamoyl amino acid.3-dibromo-2propanol and participates in enzymatic resolution in the presence of sodium bromide. Scheme 7. Scheme 7. coli O OH OBn O OH OBn OBn O O OBn 85%.423–425 Epibromohydrin racemizes via formation of 1. 99% ee Scheme 7.43 DKR of phenylglycine methyl ester via Schiff base-catalyzed racemization.44 Microbiological Baeyer–Villiger oxidation and DKR of 2-benzyloxymethylcyclopentanone. interconversion of the enantiomers of epibromohydrin via a meso haloalcohol and enantioselective nucleophilic epoxide ring opening with azide. sodium azide and haloalcohol dehalogenase HheC isolated from Agrobacterium radiobacter AD1. A similar approach allows conversion of racemic oxazol-5(4H)-ones and thiazolin-5-ones to N-protected amino acids. In most cases.45.

2 Nonenzymatic Dynamic Kinetic Resolution.428 7. Noyori and coworkers reported that chiral b-keto esters carrying either a-alkyl or a-amido substituents readily racemize under conditions compatible with (BINAP)RuBr2-catalyzed asymmetric hydrogenation.435 The combination of enantioconversion and stereoselective reduction in a single operation has proved invaluable for asymmetric synthesis of b-hydroxy esters. but it took another 30 years before the concept and scope of this methodology received significant attention.2.46 Haloalcohol dehalogenase-catalyzed DKR of epibromohydrin. Scheme 7.4.430–433 In 1989.1.3. Weygand et al.2R)-trans-b-hydroxy ester which is obtained in 98% de and 92% ee. OH O Br O Br Br O Br OH N3 slow N3 Br Br N3 fast N3 84%. the development of many dynamic kinetic resolutions has been inspired by some of the KR processes discussed in Chapter 7.429 Since then.Asymmetric Resolution and Transformation of Chiral Compounds NH2 O NH HO C R carbamoylase or HNO2 NH2 HO2C R (S)-amino acid R N H (S)-hydantoinase R O H N O N H base or racemase HO H N O HO C R N H H N O HO C 365 NH O O (R)-hydantoinase NH R carbamoylase or HNO NH R (R)-amino acid Scheme 7. and by the well-known propensity of azlactones and other important chiral building blocks to racemization. were probably first to recognize the potential of DKR as early as 1966. racemase and a hydantoinase or acylase into the large scale synthesis of several natural and unnatural (S).434. Dynamic KR of a-substituted b-keto esters has been incorporated as a key step into the total synthesis of several natural products including biphenomycin A436 and roxaticin.and (R)-amino acids.R)-DPEN].4. 94% ee Br Br Scheme 7. racemic methyl cyclopentanone-2-carboxylate is converted to the corresponding (1R. .xiv As a result.2. see Chapter 5. This reaction proceeds at room temperature and requires only 1 mmol% of trans-RuCl2[(M)-TolBINAP][(R.47.427.437 This procedure has been further refined and successfully extended to b-keto phosphonates. a-substituted ketones and piperidinones.45 Asymmetric synthesis of a-amino acids.2S)-cis-2-phenylcyclohexanol. xiv The (R)-b-keto ester and (M)-BINAP)RuBr2 constitute a matched pair.438–442 A remarkable example is the quantitative reduction of 2-phenylcyclohexanone to (1S. The (R)-enantiomer of methyl cyclopentanone-2-carboxylate is selectively reduced by the (M)-BINAP-derived ruthenium catalyst and is constantly regenerated from the less reactive (S)-enantiomer via enolization.

Figure 7.48. transition metal-catalyzed DKR of stereolabile b-keto esters. Scheme 7. O (S) H tert-BuOK O Ph tert-BuOK Ph H Ph O H H N Ru OH Ph >99%. relatively low hydrogen pressure and potassium tert-butoxide to promote enolization. Scheme 7.5% ee (9.2S)-cyclohexanol Ar P P Ar Cl H2 N N H2 Ph Ph Ru Ar Cl H (R) Ph O Ar = p-Tol Ar [(M)-TolBINAP][(R.48 [(M)-TolBINAP][(R. 93% ee PPh2 PPh2 Chapter 7 O O (M)-(BINAP)RuBr2 O 100 atm H2 OH Scheme 7.458 and 3.S)-TSDPEN](Z6-pcymene)RuCl-catalyzed reduction of benzil with formic acid as hydride source affords .366 O O (M)-(BINAP)RuBr2 O 100 atm H2 OH O O 99%.47 Noyori’s resolution of methyl cyclopentanone-2-carboxylate. It is assumed that the ruthenium complex selectively recognizes (S )-2-phenylcyclohexanone in its most heavily populated chair conformation.49. 92% ee H O O O (M)-BINAP O O 1%.460 The [(S.R)-DPEN]RuCl2-catalyzed hydrogenation of 2-phenylcyclohexanone.454–456 ketones457. borohydrides or poly(methylhydrosiloxane) as the hydrogen source. Noyori introduced a two-step reduction sequence that allows conversion of achiral diaryl ketones such as benzil and its para-substituted derivatives to chiral 1. Diastereofacial reduction then proceeds via equatorial attack and generates the cis-alcohol.12 g) 8 atm H2 H cis-(1S.R)-DPEN]RuCl2 Scheme 7.13. Alternatively. Both Genet’s443–450 and Hamada’s groups451–453 applied a ˆ series of chiral phosphine-derived ruthenium and iridium catalysts to stereoselective hydrogenation of configurationally unstable a-amino-b-keto esters and a-chloro-b-keto esters. >99.2-diols based on DKR of a stereolabile a-hydroxy ketone intermediate.5-dialkylcyclopentenones459 can be achieved with formic acid.

S)-TSDPEN-derived ruthenium complex selectively recognizes the (R)-enantiomer of benzoin and furnishes quantitative amounts of (R.and diastereoselectivity. Noteworthy examples include (S)-proline-catalyzed intermolecular aldol reaction of enolizable and th