Modern Organic Synthesis

Lecture Notes
Modern Organic
Synthesis
Dale L. Boger
The Scripps Research Institute
Coordinated by Robert M. Garbaccio
Assembled by
Conformational Analysis Steven L. Castle
Kinetics and Thermodynamics Richard J. Lee

Reaction Mechanisms
and Conformational Effects
Oxidation Reactions and Bryan M. Lewis

Alcohol Oxidation Christopher W. Boyce
Reduction Reactions and Clark A. Sehon

Hydroboration Reactions Marc A. Labroli
Enolate Chemistry and Jason Hongliu Wu

Metalation Reactions Robert M. Garbaccio
Key Ring Transformations Wenge Zhong

Jiyong Hong
Brian M. Aquila
Mark W. Ledeboer
Olefin Synthesis Gordon D. Wilkie
Conjugate Additions Robert P. Schaum
Synthetic Analysis and Design Robert M. Garbaccio
Combinatorial Chemistry Joel A. Goldberg
TSRI Press
La Jolla, CA
Copyright © 1999 TSRI Press. All rights reserved.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in
any form or by any means: electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or other-
wise, without permission in writing from the publisher.
Print First Edition 1999

CD Version 1.0 (1999)
ISBN Flexicover
The CD versions of the Lecture Notes (Versions 1.01 and 1.02) contain corrections and updates to the science and will differ
slightly from the printed text (First Edition, 1999). We anticipate that this will continue on an annual basis, as with any set of
classroom lecture notes. Consequently, we would like to encourage you to inform us of mistakes you might find and we
welcome suggestions for additions to the content. In fact, if we are provided ChemDraw files of science you would like to see
included, the barriers to its incorporation are minimized.
The text of the CD may be searched by Adobe Acrobat Reader and this may be used in lieu of an index.
Printed and Bound in the U.S.A. by Rush Press, San Diego, California
Introduction
Dale L. Boger
Preface
The notes have been used as the introductory section of a course on Modern Organic Synthesis that com-
poses 6 weeks or a little more than one-half of a quarter course at The Scripps Research Institute, Department of
Chemistry. Consequently, an exhaustive treatment of the individual topics is beyond the scope of this portion of
the course. The remaining 4 weeks of the quarter delve into more detail on various topics and introduce concepts
in multistep organic synthesis (E. Sorensen). For our students, this is accompanied by a full quarter course in
physical organic chemistry and is followed by a full quarter course on state of the art natural products total
synthesis (K. C. Nicolaou, E. Sorensen) and a quarter elective course on transition metal chemistry. Complemen-
tary to these synthetic and mechanistic courses, two quarter courses on bioorganic chemsitry and an elective
course on the principles of molecular biology and immunology are available to our students. Efforts have been
made to not duplicate the content of these courses. For those who might examine or use the notes, I apologize for
the inevitable oversight of seminal work, the misattribution of credit, and the missing citations to work presented.
The original notes were not assembled with special attention to this detail, but rather for the basic content and the
‘nuts and bolts’ laboratory elements of organic synthesis. In addition, some efforts were made to highlight the
chemistry and contributions of my group and those of my colleagues for the intrinsic interest and general apprecia-
tion of our students. I hope this is not mistaken for an effort to unduly attribute credit where this was not intended.
We welcome any suggestions for content additions or corrections and we would be especially pleased to receive
even minor corrections that you might find. – Dale L. Boger
Heinrich Friedrich von Delius (1720–1791)

is credited with introducing chemistry into the
academic curriculum.
Acknowledgments
Significant elements of the material in the notes were obtained from the graduate level organic synthesis
course notes of P. Fuchs (Purdue University) and were influenced by my own graduate level course taught by E. J.
Corey (Harvard). They represent a set of course notes that continue to evolve as a consequence of the pleasure of
introducing young colleagues to the essence and breadth of modern organic synthesis and I thank them for the
opportunity, incentive, and stimulation that led to the assemblage of the notes. Those familiar with ChemDraw
know the efforts that went into reducing my hand drafted notes and those maintained by Robert J. Mathvink
(Purdue University) and Jiacheng Zhou (The Scripps Research Institute) to a ChemDraw representation. For this,
I would like to thank Robert M. Garbaccio for initiating, coordinating, proofing and driving the efforts, and Steve,
Richard, Chris, Bryan, Clark, Marc, Jason, Rob, Wenge, Jiyong, Brian, Mark, Gordon, Robert and Joel for reduc-
ing the painful task to a reality. Subsequent updates have been made by Steven L. Castle (Version 1.01) and Jiyong Hong
(Version 1.02).
i
Modern Organic Chemistry
It is a pleasure to dedicate this book and set of notes to Richard Lerner who is responsible for their appearance.
His vision to create a chemistry program within Scripps, his energy and enthusiasm that brought it to fruition, his support for
the graduate program and committment to its excellence, and his personal encouragement to this particular endeavour of
developing a graduate level teaching tool for organic synthesis, which dates back to 1991, made this a reality.
Antoine L. Lavoisier, universally regarded as the founder of modern chemistry, published in 1789 his
Elementary Treatise on Chemistry that distinguished between elements and compounds, initiated
the modern system of nomenclature, and established the oxygen theory of combustion. He and his
colleagues founded Annales de Chemie in 1789, he earned his living as a tax official and his “chemi-
cal revolution” of 1789 coincided with the start of the violent French Revolution (1789−1799). He
was executed by guillotine in 1794.
Jons Jacob Berzelius (1779–1848), a Swedish chemist, discovered cerium, produced a precise
table of experimentally determined atomic masses, introduced such laboratory equipment as test
tubes, beakers, and wash bottles, and introduced (1813) a new set of elemental symbols based on the
first letters of the element names as a substitute for the traditional graphic symbols. He also coined the
term “organic compound” (1807) to define substances made by and isolated from living organisms
which gave rise to the field of organic chemistry.
ii
Introduction
Dale L. Boger
Table of Contents
I. Conformational Analysis 1
A. Acyclic sp3–sp 3 Systems 1
B. Cyclohexane and Substituted Cyclohexanes, A Values (∆G°) 2
C. Cyclohexene 7
D. Decalins 7
E. Acyclic sp3–sp2 Systems 8
F. Anomeric Effect 12
G. Strain 14
H. pKa of Common Organic Acids 16
II. Kinetics and Thermodynamics of Organic Reactions 17

A. Free Energy Relationships 17
B. Transition State Theory 18
C. Intramolecular Versus Intermolecular Reactions 18
D. Kinetic and Thermodynamic Control 20
E. Hammond Postulate 21
F. Principle of Microscopic Reversibility 22
III. Reaction Mechanisms and Conformational Effects on Reactivity 23

A. Ester Hydrolysis 23
B. Alcohol Oxidations 25
C. SN2 Reactions 25
D. Elimination Reactions 26
E. Epoxidation by Intramolecular Closure of Halohydrins 29
F. Epoxide Openings (SN2) 29
G. Electrophilic Additions to Olefins 30
H. Rearrangement Reactions 31
I. Pericyclic Reactions 33
J. Subtle Conformational and Stereoelectronic Effects on Reactivity 36
K. Methods for the Synthesis of Optically Active Materials 39
IV. Oxidation Reactions 41

A. Epoxidation Reactions 41
B. Additional Methods for Epoxidation of Olefins 51
C. Catalytic Asymmetric Epoxidation 56
D. Stoichiometric Asymmetric Epoxidation 67
E. Baeyer–Villiger and Related Reactions 67
F. Beckmann Rearrangement and Related Reactions 70
G. Olefin Dihydroxylation 74
H. Catalytic and Stoichiometric Asymmetric Dihydroxylation 81
I. Catalytic Asymmetric Aminohydroxylation 84
J. Ozonolysis 86
V. Oxidation of Alcohols 87
A. Chromium-based Oxidation Reagents 87
iii
B. Manganese-based Oxidation Reagents 89
C. Other Oxidation Reagents 90
D. Swern Oxidation and Related Oxidation Reactions 93
VI. Reductions Reactions 95

A. Conformational Effects on Carbonyl Reactivity 95
B. Reactions of Carbonyl Groups 96
C. Reversible Reduction Reactions: Stereochemistry 96
D. Irreversible Reduction Reactions: Stereochemistry of Hydride Reduction Reactions 97
and Other Nucleophilic Additions to Carbonyl Compounds
E. Aluminum Hydride Reducing Agents 112
F. Borohydride Reducing Agents 113
G. Hydride Reductions of Functional Groups 115
H. Characteristics of Hydride Reducing Agents 118
I. Asymmetric Carbonyl Reductions 124
J. Catalytic Hydrogenation 127
K. Dissolving Metal Reductions 128
L. Amalgam-derived Reducing Agents 134
M. Other Reduction Methods 136
VII. Hydroboration–Oxidation 139

A. Mechanism 139
B. Regioselectivity 140
C. Diastereoselectivity 140
D. Metal-catalyzed Hydroboration 143
E. Directed Hydroboration 144
F. Asymmetric Hydroboration 144
VIII. Enolate Chemistry 147

A. Acidic Methylene Compounds 147
B. Enolate Structure 155
C. Enolate Alkylations 156
D. Enolate Generation 159
E. Alkylation Reactions: Stereochemistry 168
F. Asymmetric Alkylations 175
G. Aldol Addition (Condensation) 179
H. Aldol Equivalents 197
I. Enolate-imine Addition Reactions 199
J. Claisen Condensation 200
K. Dieckmann Condensation 201
L. Enolate Dianions 203
M. Metalloimines, Enamines and Related Enolate Equivalents 203
N. Alkylation of Extended Enolates 206
IX. Metalation Reactions 207

A. Directed Metalation 207
B. Organolithium Compounds by Metal–Halogen Exchnage 210
C. Organolithium Compounds by Metal–Metal Exchange (Transmetalation) 211
D. Organolithium Compounds from the Shapiro Reaction 211
E. Key Organometallic Reactions Enlisting Metalation or Transmetalation Reactions 212
iv
Introduction
Dale L. Boger
X. Key Ring Forming Reactions 213
A. Diels–Alder Reaction 213
B. Robinson Annulation 271
C. Birch Reduction 287
D. Dieckmann Condensation 287
E. Intramolecular Nucleophilic Alkylation 287
F. Intramolecular Aldol Condensation 288
G. Intramolecular Michael Reaction 288
H. Cation–Olefin Cyclizations 289
I. Free Radical Cyclizations 301
J. Anionic Cyclizations 321
K. 1,3-Dipolar Cycloadditions 322
L. [1,3]-Sigmatropic Rearrangements 326
M. Electrocyclic Reactions 328
N. Nazarov Cyclization 328
O. Divinylcyclopropane Rearrangement 330
P. Carbene Cycloaddition to Alkenes 331
Q. [2 + 3] Cycloadditions for 5-Membered Ring Formation 336
R. Cyclopropenone Ketal Cycloaddition Reactions 339
S. [2 + 2] Cycloadditions 343
T. Arene–Olefin Photoadditions 346
U. Intramolecular Ene Reaction 347
V. Oxy–Ene Reaction: Conia Reaction 349
W. Cyclopentenone Annulation Methodology 350
X. Pauson–Khand Reaction 353
Y. Carbonylation Cyclizations 355
Z. Olefin Ring Closing Metathesis 356
XI. Olefin Synthesis 359

A. Wittig Reaction 359
B. Wadsworth–Horner–Emmons Reaction 365
C. Peterson Olefination 367
D. Tebbe Reaction and Related Titanium-stabilized Methylenations 370
E. Other Methods for Terminal Methylene Formation 371
F. Olefin Inversion Reactions 372
G. [3,3]-Sigmatropic Rearrangements: Claisen and Cope Rearrangements 374
H. [2,3]-Sigmatropic Rearrangements 378
I. Olefin Synthesis Illustrated with Juvenile Hormone 381
XII. Conjugate Additions: Organocuprate 1,4-Additions 395
XIII. Synthetic Analysis and Design 427

A. Classifications 428
B. Retrosynthetic Analysis 431
C. Strategic Bond Analysis 440
D. Total Synthesis Exemplified with Longifolene 443
XIV. Combinatorial Chemistry 461
v
Conformational Analysis
Dale L. Boger
I. Conformational Analysis
A. Acyclic sp3–sp3 Systems: Ethane, Propane, Butane

eclipsed staggered E E E
3
H H H H rel. E
H 2
1. Ethane (kcal)
1 3.0 kcal
H H H
H H H H S S S
1.0 kcal
H 0 60 120 180 240 300 360
H 60° rotation H 60° rotation
H H dihedral angle
HH HH H H
H
- Two extreme conformations, barrier to rotation is 3.0 kcal/mol.
eclipsed staggered 4 E E E
H CH3 H H rel. E 3
CH3 (kcal) 2
2. Propane 3.3 kcal
H H H 1
H H H H S S S
1.3 kcal
H 0 60 120 180 240 300 360
CH3 H
60° rotation H CH3 60° rotation dihedral angle
HH HH H H
H - Barrier to rotation is 3.3 kcal/mol.
1.0 kcal each - Note: H/H (1.0 kcal) and Me/H (1.3 kcal) eclipsing interactions are
comparable and this is important in our discussions of torsional strain.
fully eclipsed gauche eclipsed staggered

(synperiplanar) (synclinal) (anticlinal) (antiperiplanar)
H3C CH3 H3C H H3C H H3C H

CH3 H
3. Butane
H H H H H H
H H H CH3 H H
H CH3
4.0 kcal gauche interaction
0.9 kcal 1.3 kcal each
H3C H3C
CH3 CH3 H CH3
60° rotation H CH3 60° rotation 60° rotation H H
H
HH HH H H HH CH3 H H
H CH3
1.0 kcal each 1.0 kcal
FE FE - Note: the gauche butane

6
interaction and its magnitude
5
(0.9 kcal) are very important
rel. E 4 E E
and we will discuss it frequently.
(kcal) 3 6.0
2 kcal
1 G 3.6 kcal G
0.9 kcal S
0 60 120 180 240 300 360

dihedral angle
1
4. Substituted Ethanes
- There are some exceptions to the lowest energy conformation. Sometimes, a gauche
conformation is preferred over staggered if X,Y are electronegative substituents.
cf: Kingsbury J. Chem. Ed. 1979, 56, 431.
X X
H Y X Y H H X H
H H
H H H H H H
H H H Y
H Y
gauche staggered
Egauche < Estaggered if X = OH, OAc and Y = Cl, F
5. Rotational Barriers
H H H H
H H H CH3 H CH3 H3 C CH3
H H H H H H H H
H H CH3 CH3
2.88 kcal/mol 3.40 kcal/mol 3.90 kcal/mol 4.70 kcal/mol - Experimental
(3.0 kcal/mol 3.3 kcal/mol 3.6 kcal/mol 3.9 kcal/mol) - Simple prediction
- The rotational barrier increases with the number of CH3/H eclipsing interactions.
H H H
H H H H H ••
N O
H H H •• H H •• H
H
2.88 kcal/mol 1.98 kcal/mol 1.07 kcal/mol - Experimental
(3.0 kcal/mol 2.0 kcal/mol 1.0 kcal/mol) - Simple prediction
- The rotational barrier increases with the number of H/H eclipsing interactions.
B. Cyclohexane and Substituted Cyclohexanes, A Values (∆G°)

1. Cyclohexane
Hax 4 5 6
5 6 1 Heq
Heq 3 2 1
4 3 2 Hax
Ea = 10 kcal
chair chair
4 atoms in plane
H H
H H
HH H H H H HH
H HH H H HH H
H H H
H
half chair twist boat half chair
(rel E = 10 kcal) (rel E = 5.3 kcal) (rel E = 10 kcal)
2
Dale L. Boger
- Chair conformation (all bonds staggered)
Hax Hax Hax

Heq Heq
Heq Heq
Hax Hax Hax
- Rapid interconversion at 25 °C (Ea = 10 kcal/mol, 20 kcal/mol available at 25 °C).

- Hax and Heq are indistinguishable by 1H NMR at 25 °C.
- At temperatures < –70 °C, Heq and Hax become distinct in 1H NMR.
- Boat conformation
2.9 kcal
flagpole interaction
H Hax H
H H
Heq Heq
H
H H
1.0 kcal
each (4x)
H H
Hax Hax
- Rel E = 6.9 kcal, not local minimum on energy surface.

- More stable boat can be obtained by twisting (relieves
flagpole interaction somewhat).
- Twist boat conformation (rel E = 5.3 kcal) does represent
an energy minimum.
- The boat conformation becomes realistic if flagpole
interactions are removed, i.e. O
X
- Half chair conformation
H
D.H.R. Barton received the 1969
HH H Nobel Prize in Chemistry for his
contributions to conformational
H HH analysis, especially as it relates to
H steroids and six-membered rings.
Barton Experientia 1950, 6, 316.
- Energy maximum (rel E = 10.0 kcal)
half half
chair chair
10
rel E
(kcal)
5 twist boat
10 kcal
5.3 kcal
0
chair chair
3
2. Substituted Cyclohexanes
- Methylcyclohexane
H CH3
H
H ∆G° = –RT(ln K)
CH3
–1.8 × 1000
H 1.99 × 298 = –ln K
1.8 kcal more stable K = 21
- The gauche butane interaction is most often identifiable as 1,3-diaxial interactions.
H H CH3 H H H
H H H CH3
H H H H
H H H H H H
2 gauche butane interactions 0 gauche butane interactions

2 × 0.9 kcal = 1.8 kcal
(experimental 1.8 kcal)
- A Value (–∆G°) = Free energy difference between equatorial and axial

substituent on a cyclohexane ring.
Typical A Values
R A Value (kcal/mol) R A Value (kcal/mol)

F 0.25 CN 0.2 Small, linear
Cl 0.52 C CH 0.41 groups
Br 0.5–0.6 ca. 0.5 kcal NO2 1.1
I 0.46 CH=CH2 1.7
OH 0.7 (0.9) ca. 0.7 kcal CH3 1.8
OCH3 0.75 (2nd atom effect CH2CH3 1.9 (1.8) 2nd atom
OCOCH3 0.71 very small) nC H effect very
3 7 2.1
NH2 1.8 (1.4) nC H small
4 9 2.1
NR2 2.1 CH(CH3)2 2.1
CO2H 1.2 (1.4) C(CH3)3 >4.5 (ca. 5.4)
CO2Na 2.3 C6H5 3.1 (2.9)
CO2Et 1.1
SO2Ph 2.5
- Note on difference between iPr and tBu A values.

H CH3
H iPrgroup can position
H CH3
H toward "inside,"
H3C CH3
H but tBu group cannot.
H CH3
Very serious interaction, 7.2 kcal.
4
Dale L. Boger
- Determination of A value for tBu group.
0.9 kcal
7.2 kcal H3C CH3 ∆G° = (9.0 kcal – 3.6 kcal)
H H
H H CH3 = 5.4 kcal H CH3
H 0.9 kcal each
H 0.9 kcal CH3
H CH3
7.2 kcal + (2 × 0.9 kcal) = 9.0 kcal
4 × 0.9 kcal = 3.6 kcal
- Note on interconversion between axial and equatorial positions.

H
Cl H
Cl
t1/2 = 22 years at –160 °C
Even though Cl has a small A value (i.e., small ∆G° between rings
with equatorial and axial Cl group), the Ea (energy of activation)
is high (it must go through half chair conformation).
trans-1,2-dimethylcyclohexane cis-1,2-dimethylcyclohexane
H CH3 H H CH3 H
H H H
CH3 CH2
CH3 CH2
H H H
H CH3 H H H CH3
2.7 kcal/mol more stable ∆E = 0 kcal/mol
H H CH3 H H H H H CH3 H H H H
H H H CH3 H CH2 H H
H H H CH3 H H H CH2
H H CH3 H H H H H H H H CH3 H
4 × (gauche interaction) 1 × (gauche interaction) 3 × (gauche interaction) 3 × (gauche interaction)
4 × (0.9 kcal) = 3.6 kcal 1 × (0.9 kcal) = 0.9 kcal 3 × (0.9 kcal) = 2.7 kcal 3 × (0.9 kcal) = 2.7 kcal
CH3 H2/Pt CH3
CH3 CH3
∆G = 1.87 kcal/mol (exp)

∆G = 1.80 kcal/mol (calcd)
5
trans-1,3-dimethylcyclohexane cis-1,3-dimethylcyclohexane
H CH3 H CH3
H CH3
H H CH3 CH3 CH3
CH3 H H
CH3 H
H H CH3 H H H CH3 H CH3 H H H

H H H CH3 H H CH3 CH3
CH3 H H H H H H H
H H H CH3 H H H H H H H H
2 × (gauche interaction) 2 × (gauche interaction) 2 × (gauche interaction) + 0 × (gauche interaction)

2 × (0.9 kcal) = 1.8 kcal 2 × (0.9 kcal) = 1.8 kcal 1 × (Me–Me 1,3 diaxial int) 0 × (0.9 kcal) = 0 kcal
2 × (0.9 kcal) + 3.7 kcal
= 5.5 kcal
CH3 H2/Pt CH3
CH3 CH3
∆G = 1.80 kcal/mol (exp and calcd)
- Determination of energy value of Me–Me 1,3-diaxial interaction.
CH3 CH3 H CH3

CH3 CH3 H2/Pt CH3 H
H CH3 CH3 CH3 H CH3 CH3
CH3 H 500 °C CH3 CH3
CH3 H CH3 H
3 × Me–Me 1,3-diaxial 2 × (gauche interaction) 2 × (gauche interaction) + 2 × (gauche interaction) +
interaction 2 × (0.9 kcal) = 1.8 kcal 1 × (Me–Me 1,3 diaxial int) = 1 × (Me–Me 1,3 diaxial int) =
2 × (0.9 kcal) + ? 2 x (0.9 kcal) + ?
∆G = 3.7 kcal/mol (exp)

So, Me–Me 1,3-diaxial interaction = 3.7 kcal/mol.
1,3-diaxial interactions ∆G° of common interactions
R/R ∆G° ax OH ax CH3 eq OH

OH/OH 1.9 kcal ax H 0.45* 0.9 0.0
OAc/OAc 2.0 kcal ax OH 1.9 1.6 0.35
OH/CH3 2.4 (1.6) kcal eq OH 0.35 0.35 0.35
CH3/CH3 3.7 kcal eq CH3 0.35 0.9 0.35
*1/2 of A value
6
Dale L. Boger
C. Cyclohexene
One 1,3-diaxial interaction removed - half-chair

One 1,3-diaxial interaction reduced - Ea for ring interconversion = 5.3 kcal/mol
- the preference for equatorial orientation of a
methyl group in cyclohexene is less than in
pseudoequatorial
cyclohexane because of the ring distortion and the
pseudoaxial removal of one 1,3-diaxial interaction (1 kcal/mol)
D. Decalins
trans-decalin cis-decalin
H
HH H H
H
H H
two conformations equivalent
H
H H
H
H H H H H H H H
H H H
H
H H H H
H H H H H H H H
0.0 kcal 3 gauche interactions
3 × 0.9 kcal = 2.7 kcal
∆E between cis- and trans-decalin = 2.7 kcal/mol
trans-9-methyldecalin cis-9-methyldecalin
H CH3 H H H H
H H H H
CH3 H
H CH3
H H H H
two conformations equivalent
H
H H
H
H H CH3 H H H H H
H H H
H
H H H CH3
H H H H H H H H
4 gauche interactions 5 gauche interactions

4 × 0.9 = 3.6 kcal 5 × 0.9 = 4.5 kcal
∆E between cis- and trans-9-methyldecalin = 0.9 kcal/mol
7
E. Acyclic sp3–sp2 Systems

- Key references
- Origin of destabilization for eclipsed conformations:
Lowe Prog. Phys. Org. Chem. 1968, 6, 1.

Oosterhoff Pure Appl. Chem. 1971, 25, 563.
Wyn-Jones, Pethrick Top. Stereochem. 1970, 5, 205.
Quat. Rev., Chem. Soc. 1969, 23, 301.
Brier J. Mol. Struct. 1970, 6, 23.
Lowe Science 1973, 179, 527.
- Molecular orbital calculations: Repulsion of overlapping filled orbitals:

Pitzer Acc. Chem. Res. 1983, 16, 207.
- Propionaldehyde: Butcher, Wilson J. Chem. Phys. 1964, 40, 1671.

Allinger, Hickey J. Mol. Struct. 1973, 17, 233.
Allinger J. Am. Chem. Soc. 1969, 91, 337.
- Propene: Allinger J. Am. Chem. Soc. 1968, 90, 5773.

Herschbach J. Chem. Phys. 1958, 28, 728.
- 1-Butene: Geise J. Am. Chem. Soc. 1980, 102, 2189.
- Allylic 1,3-strain: Houk, Hoffmann J. Am. Chem. Soc. 1991, 113, 5006.
Hoffmann Chem. Rev. 1989, 89, 1841.
Jacobus van't Hoff studied with both Kekule and Wurtz and received the first Nobel Prize in Chemistry
(1901) in recognition of his discovery of the laws of chemical kinetics and the laws governing the
osmotic pressure of solutions. More than any other person, he created the formal structure of physical
chemistry and he developed chemical stereochemistry which led chemists to picture molecules as
objects with three dimensional shapes. He published his revolutionary ideas about chemistry in three
dimensions just after his 22nd birthday in 1874, before he completed his Ph.D, in a 15 page pamphlet
which included the models of organic molecules with atoms surrounding a carbon atom situated at the
apexes of a tetrahedron. Independently and two months later, Joseph A. Le Bel, who also studied with
Kekule at the same time as van't Hoff, described a similar theory to the Paris Chem. Soc. Kekule
himself had tetrahedral models in the lab and historians concur that they must have influenced van't
Hoff and Le Bel. Interestingly, these proposals which serve as the very basis of stereochemistry today
were met with bitter criticism.
8
Dale L. Boger
1. Acetaldehyde
O O
60° rotation H 60° rotation
H H
H H
HH H
eclipsed bisected 2
rel E B B B
H H (kcal) 1
HO E E E
H O HH
H H 0 60 120 180 240 300 360
relative energies (kcal) dihedral angle
Exp 0.0 1.0 - Two extreme conformations.

MM2 0.0 1.1–1.2 - Barrier to rotation is 1.0 kcal/mol.
- H-eclipsed conformation more stable.
2. Propionaldehyde
O O O O
60° rotation H 60° rotation 60° rotation H
Me Me H H
H H H H
HH H H Me Me
eclipsed bisected eclipsed bisected
H Me Me H
Me O H O HH HO H O H Me
H H H H
relative energies (kcal)

Exp 0.0 1.25, 2.28 0.8, 0.9, 1.0 unknown
MM2 0.0 2.1 0.8, 0.9 1.0, 2.3–1.7, 1.5
Ab initio 0.0 1.7 0.4 0.7
2
B1 B1
rel E E2 B2 E2
(kcal) 1 - J. Chem. Phys. 1964, 40, 1671.
E1 E1 - J. Mol. Struct. 1973, 17, 233.
- J. Am. Chem. Soc. 1969, 91, 337.
0 60 120 180 240 300 360
dihedral angle
O O
tBu 120° rotation - Alkyl eclipsed conformation more stable than
H
H H H-eclipsed and exceptions occur only if alkyl
HH H tBu
group is very bulky (i.e., tBu).
alkyl eclipsed H-eclipsed - Because E differences are quite low, it is difficult
relative energies (kcal) to relate ground state conformation to experimental
results. All will be populated at room temperature.
Exp 2.5 0.0
9
3. Propene
H H H H
C C
60° rotation H 60° rotation
H H
H H
HH H
eclipsed bisected B B B
2
rel E
H H (kcal) 1
HH C E E E
2 H H2C HH
H H 0 60 120 180 240 300 360
relative energies (kcal) dihedral angle

- Two extreme conformations
Exp 0.0 2.0 - Barrier to rotation is 2.0 kcal/mol
MM2 0.0 2.1–2.2
Note:
H H H
O vs. C
H H H
4. 1-Butene
H H H H H H H H
C C C C
Me Me H H
H H H H
HH H H Me Me
H Me Me H
MeH C H H2C HH HH C H H2C H Me
2 2
H H H H

Exp 0.0, 0.2, 0.4, 0.5 - 0.0 -
MM2 0.5, 0.7 1.4–1.7 (2.6) 0.0 1.4–1.8 (2.6)
Ab initio 0.6 - 0.0 2.0
B2
2
B1 B1
rel E
(kcal) 1 E1 E1
E2 E2
0 60 120 180 240 300 360

dihedral angle
H H H H
C C - There is an additional destabilization of placing
tBu 120° rotation
H the alkyl group eclipsed with C=C. This is due
H H
HH H tBu to the larger steric size of olefinic CH compared
to carbonyl C=O.
eclipsed (E1) eclipsed (E2)
- The eclipsed conformations (even with an
relative energies (kcal) α-tBu) are both more stable than the bisected
Exp B1, B2 > E1 >> E2 conformations.
10
Dale L. Boger
5. E-2-Pentene
H Me H Me H Me H Me
C C C C
Me Me H H
H H H H
HH H H Me Me
H Me Me H
H Me H H H H
C H C HH C H C H Me
Me Me Me Me
H H H H

Exp 0.0 (0.0–0.4) - 0.0 -
MM2 0.6 1.4–1.7 (2.6) 0.0 1.5–1.8 (2.6)
3
- Analogous to 1-butene.
B2
2
B1 B1
rel E
(kcal) 1 E1 E1
E2 E2
0 60 120 180 240 300 360

dihedral angle
6. Z-2-Pentene
Me H Me H Me H Me H Me H
C C C C C
60° rotation H 30° rotation 30° rotation 60° rotation H
Me Me H H H
H H Me H H H
HH H H H Me Me
eclipsed bisected perpendicular eclipsed bisected
H Me Me Me H
Me Me Me Me Me H Me
C H C HH C H C H C H Me
H H H H H
H H H H H H

MM2 3.9 4.9 0.0 0.6 0.5
B1 B1
5
E1 E1
4
H H H H H
H
H CH3 CH3 3
H3C CH3
rel E H
- Serious destabilizing (kcal) - The analogous H/CH3
2
interaction, often eclipsing interaction in
referred to as the bisected conformation
1 E2 E2
allylic 1,3-strain B2 is often referred to
(A 1,3-strain). P1 P1 as allylic 1,2-strain
(A 1,2-strain).
0 60 120 180 240 300 360
dihedral angle
11
7. 3-Methyl-1-butene
H H H H H H H H
C C C C
Me 60° rotation 60° rotation H 60° rotation
Me Me Me H
H H H H
H H Me Me Me Me
bisected eclipsed bisected eclipsed
Me Me Me Me
H C
2 HH MeH C
2 H H C
2 H Me HH C
2 H
Me H H Me
Ab initio 2.4–3.0 0.73–1.19 2.60–2.94 0.0
3 B2 B2
B1 B1
2
rel E E1 E1 - J. Am. Chem. Soc. 1991, 113, 5006.
(kcal) 1 - Chem. Rev. 1989, 89, 1841.
E2
0 60 120 180 240 300 360

dihedral angle
8. 4-Methyl-2-pentene
Me H Me H Me H Me H
C C C C
Me 60° rotation 60° rotation H 60° rotation
Me Me Me H
H H H H
H H Me Me Me Me
bisected eclipsed bisected eclipsed
Me Me Me Me
Me H Me Me Me Me Me H
C H C H C H C H
H H H H
Me H H Me
Ab initio 3.4–4.3 - 4.9–5.9 0.0
6 B2 B2
B1 B1
4
E1? E1? - Only H-eclipsed
rel E conformation is
(kcal) 2 reasonable.
E2
0 60 120 180 240 300 360

dihedral angle
F. Anomeric Effect
1. Tetrahydropyrans (e.g., Carbohydrates)
R
C H H R H C X
O
X = OR'
C O C
X R'O H
OR'
Dipoles opposed Dipoles aligned
→ preferred → destabilizing
R = H, preferred conformation. ∆G° = 0.85 kcal/mol
- generally 0–2 kcal/mol, depends on C2/C3 substituents
- effect greater in non-polar solvent
12
Dale L. Boger
Comprehensive Org. Chem. Vol. 5, 693.
Comprehensive Het. Chem. Vol. 3, 629.
Review: Tetrahedron 1992, 48, 5019.
1. A value for R group will be smaller, less preference for equatorial vs axial C3 or C5 substituent
since one 1,3-diaxial interaction is with a lone pair versus C–H bond.
2. Polar, electronegative group (e.g., OR and Cl) adjacent to oxygen prefers axial position.
3. Alkyl group adjacent to oxygen prefers equatorial position.
4. Electropositive group (such as +NR3, NO2, SOCH3) adjacent to oxygen strongly prefers equatorial
position. ⇒ Reverse Anomeric Effect
- Explanations Advanced:
1. Dipole stabilization
C H C OR
opposing dipoles, dipoles aligned,
stabilizing C C destabilizing
OR H
2. Electrostatic repulsion
minimizes electrostatic
C H C OR maximizes destabilizing
repulsion between
electrostatic interaction
lone pairs and the C C between electronegative
electronegative OR H
centers (charge repulsion)
substituent
3. Electronic stabilization
n–σ* orbital stabilizing interaction
n electron C H C OR
delocalization no stabilization possible
C C
into σ* orbital H
4. Gauche interaction involving lone pairs is large (i.e., steric)

1 lone pair / OR
2 lone pair / OR
gauche interaction C H C OR gauche interactions,
+ 1 C/OR but would require that
C C
gauche interaction OR H they be ~1.2 kcal/mol
(0.35 kcal/mol)
2. Anomeric Effect and 1,3-Dioxanes
H
O R
O OO H
R
lone pair / R interaction
1. Polar, electronegative C2/C4 substituents prefer axial orientation.
2. The lone pair on oxygen has a smaller steric requirement than a C–H bond.
∆G° is much lower, lower preference between axial and equatorial C5 substituent
3. Polar electropositive groups C2 equatorial position preferred:
C5 axial position may be preferred for F, NO2, SOCH3, +NMe3.
tBu
CH3 H
O H
CH3 O O tBu
O
preferred
conformation Eliel J. Am. Chem. Soc. 1968, 90, 3444.
13
A Value (kcal/mol) for Substituents on Tetrahydropyran and 1,3-Dioxane versus Cyclohexane
Group Cyclohexane Tetrahydropyran C2 1,3-Dioxane C2 1,3-Dioxane C5
CH3 1.8 2.9 4.0 0.8

Et 1.8 4.0 0.7
iPr 2.1 4.2 1.0
t
Bu >4.5 1.4
3. Exo Anomeric Effect

preferred orientation
55°
H H H
O R R
O O O
O R
R
α-axial-glycosides 1 R/OR gauche 1 R/R gauche 1 R/OR gauche
1 R/R gauche
Rel. E = 0.35 kcal/mol 0.9 kcal/mol 1.25 kcal/mol
55°
H H H
O R H H R H H
O O O
H H R
H2C
R
Kishi J. Org. Chem. 1991, 56, 6412.
G. Strain
Cyclic Hydrocarbon, Heats of Combustion/Methylene Group (gas phase)
Ring Size –∆Hc (kcal/mol) Ring Size –∆Hc (kcal/mol)
3 166.3 10 158.6
4 163.9 11 158.4
5 158.7 12 157.8
strain free 6 157.4 13 157.7
7 158.3 14 157.4 largely strain free
8 158.6 15 157.5
9 158.8 16 157.5
1. Small rings (3- and 4-membered rings): small angle strain

For cyclopropane, reduction of bond angle from ideal 109.5° to 60°
27.5 kcal/mol of strain energy.
For cyclopropene, reduction of bond angle from ideal 120° to 60°
52.6 kcal/mol of strain energy.
To form a small ring in synthetic sequences, must overcome the energy barrier
implicated in forming a strained high energy product.
2. Common rings (5-, 6-, and 7-membered rings):
- largely unstrained and the strain that is present is largely torsional strain (Pitzer strain).
14
Dale L. Boger
3. Medium rings (8- to 11-membered rings):
a. large angle strain
- bond angles enlarged from ideal 109.5° to 115–120°.
- bond angles enlarged to reduce transannular interactions.
b. steric (transannular) interactions
- analogous to 1,3-diaxial interactions in cyclohexanes, but can be 1,3-, 1,4-, or 1,5- ...
c. torsional strain (Pitzer strain)

in cyclohexanes in medium rings
- deviation from ideal φ of 60° and
60° approach an eclipsing interaction.
H H
H H
H H C
(CH2)n
H H C
just like gauche butane. 40°
4. Large rings (12-membered and up):
- little or no strain.
5. Some highly strained molecules:
Buckminsterfullerene (C60) has a strain energy of 480 kcal/mol and is one of the highest strain
energies ever computed. However, since there are 60 atoms, this averages to ca. 8 kcal/mol per
carbon atom - not particularly unusual.
First isolated in 1990: Robert Curl, Harold Kroto, and Richard Smalley
Kroto, Heath, O'Brian, Curl, and Smalley shared the 1996 Nobel Prize in Chemistry for
Nature 1985, 318, 162. the discovery of fullerenes.
[1.1.1] propellane Wiberg J. Am. Chem. Soc. 1982, 104, 5239.
strain energy = 98 kcal/mol
note: the higher homologs are not stable at 25 °C.
Wiberg J. Am. Chem. Soc. 1983, 105, 1227.
cubane Eaton J. Am. Chem. Soc. 1964, 86, 3157.
note: kinetically very stable, may be prepared in kg quantities.
cyclopropabenzene Vogel Tetrahedron Lett. 1965, 3625.

note: even traces of this substance provides an intolerable smell and efforts to establish
its properties had to be cancelled at the Univ. of Heidelberg.
15
H. pKa of Common Organic Acids
Acid pKa Acid pKa
cyclohexane 45 (CH3)2CHOH 18
ethane 42 CH3CH2OH 17
benzene 37 cyclic ketones 17
ethylene 36 e.g. cyclohexanone 17
Et2NH 36 CH3OH 16 (16−18)
NH3 (ammonia) 35 CH3CONHCH3 16−17
toluene, propene 35 PhCH2COPh 16
(C6H5)3CH 28−33 H2O 16
DMSO (CH3S(O)CH3) 31 cyclopentadiene 15
C6H5NH2 27 CH2(CO2Et)2 13
HC CH 25 CH2(CN)2 11
CH3CN 25 CH3COCH2CO2Et 11
CH3CO2Et 25 CH3NO2 10
CH3SO2CH3 23−27 phenol 10
CH3CONMe2 25 R3NH+Cl− 10
aliphatic ketones 20−23 HCN 9
(CH3)3CCOCH(CH3)2 23 CH3CH2NO2 9
(CH3)3CCOCH3 21 CH3COCH2COCH3 9
CH3COCH3 20 CH2(CN)CO2Et 9
CH3COC6H5 19 CH3CO2H 5
(CH3)3COH 19 py•HCl 5
C6H5C CH 19 C6H5NH3+Cl− 5
XH H+ + X− Ka = [H+][X−]
[HX]
pKa = −logKa = −log[H+]
Increase in pKa means decrease in [H+] and acidity
Decrease in pKa means increase in [H+] and acidity
For more extensive lists, see:

The Chemist's Companion, p 58–63.
Familiarity with these pKa's will allow prediction/estimation of acidities
of other compounds. This is important, since many organic reactions
have a pKa basis (i.e., enolate alkylations).
Alfred Werner, who received the 1913 Nobel Prize in Chemistry for
his studies of stereochemistry and inorganic complexes, is also
responsible for the redefinition of (acids and) bases as compounds
that have varying degrees of ability to attack hydrogen ions in water
resulting in an increase in hydroxide ion.
The most acidic natural product is the mycotoxin monliformin also known as semisquaric acid,
pKa = 0.88
O O
Springer, Clardy J. Am. Chem. Soc. 1974, 96, 2267.
OH
Compare the strength of the following neutral bases:
tBu
DBU
R N R R
N
Me3N R P N P N P N P R R=N
N R N R R
pKb = 4.1 pKb = 24.3 R P R pKb = 46.9
R
Schwesinger Liebigs Ann. 1996, 1055.
16
Kinetics and Thermodynamics of Organic Reactions
Dale L. Boger
II. Kinetics and Thermodynamics of Organic Reactions

A. Free Energy Relationships
∆G = ∆H − T∆S
The equilibrium for the reaction can be described by
∆G
ln Keq = −
RT
To achieve a high ratio of two products (desired product and undesired product) in a thermodynamically
controlled reaction run under reversible conditions, one needs the following ∆G's:
K (25 °C) ∆G (kcal/mol) K (0 °C) ∆G (kcal/mol) K (−78 °C) ∆G (kcal/mol)
2 (67:33) 0.41 2.1 (68:32) 0.41 2.9 (75:25) 0.41

5 (83:17) 0.95 5.7 (85:15) 0.95 11.6 (92:8) 0.95
9 (90:10) 1.30 10.9 (92:18) 1.30 28.5 (97:3) 1.30
20 (95:5) 1.74 27.5 (96:4) 1.80 103.3 (99:1) 1.80
99 (99:1) 2.73
999 (99.9:0.1) 4.09
Hydrogenation reaction: H H
H2C CH2 + H2 H2C CH2
bonds broken bonds formed
1 C C 163 kcal/mol 1 C C 88 kcal/mol

1 H H 104 kcal/mol 2 C H 2 × 98 kcal/mol
267 kcal/mol 284 kcal/mol
-Overall reaction is exothermic -> ∆G = −17 kcal/mol, so reaction is favorable, spontaneous.
-To calculate equilibrium constant:

∆G
ln Keq = −
RT
2.303 log Keq = 17 kcal × 1000 cal/mol / (298 K) × 1.99

log Keq = 12.45
Keq = 2.8 × 1012
- But experimentally this reaction is very slow.

- Molecule rate (experimentally) = 1012 molecules/sec
6.023 × 1023 molecules/mol

mole rate = = 2 × 104 years
(10 molecules/sec) × (60 sec/min) × (60 min/hour)
12
× (24 hour/day) × (365 day/year)
i.e., 2 × 104 years to hydrogenate one mole of ethylene (without catalyst).
17
E
Transition State: A transition state (TS)
possesses a defined geometry and
∆G‡uncat. = 33.87 kcal charge delocalization but has no finite
existence. At TS, energy usually higher
and although many reactant bonds are
broken or partially broken, the product
∆G‡cat. = 20 kcal bonds are not yet completely formed.
Svante Arrhenius received the 1903 Nobel Prize in

∆G° = –17 kcal Chemistry in recognition of his theory of electrolytic
dissociation where he introduced the idea that many
substances dissociate into positive and negative ions
H2C=CH2 H3C–CH3 reaction coordinate (NaCl Na+ + Cl–) in water including the partial
dissociation of weak acids like HOAc, where the
equilibrium amount depends on the concentration.
uncatalyzed reaction His qualitative ideas on the exponential increase in
catalyzed reaction the rate of reactions when temperature is increased
are retained in modern theories that relate kinetic
rate constants to temperature by means of an energy
of activation.
B. Transition State Theory Ahmed Zewail was awarded the 1999

Nobel Prize in Chemistry for his studies of
∆G‡ = ∆H‡ – T∆S‡ the transition states of chemical reactions
using femtosecond spectroscopy.
- Free Energy of Activation (∆G‡)
- Enthalpy of Activation (∆H‡): Difference in bond energy between reactants and the transition state.
- Entropy of Activation (–T∆S‡): ∆S‡ usually negative, making the change more endothermic.
From ∆G‡ = ∆H‡ – T∆S‡ , ∆G‡ = – RT ln K‡

for uncatalyzed H2 reaction ∆G‡ = 33.9 kcal/mol
catalyzed H2 reaction ∆G‡ = 20 kcal/mol
and for the rate
for uncatalyzed H2 reaction k = 1.0 × 1012 mol/sec
catalyzed H2 reaction k = 1.0 × 1022 mol/sec
C. Intramolecular Versus Intermolecular Reactions

O H+ O
CH3OH + CH3 C OH CH3 C OCH3 ∆S‡1
k1
O
O
OH H+
O ∆S‡2
OH k2
O
O
OH H+
OH O ∆S‡3
k3
k3 > k2 > k1 –T∆S‡1 > –T∆S‡2 > –T∆S‡3 > 0

∆S‡1 < ∆S‡2 < ∆S‡3 < 0
∆G‡3 < ∆G‡2 < ∆G‡1
18
Dale L. Boger
- Intramolecular versus intermolecular reactions benefit from a far more favorable entropy of activation (∆S‡).
- In forming small rings, ring strain developing in the product decelerates the rate of reaction (large ∆H‡)
and that can offset the favorable ∆S‡ rate acceleration.
O OH H+ O
OH very slow O
Examples:
O O
H2O aq DMSO
(CH2)n O O
Br (CH2)n NH2
25 °C NH n 50 °C n
Br
Ring size Rel. Rate Ring size Rel. Rate Ring size Rel. Rate
3 70 3 21.7 11 8.51
4 1.0 4 5.4 × 103 12 10.6
5 10000 5 1.5 × 106 13 32.2
6 1000 6 1.7 × 104 14 41.9
7 2 7 97.3 15 45.1
8 1.00 16 52.0
9 1.12 17 51.2
10 3.35 18 60.4
- gem dimethyl effect

Rel. Rate
HO aq. NaOH O
Cl 1.0
18 °C
HO O
Cl 325
HO O
Cl 39000
Compare to relative rates of intermolecular SN2 displacement where the more substituted alkoxide reacts slowest:
k1 O
CH3OH + CH3Cl
k2
OH + CH3Cl O
k1 > k2 > k3 > k4
OH k3 O
+ CH3Cl
OH k4 O
+ CH3Cl
DeTar J. Am. Chem. Soc. 1980, 102, 4505.

Winnik Chem. Rev. 1981, 81, 491.
Mandolini J. Am. Chem. Soc. 1978, 100, 550.
Illuminati J. Am. Chem. Soc. 1977, 99, 2591.
Mandolini, Illuminati Acc. Chem. Res. 1981, 14, 95.
For the intramolecular case:

The reactive conformation is more favorable and populated to a greater extent in the more substituted case
⇒ One must consider both the length of the chain (i.e., ring size being formed) and the nature of the atoms
in the chain (i.e., conformation, hybridization).
19
D. Kinetic and Thermodynamic Control
– For competitive reactions:
transition state:
possesses a defined geometry,
charge delocalization,
E but has no finite existence
∆∆G‡
∆Gc‡
∆GB‡
Free E of ∆GB
∆Gc Activation
∆∆G kinetic product
thermodynamic product
C A B reaction coordinate
If this is an irreversible reaction, most of the reaction product will be B (kinetic product).
If this is a reversible reaction, most of the product will be C (more stable, thermodynamic
product).
OLi O OLi
Me LDA Me LDA Me
thermodynamic kinetic
product product
more favorable ∆G more favorable ∆G‡
A beautiful example of this was observed in the kinetic versus thermodynamic asymmetric
Dieckmann-like condensation illustrated below. The most stable product (lower ∆G) was
observed upon conducting the reaction under equilibrating conditions for the reversible
reaction while the alternative kinetic product (lower ∆G‡) was observed when the reaction
was conducted under lower temperature and nonequilibrating conditions (kinetic conditions).
20
Dale L. Boger
epi-(+)-Duocarmycin A (+)-Duocarmycin A
Thermodynamic Kinetic
control: single control: 5 – 7:1
TBDMSO diastereomer TBDMSO diastereomers TBDMSO
HN HN
Me NBOC NC NBOC XcOC NBOC
LDA Me LDA
XcOC N THF O N
N THF Me N
81% 58%
BOC OBn –78 to –40 °C O O BOC OBn –78 °C, 30 min BOC OBn
Divergent Control of C6-Stereochemistry
Kinetic Thermodynamic
control: 5 – 7:1 control: single
TBDMSO diastereomers TBDMSO diastereomer TBDMSO
HN HN
LDA Me LDA
XcOC N THF O N
N
THF Me N
58% 81%
BOC OBn –78 °C O BOC OBn –78 to –40 °C BOC OBn
O
30 min
CO2tBu > CHO
Chelated Z-enolate anti-carbonyls
O O O
iPr Li Me NH iPr
Me N O N O
O N NH
O N N O
iPr N
N iPr N R
Me N O N
O O Me
Li R O
R R
∆E = 0.76 kcal/mol
Boger J. Am. Chem. Soc. 1997, 119, 311.
E. Hammond Postulate
The geometry of the transition state for a step most closely resembles the
side (i.e., reactant or product) to which it is closer in energy.
Transition state can not be studied experimentally – has zero lifetime (transient species)
→ information obtained indirectly
⇒ Hammond postulate
Examples:
1) Thermoneutral reactions:
CH3–1I + 2–
I CH3–2I + 1–
I
21
H H H
H 1I 1I 2I
2I– +
H H
symmetrical
T.S.
E
Thermoneutral reaction –
transition state resembles both
starting material and product equally
s p
2) For reactions which proceed through an intermediate: solvolysis of tertiary alcohol
A [X] B
X: discrete intermediate
R R R R
R C HCl C Cl– R C
OH R
R R
Cl
T.S. G. A. Olah received the 1994 Nobel Prize in

E T.S. Chemistry for his contributions to carbocation
chemistry.
I
Resemble the geometry of the carbocation
s intermediate and not that of the reactant (alcohol)
p or product (alkyl chloride).
Intermediate (for this reaction it will be C+ so T.S. ⇒ I )
Notes
a. 20 kcal/mol energy available at 25 °C for free energy of activation.
b. Increase reaction temperature, increase the rate of reaction.
c. Decrease reaction temperature, decrease the rate of reaction, but increase the
selectivity of the reaction.
Hammond J. Am. Chem. Soc. 1955, 77, 334.

Farcasiu J. Chem. Ed. 1975, 52, 76.
F. Principle of Microscopic Reversibility

The forward or reverse reactions, run under identical conditions, must proceed by the same mechanism
i.e., if forward reaction proceeds via intermediate X
A [X] B
then reverse reaction also goes through X.
B [X] A
22
Reaction Mechanisms and Conformational Effects on Reactivity
Dale L. Boger
III. Reaction Mechanisms and Conformational Effects on Reactivity
A. Ester Hydrolysis
pKa = 15 pKa = 5
O OH– O O O
CH3 C OEt CH3 C OEt CH3 C OH CH3 C O
OH
sp2 sp3 + –OEt + EtOH
pKa = 17
Reaction driven to completion by final, irreversible step (compare pKa = 17 to pKa = 5).
a O
a O CH3 +
O OH– HO OEt
OEt
CH3 C OEt CH3 C
b
OH
c b O
+ OEt
HO CH3
O
+ H2O
H2C OEt
O
+ EtOH
O CH3
- So, possible competing reaction is α-H removal, but pKa difference means equilibrium strongly favors
ester and OH–, i.e.;
O O
HO– + CH3 C OCH2CH3 H2O + H2C C OCH2CH3
- To deprotonate an ester, must use a strong base which is non-nucleophilic, such as tBuOK or LDA.
O
CH3COOCH2CH3 H2C C OCH2CH3
pKa = 25
1. tBuOK (pKa of tBuOH = 19) → generates low concentration of anion, and a significant amount of
ester always present
⇒ self (Claisen) condensation
2. LDA (pKa of iPr2NH = 36) → generates a high concentration of enolate and thus is a good
base to carry out stoichiometric alkylation of ester
23
1. Kinetics of Ester Hydrolysis (Stereochemistry and Rates of Reactions)
‡
NaOH OEt
tBu COOEt tBu tBu COOH
O OH
Steric Effect no way to avoid a severe tBu-like 1,3-diaxial interaction

OH ‡
COOEt H
O COOH
NaOH OEt
H
tBu tBu tBu
A value = 1.2 kcal A value = 2.3 kcal
ktrans The rate determining step for ester hydrolysis is the

= 19.8 formation of tetrahedral intermediate and the ratio of
kcis ktrans/kcis >> 1.
Eliel J. Am. Chem. Soc. 1961, 83, 2351.
- Difference in rates much greater than expected if simply considering the difference in either the
product or reactant A values.
- Reaction of axial ester decelerated due to more severe developing 1,3-diaxial interactions in
transition state (i.e., an axial tBu-like group).
2. Same effect is observed, but to a lesser extent with acetate hydrolysis
O O
OH
OH–
tBu O CH3 tBu OH tBu O
CH3
ktrans
O O
OH
O CH3 OH O
OH– CH3
tBu tBu tBu
kcis
A value = 0.7 kcal/mol
ktrans
= 6.65 effect is smaller because of the more remote
kcis distance of the steric interactions
Similarly, the rates of acetylation are ktrans / kcis = 3.7
24
Dale L. Boger
B. Alcohol Oxidations
R H O fast R H slow R OH
O
+ HO Cr OH O + Cr O
R' OH R' O Cr
O OH R' OH
O
( CrO3 + H2O )
Westheimer J. Am. Chem. Soc. 1951, 73, 65.
O
slow O
fast Cr
tBu OH tBu O OH
tBu
O ktrans
O
Cr
H O OH
OH O
H slow O
tBu
fast tBu
tBu H
kcis
kcis The rate determining step for the alcohol oxidation is break down
= 4 of the chromate ester with cleavage of C–H bond and O–Cr bond.
ktrans
Destabilizing 1,3-diaxial interactions in cis chromate ester

accelerate its breakdown to the ketone (would be slower if the
slow step for the reaction were formation of chromate ester).
C. SN2 Reactions
PhS
H SPh
H less stable product
PhS Na
tBu X tBu formed and proceeds
through a less stable T.S.
inversion
trans ktrans cis'
H X
H
PhS Na
tBu tBu SPh
inversion
cis PhS kcis trans'
25
- The free energy of activation (Ea, or ∆G‡) for

reaction of the trans isomer is higher due to ∆∆G‡
steric interactions felt in the transition state
(interactions of incoming nucleophile with E
axial H's).
cis
→ kcis > ktrans cis'

trans
∆∆G‡ greater than ∆∆G of products.
∆∆G
- The reaction of the trans isomer is kinetically trans'
slower and thermodynamically less favorable.
reaction coordinate
D. Elimination Reactions
H
B
H
X trans
X
antiperiplanar
E2 elimination
H
must have a good orbital overlap
(i.e., via trans antiperiplanar orientation
of C–H bond and C–X bond).
X
Stereoelectronic Effect
- Alternatively, if dihedral angle = 0° (i.e., eclipsed X and H), elimination can take place (orbital overlap good).
1.0 ~ 1.3 kcal

B
H Cl
eclipsed conformation is 3.0–3.3 kcal/mol
H Cl higher in E, so elimination takes place mainly
H
HH H 1.0 kcal through trans antiperiplanar arrangement.
H H
H H
1.0 kcal
- Alternate mechanisms also possible:
E1 mechanism E1cB mechanism
D E A D H H H
A B E X H
H
B
via free carbocation large groups (A,E) trans
26
Dale L. Boger
Acyclic Substrate
– Examples: C2H5
51%
CH3
EtONa trans
CH3CH CH2 C2H5 CH3CH CH C2H5
Br
69% CH3 C2H5
18%
Anti elimination
cis
0.5 kcal
Br
Br H Et EtONa H
H Et
H
Et
H Me H Me H 18%
H Me cis
0.9 kcal
∆E = 0.9 kcal trans is more stable than
cis (1.0 kcal/mol)
0.5 kcal
Br Et
Et H Br Et H EtONa H
H
H Me
H
H Me H 51% Me trans
– For other possible mechanisms:
Syn elimination
1.0 ~ 1.3 kcal
1.0 H
H Br H
Br H
Et
Et H
Et
HH Me H Me Me cis
4.0 kcal
syn elimination also strongly favors
1.0 ~ 1.3 kcal formation of trans product
H Br 1.3 H Et
Br Et H
H H H
H Me H Me
Et Me trans
1.3 kcal
Both are very much destabilized relative to anti-elimination T.S. / conformations.

Neither contribute to ground state conformation of bromide at room temperature.
And, there is another product formed:
H Br Br
Br H
H H Br H H H Et H H H H
H or H
H H
H CH3 H CH3Et H H Et
H Et
Et
H HH
27
Cyclic Substrate
Consider E2 elimination of
Cl Cl
neomenthyl chloride menthyl chloride
Look at all conformations of each:
0.45 kcal 2.1 kcal 2.1 kcal

0.25 kcal
0.25 kcal H
H H H
Cl H H
CH3 CH3 0.9 kcal
Cl
H Cl H
H H CH3 Cl CH3
H 0.25 kcal
0.25 kcal
1.8 kcal ~1.5–2.0 kcal
A ∆E= ~3.4 kcal/mol B C D
>99 :1 ratio for A : B 4.5–5 kcal/mol more stable
k1 k2
reactive conformer
because it is the only
one that can achieve
CH3 CH3 a trans antiperiplanar CH3
relationship between
+ the H atom and the Cl
> 4 kcal/mol energy

difference between
ground state
78 : 22 conformation and the only product !
reactive conformation
The reaction of the neomenthyl chloride is much faster (k1/k2 = 193:1)
From D (menthyl chloride) – only one product is possible
Curtin–Hammett principle : Ground state conformation need not

be decisive in determining product of
a reaction.
28
Dale L. Boger
E. Epoxidation by Intramolecular Closure of Halohydrins
– Must involve backside displacement → geomerical constraints !
CH3 CH3
K2CO3
Br
HO O
72 h, 25 °C
H
backside attack
not geometrically OH–
feasible
CH3
5 ~ 10 kcal CH3
CH3
Br O O
O
Br
H
available at room reaction proceeds
temperature through very minor
conformation
Again, ground state conformation of reactant is not a determinant in reaction product

(Curtin–Hammett principle).
– Another example:
Br CH3 Br CH3 CH3

K2CO3
OH H O H 1 min, 25 °C O H
reaction much faster and proceeds
from a ground state conformation
F. Epoxide Openings (SN2)

(a) (b) twist boat conformation
CH3 CH3 SPh
CH3
(b)
O O
H O H
Nu sp2.27 H
atom under attack (a) nucleophile can attack
in epoxide moves at either carbon atom
towards Nu: O
1,3-diaxial CH3
H3C H3C
SPh SPh
SPh
HO
OH O
less stable product chair conformation more stable product
This is the only product formed!
Product ratio dependent on Ea (i.e., relative energy of two T.S.), route (a)
proceeding through chair conformation and destabilizing 1,3-diaxial interaction is of
lower energy than route (b) proceeding through twist boat T.S.
- Conformational effects determine regioselectivity
29
G. Electrophilic Additions to Olefins
Follows same principles
CH3 CH3 Br CH3

Br2 Br Br
HH
H Br attacks H trans- Br H
from the less diaxial
hindered face opening
PhSX,
PhSeX,
or HgX2
CH3 SPh CH3

PhS
H kinetic product
H
∆
H X H
reversible
CH3 CH3 X
X b
H
H a X
b
a
twist boat
episulfonium ion H3C CH3
X
X
H
H X HX
kinetic thermodynamic
CH3 H CH3
PhS X thermodynamic product
PhS
X
H H H
- Conformational effects control regioselectivity and stereochemistry

But, it is not always possible to obtain the thermodynamic product
⇒ must have the 20–30 kcal/mol of energy required and a mechanism to reverse the reaction.
30
Dale L. Boger
H. Rearrangement Reactions
pinacol → pinacolone rearrangement
HO OH HO OH2 O
CH3 CH3
+ H+
CH3 CH3
pinacolone
– Prototype of rearrangement:
heteroatom:
O L.G. leaving group This process is
conformationally
–OH2+ dependent!
M.G.
–OSO2R
migrating group –N2+ diazonium ion
H2 OH OH2
NH2 + H O N OH N N NH N
OH OH
(HONO,
H2ONO - protonated)
NH N OH
HCl + NaNO2
+ N2 ↑ N N N N OH2
Tiffeneau−Demjanov Reaction
Ring expansion of cyclic β-amino alcohols

O
HO NH2
HONO Tiffeneau Compt. rend. 1937, 205, 54.
review: Org. React. 1960, 11,157.
The course of rearrangement is conformationally dependent:
A value of NH2/NH3+ (1.8–1.4 kcal)

H NH2
H
H NH2
H OH gauche (0.35–0.9 kcal)
H
H OH ∆E = 1.6 ~ 2.2 kcal
A value of OH HONO
(0.7 kcal)
backside attack
Stereoelectronic
Effect N2
N OH
OH
H O
trans periplanar only product
arrangement observed
31
Compare to:
NH2 N2+ H
H HONO H H
OH O
H
H H O
Stereoelectronic
effects dominate both good:
~ 50:50 trans periplanar both products
the control of mixture observed
regioselectivity relationships
H H
NH2 N2 +
H
OH O
H H O
Explain the following results:
H3C NH2 CH3

HO
HONO O
H CH3
CH3
H +
H3C N
O 2
H
CH3
H3C NH2
H3 C H3C
HONO H3 C H
H
OH
+ O
H3C N
H3 C 2
H
O
H
H3C H CH3 H
HO
NH2 HONO CH3
CH3 O
H3C H
OH
N2+
CH3
H3C H CH3 H
H3 C
HONO CH3
NH2
OH O
H3C H3CH
N2+
OH
32
Dale L. Boger
- Additional examples
OSO2Ar O migrating bond

HO H
KOtBu
H H
89% OSO2Ar
H H Me Me
Me O
Büchi J. Am. Chem. Soc. 1966, 88, 4113.
O O O O O
ArO2SO O O O O
AcO CH3
AcO AcO
Heathcock J. Am. Chem. Soc. 1982, 104, 1907.
I. Pericyclic Reactions
1. Conservation of Orbital Symmetry, FMO Analysis
- Concerted reactions where there is a single transition state and no intermediates

proceed through cyclic transition states.
- Cyclic transition state corresponds to an allowed arrangement of participating orbitals that can
maintain a bonding interaction between the reaction components throughout the course of
the reaction. This dictates features of relative reactivity, regioselectivity, and
diastereoselectivity.
- This also established and formalized the viability of utilizing Frontier Molecular Orbitals
(FMO) composed of the Highest Occupied Molecular Orbital (HOMO) and Lowest
Unoccupied Molecular Orbital (LUMO) to analyze pericyclic reactions.
Woodward, Hoffmann The Conservation of Orbital Symmetry, Academic: New York, 1970.
J. Am. Chem. Soc. 1965, 87, 395.
Fukui Acc. Chem. Res. 1971, 4, 57; Angew. Chem., Int. Ed. Eng. 1982, 21, 801.
Encouraged by E. J. Corey, Hoffmann

began examining mechanistic problems in R. Hoffmann received the 1981 Nobel
organic chemistry and, as a junior fellow Prize in Chemistry for the launch and
at Harvard, entered into a collaboration development of the concept of orbital
with R. B. Woodward that combined his symmetry conservation.
insights in MO theory with Woodward's
knowledge of experimental pericyclic
reactions. This led to five papers in 1965 K. Fukui received the 1981 Nobel
before he was 30 years old, that were the
Prize in Chemistry for his Frontier
foundation of what we now refer to as the
Woodward–Hoffmann rules. Orbital theory of chemical reactivity.
This followed and was not included in the 1965 Nobel Prize in Chemistry
awarded to R. B. Woodward for his contributions to the "art of organic synthesis".
33
2. Electrocyclic Reactions
- This is composed of a series of reactions in which a ring closure occurs with formation of a
single bond at the ends of a linear, conjugated system of π electrons and the corresponding
reverse reaction with ring opening.
Thermal Reaction hν Reaction

System π electrons Ground State (HOMO) Excited State (LUMO)
4 π e– conrotatory disrotatory
6 π e– disrotatory conrotatory
4 π e– thermal reaction (ground state, HOMO)
R R
- Stereochemistry dictated
by orbital symmetry
R allowed reaction course
R
conrotatory movement bonding interaction
6 π e– thermal reaction (ground state, HOMO)

R
R
R
R
disroratory movement bonding interaction
- Generalization:
No. of π electrons Thermal hν
4n π electrons (n = 0,1,...) conrotatory disrotatory

4n + 2 π electrons (n = 0,1,...) disrotatory conrotatory
34
Dale L. Boger
3. Cycloadditions and Cycloreversions
- These are discussed in terms of suprafacial or antarafacial addition to the ends of a π system.
Suprafacial Antarafacial
- Generalization:
Total π electrons Allowed in Ground State Allowed in Excited State
4n ms + na ms + ns
ma + n s ma + n a
4n + 2 ms + ns ms + na
ma + n a ma + n s
suprafacial (s) or
- Notations orbital type π2s
π, σ, ω antarafacial (a)
number of e–
- Diels-Alder Reaction (6π e–), Ground State Thermal Reaction

Inverse Electron Demand
Normal Diels–Alder Reaction Diels–Alder Reaction
HOMO diene LUMO diene
bonding bonding
interaction interaction
LUMO HOMO
dienophile dienophile
[π4s + π2s] cycloaddition

- Suprafacial with respect to both reacting components and this defines the orientation
with which the two reactants approach: boat transition state.
- The FMO analysis may also be used to predict relative rates, regioselectivity,
and diastereoselectivity (endo effect) and we will discuss this in detail along
with the Diels–Alder reaction.
- [2 + 2] Cycloaddition (4π e–)
Ground State (thermal) Excited State (hν)
bonding
interactions LUMO (antarafacial) LUMO (suprafacial)
HOMO (suprafacial) bonding interactions

Excited state HOMO
(SOMO) (suprafacial)
[π2a + π2s] cycloaddition [π2s + π2s] cycloaddition
- Antarafacial with respect to one - Suprafacial with respect
olefin and suprafacial with respect to to both olefins.
the second, dicates perpendicular
approach to permit bonding.
35
4. Sigmatropic Rearrangements
- Class of reactions characterized by migration of an allylic group from one end of a π system to the other.
- Generalization:
Total π electrons Ground State Excited State
4n antara - supra antara - antara

supra - antara supra - supra
4n + 2 supra - supra antara - supra

antara - antara supra - antara
- These include a wide range of rearrangements including [1,3]-, [1,5]-, [1,7]-, [3,3]-, and [2,3]-
sigmatropic reactions which we will discuss in detail.
J. Subtle Conformational and Stereoelectronic Effects on

Reactivity and Reaction Regioselectivity
1. Kinetics, Stereochemistry, and Reaction Mechanisms
- Two of the cornerstones of defining a mechanism rest with the establishment of the stereochemistry
of the reaction in conjunction with kinetic studies of the reaction.
- For example, for a reaction that might entail acid or base catalysis, it is common to examine
the pH rate profile.
OH OH
+
H2O single enantiomer with clean
inversion of absolute
O OH OH
stereochemistry, therefore
optically active 1 : 15 SN2, not SN1, ring opening.
acid-catalyzed reaction - Below pH 4, H+ catalyzed

reaction dominates.
(k = 0.093 M–1s–1)
kobs
- Above pH 4 (pH 4–12), the
uncatalyzed reaction uncatalyzed direct SN2
(k = 4.2 x 10–5 s–1) addition reaction dominates.
0
2 4 6 8 10 12
pH
Boger J. Org. Chem. 1998, 63, 8004; J. Org. Chem. 1999, 64, 5666.
36
Dale L. Boger
2. Substituent Effects
- These can be quantitated using a Hammett treatment and can provide insights into reaction
mechanisms.
ρ = −0.3 : small, almost negligible effect
- C7 substituents (R) have little
ρ = −3.0 : huge effect effect on reactivity
R C7 N R' - N substituent (R') has a pronounced
effect on reactivity and even subtle
perturbations will change reactivity
greatly (-SO2R → -CO2R, 10 ×)
O
ρ values are characterized in a log scale
- The negative ρ value indicates δ+ charge buildup in the rate-determining step of the reaction.
- 5.2 - 5.2
-CONCH3
r = 1.0 R R'
- 5.4 - 5.4
ρ = –0.30 -CO2CH3
- 5.6 - 5.6
-OMe
log k log k -COEt
-H
- 5.8 - 5.8
-CN
- 6.0 - 6.0
r = 0.983
- 6.2
ρ = slope - 6.2 ρ = –3.0
-SO2Et
- 6.4 - 6.4
- 0.4 - 0.2 0.0 0.2 0.4 0.6 0.8 - 0.2 0.0 0.2 0.4 0.6 0.8
σp σp
J. Org. Chem. 1996, 61, 1710 and 4894.
3. Structure versus Reactivity and Reaction Regioselectivity
- Structure can have a pronounced effect on reactivity and reaction regioselectivity.
One nice example of this can be illustrated with a series of analogues related to CC-1065 and the
duocarmycins which are potent antitumor antibiotics that derive their biological properties from a
sequence-selective DNA alkylation reaction. The reactivity changes that one sees as a consequence of
the loss of the vinylogous amide stabilization are related to the source of DNA alkylation catalysis.
Binding-induced conformational change: shape-selective catalysis

MeO2C MeO2C
χ1 = 25–40°
Alexander R. Todd HN HN χ2 = 0°
received the 1957 Nobel
χ1
Prize in Chemistry for his
work on the synthesis of O N OMe O N χ2 OMe
nucleotides and
nucleotide coenzymes. O N OMe O N OMe
H H
OMe OMe
- DNA bound agent adopts helical conformation, twist adjusted at linking amide.
Francis Crick and James - DNA bound agent maintains full amide. (χ2 = 0°)
Watson shared the 1962
Nobel Prize in Physiology - Vinylogous amide stabilization diminished. (χ1 = 25–40°)
and Medicine for their - Cyclohexadienone structure destabilized.
elucidation of the structure - Shape-dependent catalysis: Preferential activation in AT-rich minor groove.
of DNA.
Binding induced twist greatest in the narrower, deeper AT-rich minor groove.
- Shape-selective recognition: Preferential binding in AT-rich minor groove.
Boger J. Am. Chem. Soc. 1997, 119, 4977 and 4987.
Boger, Garbaccio Bioorg. Med. Chem. 1997, 5, 263.
Acc. Chem. Res. 1999, 32, 1043.
37
- N-Acylation and its effect on vinylogous amide and cyclopropane conjugation.
(+)-CBI (+)-N-BOC-CBI (–)-CBQ (–)-N-BOC-CBQ ca. 10–50 ×

increase in
reactivity
vs and vs
O N O N O N O N
H OtBu ° H °
°
1.337 A °
1.390 A 1.336 A 1.415 A
O O OtBu
t1/2 = 920 h (pH 3) t1/2 = 133 h (pH 3) t1/2 = 91 h (pH 3) t1/2 = 2.1 h (pH 3)
t1/2 = stable (pH 7) t1/2 = 544 h (pH 7)
X-ray X-ray
° ° °
1.525 A °
1.528 A
1.508 A 1.521 A
10a 28.7°
9a 12.7° 9a 16.5° 10a 19.8°
°
1.476 A
° ° °
8b 1.468 A 8b 1.468 A 9b 1.445 A 9b
10 28.7°
9 45.0° 9 40.9° 10 36.4°
° ° ° °
1.532 A 1.544 A 1.539 A 1.543 A
- N-acylation decreases the cross-conjugated vinylogous amide conjugation, increases the

cyclopropane conjugation and bond lengths, and increases cyclopropane reactiviity. This can be
observed in the corresponding X-ray crystal structures.
- Amide twist effect on the vinylogous amide and cyclopropane conjugation.
χ1 = 6.9° χ1 = 34.2° χ1 = 86.4°
O N O N O N
° OtBu °
1.390 A 1.415 A° O 1.428 A
O O OtBu OtBu
H+ catalyzed
reaction t1/2 = 133 h (pH 3) t1/2 = 2.1 h (pH 3) t1/2 = 0.03 h (pH 3) 104 ×
Uncatalyzed t1/2 = stable (pH 7) t1/2 = 544 h (pH 7) t1/2 = 2.1 h (pH 7) increase in
reaction reactivity
- Decreases vinylogous - Increases cyclopropane - Increases cyclopropane
and rates
amide cross-conjugation conjugation (bond lengths) reactivity
X-ray
°
1.521 A °
1.528 A °
1.565 A
11a
10a 28.7° 38.5°
9a 16.5°
8b 9b
10b
10
11 18.5°
9 40.9° 28.7°
1.544 A° °
1.543 A °
1.525 A
regioselectivity: > 20 : 1 3:2 < 1 : 20
- Note the change in solvolysis regioselectivity where the stereoelectronically aligned

cyclopropane bond is the bond which is cleaved. The stereoelectronically aligned bond is complete
that which is positioned to best overlap with the developing π-system of the product phenol. reversal of
reaction
- In each case, the ring expansion occurred with generation of a single enantiomer by a SN2 regioselectivity
mechanism.
Boger J. Org. Chem. 1997, 62, 5849; J. Am. Chem. Soc. 1997, 119, 4977.
38
Dale L. Boger
K. Methods for the Synthesis of Optically Active Materials
Morrison Asymmetric Synthesis, Academic: New York, 1983; Vol. 1–5.
Note: A summary of approaches which will be highlighted throughout the following material.
1. Partial Synthesis
- From readily available, naturally-derived optically active materials, examples include
a. Progesterone from sapogenin diosgenin.
b. Synthetic penicillins from the fermentation product 6-aminopenicillanic acid (6-APA).
c. Vitamin D3 (1-hydroxycholecalciferol) from cholesterol.
Louis Pasteur (1822–1895) conducted the first separation of a racemate into its
enantiomers (by hand!) and by fractional crystallization. Thus, he conducted the first
diastereomeric resolution (tartaric acid + quinine). His investigations into the
process of fermentation led to the development of microbiology and the important
method of preserving foods known as pasteurization. His research into immunity led
to preventative vaccinations using weakened strains of bacteria. He developed the
first vaccines for rabies.
2. Resolution
a. Diastereomeric salts and selective crystallization.
b. Diastereomeric derivatization and chromatography or selective crystallization.
c. Direct chromatographic resolution of enantiomers on an optically active stationary support.
d. Enzymatic resolution.
e. Kinetic resolution with selective production of desired enantiomer or
selective consumption of undesired enantiomer.
Advantage: Both enantiomers are made available.
Disadvantage: 1/2 of the material is wasted if only one enantiomer is desired.
Ambiguous assignment of absolute configuration.
See: Jacques, Collet, Wilen Enantiomers, Racemates, and Resolutions, Wiley: New York, 1981.
A. J. P. Martin and B. L. M. Synge shared the 1952 Nobel Prize in Chemistry for
developing the technique of liquid–liquid partition chromatography. Their collaboration
also led to the invention of gas–liquid partition chromatography (GLC). The use of
chromatography can be traced back to a Russian botanist, M. Tswett, who separated
plant pigments by such methods in 1906. Martin and Synge pioneered the rapid
progress in this area made in the 1940's and early 1950's.
3. Synthesis from Chiral Pool O. Wallach, a colleague and

- Readily available, abundant or naturally collaborator of A. Kekule, received the
occurring starting materials. 1910 Nobel Prize in Chemistry for his
work on essential oils that converted
a. Carbohydrates the field of natural products from a
b. Amino acids disorganized collection of confusing
c. α-Hydroxy carboxylic acids observations into a complete,
d. Terpenes organized and integrated field. He
established the isoprene rule.
e. Readily available, abundant natural products
39
4. Asymmetric Synthesis
a. Optically active reagent (Stoichiometric)
b. Optically active auxiliary incorporated into substrate (Stoichiometric)
c. Optically active catalyst (Catalytic)
See: Koskinen Asymmetric Synthesis of Natural Products; Wiley: New York, 1993.
Gawley, Aube Principles of Asymmetric Synthesis; Elsevier: Amsterdam, 1996.
5. Microbial, Enzymatic, or Catalytic Antibody Transformation
See: Wong, Whitesides Enzymes in Synthetic Organic Chemistry; Pergamon: Oxford, 1994.
40
Oxidation Reactions
Dale L. Boger
IV. Oxidation Reactions
A. Epoxidation Reactions: Oxidation of Carbon–Carbon Double Bonds

Comprehensive Org. Syn.; Vol. 1, 819; Vol. 7, pp. 357 and 389 (asymmetric).
First report: Prilezhaev Ber. 1909, 42, 4811.
O H O O
O + C C +
R O R OH
1. Peracid Reactivity
CO2H
Rate increases: R = CH3 < C6H5 < m-ClC6H4 < H < p-NO2C6H4 < < CF3
pKa of acid (RCO2H): 4.8 4.2 3.9 3.8 3.4 2.9 0
The lower the pKa, the greater the reactivity (i.e., the better the leaving group).
2. Mechanism
R
R O R O
H O O
O H O O H
O +
O
Butterfly mechanism Refined representation:

(usual representation) trans antiperiplanar arrangement of O–O
Bartlett Rec. Chem. Prog. 1950, 11, 47. bond and reacting alkene, n-π* stabilization
by reacting lone pair in plane.
The synchronicity of epoxide C–O bond formation and an overall transition state structure
postulated using ab initio calculations and experimental kinetic isotope effects.
Singleton, Houk J. Am. Chem. Soc. 1997, 119, 3385.
3. Stereochemistry
a. Stereochemistry of olefin is maintained: diastereospecific.

b. Reaction rate is insensitive to solvent polarity implying concerted mechanism without
intermediacy of ionic intermediates.
c. Less hindered face of olefin is epoxidized.
R R R R R R
m-CPBA
O +
CH2Cl2
O
R=H 20 min, 25 °C 99% 1%

R = CH3 24 h, 25 °C < 10% 90%
Brown J. Am. Chem. Soc. 1970, 92, 6914.
41
4. Chemoselectivity
_ Electrophilic reagent: most nucleophilic C=C reacts fastest.
> >
RO R EWG
> > > ≥ >
- Examples
O
m-CPBA
cis : trans 1 : 1
–10 °C, 1 h
C6H5CO3H
O
CHCl3, 10 min Concave face
0 °C hindered toward
peracid attack
HO2C O HO2C O H
H H CO2H
C6H5CO3H
O OH O
H
C6H6–dioxane
H 25 °C, 24 h H
OH OH
Hückel Chem. Ber. 1955, 88, 346. H
80%
Woodward Tetrahedron 1958, 2, 1. Convex face
Tamm Helv. Chim. Acta 1975, 58, 1162. open to peracid
attack
5. Diastereoselectivity
a. Endocyclic Olefins Rickborn J. Org. Chem. 1965, 30, 2212.
Destabilizing steric interaction
between reagent and axial Me
H H H Me
Me Me Me
m-CPBA H
O + O
Me 25 °C, Et2O Me Me Me
H H H
87 : 13 H
Attack principally
from this face
42
Oxidation Reactions
Dale L. Boger
R
O O
Me
O
∆∆G H
H Me
O
H
O O
R
Me Me
∆∆G O
vs.
Me O Me
H H
Small difference for products: but larger difference

for reagent approach in transition state.
b. Exocyclic Olefins
more hindered face
Me Me Me O
RCO3H O
Me Me + Me
Me Me Me
less hindered face less stable product

_ Solvent dependent CCl4 75% 25%
C6H6 80% 20%
CH2Cl2 or CHCl3 83% 17%
Henbest J. Chem. Soc., Chem. Commun. 1967, 1085.
_ The effective size of the reagent increases with increasing solvent polarity, i.e., the solvation shell of
the reagent increases in size.
_ Small reagent preference: axial attack and 1,3-diaxial interactions vary with size of the
reagent.
H H H O
H RCO3H H O H
+
H H H
H H H H H H
41 : 59
_ Large reagent preference: equatorial attack and 1,2-interactions (torsional strain) are
relatively invariant with the size of the reagent.
Carlson J. Org. Chem. 1967, 32, 1363.
43
c. Allylic Alcohols (endocyclic)
Henbest J. Chem. Soc. 1957, 1958; Proc. Chem. Soc. 1963, 159.
O O
OR OR OR
m-CPBA
+
R = COCH3 20 °C C6H6 43% 57% 38% yield

R=H 5 °C C6H6 9% 91% 86% yield
_ Diastereoselectivity and rate (ca. 10×) of reaction accelerated by unprotected allylic alcohol.
OH O O
m-CPBA OH OH
+
tBu tBu tBu
Prefers equatorial position, 4% 96%

locking conformation of substrate
_ Original proposal for the origin of selectivity:
O H-bonding to proximal peroxide oxygen directs epoxidation to the

R
same face as OH group and accelerates/facilitates the reaction.
O H
H O
O R = H, tBu 120°
120° R HO
_
R
Equivalent to the ground state eclipsed conformation of acyclic allylic alcohols: H
_ Metal-catalyzed epoxidations of allylic alcohols exhibit a more powerful directing effect and rate
acceleration (ca. 1000×). Metal bound substrate (as an alkoxide) delivers olefin to metal bound peroxide
(tighter association than H-bonding).
OH O O
tBuOOH OH OH
+
VO(acac)2
tBu tBu tBu
83% 0% 100%
Sharpless Aldrichimica Acta 1979, 12, 63.
_
This may also be utilized to chemoselectively epoxidize an allylic alcohol vs. unactivated olefin.
44
Oxidation Reactions
Dale L. Boger
d. Allylic Alcohols (exocyclic)
Early transition state and the asynchronous bond formation
small places the reagent further from 1,3-interactions.
reagent
H O
H O
m-CPBA tBu tBu
tBu
R2 R2 + R2
R1 large R1 R1
reagent axial equatorial
R1 R2 H(R2)
H H 69 : 31 HO
H OH Equatorial 60 : 40
H OCH3 substitution 60 : 40
CH3 OCH3 88 : 12
H OAc 75 : 25
Axial substitution
axial OH directs
OH H blocks equatorial 11 : 89 epoxidation to
OH CH3 reagent delivery 13 : 87 the syn-face of
OCH3 H 83 : 17 the exocyclic
OCH3 CH3 83 : 17 double bond
Vedejs and Dent J. Am. Chem. Soc. 1989, 111, 6861.
e. Acyclic Allylic Alcohols
Generalizations: Eclipsed Conformations in m-CPBA Epoxidation

HO H
H R4 R1 R4
R2 R2
R3 R3
R1 HO
O OH
OH
R4 R2 R4
R2
R3 R3
R1 H R1 HO
Threo Product Erythro Product
OMet R1
R4 R4
R2 R2
R1 R3 H R3
H OMet
Bisected Conformations in Metal-Catalyzed Epoxidation
45
_Examples
R1
threo erythro
OH H vs. alkyl eclipsing
interaction with HO
double bond has little H H
R1 = Me m-CPBA 60 40 H
to no effect on H
VO(acac)2, tBuOOH 20 80
selectivity. H eclipsing R1
interaction slightly threo
= Et m-CPBA 61 39 more stable.
VO(acac)2, tBuOOH 20 80
R1
H,H eclipsing in
= iPr m-CPBA 58 42 H
erythro T.S. favored H H
VO(acac)2, tBuOOH 15 85 over H,alkyl eclipsing H
OMet
in threo T.S.
erythro
R2 R1
threo erythro H
Me H
OH Me
H
Erythro slightly favored HO
R1,R2 = Me m-CPBA 45 55
due to Me,Me gauche
VO(acac)2, tBuOOH 5 95 erythro
interaction in threo T.S.
R1 = Me m-CPBA 41 59 Me
R2 = nBu H,Bu eclipsing in
VO(acac)2, tBuOOH 2 98 H
erythro T.S. favored Bu H
over Me,Bu eclipsing H
OMet
in threo T.S.
erythro
R1
threo erythro
R4 OH
Similar to R4 = H. R4 does not sterically
R1,R4 = Me m-CPBA 64 36
29 71 influence either T.S. The R1 steric effect
VO(acac)2, tBuOOH
predominates.
R1
threo erythro
OH HO
H H
R3 m-CPBA 95 5 Large 1,3-allylic H
strain avoided. Me
R1,R3 = Me VO(acac)2, tBuOOH 71 29 Me
threo
Me
threo erythro
OMet
Me OH m-CPBA 95 5 Large 1,3-allylic Me
Me VO(acac)2, tBuOOH 86 14 strain avoided. H
Me Me
H
threo
46
Oxidation Reactions
Dale L. Boger
f. Refined Models for Directed Epoxidation of Acyclic Allylic Alcohols
R
_ Peracid Mediated Epoxidation Sharpless Tetrahedron Lett. 1979, 4733. O O
O
1. Trans antiperiplanar arrangement of O–O bond with alkene C=C. O O
2. H-bonding to distal oxygen of peroxide through the lone pair out of H H H H
O
the plane of reaction. Top View
3. Lone pair in plane of reaction provides π∗−lone pair (n-π∗) stabilization. 120°
4. Secondary isotope effect suggests that the formation of the C–O bonds is asynchronous.
_ Eclipsed Conformations in m-CPBA Epoxidation Sharpless Aldrichimica Acta 1979, 12, 63.
HO H
H R4 R1 R4
R2 R2
R3 R3
R1 HO
OH O O OH
R2 R4 R4 R2
R3 R3
R1 H R1 H
threo product erythro product
_ Transition-metal Catalyzed Epoxidation

R
1. Trans antiperiplanar arrangement
O O
Met
2. 50° dihedral angle O O Met
O
3. In-plane lone pair
4. Lone pair bisects C=C bond R Top View
_ Curtin-Hammett Principle:
- The reactive conformation is not necessarily related to the ground state conformation.
- The substrate is forced into a non-ground state conformation due to the geometrical constraints of the
reaction.
_ Bisected Conformations in Metal-Catalyzed Epoxidation
OMet R1
R4 R4
R2 R2 H
R1 R3 R3
H OMet
O
OH O OH
R4 R4 R2
R2
R3 R3
R1 H R1 H
Threo Product Erythro Product
47
Take Home Problem
Epoxidations of 3 of the 4 olefins below are diastereoselective; the fourth is not. Why?
O
Me Me
BnO BnO
Me Me
OH OH
H O
BnO H
BnO
Me Me
OH OH
O
BnO OH BnO OH
Me Me Me Me
O
BnO OH
BnO OH 60%
Me H
Me H
+
O
references: Kishi Tetrahedron Lett. 1980, 21, 4229. BnO OH 40%
Tetrahedron Lett. 1979, 20, 4343 and 4347. Me H
g. Homoallylic Alcohols
H
VO(OnPr)3
t
L
OH BuOOH OH
Ph O
Me CH2Cl2, 95% O V Me
Me L Ot
O Me Bu
Ph Ph
Me Me
OTBDPS H OTBDPS
OTBDPS
_
Alternative chair has two axial substituents.
_ Intramolecular oxygen delivery occurs through most stable chair-like
transition state.
VS.
m-CPBA major
OAc
OAc CH2Cl2, 25 °C Me O
94% Me
Me Ph
Ph OTBDPS
H Me
Me OTBDPS
OTBDPS Ph
OAc 5:1
minor
_ H-Eclipsed conformation
_
Epoxidation from least hindered face
_
Not a directed epoxidation!
_
Diastereoselectivity still good and through H-eclipsed conformation.
Schreiber Tetrahedron Lett. 1990, 31, 31.
Hanessian J. Am. Chem. Soc. 1990, 112, 5276.
Mihelich J. Am. Chem. Soc. 1981, 103, 7690.
48
Oxidation Reactions
Dale L. Boger
h. Other Directed Epoxidations
_ Studies suggest axial -NHCBZ delivers syn epoxide while equatorial does not.
R m-CPBA R R
O + O
CH2Cl2, 25 °C
NHCBZ NHCBZ NHCBZ
R = NHCBZ 86% 100 0

= CH2OH 83% 100 0
= CH2OAc 72% 100 0
= CO2Me 59% 100 0
= CH2NHCBZ 81% 100 0
= CH2OTBDMS 54% 0 100
Presence of H-bonding, directing substituent Witiak J. Med. Chem. 1989, 32, 214.
enhances rate and yield of reaction. Rotella Tetrahedron Lett. 1989, 30, 1913.
O O O
iPr iPr iPr
X m-CPBA X X
+
CH2Cl2, 25 °C
O O
n n n
n = 1, X = NH 80% 20 1
X=O 3 1
n = 2, X = NH 20 1
X=O 3 1
Mohamadi Tetrahedron Lett. 1989, 30, 1309.
OH O OH O OH O
+
O O
H2O2 / NaOH / MeOH / 0 °C 40 : 60

Ti(iPrO)4 / tBuOOH / CH2Cl2 / –15 °C >99 : 1
Ollis Tetrahedron Lett. 1991, 32, 2687.
49
6. Scope and Limitations
Peracid + O
a. Olefin geometry is maintained.
b. Reaction is diastereospecific: the stereochemistry of the reactant and product bear a definite
relationship to one another.
c. Reaction can be buffered to prevent epoxide opening. The pKa of parent acid is much lower than that
of the peracid, and the peracid is not nearly as acidic. Reaction requires the protonated peracid so the
buffer must not deprotonate the peracid but should deprotonate the product carboxylic acid.
H OH
H2O2 NaOH OH
O
O
HCOOH O H OH
H
Na2CO3 / NaHCO3 These reagents can be used as a buffer when the

CH3COOH / NaOAc peracids are used as epoxidation reagents.
CF3CO3H / Na2HPO4 – NaH2PO4
e.g. HCOOH pKa 3.6 CH3COOH pKa 4.8
HCO3H pKa 7.1 CH3CO3H pKa 8.2
_ So, choose bases (Na2CO3, NaHCO3, Na2HPO4) to deprotonate only the RCOOH formed.
d. Also, at higher temperatures, a free radical scavenger may be used to avoid peracid decomposition.
e. Common side reactions
1. Baeyer–Villiger reactions of ketones and aldehydes

O O
O O
e.g. m-CPBA not
O
_ When peracids are used to oxidize olefins to epoxides in the presence of carbonyl
functionality (ketones or aldehydes), protection of the carbonyl group may be necessary.
_ One may choose to select a reagent which attacks olefins preferentially.
2. Oxidation of amines m-CPBA +N
N O–
_ Nitrogen must be protected (e.g., as amide) or another reagent selected.
O
3. Imine oxidation N m-CPBA
N
R R
R R R R
4. Sulfur oxidation R R m-CPBA S + S
S O O
O
m-CPBA Typical Peracids
CO3H CO3H
CO3H CO3H
CO2H CF3CO3H
O2N O2N NO2
Cl
50
Oxidation Reactions
Dale L. Boger
7. Epoxidation of Electron-deficient Olefins
a. α,β-unsaturated esters: can choose a strong peracid or vigorous reaction conditions
Me CF3CO3H Me
Na2HPO4 84% Emmons J. Am. Chem.
CO2CH3 CH2Cl2, reflux O CO2CH3 Soc. 1955, 77, 89.
Ph m-CPBA Ph
CH2Cl2, reflux 47% MacPeek J. Am. Chem.
CO2CH3 O CO2CH3 Soc. 1959, 81, 680.
b. α,β-unsaturated ketones: Baeyer–Villiger competes with epoxidation
O
R R1
Epoxidation Baeyer–Villiger Reaction

Solution: different conditions (reagents) are needed
B. Additional Methods for Epoxidation of Olefins

1. H2O2, NaOH
O O– O
H2O2, NaOH H
O O 70%
O
_ The following reaction is diastereoselective (but not diastereospecific): a single stereoisomer of

the product is formed which bears no relationship to the reactant.
Me Me Me O Me Me CO2CH3
H2O2, NaOH H2O2, NaOH
CO2CH3 H CO2CH3 Me
The reaction occurs via a reversible process:
Me Me
Me Me Me CO2CH3
HO OCH3
CO2CH3 Me
H O O–
Similarly,
tBuOOH/Triton + –OH
B Payne J. Org. Chem. 1961, 26, 651. Triton B = Ph N
Ph3COOH/R4NOH Corey J. Am. Chem. Soc. 1988, 110, 649.
tBuOOH/nBuLi Jackson Tetrahedron 1988, 29, 4889.
2. Peroxyimidate
H2O2 NH O
RCN O O +
R O H R NH2
_ This reagent permits the use of neutral reaction conditions. Unlike m-CPBA,
the reagent behaves as a large reagent and thus approaches from the equatorial face
of an exocyclic double bond.
O
O
+
small reagent m-CPBA 59 41

large reagent PhCN / H2O2 14 86
51
1,3
m-CPBA
H small reagent, but the interaction will
H increase with the size of the reagent
Carlson J. Org. Chem. 1967, 32, 1363.
(m-CPBA & PhCN/H2O2)
Vedejs J. Am. Chem. Soc. 1989, 111, 6861. H

(m-CPBA) PhCN/H2O2
H
1,2 larger reagent, but the interaction will
not vary with size, predominately
equatorial attack
Ph N C O H
_ N O
Analogous reagent: + Ph O Christl Angew. Chem., Int. Ed. Eng.
H2O2 1980, 19, 458.
O H
Mechanism Problem
Provide mechanism for:

AcO
m-CPBA, CHCl3
H
AcO –5 °C then ∆, 160 °C O
H H
AcO
m-CPBA, CHCl3
AcO –5 °C then ∆, 160 °C O

H H
Johnson J. Org. Chem. 1961,
26, 4563.
H
O
OO +
O
O H O– H
Why does this reaction need to be heated to 160 °C?

Me half-chair conformation
Me
OAc
AcO
H
H
reagent attack from this face
Me + Me
OAc Me O O O
O
H
O O
H H O
H H
H+
52
Oxidation Reactions
Dale L. Boger
3. Sulfur Ylides
Me
tBu S CH2 O tBu tBu
Me +
O O
77%
87 : 13
Me nBuLi, Me dimethylsulfonium methylide
S+ Me I– <0 °C S CH2 small reagent that prefers axial delivery
Me Me
_ This is the result of kinetic control: reaction gives the thermodynamically less stable epoxide product.
S+ H
H tBu
tBu
O
O– Equatorial Delivery
1,2-interaction disfavored 13%
tBu
O
–O
tBu
O tBu
H
H
S+
Axial Delivery
1,3-interaction favored over 1,2 87%
Me O
S+ CH2–
tBu Me O tBu tBu
+
O 89% O thermodynamic
0 : 100 product
NaH, THF
Me O reflux Me O dimethyloxo sulfonium methylide
S+ CH3 S+ CH2– small reagent that prefers axial attack
Me I– Me
Corey, Chaykovsky J. Am. Chem. Soc. 1965, 87, 1353.
OH
S+ H
tBu
tBu
equatorial rapidly goes O

O–
attack on to product 100%
tBu
O
–O
tBu –O
tBu
H
O H OH
axial attack S+ fails to go on H
S+
predominant to product
backside attack not possible due

to destabilizing 1,3-interactions
For this reaction: Initial reaction is reversible and is not capable of generating the axial delivery
product because of the destabilizing 1,3-interactions in the transition state
required for epoxide closure.
53
Summary of Exocyclic Epoxide Formation
Note: defined conformation of 6-membered ring required for comparisons
or O
X O
X=O S axial X
attack
X = CH2 m-CPBA X
O
X=O X
S+ CH2–
equatorial
NH H attack
X = CH2 X
O
R O
R = large group
Sulfur ylides deliver "CH2" Learn reagents by:
Peroxides deliver "O" 1) Conditions required
2) Advantages and disadvantages
3) Competitive reactions
4) Stereochemistry limitations / highlights
4. Dimethyl Dioxirane (DMDO)

Murray J. Am. Chem. Soc. 1986, 108, 2470.
O Acc. Chem. Res. 1989, 22, 205.
A mild neutral reagent
O
DMDO Peracid reaction suffers from H+

O catalyzed epoxide opening
O O
O acetone, 96% O Adam Tetrahedron Lett. 1989, 30, 4223.
O
Curci Tetrahedron Lett. 1989, 30, 257.
O O CF3 Excellent for oxidation of
O
highly substituted enol ethers
O CH3
O Boyd Tetrahedron Lett. 1989, 30, 123.
O
Crandall J. Org. Chem. 1988, 53, 1338.
• Tetrahedron Lett. 1988, 29, 4791.
O
O O
BnO BnO
O
Danishefsky J. Am. Chem. Soc. 1989, 111, 6661.
BnO BnO Useful for glycosidation reactions.
OBn OBn
O
R3SiO R3SiO O
OSiR3
stable and characterizable

Danishefsky J. Org. Chem. 1989, 54, 4249.
pH dependence: rate at pH 11 > 7, acetone−oxone Shi J. Org. Chem. 1998, 63, 6425.
54
Oxidation Reactions
Dale L. Boger
5. Summary of Other Methods of Epoxide Formation
a. Cyclization of Halohydrins
HO O
+ X2 + H2O OH–
X
X
X
tBu tBu
axial equatorial
H2O H2O
NXS– CH2X OH O
H2O O
t t t t t
Bu Bu OH + Bu CH2X Bu + Bu
major minor
Increased NCS–H2O 90 : 10 90 : 10
reagent size NBS–H2O 82 : 18 vs
yields increased NIS–H2O 55 : 45
equatorial Analogous results observed with: 31 : 69
approach Br , ClCH CH Cl 70 : 30 For m-CPBA,
2 2 2
Br2, MeOH 90 : 10 complementary
stereochemistries
-The electrophilic reagents behave as small reagents and approach from the axial direction
Chiappe J. Org. Chem. 1995, 60, 6214.
-For acyclic systems: E+ LUMO electrophile

HOMO alkene
Houk Acc. Chem. Res. 1990, 23, 107.
L -Large or electropositive group

b. Cyclization of 1,2-diols
R TsCl R R
OH OTs
O
OH OH
_ primary alcohol > secondary alcohol for tosylation reaction
c. Epoxides from carbonyl compounds

Cl O R
d. O + Li R Köbrich Angew. Chem., Int. Ed. Eng. 1972, 11, 473.
R1 R1
O
e. O + S CH2
O O
O + S CH2–
Darzen's Condensation:
O First Example: Erlenmeyer Ann. 1892, 271, 161.
R R O Generalized by Darzen through years 1904–1937
f. O + Cl
X Compt. rend. 1904, 139, 1214.
H O O
Comprehensive Org. Syn., Vol. 2, p 409.
X Newman, Magerlein Org. React. 1968, 5, 413.
X = OR, R, N O Asymmetric variants:
Lantos J. Am. Chem. Soc. 1986, 108, 4595.
R Shioiri Tetrahedron 1999, 55, 6375.
55
C. Catalytic Asymmetric Epoxidation
1. Sharpless Catalytic Asymmetric Epoxidation (AE Reaction)
Key references: Asymmetric Synthesis: Vol. 5, Morrison, J.D. Ed., Academic Press, Chapters 7 and 8.
Reviews: Katsuki, Martin Org. React. 1996, 48, 1.
Comprehensive Org. Syn.; Vol. 7, pp 389–436.
Sharpless J. Am. Chem. Soc. 1980, 102, 5974; 1987, 109, 5765; 1981, 103, 6237;
1984, 106, 6430; 1991, 113, 106, 113; 1987, 109, 1279.
1. The enantiofacial selectivity of the reaction is general and dependable for assignments.
D-(–)-DIPT
R2 R2
R1 tBuOOH, Ti(OiPr)4 O R1
R3 R3
OH CH2Cl2, –20 °C, DET or DIPT OH
°
4 A molecular sieves anhydrous
L-(+)-DIPT
2. Selectivity is catalyst dependent

Ti(OiPr)4 95% ee Zr(OiPr)4 10% ee
Al(OtBu)3 5% ee Hf(OiPr)4 3% ee
MoO2(acac)2 15% ee Nb(OEt)3 5% ee
VO(OiPr)3 17% ee Ta(OiPr)5 39% ee
Sn(OiPr)4 NR
yield
3. Chemical Conversion
unsubstituted R1 = R2 = R3 = H 95% ee 15% (isolation problematic)
trans-disubstituted R1, R3 = H >95% ee 70–90%
cis-disubstituted R2, R3 = H 85–95% ee 70–90%
1,1-disubstituted R1 = R2 = H 85–95% ee 70–90%
trans-1,1,2-trisub. R1 = H >95% ee 70–90%
cis-1,1,2-trisub. R2 = H >90% ee 70–90%
1,2,2-trisubstituted R3 = H >95% ee 70–80%
4. Sharpless asymmetric epoxidation is one of the best known and practical asymmetric reactions
utilized in organic synthesis. Discovered in 1980, this catalytic process utilizes an optically active
ligand to direct a transition metal catalyzed reaction. Epoxidation from a single face of a
prostereogenic allylic alcohol:
H
H
E
HO OH RO O R = Et DET
RO E O Ti O R = iPr DIPT
RO2C CO2R O Ti O O R'
OE
2
O tBu
C symmetry
RO E = CO2R
(Useful in ligand design- predictable and repetitive structural units
which reduce number of diastereomeric transition states)
a. Match of Ti / Tartrate such that a single complex dominates the chemistry.
The concentration of each complex in the mixture of complexes is dictated by thermodynamic

considerations. However, it could not be predicted that a single species would dominate the
Ti–tartrate equilibrium mixture and that this species would be so kinetically active. The tartrate–Ti
complex is perfectly matched and slight deviations in the ligand structure or change in the metal
alkoxide reduces the effectiveness of the reaction.
56
Oxidation Reactions
Dale L. Boger
b. Ligand acceleration of reaction.
This is not essential but extremely beneficial. It ensures that the enantioselective version of
the reaction (the one in which the auxiliary ligand is present) will be the most viable kinetic pathway.
c. Steric and stereoelectronic features of reaction control enantioselectivity.
Stereoelectronic:
1. Alkyl peroxide is activated by bidentate coordination to the Ti(IV) center.
2. The olefin is constrained to attack the coordinated peroxide along the O–O bond axis.
(stereoelectronic effect)
3. The epoxide C–O bonds are formed simultaneously.
Steric factors:
1. Bulky hydroperoxide is forced to adopt a single orientation when bound in a bidentate fashion.
2. The allylic alkoxide is thereby restricted to reaction at a single coordination site on the metal center.
Steric interactions of the bound substrate with the catalyst framework provide for the kinetic
resolution patterns.
3. Efficient catalytic turnover provided by the labile coordinated ester, permitting rapid
alkoxide–alcohol exchange.
Scope R2 R1
Epoxidation with Titanium–Tartrate Catalysts
OH yield
R3
unsubstituted (R1 = R2 = R3 = H) 95% ee 15%
trans-disubstituted (R1 = R3 = H) R2 = CH3 >95% ee 45%
R2 = nC10H21 >95% ee 79%
R2 = (CH2)3CH=CH2 >95% ee 80%
R2 = Me3Si >95% ee 60%
R2 = tBu >95% ee
R2 = Ar ≥95% ee 0–90%
R2 = CH2OBn 98% ee 85%
R2 = >95% ee 78–85%
O
O
R2 = >95% ee 70%
BnO O
O
O
R2 = >99% ee 76%
BnO
O
R2 = >99% ee 70%
BnO
R2 = >93% ee 70–88%
Ph O OSiEt3
O
BnO
R R = OBn, OH
cis-disubstituted (R2 = R3 = H) R1 = nC H
10 21 90% ee 82%
R1 = CH2Ph 91% ee 83%
R1 = CH2OBn 92% ee 84%
R1 = O 96% ee 55%
O
57
1,1-disubstituted (R1 = R2 = H) R3 = -cyclohexyl >95% ee 81%
R3 = nC14H29 >95% ee 51%
R3 = tBu 85% ee
trans-1,1,2-trisubstitued (R1 = H) R3 = R2 = Ph >95% ee 87%

R3 = Me, R2 = Et >95% ee 79%
R3 = Me, R2 = >95% ee 70%
AcO
R3 = Me, R2 = >95% ee 92%
O
O
cis-1,1,2-trisubstituted (R2 = H) R3 = CH3, R1= Bn 91% ee 90%
1,2,2-trisubstituted (R3 = H) R2 = (CH2)2CH=C(CH3)2, R1 = CH3 >95% ee 77%

R2 = CH3, R1 = (CH2)2CH=C(CH3)2 94% ee 79%
tetrasubstituted R3 = CH3, R2 = Ph, R1 = Bn 94% ee 90%
94% ee 90%
OH
Allylic Alcohols Undergoing Kinetic Resolution R4 R5

with Relative Rates >15 at –20 °C
OH
R3 2
R R1
R1 = nC6H13 R1 = nC4H9, R3 = CH3
R1 = (CH2)2Ph R1 = cyclohexyl, R3 = CH3 OH
R1 = O R1 = nC4H9, R4 = Et or CH3
R1 = cyclohexyl, R4 = CH3 HO
O
R1 = cyclohexyl R1 = Et, R4 = Ph
R1 = R1 = CH2CH(CH3)2, R4 = CH3
R1 = R5 = CH3
R1 = Et, R4 = nC6H13 OH
Poor Substrates for Asymmetric Epoxidation or

Kinetic Resolution Catalyzed by Titanium−Tartrates
O BnO O
t
Ph Bu O
O
OH OH tBu OH OH
OH OH
OBn CH3O
O O O H3CO2C
O
OH
OH OH
OH OH
OH OH OH OH OH
tBu tBu
OH Ph
OH
58
Oxidation Reactions
Dale L. Boger
5. Kinetic Resolution
Sharpless J. Am. Chem. Soc. 1981, 103, 6237.
Pure Appl. Chem. 1983, 55, 589.
_ Sharpless epoxidation product is different from the directed oxidation

of allylic alcohols by peracids (m-CPBA).
Sharpless
HO O Epoxidation HO HO O
m-CPBA
R H R H R H
L-(+)-DIPT (1.2 equiv)

1.0 equiv Ti(OiPr)4,
OH O
0.6 equiv tBuOOH, O
OH OH OH
CH2Cl2, –20 °C, 15 h +
H H H
racemic 2
98 (R)-enantiomer recovered
relative rates = kS / kR = 104

(S)-enantiomer reacts
1.0 equiv Ti(OiPr)4 0.8 equiv Ti(OiPr)4

1.5 equiv D-(–)-DIPT 0.8 equiv L-(+)-DET
0.4 equiv tBuOOH 0.8 equiv tBuOOH
O CH2Cl2, –20 °C O
CH2Cl2, –20 °C +
OH OH OH OH
27% yield 33% yield 75% yield
>95% ee 72% ee 95% ee
Roush J. Org. Chem. 1982, 47, 1371.
HO O Me HO O Me
OH OH
OH OH
Sato Tetrahedron Lett. 1987, 28, 6351.
I Sharpless epoxidation
Kinetic resolution
OH
59
6. Total Synthesis of the L-Hexoses
Sharpless, Masamune Science 1983, 220, 949.
Tetrahedron 1990, 46, 245.
"Reagent-control" Strategy: selection of reagent dictates ultimate absolute stereochemistry of reaction
products irrespective of stereofacial bias of substrate.
"Substrate-control" Strategy: stereochemistry of reaction products dictated by the inherent stereofacial
bias of the substrate.
Masamune Angew. Chem., Int. Ed. Eng. 1985, 97, 1.
Sharpless Chemica Scripta 1985, 25, 71.
O O O
O O + O
OH OH OH
O O
threo erythro
Reagent Product Ratio (threo:erythro)
m-CPBA 1 : 1.4 achiral reagents
VO(acac)2–TBHP 1 : 1.8 "substrate control"
i 1 : 2.3
Ti(O Pr)4–TBHP
i
Ti(O Pr)4–(–)-tartrate–TBHP 1 : 90 "matched pair"
i
Ti(O Pr)4–(+)-tartrate–TBHP 22 : 1 "mismatched pair"
"reagent control"
-Reiterative two-carbon extension cycle employed for the synthesis of all L-hexoses:
OR'OR'
R-CH-CH-CH=CH-CH2-OH
Homologation AE
R-CH=CH-CH2-OH AE
OR'OR' Homologation And so on...

O
R-CH-CH-CHO R-CHO R-CH-CH-CH2-OH
* *
OR'OR'
Pummerer Payne
Reaction R-CH-CH-CH2-SPh Rearrangement
Ti(OiPr)4, (+)-DIPT, AcO

OH PhSH, 0.5 N NaOH, SPh m-CPBA; SPh
tBuOOH, CH Cl tBuOH, reflux (4:1);
OH
2 2
O Ac2O, NaOAc O
RO 4A° mol. sieves O (MeO)2CMe2, O O
93%
–20 °C, 92% OR cat. POCl3, 71% OR OR
R = CHPh2 >95% ee
(>20:1) Diverging
Intermediate
CHO
erythro
DIBAL-H O corresponds to C4 and C5 of allose,
AcO 84% O altrose, mannose, and glucose
SPh (>20:1)
OR
O
O CHO
OR O threo
K2CO3,
corresponds to C4 and C5 of gulose,
MeOH, 93% O
idose, talose, and galactose
(>20:1) OR
60
Oxidation Reactions
Dale L. Boger
CHO CHO
O O
O O
OR OR
erythro threo
Ph3P=CHCHO Ph3P=CHCHO
benzene; benzene;
NaBH4 NaBH4
MeOH MeOH
OH OH
O O
O O
OR OR
(+)-AE (–)-AE (+)-AE (–)-AE

76% 84% 71% 73%
(>20:1) (>20:1) (>20:1) (>20:1)
OH OH OH OH
O O O O
O O O O
O O O O
t
OR t
OR t
OR t OR
BuOH, PhSH BuOH, PhSH BuOH, PhSH BuOH, PhSH
NaOH NaOH NaOH NaOH
reflux (16:1) reflux (7:3) reflux (7:1) reflux (15:1)
77% 63% 79% 86%
SPh SPh SPh SPh
O O O O
O O O O
O O O O
O O O O
OR OR OR OR
a b c d e f g h
CHO CHO CHO CHO CHO CHO CHO CHO

HO OH OH HO HO OH OH HO
HO HO OH OH HO HO OH OH
HO HO HO HO OH OH OH OH
HO HO HO HO HO HO HO HO
OH OH OH OH OH OH OH OH
L-Allose L-Altrose L-Mannose L-Glucose L-Gulose L-Idose L-Talose L-Galactose
For a, c, e, and g: 1. Pummerer reaction, 2. DIBAL-H, 3. Deprotection.

For b, d, f, and h: 1. Pummerer reaction, 2. K2CO3/MeOH, 3. Deprotection.
61
-Payne Rearrangement
Payne J. Org. Chem. 1962, 27, 3819.
Base-catalyzed (aq. NaOH) migration of α,β-epoxy alcohols:
O CH3 0.5 N NaOH CH3 O OH
CH3 H H
1h HO CH3 CH3 CH2OH CH3
OH O O
8% 92% 58% 42%, threo
O OH OH CH3
CH3 H O
H CH3
H CH2OH CH3 OH CH3
O CH3 H O
93% 7%, erythro 44% 56%, erythro
O OH CH3
H H
CH3 CH3
CH3 CH3
CH3
OH O
5% 95%, threo
1. In general, the more substituted epoxide is favored as the reaction product.
2. However, steric factors and relative alcohol acidities (1° > 2° > 3°) are additional factors which
determine the ultimate composition of the equilibrium mixture.
3. The more reactive epoxide can be trapped by strong nucleophiles (e.g., PhSH).
O OH OH
ROCH2 H PhSH
H CH2OH ROCH2 ROCH2 SPh
O
OH
Emil Fischer attended the lectures of A. Kekule, worked with A. Baeyer as a student and
received the 1902 Nobel Prize in Chemistry for his work on carbohydrate and purine syntheses.
Discoverer of the Fischer indole synthesis using arylhydrazones, he utilized phenylhydrazine to
derivatize carbohydrates as crystalline solids for characterization that enabled him to elucidate
their chemistry and structure. From the work of Le Bel and van't Hoff he knew glucose must
have 16 stereoisomers and in the now classic studies synthesized most of them and established
the correct configuration of glucose. He introduced the use of Fischer projection formulas. He
proposed structures for uric acid, caffeine, theobromide, xanthine, and guanine and later
synthesized theophylline and caffeine (1895), uric acid (1897), and coined the term purine. By
1900 he prepared more than 130 derivatives including hypoxanthine, xanthine, theobromide,
adenine, and guanine. In 1914, he made glucose derivatives and from them the nucleosides.
He is responsible for the "lock and key" analogy for describing enzyme–substrate interactions,
prepared the D- and L-amino acids with fractional crystallization resolution and made a peptide
of 18 amino acids. Having suffered from the effects phenylhydrazine, he is also among the first to
implement safety precautions (ventilation) and designed the first exhaust system put into general
use.
"...the intimate contact between the molecules...is possible only with similar geometrical
configurations. To use a picture, I would say that the enzyme and the substrate must fit together
like a lock and key." Emil Fischer, 1895
W. Haworth received the 1937 Nobel Prize in Chemistry for his investigations on the structure
determination of carbohydrates (cyclic monosaccharides, disaccharides, and polysaccharides)
including their derivitization as methyl ethers and vitamin C. The latter was accepted with wide
acclaim and Haworth was also one of the first to prepare vitamin C, the first vitamin to be prepared
by synthesis. This made vitamin C available to the world population for the treatment of scurvy,
eliminating the need for treatment with fresh limes or lemons.
Albert Szent-Gyorgyi von Nagyrapolt received the 1937 Nobel Prize in Medicine. He was
responsible for the isolation of vitamin C for the first time, but was recognized for his investigations
into biological mechanisms of oxidation.
62
Oxidation Reactions
Dale L. Boger
Vitamins represent one of the great success stories of organic synthesis. They are necessary require-
ments of both animals and humans, but cannot be made by these species. The needs are met by
dietary sources or through symbiotic relationships with microorganisms (intestinal bacteria). There are
now 13 vitamins. All, except vitamin B12 which is produced by fermentation, are made commercially
by chemical means.
vitamin C (60,000 metric tons/yr)* - humans
vitamin E (22,500 metric tons/yr)* - 75% for animal nutrition
niacin (21,600 metric tons/yr)* - 75% for animal nutrition
vitamin B12 (14 metric tons/yr)* - 55% animal/45% human * for 1994
OH OH
OH N N OH
Vitamin A Vitamin B1 Vitamin B2
H2N OH
N N O
N S
HSO4− NH
N
OH
OH O
O
HO
NH2 OH
N Vitamin B3 N Vitamin B6
H2NOC
CONH2
HO CN
HO H N N CONH2
O O H2NOC Co
N N
HO OH H
H2NOC
Vitamin C Vitamin D3
O CONH2
N
HO NH
N
HO
HO O
−O P
O Vitamin B12
O O
O
Vitamin E OH
O O
HN NH
Vitamin K1 Biotin
O OH
S
CO2H O
O OH
H
HN N OH
N HO
HN N CO2H
H O O O
H2N N N
Folic acid Pantothenic acid
63
Paul Karrer received the 1937 Nobel Prize in Chemistry for his research on carotenoids, flavins, and vitamin A
and B2. He published over 1000 papers in his career and his textbook on organic chemistry was a classic in the
field (13 editions). He along with Hans von Euler-Chelpin (Nobel, 1929) discovered that carotene and vitamin A
had the same activity and that the addition of two molecules of H2O to carotene produces two molecules of
vitamin A, elucidating its structure before it had been isolated. It was in Karrer's lab that George Wald (Nobel
Prize in Physiology or Medicine, 1967) showed that vitamin A plays an important role in the chemistry of vision.
The total synthesis of the carotenoids was accomplished by Karrer in 1950. In 1931, he synthesized squalene,
he confirmed the structure of vitamin C, and he completed the total synthesis of riboflavin and vitamin B2 (in
1934), and he completed the first total synthesis of vitamin E (tocopherols) in 1938. He also isolated vitamin K,
at the same time as Henrik Dam (Nobel Prize in Physiology or Medicine, 1943) and Edward Doisy (Nobel Prize in
Physiology or Medicine, 1943). He and Warburg (Nobel Prize in Physiology or Medicine, 1931) unraveled the
role of NADPH and he prepared other coenzymes including thiamine pyrophosphate and pyridoxal-5-phosphate.
Richard Kuhn received the 1938 Nobel Prize in Chemistry for his work on carotenoids and vitamins. He also put
forth the concept of and coined the term atropisomerism. He isolated ca. 1 g of riboflavin, vitamin B2, from 5300
L of skim milk and carried out structural studies that led to its structure identification and a synthesis that
confirmed it. Kuhn proved the structure of riboflavin-5-phosphate which clarified its double role as an enzyme
cofactor (coenzyme) and a vitamin. Similar efforts led to the isolation, structure determination, and synthesis of
vitamin B6, pyridoxol.
Sulfonamides G. Domagk received the 1939 Nobel Prize in Medicine for discovering in 1932
that prontosil protected mice from fatal infections of Streptococci. By the end of
SO2NH2 1936, sulfa drugs were well on their way to becoming the first antibiotics in wide
clinical usage. They are structural analogs of p-aminobenzoic acid and inhibit
H2N the bacterial formation of folic acid (antimetabolite), which we receive from our
diet, selectively preventing bacteria from replicating without exhibiting mammalian
Prontosil-1938 toxicity.
2. Jacobsen Epoxidation
-Unactivated alkenes
Jacobsen J. Am. Chem. Soc. 1991, 113, 7063. Me Ph
d
H H
disfavored by bulky
phenyl groups
Ph Ph
Ph R1 R1
H N N
a N N
Mn b Mn
H Me O O Me disfavored by R2 O O R2
Cl Cl
Me phenyl group
t t
Bu Bu t
Bu t
Bu
side-on 1 R1
R2
perpendicular c
approach to 2 Me Me
disfavored by tBu groups
metal oxo species 3 H Me
4 t
Me Bu
5 t
H Bu
Styrene still low: 70% ee
5 mol% cat. Ph Me
Ph Me + NaOCl
CH2Cl2 H H
O
R,R-1 88% 84% ee 1R,2S
S,S-2 54% 49% ee 1S,2R
S,S-3 87% 80% ee 1S,2R
S,S-4 56% 55% ee 1S,2R
S,S-5 81% 92% ee 1S,2R
64
Oxidation Reactions
Dale L. Boger
catalyst 5
Ph Me 84% 92% ee cat. 0.04 equiv
p-ClC6H4 Me 67% 92% ee 0.04 equiv
O
72% 98% ee 0.02 equiv
O
96% 97% ee 0.03 equiv
NC
O
63% 94% ee 0.15 equiv
O
Ph CO2Me 65% 89% ee 0.10 equiv
The above studies focused on steric effects of the catalyst.
_ Electronic effects of the catalyst
Jacobsen J. Am. Chem. Soc. 1991, 113, 6703.

R R Hammett Plot
N N 2
Mn O
X O O X log
Cl
enant.
tBu tBu ratio 1
1 R = Ph
2 = (CH2)4
1a X = OMe 96% ee
1b = Me -0.4 -0.2 0 0.2 0.4 0.6 0.8
1c =H σ (para substituent)
1d = Cl - conformational effects on catalyst?
1. ∆∆G 2.0 kcal/mol - provoke changes in Mn–oxo bond length?
1e = NO2 22% ee
2. 1e / 1a krel = 4 reactivity vs transition state structure:
- the less reactive catalyst providing a
tighter, more product-like T.S.
-Example
0.05 equiv cat. OH
5 equiv NMO O
2 equiv m-CPBA
Bu3P NBOC
NBOC –78 °C, 30 min NBOC Dibal-H NBOC
ADDP
70%, 92% ee 86% 72%
OBn OBn OR O
H H H2, Pd-C R = Bn
N N 97% R=H
Mn
tBu O O tBu Boger, Boyce Synlett 1997, 515.
Cl
tBu tBu
65
3. Chiral Dioxiranes
_Examples of trans and trisubstituted olefins
1 Ph H
Ph
O O Ph (pH 10, K2CO3)
O oxone, O H O Ph
H O CH3CN H O 73% yield
>95% ee
O O O O O O C3H7 H
O C3H7 OTBS
80% yield H O OTBS
catalytic 93% ee
1 Ph Ph
amounts O
Shi J. Am. Chem. Soc. 1996, 118, 9806.
J. Am. Chem. Soc. 1997, 119, 11224. 69% yield
J. Org. Chem. 1997, 62, 2328; 1998, 63, 8475. 91% ee
J. Org. Chem. 1998, 63, 2948. - pH 10 (K2CO3) suppresses
(conjugated dienes) Baeyer–Villiger reaction of
ketone precursor.
Reagent generation with H2O2−CH3CN via in situ generation of CH3C(=NH)O2H
Shi Tetrahedron Lett. 1999, 40, 8721.
Terminal, disubstituted alkenes via vinylsilanes
Me Me Bu4NF Me
1
TMS TMS
Ph 74% Ph 82% Ph
O O
94% ee 94% ee
Shi J. Org. Chem. 1999, 64, 7675.
Kinetic resolution
OTMS OTMS OTMS
Ph 1 Ph Ph Shi J. Am. Chem. Soc.
+ 1999, 121, 7718.
49% conv. O
96% ee 95% ee
kf/ks > 100 > 20:1 trans:cis
Enol ethers and esters
O O OAc O
K2CO3−MeOH 195 °C K2CO3−MeOH
Ph Ph 92% Ph 90% Ph
OH OAc O OH
88% ee 90% ee 91% ee, 66% 94% ee
Shi Tetrahedron Lett. 1998, 39, 7819.
O PhOCO O
O
OCOPh YbCl3 TsOH OCOPh
CH2Cl2 CH3NO2
84% 77%
96% ee 97% ee 97% ee
Shi J. Am. Chem. Soc. 1999, 121, 4080.
O R R
O
Note the stereoelectronic O
alignment of lone pair R O R
with spiro T.S.
Spiro vs Planar Transition

consistent with State
66
Oxidation Reactions
Dale L. Boger
Yang J. Am. Chem. Soc. 1996, 118, 11311; 1998, 120, 5943.
O
10 mol% 1,
5 equiv oxone,
X O O X NaHCO3
Ph CH3CN–H2O, 25 °C Ph
Ph Ph O
90–95% yield
32–76% ee
1 X=H 47% ee 5 X = Me 56% ee OXONE = 2KHSO5•KHSO4•K2SO4
2 X = Cl 76% ee 6 X = CH2OCH3 66% ee

O
3 X = Br 75% ee 7 X= 71% ee
O
4 X=I 32% ee 8 X = SiMe3 44% ee
4. Polymer Supported Poly Amino Acids Review: Roberts Bioorg. Med. Chem. 1999, 7, 2145.
(CHCH2)n
Ph H2O2, NaOH Ph H
polyleucine: Ph Ph
H
92% yield, 99% ee toluene, catalyst O
O O O
H
N Ar
N General for Ar : 83–98%; 87–99% ee
H n
Itsuno J. Org. Chem. 1990, 55, 6047. O
Vega Angew. Chem., Int. Ed. Eng. 1980, 19, 929.
D. Stoichiometric Asymmetric Epoxidation

_
1. Chiral Peracids CO2H To date, ee's are modest (<10%)
_
Not catalytic, but stoichiometric reagent
CO3H
Ewins J. Chem. Soc., Chem. Commun. 1967, 1085.
Montanari J. Chem. Soc., Chem. Commun. 1969, 135.
Rebek J. Am. Chem. Soc. 1980, 102, 5602.
Curci J. Chem. Soc., Chem. Commun. 1984, 155.
2. Chiral N-sulfamyloxaziridines
Bn
C6F5
N N
Ph S H O _
O O Good ee's
2 _ Stoichiometric reagent
65% ee
Davis J. Am. Chem. Soc. 1983, 105, 3123.
Tetrahedron Lett. 1986, 27, 5079.
E. Baeyer–Villiger and Related Reactions

Comprehensive Org. Syn. Vol. 7, pp 671–688. A. Baeyer received the 1905 Nobel Prize in Chemistry for
Org. React. 1957, 9, 73; 1993, 43, 251. his work on dyes (indigo). He also discovered barbituric
acid and named it after his girlfriend Barbara.
1. Baeyer–Villiger Reaction
O
O Baeyer, Villiger
R R2 O H O NaOH O
+ 1
R OH Ber. 1899, 32, 3625.
O R1 H Ber. 1900, 33, 858.
R1 R O R O
67
Note: Sometimes the Baeyer–Villiger reaction is used not only for preparing carboxylic acids or esters, but
also for ROH.
_ Mechanism: (Peracid nucleophilic addition reaction)
R O–
R O O
Peracids
O O O R1 +
R1 R2 R2 O–
R1 R O
_ Notes: O
1. Alkyl group that migrates does so with retention of configuration.
2. The more electron-rich (most-substituted) alkyl group migrates in preference (in general).
talkyl > salkyl > benzyl > phenyl > nalkyl > methyl
Thus, methyl ketones invariably provide acetates.
_ O C6H5CO3H, O
Examples:
CHCl3, 25 °C
Friess J. Am. Chem. Soc. O 71%
1949, 71, 2571.
O
CHO O H
Ogata J. Org. Chem. C6H5CO3H
OH +
1969, 34, 3985. MeOH–H2O, 5 °C O
X X
X
X=H 90% 0%
X = OCH3 19% 73%
CH3CO3H
Meinwald J. Am. Chem.
Soc. 1960, 82, 5235. 2 h, 25 °C, 88% O _ Nucleophilic attack from
O
least hindered exo face.
O
_ Most substituted
Migrating C–C bond O (electron-rich) carbon
and O–O bond must O migrates.
O
be trans antiperiplanar O–
R O
trans antiperiplanar
_
O
Antiperiplanar arrangement of C–Rm bond and the breaking O
O–O bond (stereoelectronic requirement). H
_
O
Hydroxyl lone pair or O–H bond antiperiplanar to the migrating Rm R
C–Rm bond.
Me
Me CH3CO3H
Me
Sauers J. Am. Chem. Soc. NaOAc, HOAc _ In contrast to simple
1961, 83, 2759. 5 d, 25 °C, 94%
O expectations, the less
O O electron-rich bond migrates
Me due to stereoelectronic
Me
Me considerations.
O _
Nucleophilic attack from
H endo face, exo face blocked
O
by Me's.
O
_
Reaction much slower
O R than norbornone.
trans antiperiplanar
bonds
68
Oxidation Reactions
Dale L. Boger
– Bis(trimethylsilyl) Peroxide Me3Si–OO–SiMe3
H O Me3SiOOSiMe3 H
O Noyori J. Org. Chem. 1982, 47, 902.
cat., CH2Cl2 O Nozaki Bull. Chem. Soc. Jpn. 1983,
75–80% 56, 2029.
H H
cat. = Me3SiSO3CF3, SnCl4, BF3•Et2O

The Baeyer–Villiger oxidation proceeds in a regio- and chemoselective
manner and competing epoxidation does not occur.
2. Benzylic Hydroperoxide Rearrangement

– Alternative to Baeyer–Villiger Reaction
Would be oxidized by peracid
BF3•OEt2, H2O2
N N+ BF
H 3 N
R H H
OH OH
R O H
O+ Boger, Coleman
R = H, CH3 J. Org. Chem. 1986, 51, 5436.
+ RLi BF3
O J. Am. Chem. Soc. 1987, 109, 2717.
or NaBH4 Tetrahedron Lett. 1987, 28, 1027.
CH3O2C
CH3O2C
HN NH BF3•OEt2, H2O2
HN N
CH3 81% R
CH3O
CH3 CH3O OH
HO
R=H
R = CONH2 (PDE-I)
R = COCH3 (PDE-II)
OBn OH OBn
OH
TsOH, H2O2 Boger, Yohannes
J. Org. Chem. 1987, 52, 5283.
CO2CH3 60%
CO2CH3
NHCBZ NHCBZ
3. Carboxy Inversion Reaction

Me H O
Me H Me H With + Me H O O
m-CPBA Ph O
Cl O O Ar
Ph Ph Retention –O Ar Ph O O Ar
O O O +
O
69
4. Urea–H2O2: a safe alternative to H2O2 Heaney Synlett 1990, 533.
O– O
N+
O
N+ O
O– Ph
N O
S N
O O Ph
S
O
6
O 6
OH
OH
O O H2N NH2 HO-OH
O
OH O
O O
O O
O
OMe O
O
O
OMe
– Alternative to 90% H2O2 as a source of anhydrous H2O2.
– White, crystalline powder.
– Commercially available.
– Dry over CaCl2 in a desiccator.
Friedrich Wohlers' (1800–1882) synthesis of urea, an organic substance, from inorganic materials in
1828 dispelled the belief that biotic powers were needed to produce organic substances and is
considered the birth of synthetic organic chemistry. This was first described in a letter to J. J.
Berzelius. In a joint paper, the two wrote: "sugar, salicin (the natural product precursor to aspirin),
and morphium will be produced artificially. Of course, we do not know the way yet by which the end
result may be reached since the prerequisite links are unknown to us from which these materials will
develop-however, we will get to know them."
F. Beckmann Rearrangement and Related Reactions

_ An analogous rearrangement reaction can be utilized to prepare lactams and amides.
1. Beckmann Rearrangement Heldt Org. React. 1960, 11, 1.
Gawley Org. React. 1988, 35, 1.
Comprehensive Org. Syn., Vol. 7, pp 689–702.
O H H
O Ph O H
N S N N O
12 h, 0 °C
O
H2O 95%
_ Prepared from the oxime. Beckmann Ber. 1886, 19, 988.
_ A wide range of leaving groups and catalysts have been utilized.
1. Group anti to oxime leaving group migrates.

2. The alkyl group migrates with retention of configuration.
H2NOSO3H
+ NH
HCO2H N O
O 97% H O
95% 5%
70
Oxidation Reactions
Dale L. Boger
Note: Isomerization of oxime or its activated derivative may occur under the reaction conditions and
fragmentation to a nitrile may compete when the migrating center is 3°.
+
OH O NH
N NH
retention O
POCl3, pyridine 98% 2%

SOCl2, pyridine 90% 10%
20% aq. H2SO4 43% 57%
HCl / Et2O 5% 95%
2. Curtius Rearrangement Smith Org. React. 1946, 3, 337.
Curtius Ber. 1890, 23, 3023. (initially not recognized)
O H2O or H
RCO2H R N C O RNH2 or R N
R
O
R N3 ROH
O
_ (PhO) P(O)N (DPPA) is a useful reagent for the direct conversion of carboxylic acids to acyl azides
2 3
under in situ conditions for the rearrangement. Shiori, Yamada Tetrahedron 1974, 30, 2151.
_ R group migrates with retention of configuration.
-Examples
NO2 NO2
MeO MeO
N CO2Me N CO2Me
N N Boger, Panek
DPPA, Et3N (streptonigrin)
HO2C Me H2N Me J. Am. Chem. Soc.
BnO BnO 1985, 107, 5745.
MeO MeO
OMe OMe
MeO2C N CO2Me MeO2C N CO2Me

DPPA, Et3N Boger
HO2C Me H2N Me (lavendamycin)
C6H6, reflux J. Org. Chem.
Br Br
72% 1985, 50, 5782.
N OMe N OMe
Br N Br N
DPPA, Et3N Boger
BnO BnO
HO2C Me H2N Me (streptonigrone)
MOMO C6H6, reflux MOMO J. Am. Chem. Soc.
86% 1993, 115, 10733.
MeO MeO
OMe OMe
71
n R
X CO2H X NHBOC X N
DPPA, Et3N
O
t
BuOH
OBn OBn O
X = H, Br, CN, OMe n = 1–3
Boger J. Org. Chem. 1995, 60, 1271;
1996, 61, 1710 and 4894;
1997, 62, 5849.
J. Am. Chem. Soc. 1994, 116, 11335.
Synlett 1997, 515.
3. Hofmann Rearrangement Lane Org. React. 1946, 3, 267.

O O O
Br
R NH2 R N R N Br O C N R
H
Hofmann Ber. 1881, 14, 2725.
N CONH2 NaOBr, CH3OH Boger, Coleman

N N NHCO2Me
–40 °C; then 60 °C N (PDE-I, PDE-II, CC-1065)
OTBS OTBS J. Org. Chem. 1986, 51, 3250.
>80% J. Am. Chem. Soc. 1987, 109, 2717.
MeO MeO
_ Reagents employed include basic hypohalides, Pb(OAc) , PhI(OCOCF ) , PhIO.
4 3 2
_
R group migrates with retention of configuration.
4. Schmidt Reaction Schmidt Angew. Chem. 1923, 36, 511.

Wolff Org. React. 1946, 3, 307.
The Schmidt Reaction is a general name for what are three individual reactions:
A. Conversion of Ketones to Amides
H2O
O OH O
HN3 and N R –H+
R N –H2O R
R N N N N
R R Protic or R tautomerization R N
Lewis Acid H H
R = alkyl, aryl catalyst
- Most studied of Schmidt variants, similar to Beckmann Rearrangement.
- Asymmetric variant (Aube) utilizes chiral alkyl azide donors which provide products in high
- Bicyclic ketones slightly favor migration of less substituted group, opposite of Beckmann.
- Reactivity: dialkyl ketone > alkyl,aryl ketone > diaryl ketone > carboxylic acid or alcohol.
NaN3, 2.5 equiv O

O
MeSO3H, 9 equiv
Bn CHCl3, reflux, 83% NH
Bn Georg Bioorg. Med. Chem. Lett. 1991, 1, 125.
CO2Et
>95% ee CO2Et
retention of configuration
72
Oxidation Reactions
Dale L. Boger
1) BF3•OEt2;
2) NaHCO3, 90%; O
O
3) PCC
OH N3 4) NaH, THF, 57% NH
+
t t
Bu N Bu
N Aube J. Am. Chem. Soc. 1995, 117, 8047.
O
N
one diastereomer
t
Bu
B. Conversion of Carboxylic Acids to Amines

O
H+ cat. H2O
+ HN3 R N C O R–NH2
R OH
- Acid catalyst usually H2SO4, PPA, TFA–TFAA, or sometimes Lewis acid.
- Good results when R = alkyl, hindered alkyl or aryl.
- Advantage in process length over Hofmann and Curtius Rearrangements, but more drastic conditions.
- Mechanism controversy.
Hayes J. Org. Chem. 1979, 44, 3682.
Koldobskii Russ. Chem. Rev. 1978, 47, 1084.
H
O H+ O O O
+ HN3
R OH –H2O R R N N N R N N N
R–NH2 R N C O
H NaN3, H2SO4 H
CO2H CHCl3, 76% NH2 Sato Tetrahedron: Asymmetry 1992, 3, 5.
CO2H NH2
Me Me
C. Conversion of Aldehydes to Nitriles

O
H+ cat.
+ HN3 R N
R H
- Acid catalyst usually H2SO4, can be Lewis acid.
- Schmidt reaction is the usual byproduct under these conditions to provide formamide.
- More common method is to convert aldehyde to oxime with hydroxylamine, followed by dehydration.
- Aromatic aldehydes are good substrates.
OHC NaN3, SiCl4 NC
MeCN, 50%
Elmorsy Tetrahedron Lett. 1995, 36, 2639.
Br Br
N N
H H
MeO CHO MeO CN
NaN3, H2SO4 Houff J. Org. Chem. 1957, 22, 344.
70%
HO HO
The airbag restraint system in cars is inflated in a fraction of a second by the release of N2 gas.
The nitrogen comes from explosion of a mixture of NaNO3 and amorphous boron initiated by
electronic priming with NaN3.
73
5. Lossen Rearrangement Lane Org. React. 1946, 3, 269 and 366.
Comprehensive Org. Syn., Vol. 6, pp 821–823 (basic conditions)
pp 824–825 (neutral/acidic)
Lossen Liebigs Ann. Chem. 1872, 161, 347.
O O O
R2X base –OR2
OH OR2 R1 N OR2 R1 N C O
R1 N R1 N
H H
Hydroxamic acid
-prepared readily from - R2X usually AcCl, ArSO2Cl, RPO2Cl
carboxylic acids, esters - rate of reaction proportional to the acidity of leaving group conjugate acid
or acyl halides - R1 migrates with retention of configuration
O TsCl; O
F NaOH, H2O
O H3NOH 80% F
OH Braish Syn. Commun. 1992, 22, 3067.
NH
F OH F NH2
O
H H
O NaOH, H2O NH2
O 80% Bauer J. Org. Chem. 1959, 24, 1293.
H N H OH
O S
O O O
G. Olefin Osmylation (Dihydroxylation)

epoxide
RCO3H opening OH NaOH OH
O
O OH
versus trans-1,2-diol
O R
H H
O O O OH HO O
O H2O
+ Os Os O + Os O
O
O O OH HO
Os(VIII) H H
electrophilic, Diastereospecific cis-1,2-diol Os(VI)
large reagent First use: Criegee Justus Liebigs Ann. Chem. 1936, 522, 75.
Milas J. Am. Chem. Soc. 1936, 58, 1302.
1. Mechanism [2 + 2] [3 + 2]
O OO O
O or
+ Os O O product
Os Os O
O :L O
O O L
[2 + 2] Mechanism: [3 + 2] Mechanism:
Sharpless J. Am. Chem. Soc. 1977, 99, 3120. Boeseken Recl. Trav. Chim. 1922, 41, 199.
Jorgensen Chem. Rev. 1990, 90, 1483. Criegee Angew. Chem. 1938, 51, 519.
Sharpless Angew. Chem. Int. Ed. Eng. 1993, 32, 1339. Criegee Justus Liebigs Ann. Chem. 1942, 550, 99.
2. Scope Comprehensive Org. Syn., Vol. 7, pp 437–448. Chem. Rev. 1980, 80, 187.
1. OsO4 is an electrophilic reagent, and it behaves as a large reagent.

2. Strained, unhindered olefins react faster than unstrained, sterically hindered olefins.
3. Electron-rich olefins react faster than electron-deficient olefins.
4. Diastereospecific, with attack on the C=C from the least hindered face.
74
Oxidation Reactions
Dale L. Boger
- but OsO4 is expensive, volatile, and toxic
- various improvements: 1) only catalytic amount of OsO4 used
2) use of an equivalent osmium salt (K2OsO2(OH)4)
Examples:
H2O2, cat. OsO4 J. Am. Chem. Soc. 1936, 58, 1302; 1937, 59, 2345; Synthesis 1989, 295.
tBuOOH, cat. OsO
4 Sharpless J. Org. Chem. 1978, 43, 2063.
O N O or N O Tetrahedron Lett. 1976, 1973;
(NMO) Tetrahedron Lett. 1980, 21, 449.
Note: Johnson–Lemieux Oxidation (NaIO4 and catalytic OsO4 cleaves C=C bonds, forms diol and then
aldehyde: J. Org. Chem. 1956, 21, 478).
cat. OsO4 HO OH O
R R H H 2
NaIO4 R H
R R
-Alternative reagents to OsO4:
KMnO4: Synthesis 1987, 85.
Yields rarely as high as OsO4 but less hazardous and less expensive especially for large scale
RuO4 or RuO2–2H2O/RuCl3–H2O + cooxidant
More vigorous than OsO4 and olefin cleavage is observed
a. Endocyclic Olefins
OsO4 OH
OH
from least hindered side
OsO4
-endocyclic allylic alcohols
OH OsO4
OH
from least hindered side
OsO4 OH
100% 120o OH
OH
Note: m-CPBA comes in cis to the allylic -OH, but OsO4 comes in trans to the allylic -OH.
So, we obtain:
OsO4 m-CPBA
HO
OH
m-CPBA OsO4
OH OH HO
x x
HO OsO4 HO OH OH
HO
100% HO
OH
OsO4 OsO4
75
OH OH Predominant conformation at 25 °C
HO OsO4 HO OH OH
HOHO
OH
> 50:1 OH
OsO4
trans to allylic alcohol
OH OH
OsO4 OH
4:1
OH
b. Acyclic Systems
- OsO4 is delivered from face opposite the allylic hydroxyl group in the preferred (H-eclipsed)
ground state conformation. m-CPBA (cis to allylic alcohol 120°)
HO 120o
R2 R4 R4
HO R2 H
R3 R3
R1 H
R1
OsO4 (trans to allylic alcohol 120°)

- Kishi model (empirical model). Tetrahedron Lett. 1983, 24, 3943, 3947.
So, for the OsO4 oxidation: Tetrahedron 1984, 40, 2247.
HO HO R2 OH OH 4
R4 OsO4 R4 HO R4 R
H
R2 H R2 or 1 R3
R3 R3
1
R 2 R3
1 OH OH R R
OH OH
R1 R H OH
3
- Preferred ground state conformation (higher diastereoselection when R is not H).
- Also observed with allylic ethers
OsO4 OR OH OR OH
OR +
RO RO RO
OH OH
erythro threo
1) electronic effects: R = Bn 8.9 : 1
R = CO2CH3 2 : 1
R = COC6H4-NO2 1 : 1
electronic effect of alkoxy substituent directs osmylation to reverse face
2) steric effects:
OBn OBn OH
OsO4
BnO BnO 7:1, modest selectivity
H OH
- Higher diastereoselectivity of Z vs. E isomer implies eclipsed conformation important.
OX OH OX
OsO4 < 8:1, modest selectivity
R2 R1 R2 R1 (anti 1,2-diol relationship)
OH
OH OX
R2 OX OsO4
high selectivity
R2 R1
R1
OH
76
Oxidation Reactions
Dale L. Boger
OH OX
OX OsO4
moderate to high selectivity
R1
R1
HO Me
1
- As R increases in size relative to OX, the selectivity increases.
- X-effect (steric effect): smaller X provides better selectivity.
- There are additional empirical models used to explain the acyclic allylic alcohol induced
diastereoselectivity:
1. Houk Model (inside alkoxy model): H OX R3 non ground state conformation

R2
Science 1986, 231, 1108. R4
R1
H OsO4 is large reagent; steric

2. Vedejs Model:
2 R3
J. Am. Chem. Soc. 1989, 111, 6861. R 1 4
effects between reagent & allylic
R OX R substituent are important factors
3. Panek: R3 XO H2 selectivity increases:

R
J. Am. Chem. Soc. 1990, 112, 4873. R4 a) OH > OR
b) now E > Z
SiR3
c) with very large R1: inside alkoxy
or anti Si
c. Exocyclic Olefins: Vedejs J. Am. Chem. Soc. 1989, 111, 6861.
ax. axial attack equatorial attack OH
H OsO4 OH
H OH
t tBu tBu OH
Bu R2 H2O–acetone R2 + R2
eq.
R1 O NO R1 R1
(NMO)
R1 R2 ax. eq. Consistent with Kishi empirical model

OsO4 is a large reagent, H H 14 86 Inconsistent with Houk model
prefers equatorial attack H OH <5 95
H OCH3 <5 95
CH3 OCH3 20 80
H OAc 8 92
H SCH3 <5 95
OH H 33 67
H-bonding?
Exception: OH CH3 14 86
OsO4 Equatorial attack predominates,
OCH3 H 88 12
axial except with axial OCH3, OAc, SMe:
OCH3 CH3 90 10
R2 OAc CH3 67 33 In these cases, equatorial attack further
SCH3 H 92 8 retarded and proceeds at even slower
RO rate (kinetic studies)
d. H-Bonding and Directed Dihydroxylation
Cyclic allylic alcohols
OsO4 axial OH
OH OH OH
OH OH
+ tBu
t t t OH
Bu Bu OH Bu OH
cat. OsO4, NMO, acetone–H2O 94:6 (90%)
competing H-bonding delivery
1 equiv OsO4, CH2Cl2 (anhydrous) 75:25 (97%)
reduces diastereoselectivity
77
TMEDA
OR OR OR
OH OH N N
O Os O H
+ O O
tBu tBu OH tBu OH O
tBu
R = H: cat. OsO4, NMO, acetone–H2O 85:15 (91%) 120°
1 equiv OsO4, CH2Cl2 63:37 (45%) competing H-bond OsO4 angle
cat. OsO4, Me3NO, CH2Cl2 45:55 (55%) delivery equatorial OH
1 equiv OsO4, TMEDA, CH2Cl2, –78 °C 4:96 (91%) H-bond delivery
R = CH3: 1 equiv OsO4, CH2Cl2 95:5 no H-bonding
OH OH OH
OH OH
+
OH OH
cat. OsO4, NMO, acetone–H2O 80:20
OH OH OH
HO HO OH HO OH
+
OH OH
OH OH
HO HO OH HO OH
+
HO HO HO
O O O
- OsO4–TMEDA can also be utilized to effect chemoselectivity by preferentially oxidizing allylic alcohols
over unactivated (non allylic -OH) double bonds.
Donohoe Tetrahedron Lett. 1996, 37, 3407; Tetrahedron Lett. 1997, 38, 5027.
- Catalytic procedures require QNO (quinuclidine N-oxide) and a strong H-bond donor (−NHCOCCl3)
NHCOCCl3 NHCOCCl3 NHCOCCl3

OH OH
+
tBu tBu tBu
OH OH
cat. OsO4, NMO, acetone–H2O, 25 °C 1.6:1 (96%)
cat. OsO4, Me3NO, CH2Cl2, 25 °C 1:6 (81%)
cat. OsO4, QNO, CH2Cl2, 25 °C 1:13 (77%) H-bond delivery
Donohoe Tetrahedron Lett. 2000, 41, 4701.
78
Oxidation Reactions
Dale L. Boger
Acyclic allylic alcohols

N N
Os O
H O
OH OH OH OH OH O O
O
+ R
Pr Pr Pr H H
OH OH iPr
cat. OsO4, NMO, acetone–H2O 80:20 (86%) OsO4
1 equiv OsO4, TMEDA, CH2Cl2, − 78 °C 25:75 (84%) H-bond delivery (empirical model)
OH OH OH OH OH
+
Me OH Me OH
Me
cat. OsO4, NMO, acetone–H2O 90:10 (71%)
1 equiv OsO4, TMEDA, CH2Cl2, − 78 °C 67:33 (75%)
N N
Pr OH OH OH OH OH O Os O
H
+ O O
R Pr R Pr R O
OH OH H H Pr
R = Pr: cat. OsO4, NMO, acetone–H2O 38:62 (76%)
R
1 equiv OsO4, TMEDA, CH2Cl2, − 78 °C 4:>96 (74%)
R = iPr: cat. OsO4, NMO, acetone–H2O 20:80 (85%)
N N
OH OH OH O Os O
HO HO H
O O
Bu + Bu O
Bu
OH OH H H
cat. OsO4, NMO, acetone–H2O 34:66 (96%) R
- Results with OsO4/TMEDA are analogous to the m-CPBA epoxidation of acyclic allylic alcohols and are
derived from a H-bonded delivery from a H-eclipsed conformation.
Donohoe Tetrahedron Lett. 1999, 40, 6881.
4. Comparison of Diol Stereochemistry Generated by Different Methods
a. m-CPBA
H
OH trans-diol
m-CPBA H+, H2O
O
OH
H
-Epoxidation from least CH3 CH3 H2O trans diaxial opening
hindered face H H of epoxide
CH3 O CH3
m-CPBA H H
79
b. OsO4 CH3
H
OH cis-diol
OsO4 H
CH3 OH
H
- cis dihydroxylation from least OsO4 H
hindered face (OsO4 is a large reagent)
c. Via Bromohydrin
H
OH trans-diol
Br2 or NBS H+, H2O
O
H2O; NaOH OH
H
- Epoxidation on most hindered face of olefin (to give different epoxide from m-CPBA oxidation),
trans diaxial ring opening (to give same hydrolysis product as from m-CPBA oxidation)
CH3
trans diaxial OH trans diaxial
CH3 H CH3
attack OH opening of epoxide
H CH 3 H O
Br
CH3 CH 3 H CH3
Br H2O
OH
bromonium ion H H H
formation on least
hindered face Br CH3
H
-Corey Tetrahedron Lett. 1982, 23, 4217: cis dihydroxylation from most hindered olefin face.
Br Br O CN 1) H O+ OH
O NaH 3
CN O 2) NaOH
OH O OH
d. Prevost H
I2 OH - Neighboring Group Participation
Compt. rend. 1933, 196, 1128.
PhCO2Ag
OH
H Ph
Me Ph Me Ph
O2CPh Me Me O O Me Me
H trans O O O NaOH
O
trans-diol
Me anti Me H2O
I opening PhCO2
I OCOPh
H
trans-dibenzoate
e. Woodward H 1) I2
PhCO2Ag OH - Complements OsO4 reaction
J. Am. Chem. Soc. 1958, 80, 209.
2) H2O, ∆ (i.e. cis dihydroxylation
OH from most hindered face)
H
Ph Ph
Me OH2 Me C O
O O O OH
H2O NaOH
cis-diol
Me trap Me H2O
-Same intermediate as Prevost, but different conditions (+ H2O)
80
Oxidation Reactions
Dale L. Boger
H. Asymmetric Dihydroxylation Reaction Catalyzed by OsO4 and Related
Reagents
1. Catalytic Methods
Sharpless Catalytic Asymmetric Dihydroxylation (AD) Reaction, Review: Chem. Rev. 1994, 94, 2483.
J. Am. Chem. Soc. 1980, 102, 4263. J. Org. Chem. 1992, 57, 2768.
J. Am. Chem. Soc. 1988, 110, 1968. J. Am. Chem. Soc. 1992, 114, 7568, 7570.
J. Am. Chem. Soc. 1989, 111, 1123. Tetrahedron Lett. 1993, 34, 7375.
Tetrahedron Lett. 1989, 30, 2041. J. Org. Chem. 1993, 58, 3785.
Tetrahedron Lett. 1990, 31, 2999, 3003, 3817. J. Am. Chem. Soc. 1994, 116, 1278.
J. Org. Chem. 1991, 56, 4585. Angew. Chem., Int. Ed. Eng. 1996, 35, 448.
R1 DHQD: dihydroquinidine DHQ: dihydroquinine

R1 H H
(R = H) (R = H)
R2 R3 R3 R2
Et
Et
N N
K2OsO2(OH)4 or OsO4
DHQD DHQ R O O R
K3Fe(CN)6, K2CO3
tBuOH-H O H H
2 MeO OMe
R1 H 3 H R1
R2 R R3 R2
N N
HO OH HO OH
Second Generation Ligands (Alk = DHQ or DHQD) First Generation Ligands (Alk = DHQ or DHQD)
PHAL PYR AQN PHN MEQ CLB

Ph O OAlk Cl
AlkO OAlk Me
AlkO OAlk N N N
N N
Ph O OAlk OAlk OAlk O OAlk
Catalyst: OsO4 (1.25 mol%) or K2OsO2(OH)4 (0.05 mol%, nonvolatile)
Solvent: tBuOH or cyclohexane, H2O, K2CO3
Ligands: DHQD or DHQ (0.2 to 0.004 mol%)
Oxidant to recycle OsO4: K3Fe(CN)6
Note: Ligand accelerated catalysis, Sharpless Angew. Chem., Int. Ed. Eng. 1995, 34, 1059.
-Addition of pyr led to marked increase in rate of formation of cyclic osmate ester from alkene and
OsO4. First noted by Criegee Justus Liebigs Ann. Chem. 1936, 522, 75; 1940, 550, 99.
-The "Criegee effect" (or the facilitation of osmylation step by nitrogen donor) has been examined with
quinuclidine and cinchona alkaloid ligands: Sharpless J. Am. Chem. Soc. 1994, 116, 1278, 8470.
-Results:
Good to excellent selectivity (ee%) for:
R1
R1 R3
R R2 R2 R1
74–93% ee 82–88% ee 94–99% ee R2 84–93% ee
R3
Poor selectivity for: R2
R1
R1 R4
R2
81
2. Stoichiometric methods
Ph
Ph
-Tomioka J. Am. Chem. Soc. 1987, 109, 6213. N N
Ph 1
Ph
Using 1 as a chiral ligand, good selectivity for: Poor selectivity for:
R1 R3 O
R R2 R1 R2
R2 R1
- Product does not seem to reflect most favorable steric approach for [3 + 2] cycloaddition but is more
easily rationalized by [2 + 2].
H H
Ph H OsO4 (+)-1
O
O O H R2
Os Ph
Ph
N O N R1 R3
Ph
Ph
X-ray structure OsO4 (–)-1
stoichiometric reagent
(LiAlH4 to reduce off osmate ester) O
Ph Et CO2Me Ph
Ph Ph Ph Et MeO2C
ee: 90% 95% 97% 90% 93% 83% 26% 41%
-Corey J. Am. Chem. Soc. 1989, 111, 9243.
Ph Ph R2
H
NH HN Ligand accelerated reaction
OsO4, –90 °C, 2 h
N O N R2
H Ph
Os
C2-symmetry in ligand R1 O Ph R1
O O
Os (6 coordinate) 92% ee 82–98% ee 60% ee
nucleophilic equatorial oxygen
electrophilic axial oxygen
-Other stoichiometric reagents: Chem. Lett. 1986, 131. Chem. Commun. 1989, 665.
Tetrahedron Lett. 1986, 27, 3951. J. Org. Chem. 1989, 54, 5834.
Tetrahedron Lett. 1990, 31, 1741. Tetrahedron 1993, 49, 10793.
3. Examples
-Total synthesis of Bouvardin and RA-VII: Boger J. Am. Chem. Soc. 1994, 116, 8544.
OH
O
R CO2H
OH Ti(OiPr)4
(+)-DIPT, tBuOOH I NHMe
I I
90%, >98% ee R = CH2OH
(AE) PDC
R = CO2H
OH OH
CO2CH3 CO2CH3 CO2CH3
AD mix-α NaN3
90%, >95% ee OR N3
I I I
(AD) R=H
R = SO2Ar
82
Oxidation Reactions
Dale L. Boger
-Vancomycin central amino acid: Boger J. Org. Chem. 1996, 61, 3561; J. Org. Chem. 1997, 62, 4721.
OCH3 OCH3 OCH3 OCH3

BnO OBn BnO OBn 1) DPPA BnO OBn BnO OBn
AD-mix-α Ph3P–DEAD
97%, 87% ee 2) Ph3P, 65%
(AD) OR OTBDMS tBuO C
HO H2N 2 NHCBZ
H
TBDMSCl R=H
85% R = TBDMS
OCH3 CBZN(Cl)Na OCH3 OCH3
BnO OBn 4 mol% K2OsO2(OH)4 BnO OBn BnO OBn
5 mol% (DHQD)2PHAL +
50% nPrOH/H2O
(AA) NHCBZ OH
HO CBZNH
1 : 7
recrystallization 69%, 96% ee
1× 64%, >99% ee
-Luzopeptin Htp amino acid: Boger J. Org. Chem. 1998, 63, 6421; J. Am. Chem. Soc. 1999, 121, 1098.
OH
AD-mix-α 1) NaN3
80%, >99% ee 2) Ph3P CO2Bn
O O OH O OH
CO2Bn (AD) CO2Bn 87 × 93% CO2Bn N R
O O O N
OR NH2 O
NosCl R = H
68% R = Nos
-Prediction of absolute stereochemistry is so firmly documented that it may be used to assign absolute
stereochemistry. However, there are a few rare exceptions to be aware of, for example:
Boger J. Am. Chem. Soc. 1997, 119, 311. reversed enantioselectivity
OR
HO
NCOPh NHCOPh cat OsO4 NHCOPh
NMO, 95%
SnBu3 or TBDMSOTf
BF3 Et2O (DHQD)2PHAL 75%
NC OBn NC OBn 70%, 78% ee NC OBn
89%
NCOPh NHCOPh (AD) NHCOPh
TsCl, Bu2SnO R=H
94% R = Ts
OTs TBDMSO TBDMSO

TBDMSO
NHCOPh
NaH NC NCOPh NH2NH2 NC NR (+) and ent-(–)-
97% EtOH duocarmycin A
NC OBn PhCON 65% RN
H H
NHCOPh OBn OBn
Chiralcel OD BOC2O; R=H
resolution, α = 2.30 TFA, 88% R = BOC
-Appears to be general for the class of olefins ArCH2CH=CH2
83
I. Sharpless Catalytic Asymmetric Aminohydroxylation (AA)
- Reviews: Transition Metals for Fine Chemicals and Organic Synthesis; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, 1998.
Angew. Chem. Int., Ed. Eng. 1996, 35, 451, 2810 and 2813. J. Am. Chem. Soc. 1998, 120, 1207.
Angew. Chem. Int., Ed. Eng. 1997, 36, 1483 and 2637. Tetrahedron Lett. 1998, 39, 2507 and 3667.
- Development of AA reaction (reactions generally run with 4 mol% catalyst (K2OsO2(OH)4) and 5 mol%
ligand ((DHQ)2PHAL or (DHQD)2PHAL): in situ generation and reactions of RN=OsO3.
a. Sulfonamide variant
O Cl O O
-α,β-unsaturated esters: S
R S N HN R
CO2CH3 O Na CO2CH3
Ph cat. K2OsO2(OH)4 Ph
(DHQ)2PHAL OH
R= p-Tol 1:1 CH3CN–H2O 81% ee (64%) Reductive cleavage of sulfonamides

requires harsh conditions (Birch
Me 1:1 nPrOH–H2O 95% ee (65%) reduction, Red-Al, or 33% HBr/AcOH).
Me3Si 1:1 nPrOH–H2O 70% ee (48%) Sulfonamide cleaved with Bu4NF in CH3CN
83:17 regioselectivity
-α,β-unsaturated amides: no enantioselection, AA gives racemic products.

-reaction works well without a ligand.
TsN(Cl)Na Ts
O cat. K2OsO2(OH)4 TsHN O 1) MsCl, Et3N N
NMe2
Ph NMe2 tBuOH–H O Ph NMe2 2) Et N or DBU Ph
2 3
OH O
5:1 regioselectivity, racemic (94%)
b. Carbamate variant Cl O
RO N
-α,β-unsaturated esters: Na
HN OR
O
CO2CH3 CO2CH3
Ph Ph
cat. K2OsO2(OH)4
(DHQ)2PHAL OH
R= Bn 1:1 nPrOH-H2O 94% ee (65%) Amine can be deprotected

Et 1:1 nPrOH-H2O 99% ee (78%) by hydrogenolysis.
tBu 2:1 nPrOH-H2O 78% ee (71%) Amine can be deprotected by acid.
Cl O
O N SiMe3
Me3Si Na HN O
CO2iPr O CO2iPr
Ph Ph
cat. K2OsO2(OH)4 99% ee (70%)
(DHQ)2PHAL OH
Carbamate cleaved with
Bu4NF in CH3CN.
84
Oxidation Reactions
Dale L. Boger
-Reversal of regioselectivity using (DHQ)2AQN ligand
OH
CBZN(Cl)Na
CO2CH3 CO2CH3 95% ee (58%)
Ph Ph
cat. K2OsO2(OH)4
NHCBZ 79:21 regioselectivity
(DHQ)2AQN
-Styrenes:
NHCBZ OH
3 equiv
OH NHCBZ
BnOC(O)N(Cl)Na + 97% ee (76%)
cat. K2OsO2(OH)4 A B 88:12 A:B
BnO BnO BnO
1:5 nPrOH–H2O
-Influence of ligand and solvent on regioselectivity:
ligand solvent A:B
(DHQ)2PHAL nPrOH–H2O 88:12 - However, enantioselectivities for B
(DHQ)2AQN CH3CN–H2O 25:75 regioisomers are poor (0–80% ee).
t
- Bu carbamate based AA affords slightly poorer regioselectivities and yields compared to benzyl
carbamate series, but enantioselectivities approach 100% in both cases:
NHBOC OH
tBuO CN(Cl)Na OH NHBOC
2 +
99% ee (68%)
cat. K2OsO2(OH)4 C D 83:17 C:D
BnO BnO BnO
2:1 nPrOH–H2O
O
(DHQ)2PHAL
HN OR
OH
RO2CN(Cl)Na
cat. K2OsO2(OH)4
(DHQ)2PHAL
R= Bn 99% ee (70%) >10:1 regioselectivity
tBu 98% ee (70%) 88:12 regioselectivity
Me3Si
97% ee (48%) 86:14 regioselectivity
-Oxidation of α-arylglycinols to corresponding α-arylglycines, see: Boger J. Org. Chem. 1996, 61, 3561.
NHCBZ NHCBZ
OH TEMPO, NaOCl
COOH
80%
BnO BnO
80:20 mixture
of regioisomers
-Teicoplanin α-arylglycines Boger J. Am. Chem. Soc. 2000, 122, 7416.
NHBOC NHCBZ
BOCNClNa HO CBZNClNa HO
K2OsO2(OH)4 K2OsO2(OH)4
(DHQD)2PHAL (DHQ)2PHAL
F 75%, 97% ee F MeO OBn 78%, > 99% ee MeO OBn
NO2 NO2
c. Amide variant
NHAc NH3Cl
CO2iPr AcNHBr/LiOH CO2iPr 10% HCl CO2H
Ph Ph Ph
cat. K2OsO2(OH)4 OH OH
1:1 tBuOH–H2O 99% ee, 81% 77% overall
(DHQ)2PHAL (>10:1 regioselectivity)
85
J. Ozonolysis Comprehensive Org. Syn., Vol. 7, pp 541–591.
Introduced by Harries Justus Liebigs Ann. Chem. 1905, 343, 311.
P. Crutzen, M. Molina, and F. S. Rowland shared the 1995 Nobel Prize in

Chemistry for their work in atmospheric chemistry, particularly concerning
the formation and decomposition of the protective ozone layer.
-Electrophilic reagent, rate: electron-rich > neutral > electron-deficient olefin

-Chemoselectivity: O OMe
O3, MeOH; Me2S CO2Me
CO2Me H CO2Me CHO
85–90%
-O3 exhibits very light blue color, ozonolysis complete when color persists
-Controlled ozonolysis (very reactive agent): KI–starch: characteristic blue color
O3 sensitive dyes with varying reactivities and detect
color disappearance: Mitscher Synthesis 1980, 807.
-Oxidative workup: H2O2, KMnO4, Cr(VI), RuO4 -> ketones, carboxylic acids
-Reductive workup: NaBH4, LiBH4 -> alcohols
Me2S, Ph3P, Zn/HOAc, H2N , H2, Pd/CaCO3 -> aldehydes, ketones
S
H2N
-Mechanism, Review: Criegee Angew. Chem., Int. Ed. Eng. 1975, 14, 745.
O O 1,3-dipolar R R O carbonyl oxide
R O O O O O
R +
1,3-dipolar R R cycloreversion (Criegee zwitterion)
R R O R R
cycloaddition R R
RR in situ
1,3-dipolar O reduction R R
O
cycloaddition O O
-Zn/HOAc Note: Alternative recombination
Note: Ozonide explosive RR -Me2S mechanisms observed with
when isolated or concentrated. ozonide -Ph3P ketone vs. aldehyde ozonides.
86
Oxidations of Alcohols
Dale L. Boger
V. Oxidation of Alcohols
Stoichiometries:
3 R2CHOH + 2 CrO3 + 6 H+ 3 R2C=O + 2 Cr3+ + 6 H2O
5 R2CHOH + 2 MnO4 + 6 H+ 5 R2C=O + 2 Mn2+ + 8 H2O
3 R2CHOH + 2 MnO4 3 R2C=O + 2 Mn2+ + 2 H2O
A. Chromium-based Oxidation Reagents

1. Collins Reagent: Collins Tetrahedron Lett. 1968, 3363; Org. Syn. 1972, 52, 5.
-CrO3–pyr2, alkaline oxidant
-Hygroscopic, red crystalline complex
-Can also be isolated and stored, but usually generated in situ by CrO3 + pyr (Sarett Reagent)
J. Am. Chem. Soc. 1953, 75, 422. Note: Add CrO3 to pyr, not pyr to CrO3 (inflames)
-Good for acid sensitive substrates
-Ratcliffe modification: in situ preparation and use in CH2Cl2, J. Org. Chem. 1970, 35, 4000.
H
OH O RCH2OH RCHO RCOOH
no over oxidation
CrO3−pyr2 O
RCH2OH Provide a mechanism for this transformation.
CH2Cl2, DMF R O
HOAc, tBuOH
General except for ArCHO Corey, Samuelsson J. Org. Chem. 1984, 49, 4735.
Review of Cr(VI)-amine oxidizing agents: Luzzio Org. React. 1998, 53, 1.
2. Jones Reagent: Jones J. Chem. Soc. 1953, 2548; J. Chem. Soc. 1946, 39.
H2O
CrO3 in aq. H2SO4/acetone H2Cr2O7 2 H2CrO4
-Acetone solvent serves to protect substrate from over oxidation

-Not good for oxidations of acid sensitive substrates
H
OH O
OH
H2O
RCH2OH RCHO R H RCOOH
OH
-Acidic oxidation conditions, H+ catalyzed reactions possible
-Another common side reaction for primary alcohol oxidation:
OCH2R
RCH2OH
RCH2OH RCHO R H RCOOCH2R
OH
Solution: run under dilute reaction hemiacetal ester
conditions to circumvent esterification
-Brown oxidation: run under two phase reaction conditions, Et2O–H2O, J. Org. Chem. 1971, 36, 387.
-[R4N]2Cr2O7 Synth. Commun. 1980, 75. Oxidation of allylic/benzylic alcohols under neutral conditions.
87
3. Pyridinium Chlorochromate (PCC): Corey and Suggs Tetrahedron Lett. 1975, 2647.
H
O N
Cr Cl HCl + CrO3 + pyr - Chloride facilitates formation of chromate
O O ester (slow step in oxidation reaction)
- Stable, commercially available reagent
-Reaction usually carried out in CH2Cl2
-Rates: > RCH2OH and R2CHOH
R OH
O
R H RCHO R2C=O no over oxidation

-Usually only need 1–2 equiv of Cr(VI) reagent (Jones & Collins usually require 6 equiv)
-PCC slightly acidic which can cause side reactions, for example:
PCC H+ –H+
OH O OH OH O
-To avoid H+ catalyzed side reaction, use sodium acetate buffer:
PCC
CHO
OH NaOAc
-Can take advantage of acidity in PCC reaction (Boger and Corey Tetrahedron Lett. 1978, 2461):
O O
CHO CHO
78% 41%
OH O
OH O
55% 62%
OH O
R = CH3, 68%
R = Ph, 69%
R R O
-Oxidation of 3°, allylic alcohols O H O Cr O O
O
Cr
MeLi PCC O O
OH O
O Me Me Me Me
[3,3]-sigmatropic rearrangement, Dauben J. Org. Chem. 1977, 42, 682.
-Aromatic amine effect: dampens reactivity so only selective oxidation of allylic alcohols may be observed
PCC, pyr (2%) in CH2Cl2 Chem. Phys. Lipids 1980, 27, 281.
PCC, 3,5-dimethylpyrazole (2%) in CH2Cl2 J. Org. Chem. 1983, 48, 4766.
PCC, benzotriazole (2%) in CH2Cl2 Synth. Commun. 1985, 15, 393.
-3 A° MS accelerate rate of oxidation (PCC and PDC)
J. Chem. Soc., Perkin Trans. 1 1982, 1967.
-Pyridinium fluorochromate, related stable reagent that is slightly less acidic (Corey and Suggs)
- Other related reagents include bipyridinium chlorochromate (BPCC), DMAP chlorochromate,
quinolinium chlorochromate, and pyrazinium chlorochromate.
88
Dale L. Boger
4. Pyridinium Dichromate (PDC): Corey Tetrahedron Lett. 1979, 399.
CH2Cl2
RCHO
PDC DMF
Cr2O7-2 CrO3 + pyr + H2O RCH2OH RCO2H
N
H MeOH
2 RCO2Me
PDC, DMF
-Stable, commercially available reagent CO2H
-Not as acidic as PCC OH 25 °C, 7 h
83%
-Oxidations slower than PCC or other oxidation reagents
-Can selectively oxidize 1° alcohols to aldehyde or carboxylic acid depending on solvent
-2° alcohols oxidize only slowly and sometimes require an acid catalyst (pyridinium trifluoroacetate or 3° A MS)
- Note: Original reagent made in search of more acidic reagent, attempted preparation of pyridinium
trifluoroacetyl chromate (Boger, Ph.D. dissertation, Harvard Univ., 1980).
-Other related reagents include nicotinium dichromate, quinolinium dichromate, and imidazolium dichromate
- Note: Cr based reagents will oxidize amines and sulfides. Substrates with these functional groups must be
oxidized with other reagents (PDC will sometimes leave sulfides unaffected).
5. CrO3–H5IO6: Zhao and Reider Tetrahedron Lett. 1998, 39, 5323.
-Catalytic in CrO3 (1–2%, Industrial scale chromium-based oxidations)
-1° alcohols carboxylic acids with no racemization
-2° alcohols ketones
2.5 equiv H5IO6
CO2H
Ph OH 1.1 mol% CrO3 Ph Ph Ph
NHCBZ wet CH3CN NHCBZ OH 98% O
0 oC, 83%
B. Manganese-based Oxidation Reagents
1. Manganese Dioxide (MnO2)
-Very mild oxidizing reagent, special "activated" MnO2 preparation required
-Selectively oxidizes allylic and benzylic alcohols to aldehyde or ketone
-Requires nonpolar solvent (CH2Cl2, CHCl3, pentane, benzene, etc.)
-Oxidizing reagent : substrate = 10:1 (10 wt. equiv)
OH OH
CHO
OH MnO2 MnO2
HO O
-No isomerization of conjugated double bond. Cr-based reagent will cause problem due to H+ catalysis
-Chemical MnO2 (CMD), commerically available, also works well
Shioiri Synlett 1998, 35; Tetrahedron Lett. 1992, 33, 4187.
-NiO2: alternative reagent that behaves similar to MnO2
-Oxidize alcohol to ester, no isomerism of C=C bond (Corey and Ganem J. Am. Chem. Soc. 1968, 90, 5616)
MnO2 OH O
MeOH
CH2OH CHO CO2Me
R cat HOAc R R H R CN R
NaCN, MeOH CN
2. KMnO4
a. KMnO4/H2SO4
-Good for RCH2OH RCOOH
-Reaction runs in aqueous solution because of the insolubility of KMnO4 in organic solvents
b. KMnO4 in tBuOH–5% NaH2PO4 aqueous buffer (Masamune Tetrahedron Lett. 1986, 27, 4537).
-For highly oxygenated systems where multiple side reaction pathways are present with other oxidants
89
5 min, 25 °C
CHO CO2H
TBDMSO OMOM 98% TBDMSO OMOM
c. Lemieux–von Rudloff oxidation: aqueous KIO4/cat. KMnO4
-For cleavage of carbon–carbon double bonds
3. R4NMnO4
-Same capabilities as KMnO4 but soluble in organic solvents
4. Cu(MnO4)-6H2O and BaMnO4
OH OH OH BaMnO4 O OH
CO2H
C6H6
Lee J. Am. Chem. Soc. 1983, 105, 3188; J. Org. Chem. 1982, 47, 2790.
Hauser J. Am. Chem. Soc. 1984, 106, 1862.
Jefford J. Chem. Soc., Chem. Commun. 1988, 634.
Kim Tetrahedron Lett. 1989, 30, 2559.
C. Other Oxidation Reagents
1. RCH2OH or R2CHOH oxidation
a. Sodium Hypochlorite (NaOCl): Used primarily to oxidize alcohols or aldehydes to carboxylic acids.
RCH2OH RCHO RCOOH
Stevens, Chapman J. Org. Chem. 1980, 45, 2030;
b. Sodium Chlorite (NaClO2) Pinnick Tetrahedron 1981, 37, 2091. Also Calcium Hypochlorite (Ca(OCl)2):
H2O McDonald Tetrahedron Lett. 1993, 34, 2741.
RCO2H
NaClO2
RCH2OH
MeOH
RCO2Me
-Good for oxidation of sensitive aldehydes to carboxylic acids
- Becoming the method of choice for the oxidation of RCHO to RCO2H.
- Two-step procedures for RCH2OH to RCO2H (i.e., MnO2, Swern, Dess−Martin for RCH2OH to RCHO
and NaClO2 for RCHO to RCO2H most often better than single step reagent conversions.
- Scavengers are often added to trap or eliminate positive Cl species leading to byproducts. Typical
scavengers are resorcinol, 2-methyl-2-butene, DMSO, H2NSO3H.
OMe
Cl
O O
Cl
TBSO OTBS
O H O
H H R = CH2OH
N N N Dess−Martin
O N NH R = CHO
H H H H NaClO2
O O NHBOC R = CO2H
NH CN O 77% overall
H
R
OMe Boger J. Am. Chem. Soc. 1999, 121, 3226 and 10004.
MeO OMe
c. Ag2O and Ag2CO3 Ag2CO3
Ag2O Celite
RCH2OH RCHO RCOOH
or
AgO
d. AgO
RCH2OH RCHO or RCO2H
CH2OH CO2H
R R
Corey, Ganem J. Am. Chem. Soc. 1968, 90, 5616.
90
Dale L. Boger
2. m-CPBA and NaIO4 (Amine and sulfide oxidation)
NaIO4 O m-CPBA O O
S S S
R R R R R R
m-CPBA
3. TPAP, [Pr4NRuO4]
HO CO2Et O CO2Et
5% TPAP
NMO TPAP
HO ° 93%
R CH2Cl2, 4A MS OHC R
Ley J. Chem. Soc., Chem. Commun. 1987, 1625.
Aldrichim. Acta 1990, 23, 13.
Synthesis 1994, 639.
4. Dess–Martin Oxidation: Dess and Martin J. Am. Chem. Soc. 1978, 100, 300; J. Am. Chem. Soc. 1979, 101, 5294;
J. Org. Chem. 1983, 48, 4155; J. Am. Chem. Soc. 1991, 113, 7277.
AcO OAc -periodinane RCH2OH RCHO
I OAc -CH2Cl2, 25 Co R2CHOH R2C=O
O
O O
O O O
70%
MeO MeO CHO
OH Danishefsky, Coleman J. Am. Chem. Soc. 1991, 113, 3850.
HO O
I - Precursor to Dess–Martin reagent
O - Insoluble in almost all organic solvents but is soluble in DMSO and oxidations in this
solvent work effectively (25 °C): Frigerio Tetrahedron Lett. 1994, 35, 8019.
IBX O
OH O OH O
R R R R R H R H
OH O OH O
R R Ph Ph
R R Ph Ph
OH O OH OH
5. Oxoammonium Salt: Torii J. Org. Chem. 1990, 55, 462; Skarzewski Tetrahedron Lett. 1990, 31, 2177.
OCOR Bobbitt J. Org.Chem. 1998, 63, 9367.
OH OH 1
1 OH CH Cl O
CHO 2 2
OH
N OH 25 °C O
O 1 Ph Ph 72 h, 95%
6. Trityl Cation: Jung J. Am. Chem. Soc. 1976, 98, 7882.

Ph3C+BF4–
TMSO OTMS OTMS + Ph3CH
CH2Cl2 O
H 25 °C
3° carbon H abstracted faster

7. Pt–O2: Fuchs and Hutchinson J. Am. Chem. Soc. 1987, 109, 4755. 1° alcohols > 2° alcohols
-Good for oxidation of 1° alcohols directly to carboxylic acids 2° axial alcohols > 2° equatorial alcohols
HO
HO2C
Pt–O2
acetone–H2O
C5H11 57% C5H11
HO OH HO OH
91
8. Via Hypohalite
Just Tetrahedron Lett. 1980, 21, 3219. Hanessian Synthesis 1981, 394.
Doyle Tetrahedron Lett. 1980, 21, 2795. Kanemitsu Chem. Pharm. Bull. 1989, 37, 2394.
Oshima, Nozaki Tetrahedron Lett. 1982, 23, 539. Stevens Tetrahedron Lett. 1982, 23, 4647.
-For example: (Bu3Sn)2O, Br2 NiBr2, (PhCO2)2 NIS, Bu4NI NaBrO3, CAN NaOCl, HOAc
OH OH Mechanism:
Br2
O
O (Bu3Sn)2O O X
HO OMe HO OMe O
HO CHCl3, reflux H
OH O OH B:
(Bu3Sn)2O OH (Bu3Sn)2O O
Br2 Br2
OH OH CH2Cl2 O OH CH
OH 2Cl2 OH
Tetrahedron Lett. 1976, 4597. 2° alcohol > 1° alcohol
9. Oppenauer Oxidation: see Meerwein–Pondorff–Verley reduction, Review: Org. React. 1951, 6, 207.
Oppenauer Rec. Trav. Chim. 1937, 56, 137.
- Suitable for oxidation of 2° alcohol in the
SePh Cl3CCHO SePh
presence of 1° alcohol which do not react
Al2O3
OH O - Good for oxidation of substrates containing
55 °C, 24 h
easily oxidized functional groups
Posner Angew. Chem., Int. Ed. Eng. 1978, 17, 487; Tetrahedron Lett. 1977, 3227; 1976, 3499.
OH Al(OiPr) O
3
toluene
CH3O 110 °C, 1.5 h CH3O
CH3 72% CH3
Boger J. Org. Chem. 1984, 49, 4045.
10. Ruthenium Tetroxide (RuO4) RCH2OH RCO2H R2CHOH R2C=O
-in situ generation from RuO2–NaIO4 or RuO2–NaOCl: Tetrahedron Lett. 1970, 4003.
J. Org. Chem. 1987, 52, 1149.
from RuCl3–H5IO6: Sharpless J. Org. Chem. 1988, 53, 5185.
J. Org. Chem. 1981, 46, 3936.
-Note: RuO4 attacks C=C bonds and will cleave 1,2-diols.
Often used to cleave aromatic rings:
BOCHN O cat. RuCl3−NaIO4 BOCHN O
60% BnO Boger J. Org. Chem. 2000, 65, 6770.
NH2 NH2
BnBr, 80% (total synthesis of ramoplanin)
OTBS O OTBS
MeO
11. TEMPO MeCN
RCO2H
NaBrO2
-with cat. NaOCl or NaBrO2: J. Org. Chem. 1985, 50, 1332. RCH2OH
J. Org. Chem. 1987, 52, 2559. TEMPO CH2Cl2
RCHO
J. Org. Chem. 1990, 55, 462.
-with cat. Ca(OCl)2: Dess and Martin J. Org. Chem. 1983, 48, 4155.
Corey J. Am. Chem. Soc. 1996, 118, 1229.
Smith J. Am. Chem. Soc. 1989, 111, 5761.
OMe OMe
BnO OBn NaOCl BnO OBn
TEMPO Vancomycin central amino acid
J. Org. Chem. 1996, 61, 3561.
KBr, 78%
OH
CBZHN CBZHN CO2H
92
Dale L. Boger
-With NaClO2, NaOCl Zhao, Reider J. Org. Chem. 1999, 64, 2564.
NaOCl RCH2OH O
N N N
− R H
O O O O
NaOCl H R NaClO2
H
RCO2H
N
OH
12. Pd−O2: J. Org. Chem. 1976, 41, 957 and 3329.
O2 Pd(OAc)
cat. Pd(OAc)2 O
Ph OH PhCHO 100%
pyr, toluene Ph H
° MS, 80 °C H
3A +
O2
HOOPd(OAc) HPd(OAc)
OH O
RCH2OH RCHO 3A° MS absorbs or decomposes H O
2 2
100% (O2 + H2O)
OH O
Uemura J. Org. Chem. 1999, 64, 6750.
R R R R
D. Swern Oxidation and Related Oxidation Procedures
1. Swern Oxidation: J. Org. Chem. 1976, 41, 957 and 3329. Reviews: Chem. Rev. 1967, 67, 247.
O CH3 Tetrahedron 1978, 34, 1651.
Cl Synthesis 1981, 165.
DMSO + Cl S Cl [DMSO–(COCl)2] Org. React. 1990, 39, 297.
CH3
O
CH3
DMSO + TFAA S O [DMSO–TFAA]
CH3 O
CF3
-Also DMSO–Ac2O, DMSO–SO3/pyr, DMSO–SOCl2, DMSO–Cl2
DMSO–Ac2O is often referred to as the Albright–Goldman reagent
Albright, Goldman J. Am. Chem. Soc. 1965, 87, 4214, 1967, 89, 2416.
2. Corey–Kim Oxidation: Tetrahedron Lett. 1974, 287; J. Am. Chem. Soc. 1972, 94, 7586.
O
CH3 CH3
S + N Cl S Cl [DMS–NCS]
CH3 CH3
O
3. Moffatt–Pfitzner Oxidation (DCC–DMSO): J. Am. Chem. Soc. 1963, 85, 3027; J. Am. Chem. Soc. 1965, 87, 5670.
S
O
DMSO + N C N N C N [DMSO–DCC]
-Mechanism:
S
O CH3 O
H H
1. RCH2OH + N C N RCH2O S + N C N
CH3
93
H CH3
R C O S + B: RCHO + Me2S
B: H CH3
CH3 CH3 H CH3
2. RCH2OH + S X RCH2O S R C O S RCHO +
CH3 CH2 H CH2 Me2S
B: H
N
X = Cl or O C
HN
-All Swern type complexes react with alcohols, in presence of base, to give "activated alcohol complexes".
-Examples:
OH OH -Other oxidants cleave diol C–C bond
OH O -Swern oxidation run under very mild conditions
(usually –78 °C to –50 °C)
O HO H O
OH MnO2 H
O O
OH or PCC OH
CHO Boger J. Org. Chem. 1990, 55, 1919.

OH Swern
Boger J. Org. Chem. 1991, 56, 2115.
OH Boger Tetrahedron Lett. 1989, 30, 2037.
CHO
-Fredericamycin A: Boger J. Am. Chem. Soc. 1995, 117, 11839.
MOMO OMe OH MOMO MeO OH
MeO TFAA–DMSO MeO TFAA–DMSO
DBU Et3N
–78 °C, 1 h
–78 °C to 25 °C, 20 h O
MOMO OBn OH MOMO BnO BnO
BnO
EtO N
EtO N
MOMO MeO O O OH O
MeO MeO
BBr3; air
TsOH–NaBr
O O
MOMO BnO O OH
BnO HO
EtO N Fredericamycin A N O
H
Note: Kornblum oxidation, J. Am. Chem. Soc. 1957, 79, 6562 via DMSO oxygen based displacement of
halide (usually activated: benzylic or α-keto halide) to provide aldehyde or ketone.
-
Common byproducts of Swern oxidations are (methylthio)methyl ethers and the amount varies with DMSO
coactivator and reaction temperature. It is derived from alcohol trap of a Pummerer rearrangement
intermediate: CH2=+SCH3.
Note: Pummerer rearrangement is also a formal oxidation reaction
Pummerer Chem Ber. 1909, 42, 2282; Chem Ber. 1910, 43, 1401.
O OAc
Ac2O
S CO2Et S CO2Et S CO2Et S CO2Et
Ph Ph Ph Ph
H H OAc
AcO AcO
Reviews: Org. React. 1991, 40, 157. Comprehensive Org. Syn., Vol. 7, pp 194–206.
94
Reduction Reactions
Dale L. Boger
VI. Reduction Reactions
A. Conformational Effects on Carbonyl Reactivity
O
Dihedral Eclipsed conformation
O
H angle 4° H of carbonyl
Hax
H
sp2 sp3
120° 109.5°
introduces
torsional strain This torsional strain accounts for the
increased reactivity of six-membered ring
cyclic ketones over acyclic ketones.
OH
H O Nu– H
H H Nu
Overall, the addition to cyclohexanones is favorable:

1. gain 1,3-diaxial interactions (A value = 0.7 kcal/mol for OH)
2. lose the torsional strain (~3–5 kcal/mol)
- So, additions to cyclic ketones are thermodynamically and kinetically favorable.
1. Reversible Reactions
O HCN HO CN
reversible reaction
cyclohexanone
Keq for ~
~ 70
acyclic ketone
- Thermodynamically more favorable for cyclohexanone due to the loss of torsional strain.
- Thermodynamic effect of sp2 hybridization: the strain free acyclic system does not
suffer the strain destabilization of the ground state, so little gain going from sp2-> sp3.
2. Irreversible Reactions (kinetic effect is pertinent)
O HO H
LiAlH4
cyclohexanone
Rate (k) for ~
~ 335
acyclic ketone
*Implication: One can selectively reduce a cyclic carbonyl in the presence

of an acyclic carbonyl: under kinetic or thermodynamic conditions.
- Synthetic consideration: may not have to protect acyclic ketone.
95
3. Additional Conformational Effects
O
H O
H
H
Boat destabilization reduced
H Only ~2.7 kcal/mol higher in energy
-Cyclohexanones potentially have more accessible conformations available.

0.6 kcal/mol
O
Me Theoretical prediction (0.9 kcal/mol), actually this 1,3-diaxial Me–H
H interaction is only about 0.6 kcal/mol. This difference (0.3 kcal/mol) in
energies observed between theoretical and experimental results is due
to the fact that the sp2 carbonyl carbon moves these groups (Me and H)
A = 1.8 kcal/mol further away from each other: bond angle of 120° vs. 109.5°.
1/2 = 0.9 kcal/mol
Predicted!
- Substituents on the ring benefit from a reduced A value since one axial
substituent is removed and the opened bond angle of the carbonyl further
reduces the remaining 1,3-diaxial interaction (greater distance).
B. Reactions of Carbonyl Groups

- Three primary reactions which we will discuss relative to nucleophilic addition:
O HO Nu
Nu–
Nucleophilic addition: H H
X X
Me (or R) Me (or R)
O O
α-Deprotonation: Base
(enolate formation) H X
X
Me (or R) Me (or R)
O O
Addition of e–, formation e–
of radical anion: H H
X X
Me (or R) Me (or R)
- Each reagent will display competitive reactions among the three primary pathways.
Nature of each reagent and the nature of X will determine the course.
C. Reversible Reduction Reactions: Stereochemistry

- Meerwein–Ponndorf–Verley Reduction Reversible Reduction
(the reverse reaction is the Oppenauer
Oxidation).
Review: Djerassi Org. React. 1951, 6, 207.
Meerwein Justus Liebigs Ann. Chem. 1925, 444, 221.
Ponndorf Angew. Chem. 1926, 39, 138.
Verley Bull. Soc. Chim., Fr. 1925, 37, 537.
O OH
OH
+ Al O iPrOH
+
tBu 3 tBu t
95 : Bu 5
96
Reduction Reactions
Dale L. Boger
- Mechanism: Reversible Intramolecular Hydride Transfer.
O Al O
O axial H– H
H delivery
H H Al
H H O
tBu tBu
Al
O O O
Al equatorial H–
delivery H
H O
t tBu
Bu H H H H
Steric interaction
- Since it is freely reversible, one obtains the most stable alcohol from the reduction.
The reaction is driven to completion by use of excess reagent and by distilling off
the acetone formed in the reaction.
- But, the A value of OH = 0.7 kcal/mol and K = e–∆G/RT would predict a 72:28 ratio.
Why does the experimental result give better selectivity than the prediction (95:5 > 72:28)?
- We must not only consider the A value, but the larger 1,2-destabilizing steric
interactions of the isopropoxy group in the transition state for the equatorial delivery of
the hydride: that is, the larger ∆E in the transition state.
OH
O OH O OAlCl2 OH
Al(OR)3 Ph Ph
22% ee 70% ee
Doering J. Am. Chem. Soc. 1950, 72, 631. Nasipuri J. Indian Chem. Soc. 1967, 44, 165.
D. Irreversible Reduction Reactions: Stereochemistry of Hydride Reduction

Reactions and Other Nucleophilic Additions to Carbonyl Compounds
1. Cyclic Ketones
a. Examples
O H OH
H H H H H H
OH H
LiAlH4
+
t tBu H H t H H
Bu H H Bu
90 : 10
Nearly the same ratio obtained under these kinetic
H and the above thermodynamic conditions.
H
H Al Li
Why?
1,3-interactions H
O
H
H Li - Difference in the relative rates: 1,2-interactions
H slow the equatorial addition by a factor of ~ 10
H Al H
H H H - LiAlH4 = small reagent favor axial hydride delivery
1,2-interactions
- 1,3-interactions are more remote (i.e., smaller), when compared to the 1,2-interactions (larger).
- The destabilizing 1,3-interactions increase as the size of the reagent increases or with the size of
the 1,3-diaxial substituents while the 1,2-interactions are not nearly so sensitive to the size of
reagents or the size of the substituents.
97
- For the reduction of cyclohexanone and derivatives, we see the following generalizations:
Small H– Reagent
O
H
H
Large H– Reagent
R H H
Examples:
O OH H
Me Me
Me
LiAlH4 H + OH
Me Me Me
H H
Me H H
Me H Me H
45 : 55
Increased steric hinderance of the 1,3-diaxial interactions
(Me/reagent) make axial hydride delivery more difficult.
O OH H
Me Me Me
Me Me H Me OH
LiAlH4
H H +
H H H H
H H H
100 : 0
Serious 1,3-interactions preclude axial delivery of the hydride,
but the axial Me's have no effect on the 1,2-interactions.
O OH H
Me Me Me
H OH
Reagent +
Me Me Me
H H H H
Me Me H Me H
LiAlH4 52–63 : 37–48

NaBH4 55–64 : 36–45
LiAl(OMe)3H 92–98 : 2–8
Larger reagent: greater selectivity for equatorial H– delivery.
Effect of the size of the reagent

B H–K+ OH
O H
H H H
H H OH H H
+
tBu tBu H tBu H
H
H H H
3.5 : 96.5
Much larger reagent! Now, even the 1,3-H/reagent interactions are large while the
1,2-torsional interactions are not affected. Brown J. Am. Chem Soc. 1972, 94, 7159.
98
Reduction Reactions
Dale L. Boger
- Comparison of Diastereoselectivity of Hydride Reducing Reagents.
Me Me
Me
O O O
tBu Me
Me
Me O Me O
Reagent % axial OH % axial OH % axial OH % endo OH % endo OH
NaBH4 20 25 58 86 14
LiAlH4 8 24 63 89 8
LiAl(OMe)3H 9 69 92–98 98 1
LiAl(OtBu)3H 9 36 95 94 6
(sBu)3BHLi 93 98 99.8 99.6 0.4
(Me2CHCHMe)3BHLi >99 >99 - >99 no reaction
LiMeBH3 2 13 66 - -
Brown J. Am. Chem. Soc. 1970, 92, 709; 1972, 94, 7159; 1976, 98, 3383.
- Stereochemistry of Other Representative Nucleophilic Additions to Cyclohexanones.
Me
O O O
tBu Me
Me
Me
Reagent % axial OH % axial OH % axial OH Note: Typically alkyllithium

MeLi/Et2O 65 85 100 reagents behave as large
MeMgI/Et2O 53 84 100 nucleophiles and approach
from the equatorial direction
EtMgBr/Et2O 71 95 100
PhMgBr/Et2O 49 91 100
PhLi 58 88 - Ashby Chem. Rev. 1975, 75, 521.
V. Grignard received the 1912 Nobel prize in Chemistry for his discovery I Mg
of the role of organomagnesium halides in organic synthesis which he CN O
made as a graduate student working with P. A. Barbier.
Barbier Compt. rend. 1899, 128, 110.

Grignard Comp. rend. 1900, 130, 1322.
b. Origin of Diastereoselectivity
Axial attack Note: The direction of attack is not from the axial or
–
RH equatorial vector, but with a 109.5° approach of the
nucleophile. no
O yes
versus
Hax O
Steric H Torsional Strain
H– H
Interactions
Felkin - equatorial attack (largely no
torsional strain - when R = H, H H yes
worse than axial attack mode)
Eclipsed Conformation
- Stereoelectronic effects
(105°± 5°)
90° 109.5° Dunitz angle: Tetrahedron 1974, 30, 1563.
R R Good overlap and ~ approaches bond angle
O versus O required of sp3 hybridization. Better σ – π∗
R R overlap (FMO) for nucleophilic addition.
99
- Cyclic Ketones: Steric vs. Torsional Interactions.
Nu–
Ha - As the nucleophile gets larger, this steric interaction with the C3-axial H
Ha OH
He e gets worse and equatorial approach becomes the preferred line of attack.
He
Ha Ha - For C3 and C5-H substituents, this torsional interaction is worse than
Ha
the steric interaction of Nu– / C3 and C5-H's (for small, unhindered Nu–).
Nu–
- All H– reductions have transition states that resemble reactant geometry.

- Diastereoselectivity is influenced by:
1) Steric interactions (1,3-diaxial interactions)
2) Torsional strain (1,2-interactions)
3) Remote electronic effects (electrostatic interactions)
- In contrast to early theories of "product development control" / late transition state vs
"steric approach control" / early transition state.
c. Baldwin's Rules and Burgi−Dunitz Angle of Attack
Recent review: Acc. Chem. Res. 1993, 26, 476.

Dunitz angle of attack: Burgi, Dunitz Tetrahedron 1974, 30, 1563; J. Am. Chem. Soc. 1973, 95, 5065.
- Nucleophile addition to carbonyl compound takes place not at 90° (perpendicular) to

the C=O, but at an angle of ~105° ± 5°
sp2 = 105° ± 5° sp3 = 180° sp = 120°
Nu–
Nu–
Nu– SN2
120°
R R
O O 120°
R R Nu– X
Ring closure reactions

- Importance of approach trajectory first detailed by Eschenmoser
Helv. Chem. Acta 1970, 53, 2059.
- Expanded and elaborated to: Baldwin's Rules for Ring Closure
J. Chem. Soc., Chem. Commun. 1976, 734, 736.
- Vector analysis and approach trajectory on sp2, sp, and sp3 systems.
- For intramolecular reactions the favored pathways are those where the length and nature of
the linking chain enables the terminal atoms to achieve proper geometry for reaction.
Exo Endo sp3 = tet

sp2 = trig
X– X– Y
Y X Y sp = dig
X
Y
Baldwin's Rules
Rule 1: tetrahedral (sp3) systems Rule 2: trigonal (sp2) systems Rule 3: digonal (sp) systems
(a) 3 to 7-exo-tet are favored (a) 3 to 7-exo-trig are favored (a) 3 to 4-exo-dig are disfavored
(b) 5 to 6-endo-tet are disfavored (b) 3 to 5-endo-trig are disfavored (b) 5 to 7-exo-dig are favored
(c) 6 to 7-endo-trig are favored (c) 3 to 7-endo-dig are favored
100
Reduction Reactions
Dale L. Boger
-Baldwin: Approach Vector Analysis (Vector Sum establishes the approach of reagent).
O Nu– O
1 1
1. Amides R N R R N R nonequivalent contributions
1 of each resonance form
Nu– R R1
O O
not line of attack is weighted average
1 1
R N R R N R of the two contributing resonance
forms
Nu– R1 Nu– R1
Nu–
2. Carboxylate O O
R O R O
Nu– equivalent and Nu– approaches
over (eclipsing) the R group
R O
Nu–
O Nu– O
3. Cyclohexenones
substituents in the C5 and C6

position will have a more
Nu– significant effect on the rate
and the stereochemical outcome
Nu–
Examples:
Nu–
CH3 - locked trans diaxial ring fusion
- preferential axial delivery of reagent
β-face - equatorial OH is major product
O H - addition of Nu– from β-face (equatorial delivery)
α-face H suffers from repulsive interaction with axial Me
major
LiAlH4 Houk and Trost J. Org. Chem. 1991, 56, 3656.
CH3
HO 70–90%
H H
101
- vs. H-
H CH3 CH3
HO
O H
single 1,3-diaxial H
interaction
major major product
- but H–
CH3
H
Large H–/CH3 OH CH3
interaction
O H
H–
H– major
H CH3 CH3
Smaller H–/CH3 H
O interaction HO
- With enones, the substituents in the 5,6-positions play a more dominant role in
determining stereochemical outcome of nucleophilic addition to the carbonyl.
2. Acyclic Carbonyl Groups

Review: Comprehensive Org. Syn., Vol. 1, pp 49-75.
- Cram's Rule J. Am. Chem Soc. 1952, 74, 5828.
Empirical and no mechanistic interpretation is imposed on model
J. Am. Chem Soc. 1959, 81, 2748. (chelation-controlled addition)
- Prelog Helv. Chim. Acta 1953, 36, 308. (1,3-induction)
- Felkin model: Tetrahedron Lett. 1968, 2199, 2205. V. Prelog received the
(or Felkin–Anh) Tetrahedron Lett. 1976, 155, 159. 1975 Nobel prize in
Nouv. J. Chim. 1977, 1, 61. Chemistry for his research
into stereochemistry of
organic molecules and
reactions.
a. Cram's Rule
O O D. J. Cram was awarded
S M S M the 1987 Nobel prize in
- Empirical Model Chemistry for his "host –
Nu R
Nu– R L L guest" complex studies.
- Large group L eclipsed with R and not the carbonyl, Nu– approach from side of small (S) group.
- Stereoselectivity observed usually modest.
- But, most populated (most stable) conformation of acyclic ketone would be the eclipsed
carbonyl conformation.
Nu–
R' O Nu
R R RL R RL R RL
O Nu
RL R' O
R' O
RM RM RMR' RM
This is not the observed stereochemistry!
Note: Reaction is not from the ground state carbonyl eclipsed RL conformation, i.e., the
ground state conformation is not the reactive conformation (Curtin–Hammett Principle).
102
Reduction Reactions
Dale L. Boger
b. Felkin (–Anh) Model
- Large group (L) trans antiperiplanar to forming bond
the sterically next most demanding substituent is gauche to carbonyl
versus
O O
S M O OL minimizes torsional
M
L Nu– L Nu L
strain (Pitzer strain)
M R in transition state
M S S
R R S R Nu (Felkin Model)
Same as Cram Product:
sterically most demanding group is perpendicular to
the plane of the carbonyl, anti to incoming nucleophile
- Here, L is either the largest group (sterically) or the group whose bond to the α-carbon provides
the greatest σ–π* overlap (e.g. halide, alkoxy groups).
- Computational studies of Anh confirmed this is the most stable transition state and extended it to
α-chloroketones. In the latter case, this minimizes destabilizing electrostatic interactions between
the halogen (electronegative group) and the incoming nucleophile.
Anh further refined the Felkin Model, i.e.,
Felkin–Anh Model, as shown below
Nucleophile prefers approach Nu–
O O that minimizes torsional strain
M S and incorporates Burgi–Dunitz R
L versus L trajectory. Primary interaction O
S R M Nu– is now between the Nu– and the R
Nu– R small or medium substituent.
Preferred
Note: Karabatose proposed a similar model as an alternative to the original Cram empirical rationalization
based on computational studies that suggested the most favored conformation would have the
medium-sized group eclipsing the carbonyl and addition of H– occurs from the side of the small substituent.
M
O
M
Nu OH
Karabatose J. Am. Chem. Soc. 1967, 89, 1367.
L L
Nu– S S
R R
The model incorporating the Burgi–Dunitz angle has been even further refined to reflect the impact of
substantially different sized R groups on the carbonyl. As the size difference between the two substituents
increases, the incoming nucleophile would try to avoid the larger one and the approach vector would be
tilted away from the normal plane by an angle referred to as the Flippin–Lodge angle (αFL).
Nu–
)
αFL
Heathcock Aldrichchim. Acta 1990, 23, 99.
RL RS
Nu–
Examples:
O MeMgCl O
O O –75 °C, THF HO Me
Me
Cl H Cl H
Johnson J. Am. Chem. Soc. 1968, 90, 6225. 92%
Cl Cl R H R O
Me – HO Et HO Et HO
O Et Cl H R
R H R Me H H Me Cl Me Et Me Et
103
-First observed in cyclic systems: Cornforth J. W. Cornforth received the 1975 Nu–
J. Chem. Soc. 1959, 112 and 2539. Nobel prize in Chemistry jointly with V. O
J. Chem. Soc. 1957, 158. Prelog for outstanding intellectual
achievement on the stereochemistry of
reactions catalyzed by enzymes. Cl axial
-For cyclic ketones -For acyclic ketones

Axial
R' R'
H S O H O
O M D
H Equatorial L A
Allylic bonds prefer to be staggered (axial attack) with respect to the

incoming nucleophile rather than eclipsing (equatorial attack).
c. Cieplak Model J. Am. Chem. Soc. 1981, 103, 4540.
Nu– vacant σ*
σ* σ*
O O O
O
H
adjacent σ axial attack equatorial attack

bonds considered stabilization stabilization
1. C–H bond is more electron-rich, better σ e-donation in stabilization of the developing σ* of bond
formation than C–C bond, therefore axial approach preferred.
2. σ C–O > σ C–H > σ C–C > σ C–S.
3. Nucleophile can affect intensity of effect, σ* (LUMO of developing bond).
LUMO, effect, overlap/stabilization
(a) Electron donation of solvent (polarity) will increase σ*, LUMO, overlap,
equatorial attack, i.e. preferentially axial attack
(b) Counterion effect: its ability to complex/stabilize σ*, lower σ* effect, axial attack.
(c) Electron-rich Nu–: σ* nucleophile, overlap/effect, axial attack equatorial attack.
4. Heteroatom at 4-position exhibits preference for axial attack: n–σ* stabilization.
Review: Cieplak Chem. Rev. 1999, 99, 1265.
d. Additional Models
- Product development/steric approach control
Dauben: J. Am. Chem. Soc. 1956, 78, 2579.
- Torsional strain (preference for staggered conformation in the transition state) higher level calculations
Felkin: Tetrahedron Lett. 1968, 2199, 2205. than Anh or Cieplak: C–C >
Houk: J. Am. Chem. Soc. 1987, 109, 906. C–H electron donation.
J. Am. Chem. Soc. 1988, 110, 3228.
Science 1986, 231, 1108.
J. Am. Chem. Soc. 1991, 113, 5018. remote-through space
J. Am. Chem. Soc. 1993, 115, 10992. electrostatics and
Angew. Chem., Int. Ed. Eng. 1992, 31, 1019. torsional effects account
cf. Chemtracts: Org. Chem. 1988, 1, 65. for Cieplak observations.
Houk–Trost: J. Am. Chem. Soc. 1987, 109, 5560.
- Principles of least motion
Yates: J. Am. Chem. Soc. 1974, 96, 3141.
- Stereoelectronic control and smallest change in conformation
Toromanoff: Tetrahedron 1980, 36, 2809.
- Electrostatic model
Kahn, Hehre, Chamberlin: J. Am. Chem. Soc. 1987, 109, 650, 663, 666.
J. Am. Chem. Soc. 1986, 108, 7396, 7399.
104
Reduction Reactions
Dale L. Boger
- Electronic nonequivalence of carbonyl faces
Klein: Tetrahedron Lett. 1973, 4307; 1974, 30, 3349.
- Dissymmetric π-electron clouds
Fukui: J. Am. Chem. Soc. 1976, 98, 4054.
Burgess, Liotta: J. Am. Chem. Soc. 1984, 106, 4849.
- Antiperiplanar approach of Nu– to other bonds
- Preferential attack antiperiplanar to the best electronic acceptor
Anh: Tetrahedron Lett. 1976, 155, 159.
Nouv. J. Chim. 1977, 1, 61.
Top. Curr. Chem. 1980, 88, 145.
Dunitz, Eschenmoser: Helv. Chim. Acta 1980, 63, 1158.
- Preferential attack antiperiplanar to the best electronic donor
Cieplak Model: J. Am. Chem. Soc. 1981, 103, 4540.
Chem. Rev. 1999, 99, 1265.
- Others
Ashby: J. Org. Chem. 1976, 41, 2890.
Wigfield: J. Org. Chem. 1976, 41, 2396; 1977, 42, 1108.
- Bent bond or Tau-bond model
Vogel, Eschenmoser: Chem. Lett. 1987, 219.
Winter: J. Chem. Educ. 1987, 64, 587.
- Hyperconjugation
Coxon, Luibrand: Tetrahedron Lett. 1993, 34, 7097.
- Recent reviews of the various models: Chem Rev. 1999, 99, 1225−1467.
e. Comparative Examples of Diastereoselection

- Diastereoselection depends on the size of the ketone substituent.
Kobayashi, Ohno J. Am. Chem. Soc. 1988, 110, 4826.
Me Me Me Me Me
SiMe3 Nu– Nu Nu Bu 1) TMSLi Bu
R R + R Ph Ph
Me3Si OH HO SiMe3 2) Bu4NF
O O OH
1 > 50:1
Felkin Product Bu4NF Complementary stereochemistry to
Me Me Me that illustrated with acylsilanes.
H Nu– Nu + Nu
R R R Note: Desilylation proceeds with
complete retention (>99:1): Hudrlik
O OH OH
2 J. Am. Chem. Soc. 1982, 104, 6809.
From 1 From 2
nBuLi
R = Ph > 100:1 5:1
R = Ph MeLi > 40:1 4:1 Note: Typical Felkin
R = Ph SiMe3 > 100:1 2:1 diastereoselection is modest.
R = Ph MgBr 11:1 1.7:1

Note: Diastereoselection is
increased dramatically with very
R= nBuLi > 30:1 1.6:1 large ketone substituent.
MeLi > 100:1 1.9:1
SiMe3 > 30:1 1:1
MgBr 11:1 2.5:1 O M O M
R=
nBuLi 15:1 3.5:1 L L
Nu– S Nu
–
MeLi 21:1 2:1 R S SiMe3
SiMe3 > 100:1 1.5:1
Increase size, increase
MgBr 3.5:1 2:1 diastereoselectivity
105
Me Me R ratio
LiAlH4 Me 74 : 26 Felkin Tetrahedron Lett. 1968,
R R 2199 and 2205.
Ph Ph Et 76 : 24
iPr
Diastereoselectivity for reduction
O OH 83 : 17 with LiAlH4
tBu 98 : 2
R = tBu > iPr > Et > Me
- Diastereoselectivity depends on size of nucleophile.
Me Me Me
Nu–
Me Me + Me
Ph Ph Ph
O OH OH
LiAlH4 74 26 Yamamoto J. Am. Chem. Soc. 1988,
(sBu)3BHLi >99 <1 110, 4475.
Me Me Me
H Me– Nu + Nu
Ph Ph Ph
O OH OH
MeLi 65 35 Reetz Top. Curr. Chem. 1982, 106, 1.
MeMgBr 66 34 Reetz Angew. Chem., Int. Ed. Eng.
MeTi(OiPr)3 1992, 31, 342.
88 12
MeTi(OPh)3 93 7
MeMgOTs 92 8
MeMgOPiv 94 6
Felkin Product
f. Chelation-controlled Addition
- Review: Acc. Chem. Res. 1993, 26, 462.
- 1,2-chelation-controlled additions (α-chelation-controlled additions)
also formulated by Cram: J. Am. Chem. Soc. 1959, 81, 2748.
So please do not refer to as anti-Cram addition as many have!
Met
XO OMet
X Can usually provide excellent
diastereoselectivity
Nu– S L S
R Nu LR
1,2-chelation X = OH, OR
Nu– Nu
R S OR
S O
R O Met R OH
L
L
Nu– H RS RL
Axial delivery on most stable
R O Met R R chair-like transition state
RL Nu
O Asymm. Syn. Vol. 2, 125.
R syn-1,3-diol OH OH
RS
1,3-chelation
- Examples of 1,2-chelation-control
- Nicolaou J. Am. Chem. Soc. 1980, 102, 6611. Zoapatanol synthesis
H H
O R O R
MeMgBr
O O
O >95:5 HO
O O Me
106
Reduction Reactions
Dale L. Boger
-But to invert the stereochemistry
H
H O R
O R
O
O HO
O Me BrMg Me
O O
Zoapatanol
- Still J. Am. Chem. Soc. 1980, 102, 2117, 2118 and 2120. Monensin synthesis
CH3 Me OH
OTBS OTBS
O
H MgBr H
O O Ph O O Ph
Si 50:1 Stereoselectivity
TBS =
- Note that non chelation-controlled additions exhibit relatively modest stereoselectivities,

but chelation-controlled additions can exhibit very good stereocontrol.
- Kishi Tetrahedron Lett. 1978, 2745.

J. Am. Chem. Soc. 1979, 101, 260.
H Et EtMgBr H Et
Me Me
O BnO O
Me O OBn MeEt OH OBn
- Evans J. Am. Chem. Soc. 1990, 112, 5290.
H Me MeMgBr H Me
BnO O CH2Cl2−Et2O BnO O
O Met OAc Me OH OH
H H
R Nu– Nuc
O O HO R
O
Met
R = CH3 Nu– = PhMgI 100:0

Ph MeMgBr or MeLi 100:0
Ph LiAlH4 84:16
Ph (sBu)3BHLi 100:0
CH3 (sBu)3BHLi 78:22
- Chelation Model Met

O
OO Nu OH
Nu– H
H R
R chelation-controlled product
- Felkin Model O O
R OH
R O
H H
Note: here Felkin model Nu
will predict wrong product Nu– Felkin model predicted product
107
- Effect of metal and solvent
chelation product Felkin product
H C7H15
H C7H15 H C7H15
O nBuM
O O +
MEMO MEMO
O –78 °C HO Bu Bu OH
MEM
protecting group I II
solvent I II solvent I II
M = MgBr pentane 90 10 M = Li pentane 67 33

" CH2Cl2 93.5 6.5 " CH2Cl2 75 25
" Et2O 90 10 " Et2O 50 50
" THF 100 0 " THF 41 59
Note: Li is less able to coordinate to two O
Still Tetrahedron Lett. 1980, 21, 1031. atoms and THF has good solvation capabilities
(ie., removes Li+; no α-chelation control)
Me
C7H15 Me
H H C7H15
Nu–
O Nu OH
O R OR
M
chelation model chelation-controlled product
Two models provide different products
Me H Me H Nu
_
_ H
C7H15
RO Nu– RO Nu _
Me OH
OC7H15 HO C7H15 OR
Felkin model Felkin model predicted product
- Effect of protecting group

H C7H15 nBuMgBr H C7H15
RO THF, –78 °C RO
O HO Bu
R = MEM > 99:1
= MOM > 99:1 Note: THP poor for
= MTM > 99:1 chelation-control.
= CH2Ph 99.5:0.5
= CH2OCH2Ph 99:1
= THP 75:25
Still Tetrahedron Lett. 1980, 21, 1035.
RO RO RO
LiAlH4
+
O OH OH
Note: OTBS R = Bn Et2O, –10 °C 98 : 2 chelation-controlled

does not chelate : Felkin addition
R = TBS THF, –20 °C 5 95
Overman Tetrahedron Lett. 1982, 23, 2355.
108
Reduction Reactions
Dale L. Boger
H Me Nu– H Me
Et Et
R'O –78 °C R'O
O HO R
R' = CH2Ph MeMgCl Et2O > 99:1 chelation-controlled
MeLi THF 60:40 Note: Silyl ether poor
R' = TBS MeMgCl Et2O 60:40 for chelation-control.
MgCl THF 10:90 Felkin addition
Reetz J. Chem. Soc., Chem. Commun. 1986, 1600.
OH OH
Zn(BH4)2 1 anti-1,2-diol
R1 2
R 2 chelation-controlled addition
R R
Et2O, 0 °C
O OH 77–99 : 23–1
versus
OTBS 1) Red-Al OH syn-1,2-diol
Note: TBS very good at R 1
toluene, –78 °C R1 Felkin addition
R2 R2
suppressing chelation. 2) Bu4NF 76–98 : 24–2
O OH
Nakata Tetrahedron Lett. 1983, 24, 2653 and 2661.
- Effect of metal
OBn SnBu3 OBn
H
Lewis Acid
O OH
BF3•OEt2 2:3
ZnBr2 3:1
MgBr2 > 250:1
TiCl4 > 250:1
Keck Tetrahedron Lett. 1984, 25, 265.
OH O OH
K-selectride Zn(BH4)2
THF, –95 °C Et2O, –30 °C R OBn
R OBn R OBn
90:10 95:5
Felkin addition chelation-controlled
Note: Red-Al was anti selective due to coordination of OBn
Tsuji Tetrahedron Lett. 1985, 26, 5139.
Back side attack blocked

O Met by phenyl group O
O
Ph MeMgBr OH
O O
H Me H
98% de
Metal chelate and preference for H-eclipsed carbonyl
conformation provides a dominant conformation.
Whitesell Acc. Chem. Res. 1985, 18, 280.
J. Org. Chem. 1986, 51, 5443.
-1,3-Chelation-Controlled Additions (β-chelation-controlled additions):
- First highly selective method was developed with
R3B/NaBH4 and later with Et2BOCH3–NaBH4 in THF–MeOH:
Pai Tetrahedron 1984, 40, 2233.
Shapiro Tetrahedron Lett. 1987, 28, 155. (syn:anti 98:2)
- Dibal-H (> 92:8 syn:anti) Kiyooka Tetrahedron Lett. 1986, 27, 3009.
109
L L
Note: Typically easy to
M achieve chelation-
O O
Chelation control with controlled syn-1,3-diol.
external H– delivery R'
H R'' OH OH
H–
_
_
_
R' R''
H– H L
HO H O syn-1,3-diol
Axial H– or Nu–
delivery R' O M L
R' R'' O
R''
OH OH
H
O L
Controlled with – R' R''
O B L
internal H– delivery R' anti-1,3-diol
R'' H
- Examples of anti-1,3-diol preparation:

Evans, Carreira, Chapman J. Am. Chem. Soc. 1988, 110, 3560.
H OH
O
tBu tBu OH + tBu H
NaBH4 90 : 10
Me4NBH(OAc)3 no reaction
O H OH
OH OH OH
tBu tBu OH tBu H
NaBH4 1 : 1
Me4NBH(OAc)3 300 : 1
HOAc, low temperature protonates carbonyl,

activation for reduction, no reduction without HOAc
- Note that Me4NBH(OAc)3 is unreactive toward carbonyl unless carbonyl oxygen is protonated.
- The key to success is the lack of reactivity of the reagent in the intermolecular reaction, which
permits formation of complex:
First example of NaBH(OAc)3/HOAc intramolecular reduction of a ketone, see:

Saksena, Mangiaracina Tetrahedron Lett. 1983, 24, 273.
For the reduction of aldehydes in the presence of ketones which are not reduced, see:
Gribble J. Chem. Soc., Chem. Commun. 1975, 535.
AcO – OAc
B internal axial hydride delivery
HO
O
H
110
Reduction Reactions
Dale L. Boger
OH O OH OH
Me4NBH(OAc)3
HOAc
Me Me
92%
98:2
H H OAc
O has two equatorial substituents,
B
O OAc on the chair-like transition state
Me excellent diastereoselectivity
R H
H
OH O OH OH
Me4NBH(OAc)3
HOAc
Me Me
84%
98:2
H
H OAc
O
B
O OAc
axial alkyl group, but no still observe excellent
R H
destabilizing 1,3-diaxial diastereoselectivity
interactions Me
Si H
-Also, works with O O + Lewis acid (to activate carbonyl)
H
R R2 Lewis acid activation
OH O iPr
iPr
2SiHCl 2SiHO O 1) SnCl4, –80 °C OH OH
R1 R2 Et3N, DMAP R1 R2 2) HF R1 R2
Davis Tetrahedron 1988, 44, 3761. internal H– delivery anti-1,3-diol
- Nucleophiles other than H−
SnBu3 Me
Me H −78 °C Me Me H
BnO O CH2Cl2 BnO OH BnO O Lewis Acid BnO OH

CH2Cl2, −78 °C
MeMgCl, THF 40:60 TiCl4 95:5
MeTiCl3 90:10 SnCl4 95:5
BF3•OEt2 85:15
Reetz J. Am. Chem. Soc. 1983, 105, 4833. Reetz Tetrahedron Lett. 1984, 25, 729.
g. Felkin Addition to Other π-Systems
- Reetz Angew. Chem., Int. Ed. Eng. 1989, 28, 1706.
R CO2Et Bu
H
Bu2CuLi R CO2Et
H
NBn2 H
NBn2
>95:5 (R = CH2Ph)
_
_
_
NBn2 NBn2 H
- Felkin Model H H _
_ H
H CO2Et _ CO2Et
H R CO2Et H R R NBn2
Bu Bu
Nu– (Bu– )
111
But, CO2Et Bu
Bu2CuLi H
R CO2Et R CO2Et
H
H NBn2 CO2Et
NBn2
>95:5 (R = CH2Ph)
_
_
_
Bu– smaller
interaction Bu
R H R H
CO2Et
H H CH(CO2Et)2
CO2Et
NBn2 NBn2
compared with
NBn2 H Bu
CO2Et H CO2Et
H
H R CO2Et R
NBn2 CO2Et
Nu– (Bu– ) serious destabilizing interaction
- Rationalize the following results:

R CO2Et tBuOOH O O
R CO2Et R CO2Et
H +
NBn2 KOtBu H H
THF/NH3 NBn2 NBn2
R = CH3 46% > 96 : 4
R = PhCH2 60%
R= 68%
R = TBDMSOCH2 80%
E. Aluminum Hydride Reducing Agents

- LiAlH4 coordinates with carbonyl oxygen and activates it towards reduction.
O H H O O
H O O
Li H Al H H Al H H Al O
k1 k2 k3 k4
H H H H
FAST
- Rate of addition decreases as additional alkoxy groups are placed on Al: k1 > k2 > k3 > k4,
especially for hindered ketones.
- The aluminum alkoxide hydrides are stable in that they do not disproportionate.
- Reagents have been designed which are less reactive, thus more selective:
- Reactivity: LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)3H
3 ROH
LiAlH4 LiAlH(OR)3
- Most common are LiAlH(OCH3)3 and LiAlH(OtBu)3
112
Reduction Reactions
Dale L. Boger
- Examples:
more reactive
OH
towards nucleophiles
H
LiAlH4
H H
HO
O H
H
O OH
H H
O
H LiAlH(OR)3 H
0 °C, Et2O O
H H
O
H
Chemoselectivity: differentiation between
competitive functional groups
vs.
Regioselectivity: differentiate between
orientations.
- Lithium trialkoxyaluminumhydrides can be chemoselective.

OH
O
OH +
NaBH4 36–45 : 55–64
H LiAlH4 37–48 : 52–63
LiAlH(OCH3)3 2–8 : 92–98

O
LiAlH(OtBu)3 4–12 : 88–96
- this is actually dimeric in solution, so effective bulk

greater than LiAlH(OtBu)3
- degree of stereocontrol is concentration dependent
with LiAlH(OCH3)3 (dimer and higher aggregates) but
not LiAlH(OtBu)3 (monomeric)
F. Borohydride Reducing Agents

- Borohydrides (Na+, Li+, K+, Zn2+) are nucleophilic H– sources.
- Alkoxyborohydrides (RO)3B–H tend to disproportionate.
Na (RO)3BH NaBH4
- Therefore, k1 ~ k2 ~ k3 ~ k4 for the stepwise reactions and you can't typically moderate
the reactivity (electronically) by introducing alkoxy substituents.
- However, substitution with bulky alkyl groups on boron will moderate reactivity and
113
OH
O
OH +
CH3 CH3 CH3
LiAlH4 75 : 25
BH3•THF 74 : 26
21 : 79
BH
2
Li-Selectride <1 : >99

BHLi
3
K-Selectride <1 : >99

BHK
3
- NOTE: on diborane
H H H
B2H6 = B B 2 BH3 2 H3B O
H H H
- THF optimally provides uncomplexed, monomeric BH3 available for reduction (or other reactions).
- In ether (B2H6), or in the presence of amines (BH3•NR3), less reactive borane-complexes are formed.
B2H6 H3B NR3

stable reactions of B2H6 in
BH3•THF Et2O or in the presence
BH3•OEt2 B2H6 2 BH3 of 3° amines will be
BH3•SMe2 slower than reactions
run in THF
BH3•NR3 H3B O
not stable
- NaBH4 requires activation of the carbonyl by hydrogen-bonding with alcoholic solvent for reductions.
Therefore the reactions are run in alcoholic solvents. The reagent slowly reacts with solvent:
MeOH (30 min) > EtOH (slow) > iPrOH (stable) > tBuOH (stable).
H R'
O
O
R R
H
B
H H
H
- But trialkylborohydrides (R3B–HM+) are reactive enough to use in ethereal solvents
(e.g., THF) and don't require this activation of C=O by solvent.
- LiBH4 is also more reactive than NaBH4 (Li+ coordinates better to carbonyl oxygen,
activating the carbonyl toward attack by H– ).
- Differences in reactivity can give rise to Chemoselectivity:
114
Reduction Reactions
Dale L. Boger
O OH
O NaBH4 O
O O
LiBH4
Carbonyl Reduction Reagents:
Larock pp 528–552.
OH Chem. Soc. Rev. 1976, 5, 23.
J. Am. Chem. Soc. 1981, 103, 4540.
J. Org. Chem. 1991, 56, 4718.
HO Top. Stereochem. 1979, 11, 53.
G. Hydride Reductions of Functional Groups

Substrate LiAlH4 Product
RCOCl RCH2OH
decreasing reactivity
RCHO RCH2OH
RCOR' RCH(OH)R'
H
RCH2NR'2 H
R NR'2 OH
O
RCOOR' RCH2OH + R'–OH
RCOO (slow) RCH2OH

OAlR2
H2O
RCHO R RCONR'2 RCH2NH2 or RCHO
NR'2
H
requires vigorous H LiAlH4

reductant to further RC N RCH2NH2 or RCHO
reduce this R N Al
- DIBAL-H + RC N (at 0 °C) gives good yields of RCHO
OH
N NH2 NHOH
or
R R' R R' R R'
RNO2 RNH2
RCH2X RCH3
X = Br, Cl, I, OSO2R
RCHX RCH2R'
R'
115
O O
- Reductions of
R NR'2 R H
O O OAl LiAlH4
R'
R N R NR'2
R H R NR'2 R NR'2
R'
OH OH best procedure is use of DIBAL as reducing

H+
agent at –78 °C - quench with MeOH at –78 °C
R NR'2 R NR'2 quench to avoid over reduction.
H
- or other specially selected amides will cleanly give aldehyde:
enlisting these electrons disrupt
the aromaticity of pyrazole
Al O H
O
1. LiAlH4
R N R N R N
Et2O, 0 °C
very slow N
N (–20 °C) N
breakdown to iminium ion no longer aromatic

intermediate very slow
Ried Angew. Chem. 1958, 70, 165.
O O Al H
LiAlH4
2. R N R N R N
very slow
too strained
Brown J. Am. Chem. Soc. 1961, 83, 2016 and 4549.
3. Weinreb amide
- A more recent and now widely employed method for controlled reduction
and nucleophilic addition (i.e. RLi) to carboxamides was introduced by
Weinreb (Tetrahedron Lett. 1981, 22, 3815).
Al
O O O
H
OMe LiAlH4 OMe H3O
Ph N Ph N Ph H
Me Me
Chelation stabilizes
intermediate which does
not breakdown during
the reaction, but only upon
workup.
O O
OMe
N DIBAL-H H
Me 0 °C
74%
116
Reduction Reactions
Dale L. Boger
O O
OMe DIBAL-H
N H OH
+
Me 0 °C
76% 3%
O O O
O
OMe LiAlH4 OMe THF
N H RLi + H N
−78 to 25 °C R H
BOCHN Me BOCHN Me
88%
Castro Synthesis 1983, 676. Lipshutz Tetrahedron Lett. 1999, 40, 7889.
4. The Rosenmund reduction is a much older method that may be utilized to convert
carboxylic acids to aldehydes via the acid chloride.
H2
RCO2H RCOCl RCHO
Pd/BaSO4
Rosenmund Ber. 1921, 54, 425; Ber. 1918, 51, 585.
Review: Org. React. 1948, 4, 362.
Burgstahler Synthesis 1976, 767.
5. Bu3SnH will selectively reduce selenoesters to aldehydes without further reduction
by a free radical mechanism.
O Bu3SnH O - Also possible to promote
Bu3SnSePh decarbonylation prior to
R SePh 80 °C R H reduction to achieve
conversion to the
O Bu3SnH corresponding hydrocarbon.
Bu3Sn
Bu3SnSePh
R
acyl radical
Pfenninger Helv. Chim. Acta 1980, 63, 2328.
- Review of RCOX RCHO: Comprehensive Org. Syn., Vol. 8, pp 259 and 283.
6. Bu3SnH−InCl3
Bu3SnH
0.1 equiv InCl3
RCOCl RCHO
0.2 equiv Ph3P
> 80%
Baba Tetrahedron Lett. 2000, 41, 113.
7. McFadyen–Stevens reduction: J. Chem. Soc. 1936, 584.
O O O
NHTs B: N
R N R N R H
H
X CO2Me X CHO
NH NH
NH NH
X = OCH3 34%
X=H 39%
Boger J. Org. Chem. 1988, 53, 1405. (Prodigiosin)
117
- Reactions of Borane (BH3) an electrophilic reagent
Carboxylic acids
may be selectively Substrate Product
reduced in the O
presence of a wide X
RCOOH B RCH2OH
range of functional R O
groups. 3
RHC CHR' RCH2CH(B)R'
Amides may
RCONR'2 RCH2NR'2
be reduced
selectively in
the presence RCHO, RCOR' RCH2OH, RCH(OH)R'
of esters.
decreasing reactivity
RC N (slow) RCH2NH2
(very slow, Lewis acid OH

activation required)
O
RCOOR' RCH2OH
NOR NH2 or NHOH
RCOCl RCH2OH
RCOO , RNO2 no reaction
But: see Tetrahedron Lett. 1982, 23, 2475.
H. Characteristics of Hydride Reducing Agents

Borohydrides
1. NaBH4
- Review: Aldrichim. Acta 1979, 12, 3.
- Mild reducing agent used primarily for the reduction of aldehydes and ketones.
- Also available as NaBD4, NaBT4 (although somewhat less reactive) for labelling.
- H+ workup of NaBH4 reductions may form BH3 (if excess NaBH4 used)
might react with other functional groups (this is the origin of the discovery of BH3
and its hydroboration of alkenes).
- NaBH4 reacts with H2O, CH3OH at 25 °C ca. 30 min
reacts only slowly with EtOH (good solvent), is stable in iPrOH or tBuOH and can also be used
in diglyme but the latter reduction is very slow.
Although amides are not reduced by NaBH4, the corresponding imino ester salts can be
O Et3O+BF4− OEt NaBH4

Ph NEt2
Ph NEt2 CH2Cl2 Ph NEt2 EtOH, 25 °C
75%
Borch Tetrahedron Lett. 1968, 61.
2. NaCNBH3
- Less reactive than NaBH4.
- Stable in aqueous solutions even at pH > 3 (permits activation of C=O by protonation).
- Can be used in CH3OH.
- Can be used in THF but reduction very slow.
118
Reduction Reactions
Dale L. Boger
- Reductive amination (Borch reduction):
R
O NaCNBH3 N
+ H2NR
pH 3–6
relatively unreactive H+
toward NaCNBH3
Under acidic conditions
R H R the protonated imine is
HN N more reactive than
starting ketone or
very good way to make 2° amines aldehyde.
CHO NaBH3CN
+ MeNH2 N Me
CHO
Borch J. Am. Chem. Soc. 1969, 91, 3996; 1971, 93, 2897.
J. Chem. Soc., Perkin 1 1984, 717.
- Review: Comprehensive Org. Syn., Vol. 8, pp 25–78. This review also discusses the
diastereoselectivity of cyclic/acyclic imine/iminium reductions with comparisons to the
corresponding ketone. Many similarities but also many important distinctions.
3. LiBH4
- More reactive than NaBH4 (Li activates C=O by coordination).
- Can be used in THF, diglyme and non protic solvents. Reactivity: Et2O > THF = diglyme > iPrOH
- Excellent reagent for mild reductions.
O
OEt OH 98%
- clean 1,2-reduction!
- NaBH4 does not typically reduce esters
4. Me4NBH4, Et4NBH4
- Soluble in nonpolar aprotic solvents (e.g., THF, benzene).
5. Zn(BH4)2
- Good in instances of potential competing 1,4-reduction.
- Zn+2 coordinates to and activates carbonyl.
- Good for chelation-controlled reductions.
O OH OH
Zn(BH4)2 96% 4%
NaBH4 59% 41%
- Review: Narasimhan Aldrichim. Acta 1998, 31, 19.
6. NaBH4/CeCl3 (catalytic amount (0.1 equiv))
- Luche J. Am. Chem. Soc. 1981, 103, 5454; 1978, 100, 2226.
- Readily enolizable carbonyl can be reduced.
- also true of other nucleophiles O
OH
RMgBr CeCl3
RLi
R
- clean addition, no enolization
R
O O
RMgX
OH
RMgX CeCl3
Imamoto J. Am. Chem. Soc. 1989, 111, 4392.
Review: Liu Tetrahedron 1999, 55, 3803.
119
- No conjugate reduction: clean 1,2-reduction.
-Reagent comparisions for 1,2- vs. 1,4-reduction
O O
Reagent 1,2 : 1,4 1,2 : 1,4

LiAlH4 85 : 15 (100%) 94 : 6 (97%)
NaBH4 0 : 100 (100%) 59 : 41 (90%)
NaBH4/CeCl3 97 : 3 (100%) >99 : 1 (100%) !!!
LiAlH4/CeCl3 64 : 36 (99%) 98 : 2 (100%)
DIBAL-H 98 : 2 (81%) 98 : 2 (100%) Masamune J. Chem.
DIBAL-H/nBuLi 99 : 1 (83%) 94 : 6 (96%) Soc., Chem Commun.
1970, 213.
9-BBN >99 : 1 (85%) >99 : 1 (85%) Brown J. Org Chem.
LiAlH(OMe)3 90 : 10 95 : 5 1977, 42, 1197.
LiAlH(OtBu)3 0 : 100 22 : 78
7. NaBH4–CoCl2
- Selective reduction of nitriles.
H2N
NC CO2Et CO2Et
Ganem J. Am. Chem. Soc. 1982, 104, 6801

- But will also reduce olefins, allylic alcohols, and ketones.
OMOM OMOM
MOMO MOMO
OH OH
Iwata Chem. Pharm. Bull. 1990, 33, 361.

8. Me4NBH(OAc)3 and NaBH(OAc)3
- Unreactive, no intermolecular ketone reductions.
- OAc can exchange with substrate alcohol and provides opportunity for intramolecular reductions
(CH3CN–HOAc). Used to form anti-1,3-diols from acyclic β-hydroxyketones.
9. KBH(OiPr)3
- Stable (does not undergo disproportionation reaction as with other alkoxy BH), mild reagent.
- Used in THF and only reduces aldehydes and ketones; bulky reagent so it gives equatorial
attack on cyclohexanones.
H
B
10. 9-BBN
- Stable solid; more stable and less reactive/more selective.

- Gives good 1,2- vs. 1,4-reduction selectivity.
- Very selective reagent.
11. Li-Selectride K-Selectride

BHLi BHK
3 3
- Large reagents, near exclusive cyclohexanone equatorial H– delivery.
- Very bulky.
120
Reduction Reactions
Dale L. Boger
- Very reactive and give preferential 1,4-reduction.
- Reductive alkylation with
O OBR3 regiospecific enolate generation.
can alkylate
these enolates
Ganem J. Org. Chem. 1976, 41, 2194.

12. LiBHEt3 (Super Hydride)
- Very powerful (stronger than LiAlH4), so good for reductions which are otherwise slow.
O
OH
H
R X R H
Relative reactivity: Et3BH– (10,000), AlH4– (240), BH4– (1).

Brown J. Org. Chem. 1983, 48, 3085.
H S
13. NaBH4–HSCH2CH2SH B
H S
- Used in THF.
- Guida J. Org. Chem. 1984, 49, 3024.
RCO2Et THF RCH2OH

Note the selectivity
available
PhCO2iPr PhCH2OH
83%
PhCO2tBu
PhCN
Yet powerful enough

PhCONH2 PhCH2NH2
to reduce amides
Aluminum Hydrides
1. LiAlH4
- LiAlD4 and LiAlT4 are also available for labelling.
- Reductions can be conducted in ether, THF, DME, diglyme.
- Workup best conducted by 1,2,3 method:
for 1.0 g LiAlH4 used, add 1 mL H2O (slowly)
then 2 mL of 10% aqueous NaOH, then 3 mL
H2O Al salts are now easily filtered
2. NaAlH4
- Not quite as reactive as LiAlH4, but still quite strong reducing agent.
- THF, DME, diglyme solvents.
3. LiAlH(OtBu)3
LiAlH(OEt)3
LiAlH(OMe)3 this is the largest reagent (due to aggregation) of the three
- Use in THF, diglyme.
- Review on alkoxyaluminum hydrides: Org. React. 1985, 34, 1; 1988, 36, 249.
121
4. NaAlH2(OCH2CH2OMe)2 = REDAL-H
OH
benzene
80 °C
COOCH3
OH
powerful reducing
agent
CH3
OH
xylene Cerny, Malek
140 °C Tetrahedron Lett. 1969, 1739.
OH
- Xylene, benzene, toluene good solvents.
- Good for epoxide openings (especially if able to be directed by proximal OH), halide and
sulfonate reduction.
5. = DIBAL-H
AlH
2
R
- Good for RC N RCHO via NAl
H
- Because there is no metal cation (Li+, K+, etc.) in the reagent, very good for directed reductions
(i.e., chelation-controlled reductions).
- Good for 1,2- vs. 1,4-reduction.
H CO2Et H
OH
NBOC 80% NBOC
- Also good for RCOOR' RCHO

CO2Me CHO
DIBAL-H
O O Garner Org. Syn. 1992, 70, 18.
NBOC –78 °C NBOC
via O Al
R OR'
H
stable at –78 °C but breaks to get RCHO, quench must be
down at higher temperatures conducted at –78 °C (use MeOH or
to give alcohol (upon HOAc as proton source, H2O freezes
further reduction) into a solid) then warmed to 25 °C
- Also, use of noncoordinating hydrocarbon solvent (toluene) provides better control than THF for
reductions to RCHO.
6. AlH3
AlH3–NR3
- Park J. Org. Chem. 1990, 55, 2968.
RCO2H RCH2OH
CO2Et
Cl Cl OH
OH
O2N COCl O2N
122
Reduction Reactions
Dale L. Boger
O
NMe2 NMe2
CN
NH2
7. Cl2AlH
Strong electrophilic reducing agent
O Cl2AlH O O
OH OH
O AlCl3 O Cl2Al O H
Et2O, reflux
ClAlH 94%
Eliel Org. Syn. 1967, 47, 37.
A related and often overlooked alternative enlists NaBH4 + Lewis acid
CO2tBu OtBu
Me Me
NaBH4 Me H
Me H
BF3
H H diglyme, THF H H
H H
76%
Pettit J. Org. Chem. 1962, 27, 2127.
Eliel J. Org. Chem. 1964, 29, 1630. (thiol ester dialkylsulfide)
Other Representative Reagents
R F
1. Bu3SnH–Bu4NX, X = Cl, F R Sn
R H
- Shibata Chem. Lett. 1991, 307.
Br Br O OH
O OH
- Can alkylate intermediate directly:
O OSnR3 OR'
Bu3SnH R'X
Bu4NCl
OCH3 OCH3
Ph Bu3SnH Ph 100%
Bu4NF Felkin addition
O 81% OH
2. PhMe2SiH
OH O OH
1) PhMe2SiH 1) PhMe2SiH
Ph Ph Ph
Bu4NF, TFA, 0 °C
OBz HMPA, 0 °C OBz 2) KOH OBz
2) KOH 72%
Felkin addition 82% chelation-type control
96 : 4 93 : 7
Hiyama J. Org. Chem. 1988, 53, 5405 and 5415.
J. Am. Chem. Soc. 1984, 106, 4629.
123
3. Et3SiH
Et3SiH
O cat. OSiEt3
- Regioselective enolate trap, conjugate reduction.

4. (EtO)3SiH/catalytic Ti(OiPr)4
- No solvent, stable to air.
- Reduces esters to alcohols in the presence of a wide variety of functional groups.
RCO2Et RCH2OH
- Buchwald J. Org. Chem. 1992, 57, 3751.
5. [(Ph3P)CuH]6
O O
[(Ph3P)CuH]6
85% O
O H 94:6 cis:trans
Stryker Tetrahedron Lett. 1988, 29, 3749; 1989, 30, 5677; 1990, 31, 3237.
J. Am. Chem. Soc. 1988, 110, 291.
I. Asymmetric Carbonyl Reductions

- Review: Comprehensive Org. Syn., Vol. 8, pp 159.
- Itsuno Org. React. 1998, 52, 395.
1. Catalytic Asymmetric Reduction

- Corey J. Am. Chem. Soc. 1987, 109, 5551.
Ph Ph
H Ph BH3 H Ph
HN O H N O
B H3B B
H H
H Ph H Ph H Ph
Ph
Ph Ph
N O N O N O
B H3B B H3B B
H H H
Better catalyst O
80–97% ee RS
RL coordinates anti
to large substituent
- Corey J. Am. Chem. Soc. 1987, 109, 7925. (catalytic) (in plane)
H β-naph
R RS vs. RL
β-naph R O B RS in plane carbonyl
N O >90% ee N
R O lone pair
B H2B H RL complexes
R boron
intramolecular
R = H, Bn, CH3, Bu H– delivery through
boat-like T. S.
124
Reduction Reactions
Dale L. Boger
- Corey Tetrahedron Lett. 1989, 30, 6275.
H Ph
Ph
N O
B
O Bu H OH OH O
H Cl
R CCl3 O R CCl3 N3
BH R Cl
92–98% ee
O
N3 H N3 H H2 H2N H
R COCl 80–98% R CO2H Pd–C R CO2H
88–98%
- General, catalytic, enantioselective synthesis of α-amino acids.

- Corey J. Am. Chem. Soc. 1992, 114, 1906; Tetrahedron Lett. 1992, 33, 3431, 3435.
- Review: Corey Angew. Chem., Int. Ed. Eng. 1998, 37, 1986.
2. Stoichiometric Reagents for Asymmetric Carbonyl Reductions
- Bothner-By J. Am. Chem. Soc. 1951, 73, 846 (camphor ligand and first report of an asymmetric
reduction with optically active reagent). Most subsequent efforts have used chirally modified LiAlH4.
O HO H
OH
- LiAlH4/N-methylephedrine NMe2 R R
Ph
R= Me 75 % ee
R= Et 62 % ee
iPr
R= 30 % ee
tBu
R= 36 % ee
Mosher J. Am. Chem. Soc. 1972, 94, 9254; J. Org. Chem. 1973, 38, 1870.
Me N Li
R
- Al R= O
Ph OH R
O
HO H
> 90%
89% ee
R-alcohol
- Vigneron Tetrahedron Lett. 1974, 2065; 1979, 2683; Tetrahedron 1976, 32, 939; used in cationic
cyclization approach to steroids.
- Early work with acetylenic ketones, W. S. Johnson
HO
O O asymmetric total synthesis
of steroids via cation–olefin
cyclizations
84% ee
O O
Brinkmeyer J. Am. Chem. Soc. 1977, 99, 8339.

Johnson J. Am. Chem. Soc. 1977, 99, 8341.
125
Me2N
N Li
- AlH2
O
O
Me2N HO H
92%
47% ee
Seebach Chem. Ber. 1974, 107, 1748.
- LiAlH4/N-methylephedrine/N-ethylaniline or N-ethyl 2-pyridylamine (high ee's for enones: >90% ee)
- Koga, Terashima Tetrahedron Lett. 1980, 21, 2753.
O OH
- BINAL-H
Li H R R
O
Al
O OEt
R = Me 95% ee R = nBu 100% ee

(R)-BINAL-H R = Et 98% ee R = iPr 71% ee
R = nPr 100% ee R = tBu 44% ee
Noyori J. Am. Chem. Soc. 1984, 106, 6709.
O O
(S)-BINAL-H
N N
N 73%
99.9% ee N
O (–)-mappicine OH

Cl
B
- Ipc2BCl
O Cl OH
Ipc H
B
H O
Ph 72%
CH3
Me 98% ee
Midland J. Org. Chem. 1989, 54, 159.
Brown J. Org. Chem. 1989, 54, 4504.
3. Enzyme-catalyzed Ketone Reductions have been extensively used in organic synthesis

- Review: Comprehensive Org. Syn., Vol. 8, pp 183.
4. Baker's Yeast
O Baker's OH
CO2Et Yeast CO2Et Seebach Org. Syn. 1985, 63, 1
60–70%
84–87% ee
126
Reduction Reactions
Dale L. Boger
J. Catalytic Hydrogenation
- Amine and sulfur-containing groups will tend to poison catalysts (especially Pd/C).
H
- Comprehensive Org. Syn.
Li/NH3 Vol. 8, 479.
- Comprehensive Org. Syn.
H O
H Vol. 8, 524.
H Solvent cis : trans

O
EtOH–HCl 93 : 7
P. Sabatier H2–Pd/C EtOH 53 : 47
received the 1912 O DMF 79 : 21
H
Nobel Prize in
Chemistry for his 93% : 7% EtOAc 57 : 43
contributions to Et2O 58 : 42
catalysis, especially - Comprehensive Org. Syn., Vol. 8, pp 417 and 533.
- Comprehensive Org. Syn., Vol. 8, pp 471. hexane 48 : 52
the hydrogenation
of unsaturated MeOH 41 : 59
organic compounds. nPrOH
68 : 32
t
BuOH 91 : 9
1. H2 delivery from least hindered face of double bond.
2. Cis H2 delivery
- activity of catalysts toward C=C: Pd > Rh > Pt > Ni > Ru
3. Increasing substitution on olefin decreases reactivity.

- note potential isomerization of olefin and H-migration/allylic exchange in D2/T2 hydrogenations
- propensity for olefin isomerization: Pd >> Rh/Ru/Pt > Ir
4. Alkynes are more reactive than alkenes. Reagents have been developed to selectively prepare
olefins from alkynes without over reduction:
- Lindlar catalyst: Pd(CaCO3)/Pb, poisoned or deactivated catalyst
- will only reduce an alkyne to an alkene (cis) Lindlar Helv. Chim. Acta 1952, 35, 446.
R R'
R
R R' R'
H H slow
5. Many kinds of catalyst, but most common are 5–10% Pd/C or PtO2
- Pd(BaSO4): Rosenmund catalyst (RCOCl → RCHO)

Rosenmund Chem. Ber. 1918, 51, 585.
- Pd(OH)2: Pearlman catalyst, often used for difficult debenzylations where other, more
typical, Pd catalysts fail.
Pearlman Tetrahedron Lett. 1967, 17, 1663.
H2
- PtO2 Pto (Adam's catalyst)
Roger Adams (Ph.D. 1912, Harvard Univ.; postdoctoral with Diels and Willstatter) was the
central figure in US organic chemistry in the 1930−40's. He established the structures of
tetrahydrocannabinol, gossypol, chaulmoogric acid, and the Senecio alkaloids, and
contributed to the development of many fundamental organic reactions.
127
- PtO2 is particularly good for imine reduction to amines. NR' HNR'
- Amines will poison Pd/C catalyst, but not Pt(0). R R" R R"
H
- Raney-Ni (Ra–Ni) also useful (especially for removing sulfide groups).
Generally stored in alcoholic solvent, ignites upon contact with air. It loses its activity over
ca. 6 months. Various reactivities depending upon the preparation (i.e. W-1 through W-7 Ra–Ni).
N N
W-2 Ra–Ni Husson Heterocycles
1991, 32, 663.
EtOH, reflux
N 85% N
H S S H Chem. Rev. 1962, 62, 347.
Comprehensive Org. Syn. Vol. 8, p 835.
- Rh/Al2O3, the high activity of rhodium often permits the use of room temperature and
atmospheric pressure even for difficult reductions.
Rh/Al2O3 Biali J. Am. Chem. Soc. 1990,

60% 112, 9300.
1
note: what would you expect the ground state conformation of 1 to be?
Good for the reduction of nitriles and aromatic rings:

CN H2
5% Rh/Al2O3 Mendoza J. Org. Chem.
HN
25 °C, 1 atm NHTs 1991, 56, 452.
MeO2C NHTs
76% O
H
O H2 O
5% Rh/Al2O3 Tarbell J. Am. Chem. Soc.
1964, 86, 2902.
OMe 25 °C, 3 atm OMe
H
- (Ph3P)3RhCl Wilkinson's catalyst (homogeneous).
- a homogeneous catalyst (e.g., dissolve in organic solvent for reaction).
- Review: Org. React. 1976, 24, 1.
- One of the earliest, successful examples of catalytic asymmetric synthesis entailed the
homogeneous hydrogenation of enamides to provide amino acid derivatives
CO2H H2, 1 atm CO2H
G. Wilkinson H
received the Rh-diphosphine* NHAc
Nobel Prize in NHAc
Chemistry in DIOP DIPAMP NORPHOS BPPM BINAP BPPFA
1973 for
deducing the 73% ee 34% ee 90% ee 99% ee 98% ee 93% ee
structure of Kagan J. Chem. Soc., Chem. Commun. 1971, 481.
metallocenes.
Knowles (Monsanto) J. Chem. Soc., Chem. Commun. 1972, 10;
J. Am. Chem. Soc. 1977, 99, 5946.
K. Dissolving Metal Reductions
1. Birch Reduction H R'
- Reviews: Comprehensive Org. Syn., Vol. 8, 489. R R'
Org. React. 1992, 42, 1 (aromatic ring reduction). R H
Org. React. 1976, 23, 1 (carbonyl and enone reductions). trans alkene
- First reported by Wooster J. Am. Chem. Soc. 1937, 59, 596. - most stable product
- Extensively developed by Birch Quart. Rev., Chem. Soc. 1950, 4, 69.
128
Reduction Reactions
Dale L. Boger
a. Reduction potential and solubility
Metal Solubility (g/100 g NH3) Reduction Potential Arthur Birch, along with Robert Robinson,
Li 10.9 –2.99 was one of the earliest chemists to
Na 24.5 –2.59 perform biosynthetic studies using
K 47.8 –2.73 radiolabels although he is best known for
the Birch reduction of aromatic rings.
b. Solvent system
- Typical solvent system Charles A. Kraus (1875–1967)
tBuOH demonstrated that the blue color
NH3 : THF :
arising from dissolving sodium in
2 : 1 : 1 liquid ammonia is a consequence
of solvated electrons in the course
of research on ammonia.
- Liquid NH3 (bp –33 oC) is used to dissolve metal, ether cosolvent (Et2O or THF) is used to dissolve
substrate, and a proton source tBuOH; EtOH; MeOH; NH2 is used to quench the reaction.
- If proton source is absent:

NH3 NH2 isomerization of diene and overreduction
NH2 NH3 further

reduction
- Be sure to use an argon atmosphere, not N2 which forms lithium nitrides.
William Ramsay received the 1904 Nobel

Prize in Chemistry for his experimental
work that included the discovery and
isolation of the noble gas family.
Hamilton P. Cady (1843−1943) and D. McFarland (1978−1955) discovered He in natural gas in 1905 in
Bailey Hall, University of Kansas, an element that had been previously detected only on the sun. "It assures
the fact that He is no longer a rare element but a very common element existing in goodly quantities for the
uses that are yet to be found for it." A drilling company in Dexter, Kansas thought they hit paydirt with a well
that released 9 million cubic feet of gas each day. At a celebration to culminate the discovery, and stock
issuance, a burning bale of hay expected to produce a great pillar of flame was extinghuished when pushed
into contact. E. Haworth (Univ. of Kansas) collected a sample of the gas which McFarland analyzed as 15%
CH4, 72% N2, O2 (0.2 %), H2 (0.8%), and 12 % unknown. H. Cady helped indentify the remainder. Using a
method described by Sir James Dewar, all atmospheric gases except H2, Ne (and He) were completely
removed (adsorbed) by coconut charcoal at the temperature of boiling liquid air (−310 °F). What remained
exhibited spectroscopic properties identical with He detected only on the sun. One of the first secret uses
was to inflate blimps and the Allies dirigibles filled with "Gas X" did not explode like the Axis powers
zeppelines which were filled with flammable H2. Today, 60% of the He isolated is used for cryogenic
applications including NMR and MRI.
Commercial NH3 production is second in size only behind H2SO4 and is

used extensively in the production of fertilizers (>102 × 106 tons/yr, 1998).
Benzene production through the refinement of crude oil reached 37 × 106 metric tons in
1997 and serves as the starting material for a host of derivatives including styrene/EtC6H5.
129
W
W
W = COOH COO
CONR2, SiMe3, Ar (electron-withdrawing groups)
Li/NH3
- but CO2R, COR, CHO CH2O , so they are part of donor (D) grouping.
e. Common application: hydrogenolysis
Li/NH3
R PhCH3 + RO–
Ph O or H2, Pd/C
5–10% Pd on C as catalyst
H2 can be replaced by HCOONH4 or as the source of H2 and this type
of reduction is a transfer hydrogenation: Comprehensive Org. Syn., Vol. 8, 955.
f. Examples
Me Me
- Krapcho J. Am. Chem. Soc. 1959, 81, 3658.
CONMe2 CONMe2
- Schultz J. Org. Chem. 1986, 51, 4983.
OMe OMe - Dryden J. Org. Chem. 1961, 26, 3237.
O OMe O OMe
N N - Magnus Tetrahedron Lett. 1997, 38, 1341.
OMe OMe
130
Reduction Reactions
Dale L. Boger
- can also be used for enone reduction and/or reductive alkylation with alkylative trap of the final enolate
H /H2O
MeO MeO
Robinson annulation
H type product used
extensively in steroid
O O synthesis.
H
O O
H H
Li/NH3
H H dioxane NH4Cl H H
ether CH3O
CH3O
78%
Johns J. Org. Chem. 1963, 28, 1856. more stable
Dryden J. Org. Chem. 1961, 26, 3237. product -
trans ring fusion
- As opposed to cis stereochemistry
H
O O
H H2 (1 atm) H
H H H H
5% Pd/C
CH3O CH3O
EtOH
- or more vigorous Birch conditions:

H
O OH
H H H+
Li/NH3
H H tBuOH H H
CH3O CH3O
THF
H
OH
H via enone reduction with protonation
(ROH present), carbonyl reduction
H H (to give most stable equatorial alcohol)
and aromatic ring reduction.
O
2. Dissolving Metal Carbonyl Reduction
a. Ketone Reduction
- Review: Comprehensive Org. Syn., Vol. 8, 107.

- Rule: H
O Li/NH3
t tBu
Bu Et2O, tBuOH OH
98:2
Birch reduction forms the most stable product.
131
- Exception:
Li/NH3
+
EtOH H OH
O OH H
sterically hindered 87 : 13
or strained ketones endo : exo
- Mechanism:
e
O O OH
t t t
Bu Bu Bu
ROH
Li(0) Li
e H
OH
tBu tBu
ROH OH
Li(0) Li
Special variants of this reaction include the:
b. Acyloin Condensation
First report: Freund Justus Liebigs Ann. Chem. 1861, 118, 33.
CO2Me OSiMe3 Comprehensive Org. Syn.,

Na Vol. 3, 613.
(H2C)4 Org. React. 1976, 23, 259.
toluene
CO2Me TMSCl OSiMe3 Org. React. 1948, 4, 256.
- Ruhlmann modification: Synthesis 1971, 236.
- Mechanism: diketyl generation and diradical coupling or:
O O OMe OMe
OMe e OMe e
(H2C)4 (H2C)4 O O
OMe OMe
O O
O O
OMe
O O O
O e e
O O O
O
- Sheehan J. Am. Chem. Chem. 1950, 72, 3376.
- Bloomfield J. Org. Chem. 1975, 40, 393.
- Bloomfield Tetrahedron Lett. 1968, 591.
- Macrocyclization: Finley Chem. Rev. 1964, 64, 573.
c. Pinacol Coupling
- Review: Comprehensive Org. Syn., Vol. 3, 563.
O O O
2
132
Reduction Reactions
Dale L. Boger
d. McMurry Coupling
- Review: McMurry Chem. Rev. 1989, 89, 1513.
Zn–Cu/TiCl3 McMurry J. Org. Chem. 1977, 42, 2655.

olefin product
LiAlH4/TiCl3 McMurry J. Am. Chem. Soc. 1983, 105, 1660.
Mg–Hg/TiCl4 - diol product Corey J. Org. Chem. 1976, 41, 260.
e. Radical-Alkyne/Alkene Addition
- The ketyl (radical anion) can be trapped in intramolecular reactions:
- Stork J. Am. Chem. Soc. 1979, 101, 7107.

O O
Li/NH3
O O OH
O or Na/NH3
O O
O O O
O
f. Reductive Alkylation
e
O O Li OH
CH3 Li(0) Li CH3 CH3
ROH
H Et2O H H
NH3 pKa 35–36
tBuOH pK 16–18
O enol radical
a
Li(0)
e
ROH
second Li
- Regiospecific enolate generation
equivalent
O O OH
CH3 H
CH3 CH3
CH3 MeI (E ) transfer
H H
H H H
133
L. Amalgam-derived Reducing Agents

1. Na−Hg
Sodium amalgam is used for the reduction of a variety of functional groups including those leading to the
preparation of alkenes and alkynes and for the reductive cleavage of C−S and N−O bonds.
SO2Ph Ph
6% Na−Hg Lythgoe J. Chem. Soc., Perkin 1
DMSO−THF 1979, 2429.
OP(O)(OEt)2 2 h, 72%
Julia Olefin Synthesis:
SO2Ph
Na−Hg Julia Tetrahedron Lett. 1973,
4833.
Bu OAc EtOH Bu
79%
Bu 6% Na−Hg Bu Posner Tetrahedron Lett. 1973,

SO2Ph EtOH, reflux 935.
Ph Ph
92%
O O
6% Na−Hg Trost Tetrahedron Lett. 1976,
MeOH, 3477.
SPh Na2HPO4
90%
TBSO TBSO
H H
O 6% Na−Hg O Keck Tetrahedron Lett. 1978,
N N
EtOH, H 4763, 4767.
O Na2HPO4 OH
82%
2. Al−Hg
Aluminum amalgam is another metal-based reducing agent.

It is quite mild and used effectively in a number of reductions.
O 10 equiv OH
Al−Hg Cyclic ketones and aldehydes are reduced.
Acyclic ketones are inert.
THF−H2O (9:1)
−10 °C to 25 °C
70%
Hulce Tetrahedron Lett. 1988, 29, 525.
10 equiv
S nBuLi S R Al−Hg S R HgCl2
Me R CHO
N RI N Et2O−H2O N CH3CN−H2O
90% H 71%
Meyers J. Org. Chem. 1975, 40, 2021, 2025.
134
Reduction Reactions
Dale L. Boger
O2N OH H2N OH
Al−Hg It is an excellent reagent for reducing
O O O O nitro groups and azides to amines.
Et2O−MeOH
Ph 100% Ph
Trost J. Am. Chem. Soc. 1989, 111, 5902.
Shin Chem. Lett. 1976, 1095.
O O H
H OMe OMe
Al−Hg
EtOH−H2O
O THF
H 99% HO H
Green, Crabbe J. Org. Chem. 1982, 47, 2553.
O
1) Al−Hg Ph
MeS O HN
THF−H2O
Ph OAc
N
2) Ac2O SMe
O OH 41%
OAc
Keck Synth. Commun. 1979, 9, 281.
O O O O
SMe Al−Hg R
O N O N
R
Me Ph Me Ph
O O O
O
N CO2Me S N CO2Me
O Ph N CO2Me
Me
Al−Hg
Me N Me CH3COHN Me
PhSOCH2Li THF−H2O CH3COHN Me
Br Br
−15 °C Br
Boger, Panek J. Org. Chem. 1985, 50, 5790. (total synthesis of lavendamycin)
3. Zn(Hg)
Clemmensen reduction
Clemmensen Chem. Ber. 1913, 46, 1838.
Me Me
Zn(Hg)
O HCl
H 90% H
Dauben J. Am. Chem. Soc. 1954, 76, 3864.
Reviews: Martin Org. React. 1942, 1, 155.
Vedejs Org. React. 1975, 22, 401.
135
M. Other Reduction Methods

1. Diimide Reduction
- Review: Org. React. 1991, 40, 91.

Me
H CO2H H CO2H
N
+
N
H CO2H H CO2H
Me
H
CO2H
H
CO2H
CO2H
CO2H
- Mechanism: H
H
N N
+
N N (N2)
H H
- Cis delivery of H2 complements H2/cat.
same results but:
many functional groups are
- From least hindered face of olefin stable to conditions/reagent
- trans > cis olefin (rate)
- Rate decreases with substitution of olefin
- C=O, NO2, CN, S O , S S stable
KO2CN=NCO2K no reduction of
O O
endoperoxide
O –78 °C O
Adam J. Org. Chem. 1977, 42, 3987.
Relative reactivities toward diimide reduction

krel krel krel
1.0 2.04 450.0 - Decreases with alkyl
substitution
20.2 0.28 - Increases with strain
29.0
2.59 0.50
47.0
2.65
Garbisch J. Am. Chem. Soc. 1965, 87, 2932.
HN NH
OH OH Mori Tetrahedron 1972, 28, 3739.
136
Reduction Reactions
Dale L. Boger
- Formation (generation) of reagents (diimide)
H H
i. H2O2 /H2NNH2 N N old method
ii. recent method
O H
H
Me S N NH + Base N N
O H H
- related to McFadyen–Stevens Reduction.
cat H H H
iii. KO2C N N CO2K N N
25 °C, –CO2
(anhydrous)
CO2K
N N
KO2C
iv. retro Diels–Alder reaction
NH NH
+
NH NH
- Example of use:
H H
Br N N Br
Ph Ph
- Other reduction methods would give substantial debromination.
137
138
Hydroboration-Oxidation
Dale L. Boger
VII. Hydroboration–Oxidation (Reduction–Oxidation)

- Review: Comprehensive Org. Syn., Vol. 8, pp 703–732.
Brown Organic Synthesis via Boranes, Wiley: New York, 1975.
Brown Boranes in Organic Chemistry, Cornell Univ. Press: New York, 1972.
A. Mechanism
Brown J. Am. Chem. Soc. 1956, 78, 2583; Org. React. 1963, 13, 1.
H H
BR2' H2O2
+ R'2BH OH +
R R NaOH R B(OH)3
OH
R' OR'
H R' H B R' H B OR'
B R' O O
R O O H
R R
- anti-Markovnikov addition of H2O to C=C

- reversible.
H H H
B B - syn (cis) addition.
H H H
- attack from least hindered face.
- boron attaches to least substituted carbon of C=C
+ BH3
H B H B
BH3
- rate
- Increased by electron-donating substituents on olefins.
- Increased by strain of olefins.
- Increased by decreased steric hinderance of olefins.
The discovery of the unusual bridged structure of diborane vs a once more conventional
ethane-like structure H3B−BH3 (G. N. Lewis, S. H. Bauer) occupied the efforts of many of the
very best chemists, enlisting newly emerging experimental and theoretical tools, including H. I.
Schlesinger, C. Longuet-Higgins, F. Stitt and W. C. Price (IR), J. N. Shoolery (NMR), R. S.
Mulliken, K. S. Pitzer, A. D. Walsh (MO and valence bond descriptions), K. Hedberg and V.
Schomaker (electron diffraction). Essay: Laszlo Angew. Chem. Int. Ed. 2000, 39, 2071.
The reaction is characterized by a slight tendency for H (H–) to add to carbon most capable of
stabilizing a δ+ charge or, in other words, for the nucleophilic carbon to attack the electrophilic B.
However, it is also characterized by a nonpolar transition state where the rate of reaction and
regioselectivity are determined principally by steric factors with unsymmetrical olefins.
BH3 B2H6
H. C. Brown (Purdue University)
)2BH disiamylborane (Sia2BH) received the Nobel Prize in Chemistry
(1979) for the discovery and
development of the hydroboration
reaction. He is also responsible for the
BH2 thexylborane (ThxBH2) discovery and development of NaBH4
H and most of the many, subsequent
B boron and aluminum hydrides used
9-BBN widely in organic synthesis today.
139
B. Regioselectivity
1. Steric Effects
CH3
C4H9CH CH2 C6H5CH CH2 CH2
BH3•THF 6 : 94 19 : 81 43 : 57 <1 : >99 2 : 98

ThxBH2 6 : 94 6 : 94 34 : 66
Sia2BH 1 : 99 2 : 98 3 : 97
9-BBN 0.1 : 99.9 1.5 : 98.5 0.2 : 99.8
- diisoamylborane larger than BH3•THF and more selective.
2. Electronic Effects Brown J. Am. Chem. Soc. 1966, 88, 5851.
X BH3•THF X X
+
BR2' H
H BR2'
X=H 81 : 19
OCH3 93 : 7
Cl 73 : 27
CF3 66 : 34
R CH3
R1 OEt CH3
R2 Me3Si CH3
100 : 0 95 : 5 R = iPr 43 : 57 BH3
R1 = R2
= Me 3 : 97 Sia2BH
R1 = R2 = Et R = SiMe3 95 : 5 BH3
Me3Si Bu
vs
60 : 40 (BH3) 6 : 94
5 : 95 (Sia2BH) 1 : 99
0 : 100 (9-BBN) 0.1 : 99.9
C. Diastereoselectivity
1. Endocyclic Olefins
3% 13%
CH3
Me
Me t
Bu H
- predominant attack
tBu
CH3 from least hindered
face.
H
36% 48%
140
Dale L. Boger
- cis addition
H B
- from least hindered side Pasto, Klein J. Org. Chem. 1968, 33, 1468.
H3C
tBu H
- least substituted position
CH3
H
B H
38% 43%
H H
tBu with BH3•THF H H with BH3•THF Me
tBu
tBu tBu Me
Me Me
H H
62% 57%
with BH3•THF Better with bulkier boranes
2. Exocyclic Olefins
33%
R
67%
3. Acyclic Olefins
OR OH OR
R1 BH3•THF R1
R1 larger than CH3
Me Me Me Me
OH
O CH2OBn 1) BH3•THF CH2OBn
Me 2) H2O2, NaOH O
Me H Me Me
89% de
Kishi J. Am. Chem. Soc. 1979, 101, 259. (Monensin)
Considering the top case:

B H attack on least hindered
face of H-eclipsed conformation
H OR
Me
Me R1/BH2 interactions are worse
H
R1 than Me/BH2 interactions
Kishi Aldrichim. Acta 1980, 13, 23.
141
4. Allylic Alcohols and Ethers
- Cyclic allylic alcohols and ethers.
OR OR OR OR OR
OH OH
+ + +
OH OH
R=H 83 18 5 72 2 1 10 9
R = Bn 68 7 13 72 0 8 19 13
R = TBDMS 74 2 13 86 0 1 13 11
9-BBN catechol borane/Rh(I)

Evans J. Am. Chem. Soc. 1988, 110, 6917.
Minor
H
9-BBN reaction:
OR OR
- Least hindered face opposite
H H alkoxy group.
H H - Regioselectivity avoids a
R2B/H 1,3-diaxial interaction.
H B
Major
- Acyclic allylic alcohols and ethers
OR OR OR
1) 9-BBN +
nBu nBu
nBu OH OH
2) H2O2, HO
Me Me
syn anti
R=H 8 92
R = TBDMS 11 89
- Reaction takes place from H-eclipsed conformation and cis to the smaller OR group.
Still J. Am. Chem. Soc. 1983, 105, 2487.
minor
H 3C H B
nBu
nBu
attack on face syn to
H H3C
RO H smaller alkoxy substituent
H B RO in the H-eclipsed conformation.
H B
major major
142
Dale L. Boger
D. Metal-Catalyzed Hydroboration
- Diastereoselectivity (below) and regioselectivity (prior page) can be altered or even reversed
with catecholborane and Rh(I) catalyst (i.e., Wilkinson's catalyst).
O
BH OR OR
OR O +
n n
nBu
Bu OH Bu OH
Rh(I)
Me Me
syn anti
R=H 75 25
R = TBDMS 96 4
- Exocyclic allylic alcohols and ethers

OR OR OR
1) 9-BBN OH + OH
2) H2O2, HO
R=H 50 90 50 10
B H R = TBDMS 39 96 61 4
9-BBN
No distinguishing 9-BBN catecholborane/catalytic Rh(I)
RO steric interactions
B H
- Olefin reactivity, chemoselectivity

catecholborane/2% RhCl(PPh3)3 reaction times
2 min 4h 12 h unreactive
R
R R
R R
R R R R
R R
R
- Review of transition metal-catalyzed hydroboration: Beletskaya and Pelter Tetrahedron 1997, 53, 4957.
B H O H O H
–L L –L
RhClL3 RhClL2 B Rh B Rh
L O L
O Cl Cl
H reductive
+L L elimination
B Rh B + RhClL3
L
Cl
- This was utilized in the synthesis of the unusual L-gulose sugar found in the disaccharide of bleomycin A2
key step: inversion of stereochemistry
to convert readily available
O D-mannose to L-gulose derivative
BH
O OBn O OBn O OBn
HO O HO
bleomycin A2
(Ph3P)3RhCl
HO OH HO OAc HO OAc
82%
OH OBn ≥ 50:1 OBn
D-Mannose
143
E. Directed Hydroboration
O
Ph2PO OAc Ph
1. B H
O OAc Ph P
B H
O
2. H2O2, NaOH
3. Ac2O > 10:1, 55%
Ph
O
Ph2PO B H OAc P Ph
1.
O B H
O
2. H2O2, NaOH OAc

3. Ac2O > 50:1, 82%

versus
OH OH
OH
catechol
borane
major
OH OH
catechol
borane
OH
major
F. Asymmetric Hydroboration
Review: Brown J. Organometal. Chem. 1995, 500, 1.
BH2 BH
BH 2
HB
H HB ( )2
Masamune J. Am. Chem. Soc. 1985, 107, 4549.
LimBH Dilongifolyborane trans-2,5-dimethyl- IpcBH2 Ipc2BH

(Lgf2BH) borolane
monoisopinocamphenylborane
- Brown Tetrahedron 1981, 37, 3547; J. Org. Chem. 1981, 46, 2988; 1982, 47, 5065.
OH
CO2Me Ipc BH
2 CO2Me
45%
95% ee
O
O
1. MsCl
prostaglandins
2. NaOH
Partridge J. Am. Chem. Soc. 1973, 95, 7171.
144
Dale L. Boger
OH
NBOC NBOC NBOC

1. Ipc2BH
2. NaBO3–4H2O
73%
OBn 83% ee OBn O
Boger Synlett 1997, 515.
Type I Type II Type III Type IV
% ee for Asymmetric Hydroboration
Type Ipc2BH IpcBH2 Lgf2BH LimBH borolane
I 30 1.5 – – 1.4
II 98 24 78 66 95
III 13 73 – 59 97
IV 14 53 70 67 94
IV 22 66 62 45 97
- Models
H H
IpcBH2 Ipc2BH L R1
H L M L Me R2
M H 3
H R
M H H B
Me H H H H
Me
H Me Me Me
minimize R1/Me interaction
C2-symmetric
145
146
Enolate Chemistry
Dale L. Boger
VIII. Enolate Chemistry
Enolate Alkylations: Comprehensive Org. Syn., Vol. 3, 1.
Formation of Enolates: Comprehensive Org. Syn., Vol. 2, 99.
Aldol Condensation: Comprehensive Org. Syn., Vol. 2, 133, 181 and 239.
Reformatsky Reaction: Comprehensive Org. Syn., Vol. 2, 277.
Acylation of Enolates: Comprehensive Org. Syn., Vol. 2, 796.
Enol Ethers: Comprehensive Org. Syn., Vol. 2, 595 and 629.
Metalloenamines: Comprehensive Org. Syn., Vol. 2, 475.
Hydrazones: Comprehensive Org. Syn., Vol. 2, 503.
A. Acidic Methylene Compounds (i.e., Malonates)

- α-Deprotonation
pKa ~20
O O O
base RX
H alkylation formation
Keq of C–C bond
- Use of a base which stoichiometrically deprotonates the ketone completely: (i.e. Keq > 100)
O ONa
+ NaNH2 + NH3
is Keq > 100?
pKa = 17 pKa = 35
O O–
+ H+ Ka = 10–17
NH2– + H+ NH3 Ka = 1035
O O–
+ NH2–
+ NH3 1018
Therefore, a good deprotonation (essentially all ketone deprotonated)

Note: need to have pKa difference of 2 pKa units to get Keq = 100.
147
1. Estimation of pKa
H
C
W W = Cl inductive stabilization
O
W= , NO2, etc. resonance stabilization
O H
CH3 pKa = 20; CH3 pKa = 45; pKa = 35–37
- an increase in acidity of H results in a faster deprotonation (kinetic effect) as well as a stabilization of anion
formed (thermodynamic effect).
H Group (–W) pKa effect (units) Note
R W alkyl ~1–2 (decrease in acidity)

R both due to inductive effects
halogen ~1–2
~5–7
both depend on favorable orbital overlap

to allow resonance stabilization
~5–7
RS ~3–5
Others: NO2 > COR >SO2R > CO2R, CN > SOR, Ph
Compound pKa Note

O
20
CH3
O O
13
OCH3
ketone better enolate
O O stabilizer than ester
11
O O
9
H
O O 5 ~same as acetic acid
H H
H2O 14
O
25
H2C NR2
H
O
15
CH3 NR
H
148
Enolate Chemistry
Dale L. Boger
2. Ketone–Enol Tautomerism
O OH
R CH3 R CH2 - generally << 1% enol
OH O
E+ E - Usually not likely to form a bond with weak electrophile
R CH2 R CH2 (e.g., CH3I) since not present in high concentration
<< 1% - However, some ketones do exist in high enol concentration

and react via enol
Compound Enol content
0.0004%
O
< 0.002%
O OH
CO2Et CO2Et
40% (neat)
60% (EtOH)
O O
100%(neat)
95% (H2O)
2–14% (cyclohexane)
O OH
O OH
10–13% (EtOH)
CO2Et CO2Et 50% (cyclohexane) intramolecular
H-bond
O O OH O 16% (H2O)
63% (EtOH)
92% (cyclohexane) intramolecular
H-bond
O O OH O 3% (H2O)
31% (EtOH)
55% (cyclohexane) intramolecular
H-bond
149
- If a compound has a vinyl spacer, the reactivity parallels that of the parent compound.
1,3-Cyclohexadione in its enol form is a vinylogous carboxylic acid and it exhibits many properties of a
RCOOH, including low pKa, O-alkylation.
O
O
~
= OH
OH
OH O O O
nBu
base analogous to
+
nBuBr RCOOH -> RCOOnBu
O O OH OnBu
15% 37%
VINYLOGY RULE
O O
Nu–
analogous to RCOCl -> RCONu
Cl Nu
vinylogous acid chloride
3. Acetoacetic Ester Synthesis
O O NaOCH3 ONa O O O
nBuBr, ∆
OCH3 CH3OH OCH3 OCH3
nBu
pKa = 13 74%
pKa =16 stable, can be isolated
NaH nBuBr
THF (deprotonation equilibrium
K = 99.9 -> 99% deprotonated)
O O
OCH3 NaH: strong base, operates in range up to pKa = 35. Sometimes kinetically slow,
nBu
sometimes difficult to reproduce. It is insoluble and the reaction is
heterogeneous. Thought that trace –OH might be active base. Therefore,
~70% deliberately add 0.05–0.1 equiv. CH3OH to obtain reproducible reaction.
Henri Moissan, who received the 1906 Nobel Prize

in Chemistry for his investigation and isolation of the
element fluorine and for the high temperature
electric furnace named after him, prepared and
studied the alkali metal hydrides.
150
Enolate Chemistry
Dale L. Boger
- The product can be further alkylated:
O O O O
i) NaH
OCH3 ii) nC5H11Br OCH3
nBu nBu nC H
H 5 11
80%
pKa now 1–2 units higher concentration of parent enolate vs. concentration of product enolate
than parent in monoalkylation reaction is very high (> 90:10) -> monoalkylation
fairly clean.
- Hydrolysis and decarboxylation gives α-substituted ketones:
O O H
O O O
NaOH ∆
CH3 OCH3 R'
then H3O+ CH3 O 180–220 °C CH3
R R' R R'
workup R
4. Malonic Ester Alkylation
R NaOH R
i) NaOMe, MeOH
CH3O2C CO2CH3 ii) RX CH3O2C CO2CH3 CH3O2C CO2CH3
75–90%
NaOH
R R R
R
H3O+ NaOH
HO O CH3O2C CO2Na CH3O2C COONa
NaO2C CO2Na
O O
H
∆ (–CO2) requires higher temperature than acetoacetate decarboxylation
RCH2COOH
R NC CN
NC
O related stabilized enolates
CH3OOC SO2Ph CH3OOC CN
can be removed
reductively
151
250 °C
no reaction
HO2C O
O O H O OH
violates Bredts Rule,
bridgehead olefin
5. Enolates: C- vs. O-Alkylation
- Ketones which are more acidic tend to give more O-alkylation.

O
e.g.
37% O-alkylation
15% C-alkylation
OH
CH3
OH NaOH OCH3 OH
CH3X +
X=I 66 : 33
- The more reactive the alkylating agent,
the more O-alkylation observed X = OTs 100 : 0
O O
- Rarely see O-alkylation of ketone enolates
often see O-alkylation of stabilized enolates
e.g., β-diketones and β-keto esters
localized, softer, more
harder anion diffuse anion
- tends to react with harder electrophiles reacts with softer alkylating
(CH3OTs, Me3OBF4 ) agents (RI, RBr)
Meerwein's salt
more reactive or more ionized = harder
- Intramolecular constraints can affect course of C- vs. O-alkylation
HO O
O
NaOH
H
OTs 100%
OTs
152
Enolate Chemistry
Dale L. Boger
Cl
N R N R
NaH
O O
N N
H H
OH O
(+)-CC-1065
Cl OH
N R N R N R
NaH DEAD–Ph3P
MeO2C O MeO2C MeO2C
O O
N N Mitsunobu N
H H alkylation H
OH O OH
duocarmycin SA
Boger Chem. Rev. 1997, 97, 787.
- Mitsunobu alkylation
Mitsunobu, Yamada, Mukaiyama Bull. Chem. Soc., Jpn. 1967, 40, 935.
Mitsunobu Bull. Chem. Soc., Jpn. 1967, 40, 4235.
Review: Mitsunobu Synthesis 1981, 1.
Hughes Org. React. 1992, 42, 335; Castro Org. React. 1983, 29, 1.
OH
- Mechanism:
HX EtO2CN NHCO2Et R1 R2
Ph3P + EtO2CN NCO2Et
PPh3 X–
OPPh3 X– X
+ EtO2CNH NHCO2Et
R1 R2 SN2 displacement R1 R2
HX: pKa typically <15 (RCO2H, phenols, imides, malonates, β-keto esters)
Related reagents including Ph3P/CCl4, Ph3P/NXS are used to convert
an alcohol to the corresponding halide with inversion of stereochemistry.
- Factors which favor O-alkylation
O
1. Polar solvent: polar, aprotic solvents:
HMPA Me2N P NMe2
NMe2 a. separate metal cation from enolate oxygen,
making oxygen more free to react
O
DMSO CH3 S CH b. coordinate electrophile, activate and increase
3
their reactivity
c. increase rate of reaction
DMF Me2NCHO
2. Large, noncoordinating metal cation:

- again, frees up oxygen to react
M+
O M = R4N >K > Na > Li
R'
O-alkylation C-alkylation
R
rate of reaction
ion pair lithium essentially covalently
separation of charge, harder coordinated to O
more reactive anion
153
3. Aggregation/Solubility:
Homogeneous, monomeric enolates O-alkylation
Heterogeneous, aggregate enolates C-alkylation
Li enolates tend to hard for RX to get to

be more aggregated M O atom, so reacts at C
O
H
R'
R
4. Structure of alkylating agent
a. Leaving group:
(hard alkylating agents) (soft alkylating agents)
for RX: X = Me3O > OTs > Cl > Br > I

O-alkylation C-alkylation
O
O nBuX OnBu
COOCH3 +
COOCH3 K2CO3 COOCH3
100 °C nBu
C- : O-alkylation
Solvent X rel % products
acetone Cl 90 : 10
O-alkylation Polarity
of solvent CH3CN Cl 81 : 19
DMSO Cl 53 : 47
DMF Cl 54 : 46
For C-alkylation: DMF Br 67 : 33
I > Br > Cl >99 : 1
DMF I
b. Degree of substitution of alkylating agent:
O O OR
RBr
COOEt COOEt + COOEt
no solvent
R
nC 97 : 3
3H7Br
more sterically
hindered, Br 73 : 27
so "harder"
Br
Ph Br mainly C-alkylation
,
154
Enolate Chemistry
Dale L. Boger
O O
+ X
OH O
works well in polar, aprotic solvents (ie., HMPA, DMSO),

or even K2CO3, acetone will work
B. Enolate Structure
- Actually exist as higher aggregates in solution: dimer–tetramer.
- Originally suggested by House J. Org. Chem. 1971, 36, 2361 and Brown J. Organometal. Chem. 1971, 26, 57.
- Supported by NMR studies: Jackman Tetrahedron 1977, 33, 2737.
- Confirmed by X-ray: Dunitz Helv. Chim. Acta 1981, 64, 2617.
see also:
Seebach J. Am. Chem. Soc. 1985, 107, 5403. Li ° tetramer aggregates
° Li 1.35 A
Angew. Chem., Int. Ed. Eng. 1988, 27, 1624. 1.99 A
O CH2
Lynch Tetrahadron Lett. 1989, 30, 447. ° bond lengths, angles much
° Li
1.94 A
1.34 A like those of enol ether.
CH3 CH3
CH3
1.477 A° °
1.45 A
tBu t
Bu
O 1.356 A° O °
1.407 A
1.378 A° °
°
1.495 A O vs 1.304 A
° O
1.659 A
° Sit BuPh2 Li
1.37 A °
1.35 A
Ketone Enolates:
O
Ph Ph
OM
M
Keq < 1 for most metals (Li, Na, K, MgX, ZnX) negative charge, M+ on oxygen.
> 1 for M = HgI
155
Ester Enolates:
OR O
M Reformatsky Ber. 1887, 20, 1210.
OR
OM Reviews: Shriner Org. React. 1946, 1, 423.
Rathke Org. React. 1975, 22, 423.
Keq < 1 for Li Keq > 1 for ZnBr (Reformatsky reagents) Furstner Synthesis 1989, 571.
C. Enolate Alkylations: π-Facial Stereoselectivity
1. Stereoelectronic Effects
- The attacking electrophile must obey the principle of maximum overlap of the participating orbitals by
perpendicular approach to the plane of atoms which constitute the enolate (enol) function.
E+
E+
R1 H E
R1 H
R1 H R2 OLi
M O R2 O R2
- Also applies to protonation in reprotonation reaction:
H
R1 H H+ H
R1 H
O R1
M O R2 –H+ R2 R2 H
O
- Nucleophilic addition to carbonyl compound takes place not at 90° (perpendicular)

but at an angle of 105 ± 5°
Dunitz Tetrahedron 1974, 30, 1563.
- Same applies to enolate alkylations
LUMO of E+
electrophile
angle not 90°
R2 R'
H
O
enolate HOMO
156
Enolate Chemistry
Dale L. Boger
- Ramifications: E
tBu
trans
O OLi E+ O
LDA or
tBu tBu H
tBu
cis
E O
O
H
H E+
t
Bu
base removal predominant trans
of axial proton product observed
OM
axial attack proceeds

through a chair-like T.S.
- In order to get cis, must proceed through a boat-like T.S.!
tBu H O
tBu
cis
OM
E
E+
- Therefore
E O Energy of activation for formation of

the more stable cis product is higher
OM E
because it involves a boat-like T.S.
O
reaction coordinate
Corey, Sneen J. Am. Chem. Soc. 1956, 78, 6269 (origin of axial alkylation).
They also introduced the term stereoelectronic effect to describe this behavior.
This was the pioneering work that led to the now widespread predictions about reactions and reaction
products based on orbital alignment or overlap and provided the term "stereoelectronic" effect.
157
- Examples of stereoelectronic control
axial alkylation equatorial alkylation

chair-like transition state via twist boat T.S.
E+
H
O H O tBu A
t
tBu –
Bu –
R E OM
E+ E+ E+
A E
O O
O OM
tBu tBu
R + E
tBu tBu
R R
E R
House J. Org. Chem. 1968, 33, 935.

Caine J. Org. Chem. 1969, 34, 3070. M R E axial equatorial
Li H Et3O+BF4– 51 : 49
Li H EtI 54 : 46
Li H MeI 55 : 45
Li H DOAc 70 : 30
Li Et HOAc 80 : 20
Li Me CD3I 70 : 30
Li CN CH3I 77 : 23
less reactive enolates
(so more selective) Li COOCH3 CH3I 83 : 17
Kuehne J. Org. Chem. 1970, 35, 161, 171.
2. Steric Effects COX

E+ X eq
tBu
H E
ax
- Stereoelectronic effects equivalent H OM major product
for exocyclic enolates.
tBu
- Relatively insensitive to alkylating eq
agent and conditions. E
H
H E+ ax tBu
COX
Behavior as a large reagent
preferring equatorial delivery. minor product
- Transition states for enolate X E eq : ax

alkylations are thought to be
CH3 MeI 25 °C 85 : 15
REACTANT-LIKE.
OCH3 MeI –78 °C 84 : 16
House J. Org. Chem. 1968, 33, 943. nBuBr 87 : 13
OCH3 –78 °C
Krapcho J. Org. Chem. 1980, 45, 3236.
158
Enolate Chemistry
Dale L. Boger
OLi O E+
E+ E
via H major
R R
OLi
R
E+
D. Enolate Generation
1. Soluble Bases
- NaNH2, LiNH2, KNH2 strong bases, but insoluble in conventional organic solvents
- Soluble secondary amine derived bases
nBuLi
= LDA
N pKa 45 N
H
Li
pKa = 35 readily available, soluble; amine byproduct is low
MWt, volatile, and easily removed. The anion is
also nonnucleophilic (relatively hindered)
- Aggregates: Williard J. Org. Chem. 1993, 58, 1 (X-ray).
- Other widely used bases:
= Lithium isopropylcyclohexylamide (LICA)

N
Li very hindered base
= Lithium 2,2,6,6-tetramethylpiperidide ("FAT ALBERT", LTMP)

N
Li very hindered
Me3Si SiMe3 M = Li Lithium hexamethyldisilazide (LHMDS or LHDS)

N
M = Na Sodium hexamethyldisilazide (NaHMDS)
=K Potassium hexamethyldisilazide (KHMDS)
= Lithium toctyl-tbutylamide (LOBA)

N Corey Org. Syn. 1987, 65, 166; Tetrahedron Lett. 1984, 25, 491
Li and 495.
adamantyl adamantyl = Lithium bis(2-adamantyl)amide (LBAA)
N
Li Collum Tetrahedron Lett. 1993, 34, 5213.
THF or Et2O hydrocarbon solvents

Me3Si
S Me3Si N Li SiMe3
Me3Si Me3Si Li SiMe3 Li N SiMe3
N LiSn N N Me3Si N Li
Me3Si Me3Si Li SiMe3 Me3Si Li N
S Me3Si SiMe3
monomer dimer tetramer
Brown J. Organometal. Chem. 1971, 26, 57.
Collum Acc. Chem. Res. 1993, 26, 227; 1999, 32, 1035 (6Li and 15N NMR).
- X-ray structures
Williard J. Am. Chem. Soc. 1997, 119, 11855.
159
Reviews:
Conia Rec. Chem. Prog. 1963, 24, 43.
House Rec. Chem. Prog. 1967, 28, 98.
Fleming Chimica 1980, 34, 265.
Petragnani Synthesis 1982, 521.
Kaiser Synthesis 1977, 509.
d'Angelo Tetrahedron 1976, 32, 2979 (Methods for regiospecific enolate generation).
Evans Asymm. Synthesis, Morrison, Ed., Vol. 3, 1.
Collum Acc. Chem. Res. 1999, 32, 1035.
2. Kinetic and Thermodynamic Enolates

OTMS OTMS
LDA
+ +
(TMSCl OTMS
O quench)
84% 7% 9%
kinetic enolate
Et3N
TMSCl
13% 58% 29%
DMF, ∆
60 h
thermodynamic enolate
H H
Ph3CLi (1.05 equiv)
+
(TMSCl trap) TMSO TMSO
H H
conditions for kinetic
H enolate formation
13 : 87
O
H
Ph3CLi (0.95 equiv)

53 : 47
HMPA
some ketone always present, so conditions for thermodynamic enolate formation
deprotonation–reprotonation equilibrium
3. Regiospecific Enolate Generation

- In the above case, the ∆2,3 enolate cannot be cleanly obtained directly, but other approaches to this have been
developed.
H H H
Li, NH3 MeLi
TMSCl TMSO
O LiO
H H
Me4Si
isolated
See: Stork J. Am. Chem. Soc. 1961, 83, 2965; 1965, 87, 275.
H Li/NH3 H H
NCCO2Me
tBuOH Et2O
O LiO –78 to 0 °C O
–33 °C H 84% H
CO2Me
Mander Org. Syn. 1992, 70, 256.
160
Enolate Chemistry
Dale L. Boger
- Representive enolate selectivities:
O O O
Me
CH3CCH2Bu CH3CCH2Me CH3CCH
Me
100 0 (LDA, –78 °C) 71 29 (LDA, 0 °C) 99 1 (KHMDS, –78 °C)
O O O CH3
Me Me
MeCH2CCH CH3CCH2N N
Me Ph CH3 C CO2CH3
H2
95 5 (LDA, 0 °C) 75 25 (LDA, –78 °C) 18 82 (LDA, –78 °C)
O Ph O O
N Me Ph
CO2Me
LDA: 33 : 67 (kinetic) 99 : 1 (LDA, 0 °C) >99 : 1 (LDA, –78 °C)

LHMDS: 2 : 98 (thermodynamic)
Albizati J. Am. Chem. Soc. 1990, 112, 6965.
O O O
OCH3 NMe2
Me
Bu
85 : 15 (LDA, –78 °C) 98 : 2 (LDA, –78 °C) 91 : 9 (LDA, 25 °C)

98 : 2 (LHMDS, thermodynamic)
Albizati J. Am. Chem. Soc. 1990, 112, 6965.
O O OMe
C C
CH3 CH3 CH3 CH3
100 : 0 (LDA, –78 °C) 100 : 0 (LDA, –78 °C)
O O O
CH3
CH3 OnBu
100 : 0 (LDA, –78 °C) 20 : 80 (LDA, –78 °C) 100 : 0 (LHMDS, –78 °C)
Me Me
O O
Me CH3
100 : 0 (LDA, –78 °C) thermodynamic enolate

0 : 100 (NaH, 100 °C)
formation
Taken from: Evans Asymm. Synthesis, Morrison, Ed., Vol. 3, 1.
161
- Enantio- or diastereoselective protonation of ketone enolates
deprotonation:
Majewski Can. J. Chem. 1994, 72, 1699.
Simpkins Tetrahedron Lett. 1992, 33, 8141.

1989, 30, 7241.
protonation:
Fehr Angew. Chem., Int. Ed. Eng. 1994, 33, 1764.
4. Cyclic Carbonyl Compounds

- site of deprotonation
- enolate geometry fixed
O OM OM
CH3 CH3 CH3
+
Base Control Selectivity
LDA (0 °C, THF) kinetic 99 : 1

KHMDS (–78 °C) " 95 : 5
Ph3CLi (–78 °C) " 90 : 10
potassium bases not Ph3CK (–78 °C) " 67 : 33
as effective for kinetic
enolate generation. Ph3CLi thermodynamic 10 : 90
NaH " 26 : 74
Ph3CK " 38 : 62
5. Acyclic Carbonyl Compounds

- Two issues: i. site of deprotonation
ii. geometry of enolate formed cis Z-enolate (Zusammen)
OM
O CH3
R
CH3
R
OM
trans E-enolate (Entgegen)
R
CH3
- Also: the enolate has two diastereotopic faces:
For E-enolate
looking from
R OM
this face
si face counterclockwise = si
Me
M O
R Me
looking from MO R
this face
re face clockwise = re
Me
162
Enolate Chemistry
Dale L. Boger
- ASIDE: Geometry of enolate can be determined by Claisen rearrangement:
OTMS
Z-enolate
R
O
O
R
O
OTMS
R
E-enolate O
- Claisen rearrangement known to proceed through chair-like T.S.:
Me OTMS
R OTMS
H R
O
O Me
Z-enolate relative amounts easily
determined by 1H NMR
Me OTMS
H OTMS
R
O
O
R Me
E-enolate
A. Acyclic Ketones
Me
Me Me Me Me + Me
O OLi OLi
Base Z E
very hindered LTMP (–78 °C) 14 : 86 kinetic enolate

amide base
LTMP/HMPA 92 : 8 thermodynamic enolate
LDA 23 : 77
LICA 35 : 65
LHMDS 66 : 34
(PhMe2Si)2NLi 100 : 0
163
- Thermodynamic enolate formation
Me
Me Me + Me Me Me Me + Me
OLi O O OLi
HMPA or may take place by reversible aldol addition

Rathke J. Am. Chem. Soc. 1980, 102, 3959.
O OLi
For the effect of HMPA on R2NLi aggregation:
Collum, Romesberg J. Am. Chem. Soc. 1994, 116, 9198; 1993, 115, 3475.
O OLi LiO
R2 R2 +
R1 R1 R1 R2
Z-enolate E-enolate
R1 R2 Z E
Et Me LDA 23 77
Note: As R1 becomes sterically Et Me LTMP 14 86
more demanding, Z-enolate best conditions for
Et Me LTMP–LiBr 2 98
increases or predominates even E-enolate (kinetic)
under kinetic conditions. iPr Me LDA 37 63
iPr Me LTMP 33 67
iPr Me LTMP–LiBr 5 95
tBu Me LDA 98 2
tBu Me LTMP 95 5
tBu
Z-enolate only
Note: As R2 becomes sterically Me LTMP–LiBr 95 5
very large R1
more demanding, E-enolate Me Ph LDA 7 93
selectivity increases under
kinetic conditions: Ph > Me. Me Ph LTMP 8 92
Me Ph LTMP–LiBr 3 97
Collum J. Am. Chem. Soc. 1991, 113, 9571.
Et Me LOBA 2 98 kinetic E-enolate
Corey Tetrahedron Lett. 1984, 25, 491 and 495.
164
Enolate Chemistry
Dale L. Boger
B. Acyclic Esters
- Similar to ketones:
O OLi OLi
R2 +
R2 R1O
R1O R1O
R2
Z E
thermodynamic enolate kinetic enolate

(more stable)
R1 R2 base Z : E
Me Me LDA 5 : 95
tBu :
Me LDA 5 95
Me Et LDA 9 : 91 kinetic
Me Et LDA/HMPA 84 : 16 thermodynamic
tBu :
Et LDA 5 95
tBu :
Et LDA/HMPA 77 23
Role of HMPA: increase rate of equilibration, break up enolate aggregation
Me Et LOBA 5 : 95
Bn Me LDA 20 : 80
Bn Me LOBA 5 : 95
Corey Tetrahedron Lett. 1984, 25, 491 and 495.
kinetic E-enolate thermodynamic Z-enolate

OLi OLi
CO2Et +
OEt OEt
LDA THF 94 : 6
LDA THF–45% DMPU 7 : 93
LDA THF–23% HMPA 15 : 85
Ireland, Wipf J. Org. Chem. 1991, 56, 650 and 3572.
165
- Silyl Ketene Acetals
Otera Synlett 1994, 213.
O R3SiCl OSiR3 OR
+
OR OR OSiR3
R = tBu LDA >99 : 1
EtMe2C LDA 97 : 3
Ph3C LDA >99 : 1
LDA 99 : 1
iPr LDA 83 : 17
bornyl LDA 83 : 17
Et LDA 84 : 16
Me LDA 87 : 13
Me LDA–HMPA 4 : 96
or DMPU
Et " 3 : 97
bornyl " 13 : 87
iPr " 13 : 87
EtMe2C " 26 : 74
tBu " 28 : 72
C. Acyclic Amides
give only Z-enolate
O OLi LiO
R1 R1 +
R2N R2N R2N R1
Z-enolate E-enolate
R R1 base Z E
Et CH3 LDA >97 : 3
(CH2)4 CH3 LDA >97 : 3
166
Enolate Chemistry
Dale L. Boger
6. Ireland Transition State Model for Deprotonation J. Am. Chem. Soc. 1976, 98, 2868.
Tetrahedron Lett. 1975, 3975.
- For Cyclic Ketones: a b
O
R
a b
LiNR21
H O R O
R1 Li Li
R1 1,3-diaxial R, R1
N H N H
R1 R1
A B
OLi OLi
R R
R1-H interaction < R1-R interaction
ketone base A vs. B 1,3-diaxial interaction
R = CH3 iPr,
LDA 99 : 1 CH3
iPr,
Ph LDA >99 : 1 Ph
iPr,
OCH3 LDA 85 : 15 OCH3
iPr,
NMe2 LDA 98 : 2 NMe2
- More hindered bases (tBu2NLi, LiHMDS, LTMP)

would increase selectivity for kinetic enolate formation
(1,3-diaxial interactions even larger in T.S. for
thermodynamic enolate formation)
- For Acyclic Ketones, Esters, and Amides:

O
Me
X
X X
H O LiNR12 Me O
Me a b H
Li Li
R1 R1
N H N H
H Me 1,3-diaxial very little
R'1 interaction R1 A (1,2) strain
O X
H
A (1,2) strain
(torsional strain)
LiO
OLi
Me
X Me X
E-enolate in most instances, Z-enolate thermodynamically more
kinetically favored stable enolate
167
- Example:
O LDA LiO OLi

+
Me Me
X X Me X
E-enolate Z-enolate
X LDA E:Z
OCH3 95 : 5
OtBu 95 : 5 Me/R1 1,3-diaxial interaction worse

than Me/X A (1,2)-interaction
Et 77 : 23
iPr 40 : 60
tBu
0 : 100
X getting larger, so A (1,2) steric interaction
Ph 0 : 100 outweighs the Me/R1 1,3-diaxial interaction
NEt2 0 : 100
E. Alkylation Reactions: Stereochemistry

1. Exocyclic Enolates
i. 1,2-Stereocontrol in Exocyclic Enolates
OM E O E O
X X
X E+
+
R R
R
H H
H
major
OM E+
R R
X
R COX
OM
allylic (1,3) E
strain E+ X
for R = CH3, X = OMe

∆G > 3.7 kcal/mol
COX
R
OM OM
E
R X H X R
H
H-eclipsed conformation
168
Enolate Chemistry
Dale L. Boger
COOCH3 Me COOCH3 Me COOCH3
Me LDA Me Me
MeI +
Krapcho J. Org. Chem. 1980, 45, 3236. 80 : 20
COOCH3 Me COOCH3 Me COOCH3

Me LDA Me Me
MeI +
95 : 5
Me COOEt
COOEt COOEt Me
Me Ph3CNa Me + Me
MeI
MeO MeO MeO
82%
98 : 2
Hogg J. Am. Chem. Soc. 1948, 70, 161.
- Also true for other common ring sizes:
CO2Me CO2Me
LDA
OMe OMe
Br >95 : 5
OMe OMe
72%
Heathcock Tetrahedron Lett. 1979, 2115.

Me Me
CO2Me CO2Me CO2Me
LDA
+
MeI
92%
85 : 15
Clark Syn. Commun. 1979, 325.
O O
R
H i) Li, NH3 H
tBuOH (0.95 equiv)
O H H O H H
ii) RX
O reductive alkylation O
R = CH3 65% only product
R = Et 43%
Weiss, Coscia Tetrahedron 1964, 20, 357.
169
ii. 1,3-Stereocontrol
CO2Me MeO2C Me Me CO2Me
LDA
+
H MeI H H
R R R
major minor
R = CH3 90 : 10
R = OCH3 78 : 22
E+
OM E+
H
H OMe
OM
R R
E+ OMe
equatorial delivery but axial R group
of electrophile
iii. 1,4-Stereocontrol
COOCH3 Me COOCH3 CH3OOC

Me
LDA
+
MeI
H R H R H R
R = tBu 84 : 16
OCH3 84 : 16
E+
OM R
H ax
H OR1
R eq
OM
E+
OR1
Again, equatorial attack predominates due to destabilizing

steric interactions for axial approach of electrophile.
170
Enolate Chemistry
Dale L. Boger
House J. Org. Chem. 1968, 33, 943.
Ziegler, Wender J. Am. Chem. Soc. 1971, 93, 4318.
CN Me CN Me CN
LDA
+
MeI
tBu tBu tBu
71–76% : 24–29%
LiO OLi
COOH R COOH R COOH
Li, NH3 RX
+
0.95 equiv tBuOH then H3O+
tBu tBu tBu

tBu
Van Bekkum Recl. Trav. Chim. Pays-Bas 1971, 90, 137. RX
MeI 45 : 55
E+
Me EtBr 88 : 12
Me OM
Me iPrBr
OM 93 : 7
H
E+
Surprising given the distance, but Schöllkopf pronounced effect of

subsequently put such observations to effective use. Steric Effects? size of alkylating agent
on stereoselectivity.
2. Endocyclic Enolates
a. 1,2-Stereocontrol
OM O O
R2X R2 R2
+
H H H
R1 R1 R1
major
R1 R2X
nBu MeI 88 : 12
vinyl group sterically smaller,
so stereoselectivity lower CH=CH2 MeI 75 : 25
Me Br 89 : 11
Posner J. Am. Chem. Soc. 1975, 97, 107. E+

Coates J. Org. Chem. 1974, 39, 275.
R1
axial attack preferred on stereoelectronic
and steric grounds
H
LiO ax
H
E+
171
b. 1,3-Stereocontrol
O O
CH3
NaOtAm
CH3I trans delivery
70% tBu
tBu
Conia Bull. Soc. Chim., Fr. 1966, 3881 and 3888. 73 : 27
- tBu group in preferred equatorial position
Rt - axial attack favored on stereoelectronic basis,

NaO Bu
no steric bias for either face
E+
c. 1,4-Stereocontrol
OLi O O
CH3 CD3
CH3 CD3I CD3 CH3
+
tBu tBu tBu
83 : 17
House J. Org. Chem. 1973, 38, 1000.
E+
H
preferred stereoelectronic approach from most
axial stable conformation with tBu equatorial
tBu
Me OLi
H
d. 1,5-Stereocontrol
Ph
O PhO
tBuOK
Me Me
MeI
>95% one isomer

Ireland J. Org. Chem. 1970, 35, 570.
Ph
reaction from preferred conformation where
MO Me group vs Ph adopts pseudo axial position
Me R
E+ preferred stereoelectronic approach
172
Enolate Chemistry
Dale L. Boger
3. Other Conformationally Inflexible Systems
- Exocyclic Enolates of a Fixed Conformation
MeI
74%
H H
LiO OMe CO2Me >100 : 1
more severe 1,3-diaxial interaction
E+
OMe
Welsch J. Org. Chem. 1977, 42, 2879; CH3
J. Am. Chem. Soc. 1977, 99, 549. This leads to a further enhancement of the
OLi preferred equatorial delivery of electrophile.
E+
- Exocyclic Norbornanes
E+
exo LDA
Me + COOMe
MeI
endo OMe COOMe H Me
LiO 97 : 3
E+ strong exo preference
E+
OLi O O
Ph3CNa
Me + H
MeI
H H Me
E+ 97 : 3
Equilibration: 47 : 53
Corey J. Am. Chem. Soc. 1962, 84,
- Confined Endocyclic Enolates 2611.
R R R
CD3I
+
LiO O O
H CD3 H H
CD3
via 83 : 17 (R = H)
5 : 95 (R = CH3)
E+ E+
H H H CH3 severe 1,3-diaxial
steric interaction
But
LiO LiO
H H
stereoelectronic preference E+ preference for equatorial
for axial alkylation alkylation through twist boat
Matthews J. Chem. Soc., Chem. Commun. 1970, 38 and 708.

173
E+ Me
Me
–O
vs.
–O
H H
E+
- Similarly
R Me R H R
MeI H + Me
LiO O O
H H H
R = H 79 : 21
R = Me 6 : 94
Me CN Me R Me
base
NC R + NC
O RX
O 9:1 O
Kuehne J. Org. Chem. 1970, 35, 161.

- Predict the major product for
Me
base
?
R1X
O R H
Kuehne J. Org. Chem. 1970, 35, 171.
R = CN, CO2Me Morris J. Org. Chem. 1972, 37, 789.
Stork J. Am. Chem. Soc. 1961, 83, 2965; 1965, 87, 275.
OLi O O
Me Me
MeI +
H H H
axial attack
20 : 80 H
H
OLi
H
House, Trost J. Org. Chem. 1965, 30, 2502. H
equatorial attack
O O O (preferred)
H Me Me
Ar MeI Ar Ar
+
tBuOK
H H H
32 : 68
O O O
H Me Me
MeI +
Ar Ar Ar
tBuOK
H H H
removes one 1,3-diaxial interaction for

90 : 10
axial alkylation through chair-like T.S.
174
Enolate Chemistry
Dale L. Boger
4. Conjugate Addition/Alkylation: Stereochemistry
- There are also many examples of tandem conjugate addition/alkylation reactions and conjugate
reduction/alkylation reactions that combine elements of both the conjugate addition or reduction
with the subsequent alkylation.
Li
N R1Li
N
R2X R2 N
S S S
tBu tBu R1 tBu R1
R2X R2
H S N
tBu BT t
H Bu
t N
Bu S
H R1
Li
R1Li R1
axial attack
Corey and Boger Tetrahedron Lett. 1978, 5, 9, and 13.
F. Asymmetric Alkylations
Conformational or Intraannular Chirality Transfer
1. Schöllkopf asymmetric amino acid synthesis:
O CH3O
NH2 N H2N E
HO Li E+
N then H3O+
O OH
OCH3 > 90% de
(S)-valine alkylation on face opposite iPr group (1,4-stereocontrol)
Angew. Chem., Int. Ed. Eng. 1979, 18, 863; 1981, 20, 798 and 977.
Liebigs Ann. Chem. 1981, 696 and 2407.
Synthesis 1981, 966 and 969.
- Representative recent templates for asymmetric amino acid synthesis
Ph O O Me
H O O
Ph O O N O
tBu
tBu
X O
N Me Ph N Me N Me
MeO N Ph COR COR N Me
COR
X = NBOC, O
Schollkopf Ann. Spanton J. Org. Chem. Williams J. Am. Chem. Seebach Liebigs Ann. Najera J. Heterocyclic
1982, 1952. 1990, 55, 5437. Soc. 1991, 113, 9276. 1995, 217. Chem. 2000, 37, 467.
O O O
2. Seebach: H3O+
R R E
HO HO O
OH R
E OH O
tBu
tBuCHO O OLi but restored by
R
LDA R virtue of alkylation
O O
relative and absolute H diastereoselectively
stereochemistry of
O E+ O
tBu tBu
tBu group set by chirality destroyed
substrate and
incorporation into
Seebach J. Am. Chem. Soc. 1983, 105, 5390.
5-membered ring Fráter Tetrahedron Lett. 1981, 22, 4221.
175
3. Meyers: R R
O O
HO HO R1
R2
O O
OH
NH2 TsOH H2SO4
R R R
O O O R1
LDA R1 LDA
N N N R2
R1X R2X
O O O
Meyers J. Am. Chem. Soc. 1984, 106, 1146; J. Org. Chem. 1989, 54, 2509.
Chelation Enforced Chirality Transfer
4. H
LDA LDA OR'
H OH (1st equiv) H OLi (2nd equiv) Li
O
COOR' COOR' H
R R O
R
H
OH O E+ Li Li N
O O
H
R OR'
R OR'
E
E+ = Br 96 : 4 Z-enolate (note that normally removal of axial proton

get E-enolate from esters) (much more sterically
= nBuBr 97 : 3 accessible)
Seebach Angew. Chem., Int. Ed. Eng. 1981, 20, 971.
Helv. Chim. Acta 1980, 63, 197, 2005.
Fráter Tetrahedron Lett. 1981, 22, 425.
Helv. Chim. Acta 1979, 62, 2825 and 2829; 1980, 63, 1383.
Kraus Tetrahedron Lett. 1977, 18, 4575.
5. Evans' chiral imide auxiliaries: J. Am. Chem. Soc. 1982, 104, 1737.
N-acyl oxazolidinones
E+ from face opposite iPr group
Li
O O O O O O
R LDA R alkylation R
N O N O N O
H
E
from valine
Z-enolate E+ = BnBr, 120 : 1
- and Li
O O O O O O
R R R
N O LDA N O alkylation N O
H
opposite Me E
Me Ph Me Ph and Ph group Me Ph
E+
from norephedrine Z-enolate
176
Enolate Chemistry
Dale L. Boger
new chiral centers created which
Access to either enantiomer
have opposite absolute configuration.
- Factors responsible for high diastereoselectivity:

a. exclusive formation of Z-enolate.
b. chelation results in formation of rigid template, single conformation.
c. π-facial selectivity results from sterics of alkylation.
Other electrophiles beyond RX may be employed

O
Ph alcohols ArSO2N3 azides
NSO2Ph
NBS bromides
Extraannular Chirality Transfer
6. Schöllkopf Liebigs Ann. Chem. 1981, 439.

H-eclipsed
H O H OLi H O
R LDA R Ph Br R
Me N Me N Me N
Ph Ph –60 °C Ph Ph
N N N
>95 : 5
R = CH3, BnBr, 94%, >97 : 3
RS RL (E+ = D2O) R = Et, BnBr, 85%, 97.5 : 2.5
Me OEt 10 : 1 RL O
Stereoelectronic R
Me OPh 10 : 1
R
Steric Me t
Bu 9:1 H
RS
E
Me OtBu 8:1
with control of enolate geometry available,
Me StBu 7.5 : 1 reaction via H-eclipsed conformation might be
Me OMe 7:1 facially selective. To date, this has not been
extensively examined with acyclic systems.
Me CF3 5:1
Me Ph 3:1
Me i
Pr 2.3 : 1
Me Et 1.4 : 1 See: Mohrig J. Am. Chem. Soc. 1997, 119, 479.
7. Fraser Tetrahedron Lett. 1979, 20, 3929.
Me Ph Me Ph
N H N H
LDA E
E+
E+ = MeI, 3.2 : 1
Me Ph
LiN H
E+
177
Through Space Interactions/Blocking Groups
8.
H R H O
O O O R
with certain esters of chiral alcohols, H and carbonyl are eclipsed in
could see enantioselectivity via much preferred conformation
conformational control
Me Me re face is blocked
R' N
O N O
Ph Ph
O LICA O
H R' H H
O THF O
H O H OLi
kinetic enolate
generation E+
E-enolate si face alkylation
H's eclipsed with carbonyls
in ground state conformation
LICA
THF–HMPA R'
thermodynamic enolate Xc H
generation (via equilibration) E
O
1
Me
HN H
O
Ph E+
O Xc R'
H R'
O (si face attack)
H E
OLi O
+
Z-enolate E 2
R' solvent E+ 1:2 yield
CH2Ph THF MeI 95 : 5 95%
Me THF BnBr 94 : 6 96%
Me THF–HMPA BnBr 30 : 70 96%
lower diastereoselectivity due to inability to generate

exclusively the Z-enolate (70:30 = Z : E formed)
Helmchen Angew. Chem., Int. Ed. Eng. 1981, 20, 207.
Tetrahedron Lett. 1980, 21, 1137; 1983, 24, 3213.
SO2Ph
N Ar E
R E+
O N N
90−99% de R
S O S
O O O M O OO
Helmchen Oppolzer Tetrahedron Lett. 1989, 30, 5603 and 6009.

178
Enolate Chemistry
Dale L. Boger
9. Catalytic asymmetric alkylation: Corey Tetrahedron Lett. 1998, 39, 5347.
Br-
Ph O Ph O
1 (10 mol%)
N + RX N
OtBu CsOH•H2O OtBu H N
Ph Ph +
H R
N H
O O
R= -(CH2)4Cl -(CH2)2CO2CH3 -(CH2)2COEt

1
ee (%) 99 95 99 91
Additional examples of asymmetric alkylations may be found in the sections discussing enolate equivalents.
G. Aldol Addition (Condensation)

R2 OM OH O OH O
R3CHO + +
R3 R1 R3 R1
H R1
R2 R2
First report: Wurtz Bull. Soc. Chim. Fr. 1872, 17, 436. syn anti
(or threo) (or erythro)
1. Nomenclature
syn/anti J. Am. Chem. Soc. 1981, 103, 2106. (supercedes erythro/threo nomenclature)
erythro/threo Angew. Chem., Int. Ed. Eng. 1980, 19, 557.
Summary Asymm. Synth. Vol. 3, pp 111–212. (Review of aldol diastereoselection)
IUPAC Pure Appl. Chem. 1976, 45, 11.
Others Angew. Chem., Int. Ed. Eng. 1966, 5, 385. (Cahn, Ingold, Prelog)
Angew. Chem., Int. Ed. Eng. 1982, 21, 654. (Seebach, Prelog)
J. Org. Chem. 1982, 47, 3811. (Carey, Kuehne)
2. Generalizations
R2 OM OH O
R3CHO +
R3 R1
R1
R2
Z-enolate
syn
(or threo)
OH O
OM
3CHO
R + R3 R1
R2 R1 R2
E-enolate anti
(or erythro)
1. Z-enolates give predominantly syn (or threo) aldol products (thermodynamic enolates).
2. E-enolates give predominantly anti (or erythro) aldol products (kinetic enolates).
and
3. Diastereoselectivity (for syn aldol) of Z-enolates is greater than that of E-enolates (for anti).
4. Correlation for E or Z-enolate is greater when R1 is sterically demanding.
5. Correlation is stronger when R3 is large (most important for boron enolates).
6. Correlation is reversed when R2 is sterically demanding (very large).
- Advances in 1H NMR, 13C NMR permitted detection, quantification and identification.
- Issue of equilibration addressed.
179
Francis W. Aston was awarded Fritz Pregl received the 1923 R. R. Ernst received the
the 1922 Nobel Prize in Chemistry Nobel Prize in Chemistry for 1991 Nobel Prize in Chemistry
for his contributions to analytical his development of microanalytical for the development of the
chemistry and the study of atomic techniques (accurate microbalance methodology of high resolution
structure. He is primarily weighing of 1 µg−20 g) and for NMR spectroscopy.
associated with the design and refinements in characterizing organic
use of the mass spectrometer. compounds (CHNSX analysis).
3. Examples
O O OH O OH
LDA
+
CHO
EtO EtO EtO
E-enolate
formation anti syn
90–93% 7–10%
- Steric size of R1 affects diastereoselectivity
OMg OH O
PhCHO syn:anti >98:2
Ph
note: R1 = tBu > iPr

- Z-enolate
OLi OH O
PhCHO
syn:anti 90:10
Ph
OLi OH O
PhCHO syn:anti 45:55
Ph
note: Z > E, stereoselectivity
much lower with E-enolate
OLi OH O
PhCHO
syn:anti 88:12
Ph Ph
> 98:2 Z:E
OLi CH3 OH O
PhCHO
syn:anti 88:12
Ph Ar
H3C CH3
87:13 Z:E
OLi CH3 OH O
PhCHO
anti:syn 92:8
Ph Ar
note: larger R1 helps
H3C CH3
maintain high selectivity
92:8 E:Z dictated by enolate geometry
and substantially enhances
Heathcock J. Org. Chem. 1980, 45, 1066. E-enolate diastereoselectivity
180
Enolate Chemistry
Dale L. Boger
4. Origin of Diastereoselectivity
- Zimmerman–Traxler Model (J. Am. Chem. Soc. 1957, 79, 1920)

- Chair-like, closed transition state: metal coordination to both carbonyls
a. Z-enolates
R2 R2 R2 R2
HO O O O O HO
O M M O
R3 R3 H H
H H H H
H R1 H R1 R3 R1 R3 R1
syn (major)
1,3-diaxial interaction (destabilizing)
anti is minor diastereomer
gauche
interaction
OH O R2 R2 OH O
R3 O
M H O
M
R3 R1 O O R3 R1
R2 H H R2
Major product H R1 R3 R1
(syn) 1,3-diaxial interaction
1. Diastereoselectivity for Z-enolate (giving syn aldol product) is maximized when R1 and R3 are
sterically demanding (R1/R3 interaction is maximized).
2. Diastereoselectivity also increases as metal is changed to boron. This is attritubted to a tighter T.S.
(B–O bond shorter, so R1/R3 steric interactions are magnified in T.S. for anti product).
3. When R2 is very large the R3/R2 gauche interaction > R1/R3 1,3-diaxial interaction (Why?).
Li–O °
1.92–2.00 A
Mg–O °
2.01–2.03 A
Zn–O °
1.92–2.16 A Diastereoselection:
Al–O °
1.92 A
° B > Li > Na > K
B–O 1.36–1.47 A
Ti–O °
1.62–1.73 A
Zr–O °
2.15 A
b. E-enolates
H H H H
HO O O O O HO
O M M O
R3 R3 H H
2 2
R R2 R R2
H R1 H R1 R3 R1 R3 R1
anti (major)
1,3-diaxial interaction
syn (minor)
OH O H H OH O
R3 O
M H O
gauche M
R3 R1 interaction
O O R3 R1
R2 R2
R2 R2
H R1 R3 R1
Major Product gauche
interaction syn
(anti) 1,3-diaxial interaction
1. Diastereoselectivity increases as R1 and R3 become sterically large, and a switch to the boron enolate
will increase selectivity.
2. Diastereoselectivity may switch when R2 is very large (Why?).
181
5. Cyclic Ketones
- Only E-enolate and therefore anti aldol.
- Aldol addition is reversible, can get very different selectivity by allowing
reaction products to equilibrate (and equilibration can be very fast).
O O OH O OH
base H H
+
+ CHO
for kinetic
aldol product syn
anti
E-enolate (stabilization of adduct via
Dubois: base anti:syn coordinating countercation)
LiOH >95:5
KOH >95:5
Me4N+OH– 30:70 thermodynamic ratio
- Instructive examples: Majewski Tetrahedron Lett. 1989, 30, 5681.

House J. Am. Chem. Soc. 1973, 95, 3310.
Heathcock J. Org. Chem. 1980, 45, 1066.
OLi O OH O OH
Ph + Ph
+ PhCHO
anti 52:48 syn

widely quoted
- but really is the result of equilibration: Tetrahedron Lett. 1989, 30, 5681. ratio
OLi O O OH O OH
H Ar + Ar
+
R
anti syn
THF > DME R=H THF 84 : 16 75%

DME 72 : 28 50%
Et2O 76 : 24 84%
R = NMe2 THF 73 : 27 68%
R = OCH3 THF 78 : 28 68%
R = Ph THF 94 : 6 67%
R = CF3 THF 74 : 26 80%
OLi O OH O OH
Ph + Ph
+ PhCHO
axial
attack
tBu tBu tBu
anti syn
1. E-enolate -> anti aldol.
2. Axial attack of enolate THF 81 : 19 63%
(stereoelectronic control). Et2O 75 : 25 61%
Et2O–HMPA 68 : 32 68%
182
Enolate Chemistry
Dale L. Boger
6. Acyclic Enolates
- Effect of R1
OLi
+ PhCHO syn : anti aldol
R1
syn : anti ratio
R1 Z-enolate E-enolate
OMe – 1.5
OtBu – 1.0 typically:
Z > E diastereoselection
H 1.0 1.5
Et 9.0 1.5
iPr
diastereoselection
9.0 1.0
increases as size
Ph 7 – of R1 increases
tBu
70 –
mesityl >50 <0.02
7. Refined and Alternative Models
- Idealized closed, chair transition state does not account for Z > E diastereoselectivity
nor does it explain the switch in diastereoselectivity when R2 is sterically demanding.
- It has been suggested that the transition state for addition more closely resembles
an eclipsed conformation.
- Dubois, Fellmann Tetrahedron Lett. 1975, 1225; Tetrahedron 1978, 34, 1349.
- Heathcock J. Org. Chem. 1980, 45, 1066.
- For Z-enolate
R2O M R2O M
syn R3 O H O anti
H H
H R3
R2/R3 gauche R1 R1 R1/R3 interaction
Z>E
interaction is even worse than
diastereoselectivity
further minimized in staggered
- For E-enolate
HO M HO M
anti R3 O H O syn
R2 R2
H R3 1
R1 R
nearly eclipsed E < Z diastereoselectivity
much worse than gauche interaction diastereoselectivity reverses
As R2 increases in size, R2/R3 interaction competes when R2 becomes sterically
with or surpasses R1/R3 interaction demanding
- Burgi–Dunitz approach angle -skewed approach where R2/R3 come closer together than R1/R3
R1
R2
OLi 109°
H
R3
O
H
183
- An additional alternative explanation considers the boat transition states
Evans Top. Stereochem. 1982, 13, 1.
- In addition to the four idealized closed chair transition states, four closed
boat transition states must be considered as well.
- Z-enolate
R2/R3 eclipsed R2/H eclipsed
2 R2
R3 R M H M
syn O O anti
aldol aldol
H H O R3 H O
R1 R1
H/H eclipsed R3/H eclipsed
- when the R2/R3 gauche interaction is large
in chair TS, Z-enolate boat TS might become
competitive leading to the anti aldol
- E-enolate
R3/H eclipsed H/H eclipsed
H H
R3 M H M
anti O O syn
aldol 3 aldol
H R2 O R R2 O
R1 R1
R2/H eclipsed R3/R2 eclipsed
- However, the boat transition state alternative does not explain the E-enolate
switch from anti to syn aldol when R2 becomes sterically more demanding.
- Examples
OMgBr O OH O OH
CH3CHO R R
R
0 °C
E-enolate anti syn

R = Me 93.5 : 6.5
Dubois, Fellmann C. R. = Et 87.5 : 12.5
Hebd. Seances Acad. Sci. = iBu 80 : 20
Ser. C. 1972, 274, 1307. = iPr 46 : 54
= tBu 29 : 71
anti:syn ratio decreases smoothly as R becomes larger (R2 in models above)
O OH O OH
OLi tBuCHO
tBu tBu tBu tBu
tBu R
Et2O, 20 °C
R R
Z-enolate anti syn
R = Me 0 : 100
= Et 0 : 100
= nPr 2 : 98
= iBu 3 : 97
= iPr 71 : 29
= tBu 100 : 0
184
Enolate Chemistry
Dale L. Boger
8. Boron Enolates
- Often much more diastereoselective in their aldol addition reactions

- This results from a shorter B–O bond length, tighter transition state
OB(Bu)2 OH O OH O
R2CHO
R1 R2 R1 R2 R1
Z-enolates
(syn aldol)
syn anti
R1 = Me R2 = Ph
R1 = PhCH2 R2 = Ph
R1 = Ph R2 = Ph >95:5 for all cases
R1 = Ph R2 = Et
R1 = Ph R2 = iPr
OB(Bu)2 OH O OH O
R2CHO
R1 R2 R1 R2 R1
E-enolates
(anti aldol) syn anti
R1 = Me R2 = Ph 25:75
R = PhCH2 R2 = Ph
1 20:80
R1 = Ph R2 = Ph 25:75
Z > E diastereoselection E-enolates give
lower diastereoselectivity
Masamune Tetrahedron Lett. 1979, 1665.
a. Z-enolate Preparation and Reactions
O R2BOTf OBR2 OH O
PhCHO
R1
iPr
2NEt R1 Ph R1
–78 °C
Z-enolate syn aldol
R1 = Et Bu2BOTf, –78 °C >97:3 >97:3 syn/anti
R1 = Et BOTf, 0 °C 82:18 84:16 syn/anti

2
R1 = Ph 9-BBNOTf, 0 °C >95:5 >97:3 syn/anti
R1 = Ph BOTf, 0 °C >99:1 >95:5 syn/anti

2
185
b. E-enolate Preparation and Reactions
O R2BOTf OBR2 OH O
PhCHO
Me iPr Ph R1
R1 2NEt R1
Me anti aldol
R1 = iPr Bu2BOTf, –78 °C 45:55 Z:E 44:56 syn/anti
R1 = iPr BOTf, 0 °C 19:81 Z:E 18:82 syn/anti

2
- originally difficult to control but:
O R2BOTf OBR2 OH O
PhCHO
Me iPr Ph StBu
StBu 2NEt StBu
Me anti aldol
Masamune Tetrahedron Lett. 1979, 2225. E-enolate
Bu2BOTf, 0 °C >95:5 10:90 syn/anti
BOTf, 0 °C >95:5 5:95 syn/anti

2
E-enolates very accessible using tbutylthiol esters
c. Examples of more recent methods to control boron enolate geometry

B B OBChx2
OBBN O O
R
R HR H RR R
R Z E
H H R
iPr Cl–B(Chx)2/Et3N
9-BBN–Cl/ 2NEt (hindered base)
Z-enolate E-enolate
thermodynamic enolate kinetic enolate
E1 elimination mechanism E2 elimination mechanism
Cl–B(Chx)2
O OB(Chx)2 O OH
BCl
2 i) PhCHO Ph
Et3N, 0 °C ii) H2O2
workup
>99% E >95:5 anti:syn
OBBN O OH
9-BBN–Cl i) PhCHO
Ph
iPr
2NEt, 0 °C ii) H2O2
workup
>99% Z 98:2 syn:anti
-These results are difficult to achieve with boron triflates
Brown J. Am. Chem. Soc. 1989, 111, 3441.
186
Enolate Chemistry
Dale L. Boger
- Examples
BCl
9-BBN–Cl 2
O
99:1 (Z:E) <1:99 (Z:E)
O
>99:1 15:85
O
98:2 (via equilibration) <1:99
O
96:4 (via equilibration) <1:99
O
99:1 (via equilibration) 21:79
Z-enolate is easy to access: thermodynamic enolate

E-enolate is less stable, more difficult to generate without equilibration
(also still difficult to prepare unless alkyl groups are bulky).
- see also Brown J. Org. Chem. 1992, 57, 499 and 2716.
Brown J. Org. Chem. 1994, 59, 2336.
O Chx2BX OBChx2 OBChx2

R iPr R
OEt 2NEt OEt OEt
or Et3N
R
CCl4 Z E
R = CH3 X=I >97 : 3
R = CH3 X = Br 84 : 17
R = Et X=I 95 : 5
R = iPr X=I <3 : >97
R = tBu X=I <3 : >97
R = Ph X=I <3 : >97
O Chx2BI OBChx2 OBChx2
OR CCl4 OR OR
Z E
R = CH3 Et3N >97 : <3
iPr NEt
2 >97 : <3
R = Et Et3N >97 : <3
iPr NEt
2 >97 : <3
R = iPr Et3N 86 : 14
iPr NEt
2 64 : 36
R = tBu Et3N 59 : 41
iPr NEt
2 3 : 97
9. Aldol Condensation with Chiral Aldehydes
a. Felkin Addition - Two faces of aldehyde are diastereotopic.

- Nucleophilic addition of enolate follows Cram's
empirical generalization (Felkin–Anh addition).
187
H H Nu– Nu
major RM
RL Nu–
H H RMOH RL
Nu
R H O
O M H RM RL OH
Felkin model
RL
- Example:
OM
R R
+ Ph + Ph
Ph CHO R OH O OH O
invariant diastereoselectivity syn anti
with different size of R :
3 1
MO O
O
R R
major R
H syn
H Me O
H O H Me H H MeOH
Ph Ph Ph
Ph Ph
H H
H O O OH
minor Ph
Me H H anti
Me
CH2COR
MO R Me H
R O
- Can combine all selectivities to give 3 contiguous chiral centers, if the

chiral aldehyde and enolate partners are both highly diastereoselective.
Z-enolate
OLi
tBu
+ tBu tBu
Ph CHO Ph Ph
OH O OH O
A B
- A & B represent 2,3 syn products
tBu tBu
(from Z-enolate with large R group)
Ph Ph
- A & C represent 3,4 syn products OH O OH O
C D
(from Cram/Felkin–Anh addition to aldehyde)
experimental: A:B:C:D = 86:14:0:0
- syn aldol reaction proceeds with >98% syn selectivity
- Cram/Felkin–Anh addition proceeds with 86:14 syn selectivity
E-enolate Felkin addition E-enolate
OLi
anti aldol
H StBu StBu
O O O O
MOMO O OAc O O MOMO O OAc O OH O
Woodward J. Am. Chem. Soc. 1981, 103, 3210, 3213, 3215. erythromycin
188
Enolate Chemistry
Dale L. Boger
b. Chelation Control
OLi
+
+
R CHO R OTBDMS R OTBDMS
OTBDMS OH O OH O
syn, syn syn, anti
R = Ph 81 : 19
Z-enolate (with large

R group) gives clean >98% syn aldol, 81:19 Cram addition
syn aldol product for both.
21 : 79
R = CH2OTBDMS
>98% syn aldol, 79:21 chelation-controlled addition to RCHO

Explanation of Chelation Control

1. without chelation control
OLi
OLi
Ph O
Me
OTBDMS Me
H O syn, syn aldol condensation
H Me H OTBDMS
H
H
Nu–
Nu–
Nu
Me
H
O H H Me OH 3
H Me Ph 4 OTBDMS
3,4 syn
Ph OH O
Ph
2. with chelation control

+ +
Li Li M
M
O O O O OTBDMS
OTBDMS
Me Me
syn, anti aldol
TBDMSO H TBDMSO H
H H Me syn, syn aldol H H Me
nucleophilic addition severe Me/Me interaction

opposite to larger
(Me) substituent
backside attack
-drawn another way minor
Li Me Me
H H H
O O H RO Nu
H Me Me OR
RO O OH
OR H major Li
3,4 anti
189
10. Aldol Condensation with Chiral Enolates
Evans' Chiral N-Acyl Oxazolidinones O O OH
B O N R1
O O O O R
R Bu2BOTf R R1CHO
O N O N or
iPr
2NEt O O OH
O N R1
only Z-enolate R
(independent of conditions)
two possible syn aldol products
1. Experimental results (relative to chiral center on aux.)
O O O O OH O O OH
Me Bu2BOTf
O N O N R1 O N R1
R1CHO
Me Me
R1 = nBu 99.3 : 0.7

R1 = iPr 99.8 : 0.2
R1 = Ph >99.8 : <0.2
* no anti adducts
Evans J. Am. Chem. Soc. 1981, 103, 2127, 2876, and 3099.
2. Origin of diastereoselectivity
Chair transition state
- Z-enolate (boron enolate/amide) gives syn aldol non-chelated Z-enolate
(minor syn aldol product) O
B H
O O O Xc O O
HN
CH3 OH
O N Me B
O
H R R H R
O
H H
- H–H interaction
Me
- steric interaction with iPr (facial selectivity)
- aligned dipoles less favorable Aldehyde R group equatorial
(axial would give anti aldol)
B observed syn aldol product O

O O Xc O O
H N
CH3 H
N OH B
Me O
O H R H
H R O
O - chiral auxiliary rotates R
- non-chelated enolate: opens coordination site on Me
boron required to complex and activate aldehyde
- dipoles non-aligned, more favorable
190
Enolate Chemistry
Dale L. Boger
3. For the alternative enantiomer
B O O OH
O O
Auxiliary with the Me RCHO
O N R
opposite absolute O N
configuration Me
Ph Me
or Ph Me
the more accessible syn anti
R= nBu >99.8 : <0.2 : 0 : 0
R = iPr >99.8 : <0.2 : 0 : 0
R = Ph >99.8 : <0.2 : 0 : 0
O
- Note: selectivity not good for H
Xc
O
- Solution: use removable substituent
SMe
Xc
Evans aldol overrides any chiral aldehyde directing preference:
i.e. Felkin–Anh preference.
As before - two possible transition states for syn aldol product formation
B
Me O O Xc O
Ph CH3 OH
N Me
O H R R
O H
- anti carbonyl conformation observed syn aldol product
B
O O O Xc O
CH3
O N OH
Me
H H R
Ph H H R
Me
- syn carbonyl conformation (minor syn aldol product)
- steric interactions between H's
Note: Availability of oxazolidinone alternatives S O

Fujita J. Org. Chem. 1986, 51, 2391. R
Crimmins J. Am. Chem. Soc. 1997, 119, 7883. X N X=O
X=S
Advantages: S > O for chelation and more readily cleaved
4. Ti enolate promoted Evans aldol (non-Evans syn aldol)
Ti
O O O O O O OH
R LDA R R1CHO
O N O N O N R1
ClTi(OiPr) 3
R
or TiCl4
syn anti
Et2O vs. THF Z-enolate and chelated enolate 8 : 87 : 5 : 0
as solvent higher coordination sphere of Ti
191
Thornton J. Am. Chem. Soc. 1989, 111, 5722; 1991, 113, 1299. syn aldol product but
Evans J. Am. Chem. Soc. 1991, 113, 1047. opposite absolute
Thornton J. Org. Chem. 1991, 56, 2489. stereochemistry
Heathcock J. Org. Chem. 1991, 56, 5747. (non-Evans syn aldol).
5. Origin of diastereoselectivity - chelated Z-enolate
Chelation orients chiral

O auxiliary in opposite orientation
Ti
O O O H O
CH3 HN
syn
O N Ti
O
H R H R
H O
H
Closed, chair transition state
Me with chelated Z-enolate
Ti O
O O O H O
CH3 RN anti
O N
Ti
R H O
H H H H
O
steric interaction Me
6. Chelated and non-chelated Ti enolates
OH O S O S iPr OH O S
1 equiv TiCl4 2NEt
R N O 2.5 equiv TMEDA N O 2 equiv TiCl4 R N O
Me or sparteine RCHO Me
Bn Bn Bn
Evans syn RCHO non-Evans syn
via non-chelated Z-enolate via chelated Z-enolate
O
H S O
H S
Bn N
Cl Cl H +Cl– Bn H N Cl
Cl Ti Ti Cl
O R –Cl– O
Cl H H R Cl
O O
Me Me
Crimmins J. Am. Chem. Soc. 1997, 119, 7883.
7. Anti-selective additions
- see also Heathcock Aldrichimica Acta 1990, 23, 99; J. Org. Chem. 1991, 56, 5747.
OH O Se O Se OH O Se
1.1 equiv TiCl4 1.1 equiv TiCl4
BnO BnO
Pr N O 1.15 equiv iPr2NEt N O 1.15 equiv iPr2NEt N O
Me PrCHO BnOCH2CHO−TiCl4 Me
90%, > 98% syn 90%, > 99.9% anti

non-Evans syn Silks J. Am. Chem. Soc. 2000, 122, 386. via chelated Z-enolate
192
Enolate Chemistry
Dale L. Boger
11. Asymmetric Aldol Reactions
- Review: Paterson Org. React. 1997, 51, 1.
CF3 F3C
Ph Ph
CF3
F3C N N S
S B
O
O O O
Br Corey
OH O
O Et3N OBR*2 RCHO
R*2BBr R OtBu
OtBu Me OtBu Me
E-enolate
anti aldol
(kinetic enolate)
anti:syn
toluene–hexane R = Ph 93% 98:2 94% ee
CH2Cl2 R = Ph 90% 96:4 89% ee
in plane lone pair oriented away from ester
tBu
via: + O
B O
Br H Me
E-enolate
E2 elimination
H
Et3N
non-hindered base
iPr OH O
O 2NEt Me OBR*2 RCHO
CH2Cl2 R SPh
SPh SPh Me
Z-enolate syn aldol
anti:syn
R = Ph 93% 1:99 97% ee
SPh+ B
via: SPh+
B O O
Br H Me –Br– Z-enolate
Me H
(thermodynamic)
E1 elimination
H H
i
Pr2NEt
hindered base
Facial selectivity:
Ar Ph Ph
Me SO2
R O Orientation
N determined Ar S N N SO2
B Ph B
O by the O2 Ar
H O O
N phenyl groups
H Ar SO2 Ph Me
S SPh
Ph
R H
H
- Chair transition state
- Boron enolate
- Z-enolate
193
Examples
Corey Tetrahedron Lett. 1993, 34, 1737.
O R2*BBr OBR*2 PhCHO OH O
X X Ph X
Yield Config. ee
iPr 82% S 64%
X = SPh CH2Cl2, 2NEt
X = OtBu CH2Cl2, iPr2NEt 78% S 80%
X = StBu CH2Cl2, iPr2NEt 82% S 73%
X = StBu toluene, Et3N 94% S 52%
OBR*2 OH O
PhCHO
X Ph X 1
O R2*BBr
Me
X OBR*2 PhCHO OH O OH O
X Ph X Ph X
Me Me
2a 2b
Yield syn:anti Major Prod. ee

X = SPh CH2Cl2, iPr2NEt 90% 99:1 1 97%
X = SPh toluene, Et3N 78% 94:6 1 95%
X = OtBu CH2Cl2, iPr2NEt 89% 4:96 2a 94%
Note: X = OtBu toluene, Et3N 64% 2:98 2a 94%
Z-enolate X = OBn CH2Cl2, iPr2NEt 73% 84:16 1 97%
E-enolate X = OBn toluene, Et3N 78% 15:85 2a 97%
X = SBn CH2Cl2, iPr2NEt 79% 70:30 1 81%
X = SBn toluene, Et3N 84% 9:91 2a 94%
X = StBu CH2Cl2, iPr2NEt 73% 71:29 1 50%
X = StBu toluene, Et3N 86% 6:94 2b (+ 2a) 46%
see also: Corey Tetrahedron Lett. 1992, 33, 6735.

- Mukaiyama Chem. Lett. 1973, 1011; review Org. React. 1982, 28, 203.
- Carreira's catalytic asymmetric aldol
O OSiMe3 1.1 (2-5 mol%) OH O

+ –10 °C
tBu R1 H OMe 2. Bu4NF R1 OMe
Aldehyde ee:
N
CHO 97%
O Ti O Br Me
O CHO 95%
O O Me
CHO 97%
tBu Ph
CHO 94%
tBu
Ph
1
C6H11CHO 95%
PhCHO 96%
Carreira J. Am. Chem. Soc. 1994, 116, 8837.
194
Enolate Chemistry
Dale L. Boger
- Evans C2-symmetric bisoxazoline catalysts
O OSiMe3 2 (10 mol%) R2 OH O

R1O + –78 °C 1
R O
R2 StBu StBu
O O 1N HCl
2 –OTf O O
N N R1 R2 ee:
Cu
Me3C CMe3 Me Me 99%
2 Bn Me 99%
tBu Me 99%
Me Et 94%
iBu
Me 94%
iBu
Et 36%
O OSiMe3 3 (10 mol%) OH O

EtO + –78 °C EtO
H SR2 SR2
O O 1N HCl
O R1 O R1
N N
Sn R1 R2 anti:syn ee
Bn TfO OTf Bn
3
H Ph – 98%
Me Ph 90:10 95%
Et Ph 92:8 95%
- review of catalyzed iPr Ph 93:7 95%
enantioselective aldol reaction iBu Ph 92:8 98%
Tetrahedron Asymm. 1998, 9, 357. iBu tBu 96:4 96%
iBu Et 92:8 92%
CO2H
N
H H
O O O OH
97% (H)HO N
+ O
H 96% ee R H
Me O O
H
List, Lerner, and Barbas J. Am. Chem. Soc. 2000, 122, 2395.
O O O OH regioselectivity > 20:1

62%
+ diastereoselectivity > 20:1
H 99% ee enantioselectivity > 100:1
OH OH
List J. Am. Chem. Soc. 2000, 122, 7386.
195
12. Enzyme-Catalyzed Aldol
- Wong aldolase based synthesis of carbohydrates and aza-sugars

O
HO OP = DHAP
OH
O OH 1. Phosphatase H
FDP aldolase 2. H2 / Pd–C HO N
PO
R HO
DHAP R = N3 HO
OH OH
O OH
O
H R HO
R = OH OP
OH HO
Rham-1-P OH
aldolase O OH L-Fructose 1-P
PO
DHAP R
OH OH
H2 / Pd–C H
HO N
H3C
R = N3 HO
OH
- Review: Wong Pure Appl. Chem. 1993, 65, 803.
Niels K. Jerne, Georges F. Kohler,

and Cesar Milstein shared the
- Lerner catalytic antibodies 1984 Nobel Prize in Medicine for
the preparation of monoclonal
- wide range of donors and acceptors utilized antibodies.
- commercially available
38C2 33F12
Acceptor Donor Product ee ee
O OH O
O
H >99% >99%
O
O OH O
>98% 89%
H
OH
OH
O O O
>95% >95%
O O
Lerner, Barbas J. Am. Chem. Soc. 1998, 120, 2768.
Org. Lett. 1999, 1, 59.
Kinetic resolution
Me OH O Me OH O
38C2
50%
MeO MeO
> 99% ee
catalyzes retro aldol of only one enantiomer
Lerner, Barbas J. Am. Chem. Soc. 1999, 121, 7283.

196
Enolate Chemistry
Dale L. Boger
H. Aldol Equivalents
1. Chiral Organoboranes
Brown: de% ee% yield%
OH
1. CH3CHO, –78 °C
B
99 95 78
2 2. OH–, H2O2
CH3
oxidative cleavage gives
typical aldol product
1. CH3CHO, –78 °C OH
B 99 95 75
2
2. OH–, H2O2
CH3
Brown J. Am. Chem. Soc. 1986, 108, 293 and 5919.
J. Org. Chem. 1989, 54, 1570.
The relative configuration, syn or anti, of the product is determined by the configuration of the olefin.
H OH
B
Et
O
Et
E anti
H OH
B
Et
O
Et
Z syn
B B
2 2
OH OH OH OH
CHO
BnO
BnO BnO BnO BnO
syn Z E anti
92 : 8 98 : 2
The reagent controls facial selectivity of addition and determines the absolute configuration of product.
Roush:
O
O de% ee% yield%
iPrO
2C OHC
O Me O
iPrO 80 84 80
2C B toluene, –78 °C O
O ° sieves
4A
OH
Roush and Halterman J. Am. Chem. Soc. 1986, 108, 294.
A O OR B CO2R
H O O
CO2R H
B B OR
R O O O
Me Me O O
R
H H
- asymmetric induction is a consequence of n/n electronic repulsive
interactions disfavoring transition state B relative to transition state A
197
2. Allylsilanes
Reviews: Fleming Org. React. 1989, 37, 57.
Panek Chem. Rev. 1995, 95, 1293.
A. Chiral allylsilanes yield E-olefins selectively
H H H H H
R3Si R3Si H H Anti-SE' H
H + E R E
R H R H
H
H H H H
H H H
H H Anti-SE' H
R H +R E
R3Si R3Si H E
R
A 1,3 -strain
- Chiral allylsilanes add to carbonyls in syn fashion (either synclinal or antiperiplanar T.S.)
(Unless chelation control is utilized)
LA LA
O O
Me H Me H Me Me
R R
H R R H
OH OH
SiR3 SiR3
(E)-silane reagent syn-homoallylic alcohol (Z)-silane reagent syn-homoallylic alcohol
B. Additions to Aldehydes (Opposite face of silane)
O
Me H Antiperiplanar
BnO T.S. OH
H O
BF3•OEt2 BnO
F3B CO2Me
(–78 °C) H
CO Me
BnO SiMe3 2
6.5 : 1
Bn syn-homoallylic alcohol
CO2Me
SiMe3 Br O
Mg H Me
O OH
Br O H Synclinal
BnO BnO
H H T.S. CO2Me
Me3Si
MgBr2•OEt2
(–25 °C) MeO2C 12.2 : 1
Denmark J. Org. Chem. 1994, 59, 5130. anti-homoallylic alcohol
oxidative cleavage provides aldehyde,
C. Additions to Chiral Aldehydes - BnO chelation, anti carboxylic acid (R = H) or ketone (R =
R3SiO no chelation, syn Me, Et) aldol addition products
R O OH R
+ TiCl4 R = Me 64%, 10:1
Me
CO2Me BnO H –78 °C BnO CO2Me R = Et 35%, 15:1
SiMe2Ph Me Me Me
R O OH R
+ TiCl4 R=H 85%, >30:1
Me BnO
CO2Me BnO H –78 °C CO2Me R = Et 69%, 10:1
SiMe2Ph Me Me Me
198
Enolate Chemistry
Dale L. Boger
R O OH R
TiCl4 R = H 90%, >30:1
Me
CO2Me + Ph2tBuSiO H –78 °C R3SiO CO2Me R = Me 79%, >30:1
Me R = Et 74%, 15:1
SiMe2Ph Me Me
R O OH R
Me TiCl4
CO2Me + Ph2tBuSiO H R = Me 98%, 8:1
–78 °C R3SiO CO2Me R = Et 79%, 10:1
SiMe2Ph Me Me Me
Jain and Panek J. Am. Chem. Soc. 1996, 118, 12475.
3. Allylstannanes
A. Asymmetric addition via optically active catalyst
10 mol% OH
O BINOL−TiCl2
Bu3Sn +
64% CO2Me
H CO2Me
84% syn, 86% ee
Aoki Tetrahedron 1993, 49, 1783.
Keck J. Am. Chem. Soc. 1993, 115, 8467; J. Org. Chem. 1993, 58, 6543.
- Also applicable to allylsilanes.
I. Enolate-imine Addition Reactions

- Review: Hart Chem. Rev. 1989, 89, 1447.
R1 Ph H Ph
1. LDA H H R 1
H
R1 CO2Et 2. PhCH=NSiMe3 +
NH NH
3. HCl, H2O O O
1
R yield yield
H 14% 0%
Me 41% 3%
Et 72% 0%
i
Pr 80% 1%
tBu 40% 0%
Hart J. Am. Chem. Soc. 1984, 106, 4819.
OH OH
H Ph H H
OH 1. LDA H Ph
CO2Et 2. PhCH=NPh +
N N
O Ph O Ph
Georg Tetrahedron Lett. 1985, 26, 3903. 25% 16%
NHBOC NHBOC NHBOC

OTf Xc O Xc O
CONH2 Sn CONH2 CONH2
N O O NH NH
MeS MeS
+ THF, 0 °C
MeS +
N N N O 85% N N N N
H2N CO2Et Me Ph H2N CO2Et H2N CO2Et

CH3 CH3 CH3
7:1
Boger J. Am. Chem. Soc. 1994, 116, 5619. anti:syn (>16:1)
199
J. Claisen Condensation O
OEt EtO ONa O

CH3CO2Et + NaOH (or NaOEt)
ONa OEt
H2C
Claisen Chem Ber. 1887, 20, 651. OEt
reaction driven to completion by NaO O irreversible O O

forming product which is stable
OEt OEt
to the reaction conditions.
pKa = 13 pKa = 13
- Weinreb Amide
Turner J. Org. Chem. 1989, 54, 4229.
O O
OMe Li CN CN
N +
Me 62%
O O
OLi
+ OR'
OR'
63–89% R
R
O O
OLi
+
47%
O NNMe2
NNMe2
+ Li
98%
Li
- Tetrahedral intermediate is stabilized O
- Breaks down upon workup, not in reaction O
R N Me
- Generality of Weinreb amide Ph
- Weinreb Tetrahedron Lett. 1981, 22, 3815. Me
- Knoevenagel–Doebner and Stobbe Condensation
CHO CO2Et Knoevenagel–Doebner condensation
CO2Et piperidine
+ Knoevenagel Chem. Ber. 1896, 29, 172.
OMe CO2H OMe Doebner Chem. Ber. 1900, 33, 2140.
OMe OMe
CO2Et
CO2Et Ph Stobbe condensation
Ph NaH Stobbe Chem. Ber. 1893, 26, 2312.
O +
Ph CO2Et Review: Org. React. 1951, 6, 1.
Ph CO2Et
- Example
O
R CHO (MeO)2P CO2Et R CO2Et
NaH 1. TFA
+
75–100% 2. Ac2O
CO2tBu CO2tBu
R = H, Br, OCH3
R CO2Et N R
R Boger J. Org. Chem. 1996, 61, 1710.
1996, 61, 4894.
O
OH
O
200
Enolate Chemistry
Dale L. Boger
K. Dieckmann Condensation
- Org. React. 1967, 15, 1.
- Examples
O ONa O
NaOEt H+
OEt CO2Et CO2Et 80%
EtO
O
O O
CO2Et NaOEt CO2Et H2O
CO2Et 84–89%
64–68% 180 °C
EtO2C
O O
- Org. Syn. Coll. Vol. 2, 288.
KOtBu Thorpe–Ziegler
MeO2C THF condensation
O
CN 70% H
CN Dinitrile is Ziegler condensation
Ziegler Chem. Ber. 1934, 67, 139.
Stevens J. Am. Chem. Soc. 1977, 99, 6105.
O
CO2Et Na
CO2Et EtOH
CO2Et
Dieckmann Ber. 1894, 27, 965.

Fehling Ann. 1844, 49, 192.
(1st example - product not identified)
R R R
R CO2Et
O O–
O CO2Et
CO2Et CO2Et CO2Et
2 1
- products interconvert under reaction conditions
equilibration driven to 1 by formation of enolate.
The analogous intramolecular keto ester condensation may be described as "occurring under Dieckmann conditions"
see: Org. React. 1959, 8, 79.
CO2Et
O
NNMe2 CO2Et
1. O NaH
LiCu
2 2. H3O+ benzene
O
cat. MeOH
conjugate 1,4-addition
Boger and Corey Tetrahedron Lett. 1978, 4597.
201
OMe OMe OMe
MeO MeO MeO
KOtBu H+
N 98% N aq. dioxane N
MeO MeO MeO
89%
CN
MeO2C MeO2C NH2 O
OMe OMe
MeO MeO
N R=H rufescine N
MeO R = OCH3 imeluteine MeO imerubrine
OMe O
MeO
Boger and Brotherton J. Org. Chem. 1984, 49, 4050.
Boger and Takahashi J. Am. Chem. Soc. 1995, 117, 12452.
MeO2C N OMe MeO2C N OMe

MeO2C N OMe
LDA OH Nat. and ent
CO2Me Fredericamycin A
68–85%
CO2Me O O
Me O–
Boger J. Org. Chem. 1992, 57, 3974.

- Asymmetric Dieckmann-like condensation
Kinetic Thermodynamic
control: 5–7:1 control: single
TBDMSO diastereomers TBDMSO diastereomer TBDMSO
HN HN
LDA Me LDA
XcOC N THF O N
N THF Me N
BOC OBn 58% 78% BOC OBn
O BOC OBn
–78 °C, 30 minO –40 °C, 3 h
CO2tBu > CHO (reversible and
equilibration)
Chelated Z-enolate anti-carbonyls
O O O
iPr Li Me NH iPr
Me N O N O
O N NH
O N N O
iPr N
N iPr N R
Me N O N
O O Me
Li R O
R R
∆E = 0.76 Kcal/mol
202
Enolate Chemistry
Dale L. Boger
L. Enolate Dianions
dianion
nBuLi
O O NaH ONa O or LDA O– O–
–78 °C
OMe OMe OMe
1. OH– RX
O 2. ∆ (–CO2)
R
Me O O O– O
H+
R R
OMe OMe
R 1. NaH
R' 2. R'X
O 3. OH– dianion useful for slow alkylations
(i.e. ketone enolate + epoxide
4. ∆ slow but dianion reacts quickly).
Weiler J. Am. Chem. Soc. 1974, 96, 1082.

Weiler Tetrahedron Lett. 1983, 24, 253.
Harris Org. React. 1969, 17, 155–212.
(review)
M. Metalloimines, Enamines and Related Enolate Equivalents

Metalloimines: Stork J. Am. Chem. Soc. 1963, 85, 2178.
- Stork J. Am. Chem. Soc. 1971, 93, 5938.
(Metalloimines, dimethylhydrazones)
- Corey, Enders Tetrahedron Lett. 1976, 3 and 11.
Chem. Ber. 1978, 111, 1337 and 1362.
(Dimethylhydrazones)
O OLi O
LDA RX R
O
R R
via enolate equilibration
R
O OLi OLi O O
R R R R R
R
- Simple alkylation of enolates not always straightforward.

- Can get polyalkylation mixtures.
203
- Solutions
O O O O O O
NaH NaH R OH–
R
OEt OEt
EtO OEt RX ∆ (–CO2)
O
NMe2 NMe2 NMe2
N N N O
NaH, HMPA Na BuI Bu H3O+ Bu
Stork J. Am. Chem. Soc. 1971, 93, 5938.
NMe2 NMe2 NMe2

O N N N
Me2NNH2 nBuLi MeI
Li
pKa = 20 pKa = 30
- Higher pKa so anion is more reactive
- Alkylation much faster and polyalkylation
is not a problem
NMe2 NMe2 NMe2
O N N N
Me2NNH2 n
BuLi MeI
Li
or LDA
H3O+
pKa = 20 pKa = 30 or
NaIO4
or CuCl2
Advantages:
O
- monoalkylation (more reactive than ketone enolate).
- no enolate anion equilibration.
- regioselective (deprotonation at least substituted site).
- alkylation is diastereoselective.
Corey Tetrahedron Lett. 1976, 3
Note: preference for trans product is thermodynamic in origin. Cis (kinetic) product
can also be obtained selectively (Collum J. Am. Chem. Soc. 1984, 106, 4865).
- Examples:
O O O
LDA
tBu tBu + tBu
Me
MeI
Me
55 : 45
N
MeI
tBu 90 : 10
H3O+
Enamine (Stork J. Am. Chem. Soc. 1963, 85, 207)
NNMe2 97 : 3
1. LDA
t
Bu 2. MeI
Dimethylhydrazone 3. CuCl2 (Corey Tetrahedron Lett. 1976, 3
Chem. Ber. 1978, 111, 1337)
H2O, pH = 7
204
Enolate Chemistry
Dale L. Boger
-also useful in acyclic cases
O LDA OLi
C4H9 C4H9
–78 °C
no problem to make kinetic enolate,

but if alkylation is slow, an equilibration
Me2NNH2 may compete in product formation.
NMe2 LDA NMe2 MeI NMe2

N N N
C4H9 C4H9 Li C4H9 Me
- very good as aldehyde enolate equivalents

but
H Me2NNH2 H LDA H
R R R
N O OLi
nBuLi NMe2
- aldehyde enolates
1. LDA
2. R'X difficult to generate
and alkylate cleanly.
R' polycondensation
H self condensation
R CN R
N
NMe2
Review of methods for dimethylhydrazone cleavage: Enders Acc. Chem. Res. 2000, 33, 157.
Oxidative methods: O3, 1O2, NaIO4, NaBO3, (Bu4N)2S2O8, HTIB/BTI, MMPP, m-CPBA, CH3CO3H, H2O2/SeO2, H2O2,
MeReO3/H2O2, DMDO. Note: aldehyde dimethylhydrazones provide the nitrile upon oxidative cleavage.
Hydrolytic methods: CuCl2, Cu(OAc)2, (CO2H)2, (NH4)H2PO4, MeI−HCl, HCl, SiO2−H2O, BiCl3/µW, Pd(OAc)2/SnCl2,
BF3•OEt2
Reductive methods: =NNMe2 =NH =O, TiCl3, SnCl2, Cr(OAc)2, VCl2
- Enders chiral hydrazones (SAMP and RAMP)
OMe MeO
N H H N
- alkylation from the
NH2 NH2 least hindered face
SAMP RAMP of chelated anion.
OMe OMe
N H N H
N LDA N MeI, HCl O
sBuLI 80%
or
H H H
MeI
90% de
Review: Asymm. Synth. Vol. 3, 275.
205
- Meyers chiral oxazolines
- Phenyl group shields top face to E+ attack
Ph Ph Me H Ph Me H
O LDA Me O R–X O
CO2H
Me N H N N
R R
Li
OCH3 R–X OCH3 OCH3
Z-azaenolate –95 to –105 °C S-enantiomer
(95:5 Z:E) 72–82% de
Review: Asymm. Synth. Vol. 3, 213.
N. Alkylation of Extended Enolates
O ONa O
NaH R–X R
OCH3
OCH3 α-alkylation OCH3
two possible
sites of alkylation
- For alkylation in the γ position - can use a dianion
O O LDA (2 equiv) O– O– R–X O O
OCH3 or OCH3 H3O+

OCH3
1. NaH, 0 °C R
2. nBuLi, –78 °C
- In cyclic systems
O OLi O
LDA (1.05 equiv) R'X R' NaBH4 R'
–78 °C then H3O+
OR OR OR O
R = Me, iPr kinetic enolate

Danheiser, Stork J. Org. Chem. 1973, 38, 1775.
Cargill J. Org. Chem. 1973, 38, 2125.
O OLi O
LDA or R'X
nBuLi
N N N
R'
Yoshimoto, Ishida, Hiraoka Tetrahedron Lett. 1973, 39.

Bryson, Gammill Tetrahedron Lett. 1974, 3963.
206
Metalation Reactions
Dale L. Boger
IX. Metalation Reactions

A. Directed Metalation
- Kinetic acceleration of deprotonation of a relatively non-acidic site.
- Synthesis 1983, 95.
- Acc. Chem. Res. 1982, 15, 306.
- Org. React. 1979, 26, 1. lateral lithiation: Org. React. 1995, 47, 1.
H H Li LB
LB nBuLi LB
or
H Li H
- Usually requires very strong base (nBuLi, sBuLi or tBuLi, sometimes LDA).
- Sometimes requires additives (TMEDA, DABCO) to break up Li aggregates
(make bases more reactive).
NMe2
TMEDA N
DABCO
N
NMe2
- Examples:
OCH3 nBuLi
OCH3 OCH3
E+
H Li E
OCH3 OCH3 OCH3
- All aromatic H's have approximately the same pKa
nBu
OH Li
nBuLi
Li Li
(2 equiv) H O Li O
hexane
TMEDA
1. CO2
2. H+
- TMEDA breaks up RLi aggregates Li
HO2C O
- Not limited to aromatic substrates
H NR2 Li NR2
H2C LDA H2C
O O
CH3 CH3
- Kinetic acceleration of deprotonation even

in the presence of a more acidic proton.
207
- Directed Metalation Groups
carbon based heteroatom based
Strong: CON–R Strong: N–COR

CSN–R N–CO2R
CONR2 OCONR2
CON(R)CH(Z)TMS, Z = H,TMS
CH=NR OPO(NR)2
(CH2)nNR2, n = 1,2 OCH2OMe
CH(OH)CH2NR2 OTHP
CN OPh
O
SO3R
N SO2N–R
SO2NR
Moderate: SO3–
CF3 SO2tBu
O SOtBu
NR2
Moderate: NR2
N≡C
Weak: OMe
C(OTMS)=CH2 OCH=CH2
CH(OR)2 OPO(OR)2
C≡C– O(CH2)2X, X = OMe, NR2
Ph F
R Cl
N
PO(NR)2
N PS(Ph)NR2
R
N
Weak: O–
N S–
Snieckus Chem. Rev. 1990, 90, 879.
- Examples (cooperative effect)
OMOM nBuLi
OMOM O
I
TMEDA
ICH2CH2Cl N
NBOC NBOC
H –25 °C, 80% H R
O
Boger and Garbaccio, J. Org. Chem. 1997, 62, 8875.
208
Dale L. Boger
- Representative Organolithium Compounds by Directed Metalation
OCH3 OCH3 Li OCH3
+ nBuLi Et2O, 35 °C Li
+
2h
major minor
Shirley J. Org. Chem. 1966, 31, 1221.
O NEt2 O NEt2
+ nBuLi THF, –78 °C Li

TMEDA, 1 h
Beak J. Org. Chem. 1977, 42, 1823.

Beak J. Org. Chem. 1979, 44, 4463.
CH3 CH3
N N
+ nBuLi ether, 25 °C
N TMEDA, 7 h N
CH3 CH3
Li
Harris J. Org. Chem. 1979, 44, 2004.
+ nBuLi THF, 30 °C
S 1h S Li
Jones and Moodie Org. Synth. 1988, 6, 979.
THF, 0 °C OCH3
CH2=CHOCH3 + tBuLi H2C
Li
Baldwin J. Am. Chem. Soc. 1974, 96, 7125.
THF, HMPA H
CH2=CHCH2OTMS + sBuLi H
–78 °C, 5 min H2C
Li OTMS
Still J. Org. Chem. 1976, 41, 3620.
O THF, –78 °C
+ nBuLi Ph3Si O
Ph3Si 4h
Li
Eisch J. Am. Chem. Soc. 1976, 98, 4646.
S nBuLi S
Li
S S
Corey, Seebach J. Org. Chem. 1975, 40, 231.
209
B. Organolithium Compounds by Metal–Halogen Exchange
Jones and Gilman Org. React. 1951, 6, 339.
2 equiv - configurationally stable

tBuLi - retention of configuration
Ph Ph
–120 °C
Br Li
Note: 2 equiv of reagent are required
1 equiv tBuLi
nBuLi Li Br
MeO Br –78 °C MeO Li nBuLi -> nBuBr - slower elimination

but such products may still compete
Seebach Tetrahedron Lett. 1976, 4839. with desired electrophile for reaction
Hoye J. Org. Chem. 1982, 47, 331. with the generated organolithium reagent.
- Additional examples
CH3 H CH3 H
+ tBuLi –120 °C
H Br H Li
Seebach Tetrahedron Lett. 1976, 4839.
Br + nBuLi –70 °C Li
Linstrumelle Synthesis 1975, 434.
+ tBuLi
CH3O Br CH3O Li
Corey Tetrahedron Lett. 1975, 3685.
nBu nBu
TMS TMS
+ sBuLi –70 °C
H Br H Li
Miller J. Org. Chem. 1979, 44, 4623.
NC Br NC Li
+ nBuLi –100 °C
note: metalation
Parham J. Org. Chem. 1976, 41, 1187. in presence of
reactive groups.
O2N Br O2N Li
+ nBuLi –100 °C
Br Br
Parham J. Org. Chem. 1977, 42, 257.
210
Dale L. Boger
Corey and Boger Tetrahedron Lett. 1978, 5, 9, and 13.
O
R1
CHO
R
O R
N
O
S R
Me
n N
BuLi Li
O S
–78 °C H O
O
O
N O
Li R
S
R R
OMe OMe OMOM OMOM

MeO nBuLi, –78 °C MeO MeO Br nBuLi, –78 °C MeO Li
THF, 15 min Et2O, 15 min

MeO N MeO N
Br Li OMOM OMOM
Boger J. Org. Chem. 1984, 49, 4050. Boger J. Org. Chem. 1991, 56, 2115.
J. Am. Chem. Soc. 1995, 117, 12452. J. Am. Chem. Soc. 1995, 117, 11839.
C. Organolithium Compounds by Metal–Metal Exchange

- Reactions of organotin reagents with alkyllithium reagents are particularly significant.
CH2OTHP nBuLi CH2OTHP

Proceeds in direction of placing
the more electropositive metal
Bu3Sn Li on the more electronegative
(acidic) carbon.
Corey J. Org. Chem. 1975, 40, 2265.
OR n OR n
BuLi
BuLi
R R R2NCH2SnBu3 R2NCH2Li
SnBu3 –78 °C Li 0 °C
Still J. Am. Chem. Soc. 1978, 100, 1481. Peterson J. Am. Chem. Soc. 1971, 93, 4027.
J. Am. Chem. Soc. 1980, 102, 1201.
- transmetalation with retention and
McGarvey J. Am. Chem. Soc. 1988, 110, 842.
Macdonald maintenance of configuration
D. Organolithium Compounds from the Shapiro Reaction

N-NHTs Li
2 equiv
Et nBuLi Et
TMEDA
Me Me
Bamford, Stevens J. Chem. Soc. 1952, 4735.
Shapiro Org. React. 1976, 23, 405.
Bond J. Org. Chem. 1981, 46, 1315.
Chamberlin Org. React. 1990, 39, 1.
211
E. Key Organometallic Reactions Enlisting Metalation and Transmetalation

Reactions
Heck Reaction
R' Pd(0) R'
ArX +
(RX) H (Ar)R
Heck J. Am. Chem. Soc. 1974, 96, 1133.

Org. React. 1982, 27, 345.
Acc. Chem. Res. 1979, 12, 146.
Stille Coupling Reaction

Pd(0)
RX + R'SnR3 R−R' Stille J. Am. Chem. Soc. 1978, 100, 3636.
Farina Org. React. 1997, 50, 1.
Stille Angew. Chem., Int. Ed. Eng. 1986, 25, 508.
RCOCl, X, ArX, XCH2CO2R
1) oxidative addition (R−Pd−X), generally rate determining step

2) transmetalation (R−Pd−R' + XSnR3 or XB(OH)2)
3) reductive elimination (R−R' + Pd(0))
Suzuki Reaction
Pd(0)
RX + R'B(OH)2 R−R'
I > OTf > Br >> Cl: generally the initial oxidative addition is the rate determining step.
Suzuki J. Chem. Soc., Chem. Commun. 1979, 866.
Suzuki Chem. Rev. 1995, 95, 8457.
212
Key Ring Forming Reactions
Dale L. Boger
X. Key Ring Forming Reactions

A. Diels–Alder Reaction
1. Reviews
1. General reference: Onishchenko, A. S. Diene Synthesis; Daniel Davy: New York, 1964.
2. General reference: Wasserman, A. Diels–Alder Reactions; Elsevier: New York, 1965.
3. General review: Alder, K. Newer Methods of Preparative Organic Chemistry, Vol. 1, Wiley: New York,
1948, pp 381–511.
4. General review: Huisgen, R.; Grashey, R.; Sauer, J. in Chemistry of Alkenes; S. Patai, Ed.; Wiley: New
York, 1964, pp 878–953.
5. General review: Wollweber, H. in Houben–Weyl, Methoden der Organischen Chemie; E. Muller, Ed.;
Georg Thieme: Stuttgart, 1970, pp 977–1210.
6. General reference: Wollweber, H. Diels–Alder Reaction; Georg Thieme: Stuttgart, 1972.
7. General reference: Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley: New York, 1977.
8. Diels–Alder reactions with maleic anhydride: Kloetzel, M. C. Org. React. 1948, 4, 1.
9. Diels–Alder reactions with ethylenic and acetylenic dienophiles: Holmes, H. L. Org. React. 1948, 4, 60.
10. Diels–Alder reactions with quinones: Butz, L. W.; Rytina, A. W. Org. React. 1949, 5, 136.
11. Diels–Alder reaction: preparative aspects: Sauer, J. Angew. Chem., Int. Ed. Eng. 1966, 5, 211.
12. Diels–Alder reaction: mechanism: Sauer, J. Angew. Chem., Int. Ed. Eng. 1967, 6, 16.
13. Stereochemistry of the Diels–Alder reaction: Martin, J. G.; Hill, R. K. Chem. Rev. 1961, 61, 537.
14. Regiochemistry of the Diels–Alder reaction: Titov, Y. A. Russ. Chem. Rev. 1962, 31, 267.
15. Mechanism of the Diels–Alder reaction: Seltzer, S. Adv. Alicycl. Chem. 1968, 2, 1.
16. Diels–Alder reaction of heteroatom-substituted dienes: Petrzilka, M.; Grayson, J. I. Synthesis 1981, 753.
17. Preparation and Synthetic Aspects: Wagner-Jauregg, T. Synthesis 1976, 349; Synthesis 1980, 165, 769.
18. Diels–Alder reaction of azadienes: Boger, D. L. Tetrahedron 1983, 39, 2869.
19. Review on "Danishefsky's diene" and related dienes: Danishefsky, S. Acc. Chem. Res. 1981, 14, 400.
20. Intramolecular Diels–Alder reaction: Carlson, R. G. Ann. Rep. Med. Chem. 1974, 9, 270.
21. Intramolecular Diels–Alder reaction: Oppolzer, W. Angew. Chem. 1977, 16, 10.
22. Intramolecular Diels–Alder reaction of o-quinodimethanes: Oppolzer, W. Synthesis 1978, 793.
23. Intramolecular Diels–Alder reaction: Brieger, G.; Bennett, J. N. Chem. Rev. 1980, 80, 63.
24. Intramolecular Diels–Alder reaction: Ciganek, E. Org. React. 1984, 32, 1.
25. Intramolecular Diels–Alder reaction: Fallis, A. G. Can. J. Chem. 1984, 62, 183.
26. Intermolecular Diels–Alder reaction: Oppolzer, W. in Comprehensive Organic Synthesis, Vol. 5; pp 315–399.
27. Intramolecular Diels–Alder reaction: Roush, W. R. in Comprehensive Organic Synthesis, Vol. 5; pp 513–550.
28. Retrograde Diels–Alder reactions: Sweger, R. W. in Comprehensive Organic Synthesis, Vol. 5; pp 551–592.
29. The Retro Diels–Alder reaction: Rickborn, B. Org. React. 1998, 52, 1.
30. Heterodienophile Diels–Alder reactions: Weinreb, S. M. in Comprehensive Organic Synthesis, Vol. 5; pp
401–449.
31. Heterodiene Diels–Alder reactions: Boger, D. L. in Comprehensive Organic Synthesis, Vol. 5; pp 451–512.
32. Hetero Diels–Alder reaction: Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodology in Organic Synthesis;
Academic: San Diego, 1987.
33. Catalytic Asymmetric Diels–Alder reactions: Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007.
34. Asymmetric Hetero Diels–Alder reaction: Waldermann, H. Synthesis 1994, 535.
213
2. Discovery
Wieland (Ber. 1906, 39, 1492) described the 1:1 dimerization of conjugated dienes in what was probably the
first report of a Diels–Alder reaction.
Wieland received the 1927 Nobel Prize
in Chemistry for his steroid work
unrelated to these observations.
Albrecht (Thiele) Reaction: O O

Ann. 1906, 348, 31. C5H5
Misassigned structure
O O
Staudinger Structure: O O Structure established by Diels
Die Ketene, Stuttgart and Alder, and they went on to
define scope and mechanism
1912, 59.
of the reaction. For this, they
received the 1950 Nobel Prize
O O in Chemistry.
Diels and Alder Ann. 1928, 460, 98.

In fact, von Euler had correctly, but tentatively, identified the 2:1 adduct of isoprene with p-benzoquinone before
Diels and Alder's work. von Euler, Josephson Ber. 1920, 53, 822.
O O O
or
O O O
von Euler received the 1929 Nobel Prize in Chemistry for his investigations on fermentations of
sugars and the fermentative enzymes. He had trained with Landolt, Nernst, van't Hoff, Arrhenius,
Hantzsch, and Thiele and was remarkable in his scientific pursuits. By 1910, he had already
initiated his monumental studies of enzyme structure, kinetics, and mechanism and his occasional
forays into pure organic chemistry were just as remarkable.
For an engaging description of the discovery of the Diels–Alder reaction, the competition for its exploration and
applications, and the missed opportunities, see: Berson Tetrahedron 1992, 48, 3.
Even in their first disclosure, Diels and Alder recognized the potential the reaction might hold for synthesis:
"Thus, it appears to us that the possibility of synthesis of complex compounds related to or identical with
natural products such as terpenes, sesquiterpenes, perhaps also alkaloids, has moved to a near prospect."
They also felt this could be reserved: "We explicitly reserve for ourselves the application of the reaction
discovered by us to the solution of such problems." Fortunately, this was not the case and an extraordinary
group of investigators helped define the scope and mechanism of the Diels–Alder reaction.
The first applications in total synthesis include: Cortisone by Woodward, Sondheimer J. Am. Chem. Soc. 1951,
73, 2403; Sarett (Merck) J. Am. Chem. Soc. 1952, 74, 4974. Cantharidin by Stork, Burgstahler, van Tamelen J.
Am. Chem. Soc. 1951, 73, 4501.
3. Mechanism, FMO Treatment
[π2s + π4s] Cycloaddition Alternatively:
HOMOdiene LUMOdiene Dominant interaction

This is the dominant
in an inverse electron
interaction in a normal
demand Diels–Alder
LUMOdienophile Diels–Alder reaction.
HOMOdienophile reaction.
1. Large Ea for the reactions.

2. Driving force is formation of two new σ bonds accompanying the loss of two π bonds.
214
Dale L. Boger
a. cis Principle: Geometry of dienophile and diene are maintained in the [4 + 2] cycloadduct.
e.g.
CO2CH3 CO2CH3
CO2CH3 CO2CH3
CO2CH3 CO2CH3
CH3O2C CO2CH3
Stereospecific
R R
X X
X X
R R
b. Alder's Endo Rule:
Endo product and endo transition state predominate even though

Stereoselective exo products are usually more stable; endo is the kinetic product.
e.g.
CO2CH3 H COOCH3
H COOCH3
CO2CH3 COOCH3
COOCH3 H
H
endo exo
Major Minor
Endo, boat transition state
Endo T.S. Exo T.S.
CH3OOC H H COOCH3
CH3OOC H
H COOCH3
Result: Both cis rule and endo rule Diels–Alder reaction very useful, diastereoselective
215
c. Factors influencing endo selectivity of the Diels–Alder reaction
OAc OAc
CHO CHO
Me Me
R R
via
AcO R
H H
OHC H
H CH3
i. Endo transition state is favored by stabilizing secondary orbital interactions.

ii. Endo selectivity often increases with the use of Lewis acid catalysis.
iii. Endo selectivity often increases with increase in pressure of reaction.
Endo selectivity , pressure ∆∆V = –4 to –8 cm3/mol

(endo/exo)
Raistrick J. Chem. Soc. 1939. 1761, 1770.

Jones Tetrahedron 1962, 18, 267.
R H H R Dauben demonstrated pressure-promoted
reactions are viable:
OHC H
H CHO J. Am. Chem. Soc. 1974, 96, 3664.
J. Am. Chem. Soc. 1976, 98, 1992.
endo T.S. exo T.S. J. Org. Chem. 1977, 42, 282.
-∆V is negative (–25 to –38 cm3/mol). So increase pressure, increase rate of reaction.
-And endo T.S. is more compact, so ∆∆V for endo:exo also negative.
(i.e., diastereoselectivity increases)
O
Example of Boger J. Am. Chem. Soc. 1988, 108, 6695 and 6713.
O
iv. Endo selectivity also increases with decreases in temperature at which the reaction is conducted
e.g.
COOH COOH COOH
COOH COOH COOH
temp. endo exo
75 °C only endo
90 °C 7 : 1
100 °C 4.5 : 1
Endo selectivity , temperature
110 °C 2 : 1
130 °C 1 : 1
216
Dale L. Boger
CHO
CHO
+ +
OBn
CHO
OBn OBn
conditions endo exo
10 days, 0 °C 66 : 34
6 h, 200 °C 34 : 66
Lewis acid-catalyzed BF3•OEt2, 5 min, –20 °C 90 : 10
Furukawa J. Am. Chem. Soc. 1970, 92, 6548.
Ph Ph Ph
Ph
O
H O
Ph
+ O H + O
Ph O
O O HH O
O
temp. endo exo
25 °C 100 : 0
140 °C 29 : 71
Some Diels–Alder adducts are thermally unstable (reversible) and subject to equilibration via retro
Diels–Alder reaction to provide the most stable product: Ripoll Tetrahedron 1978, 34, 19.
O O O
O + O O 100% exo
O HH O
see also: Rickborn Org. React. 1998, 52, 1.
5. Regioselectivity
a. 1-Substituted dienes react with substituted dienophiles to give the ortho product:
X X X
Y Y
+ +
Y
usually around 9:1
217
For example:
CH3 CH3 CH3
W W
+ +
W
W = CN 100 °C, 12 h, 30% 9 : 1
= COOR 200 °C, 2 h, 85% 6.8 : 1
higher temperature regioselectivity lower, because COOR not

decreases regioselectivity as strongly electron-withdrawing as CN
-Device for predicting regioselectivity: draw out "zwitterionic" representations (resonance structures) for the
reactants.
CN CN CN
more stable
resonance forms
CH3
CN CN Reaction: 100 °C, 12 h
30%, 9:1 regioselectivity
b. 2-Substituted dienes give predominantly the para product:
X Y X X Y
+ +
Y
X = CH3 Y = COOCH3 6 : 1 higher regio-

selectivity
= OCH3 = COOCH3 10 : 1 because OCH3
= CN = COOCH3 10 : 1 better donating
group than CH3.
218
Dale L. Boger
c. Complementary substitution usually provides even greater regioselectivity
-1,3-Disubstituted Dienes
X X ortho to X group
Y Y para to X' group
+
X' X'
But noncomplementary substitution may cause problems (lower regioselectivity)

-1,2-Substituted Dienes
X X X
X' Y X' Y X'
+ +
Y
relative amounts of each depend on electron

donating strength of substituents X and X'
NHCO2R > SR > OR > alkyl > H
SPh SPh O
O
CH3O CH2Cl2 CH3O
+
25 °C
85% 100:0
Cohen J. Org Chem. 1982, 47, 4005.
O
CH3O O CH3O
CH3O
+ toluene +
PhS ∆, 2 h PhS PhS
75% O
>5 : 1
NHCO2Bn NHCO2Bn
O 56 °C COPh
+ Ph 26 h, 86%
SPh SPh
Overman J. Am. Chem. Soc. 1983, 105, 6335.
d. Apparent regioselectivity can be altered by adding a controlling group that is subsequently removed
-Dienophile OAc
OAc
SO2Ph SO2Ph
+
CO2CH3 CO2CH3
-endo addition
-CO2CH3 is in meta position
-SO2Ph > CO2CH3 in controlling regioselectivity
Parsons J. Chem. Soc., Chem. Commun. 1987, 1836.
219
- Diene
O
O H
90 °C, 40 h
+
NO2 O2N
In addition to altering nBu

3SnH DBN
regioselectivity, it also 0 °C, 1 h
serves as an equivalent
O of an inaccessible cyclic O O
alkyne dienophile.
(86%) (83%)

Ono J. Chem. Soc., Perkin Trans. 1 1987, 1929.
Tanis Syn. Commun. 1986, 16, 251.
Rate of reaction generally insensitive to solvent polarity, but...
6. Lewis Acid Catalysis
140 °C
O O
8–10 h
75%
+
AlCl3
25 °C,1 h
75%
Addition of Lewis Acid Catalysts:
O
i. Lowers LUMO of dienophile, so increases rate of reaction.
ii. Increases the difference in magnitude of coefficients of dienophile

AlCl3 -----so increases regioselectivity.
δ– iii. Changes coefficient at dienophile substituent, so increases opportunity

δ+ Al of secondary orbital interactions
O
.....often increases endo stereoselectivity.
Increases: 1. Reaction Rate

2. Reaction Regioselectivity
3. Reaction Endo Diastereoselectivity
220
Dale L. Boger
-Examples
O O
+ +
O
Lutz J. Am. Chem. Soc. 1964, 86, 3899. toluene, 120 °C, 24 h 71 : 29
Yates J. Am. Chem. Soc. 1960, 82, 4436. SnCl4, benzene, 25 °C, 1 h 93 : 7
1st example: 100 °C, 3 d, dioxane vs AlCl3, 25 °C, 5 min

CO2Et
EtO2C
Diethyl fumarate
CO2CH3 CO2CH3
+
AlCl3: ∆G 9.3 kcal/mol lower than uncatalyzed reaction

Inukai, Kojima J. Org. Chem. 1967, 32, 872.
∆E endo/exo:
CO2CH3 CO2CH3 CO2CH3

+ +
uncat. reaction: 0.2 kcal/mol; AlCl3 cat. reaction: 1.8 kcal/mol
Spellmeyer , Houk J. Am. Chem. Soc. 1988, 110, 3412.

Jensen, Houk J. Am. Chem. Soc. 1987, 109, 3139.
Calculations: s-cis > s-trans
∆E for: catalyzed reaction: uncatalyzed reaction:

1.9 kcal/mol for endo 0.6 kcal/mol for endo
2.7 kcal/mol for exo 1.7 kcal/mol for exo
OCH3 O
O CH3O
Birney, Houk J. Am. Chem. Soc. 1990, 112, 4127.
221
-Lewis Acid catalysis can also alter regioselectivity
O O O
CH3
+ +
CH3O CH3O CH3O
H H
O O O
100 °C 1 : 1 80%
BF3•OEt2, –16 °C 4 : 1 >85%
cat. SnCl4, –16 °C 1 : 20 >85%
Rationalization: monodentate vs. bidentate coordination
δ– versus
O δ
F3B +
most Lewis bidentate O
basic carbonyl CH3 coordination CH3
CH3O CH3O
O Sn O δ+
-Hydrophobic effect: H2O solvent acceleration:
Breslow J. Am. Chem. Soc. 1980, 102, 7816.

Breslow, Rideout Tetrahedron Lett. 1983, 24, 1901.
also:
Sternbach J. Am. Chem. Soc. 1982, 104, 5853.
Grieco Tetrahedron Lett. 1983, 24, 1897.
Jorgensen - Hydrogen-bonding of H2O serves in the same capacity as a mild Lewis acid.
O O
δ+ H H
requires H-bonding carbonyl

requires H-bonding solvent
Jorgensen J. Am. Chem. Soc. 1991, 113, 7430.

J. Org. Chem. 1994, 59, 803.
222
Dale L. Boger
7. Detailed FMO Analysis
-Using simple computational tools now available, one can quickly and easily predict regioselectivity and
comparatively assess rate and diastereoselectivity of a Diels–Alder reaction by examining the frontier
molecular orbitals (FMO). Each of the calculations that follow took < 1 min to run.
Classification of Diels–Alder Reactions.
NORMAL NEUTRAL INVERSE

HOMOdiene-controlled LUMOdiene-controlled
EWG
EDG
EDG
EWG
LUMO
LUMO
smallest ∆E, LUMO
dominant
molecular LUMO
orbital smallest ∆E,
E dominant
interaction
HOMO molecular
orbital
HOMO HOMO interaction
HOMO
J. A. Pople (computational methods in quantum chemistry) and W. Kohn (density-functional

theory) received the 1998 Nobel Prize in Chemistry for their pioneering contributions to
theoretical and computational methods for defining properties and chemical behavior.
Common Computational Tools:
Semiempirical
MNDO: Dewar J. Am. Chem. Soc. 1977, 99, 4899.

AM1: Dewar J. Am. Chem. Soc. 1985, 107, 3902.
Ab Initio
Gaussian: Pople, Carnegie-Mellon Quantum Chem. Pub. Unit, Pittsburgh, PA.
223
AM1 Theoretical Highest Occupied π Orbital (HOMO) and Lowest Unoccupied π Orbital (LUMO)
π system E Coefficients
H2C=CH–CH=O O-1 C-2 C-3 C-4
E LUMO 0.0 eV LUMO: 0.42 –0.50 –0.43 0.63

E HOMO –10.9 eV HOMO: 0.35 0.05 –0.68 –0.65
H2C=CH–CH=OH+
E LUMO –7.0 eV LUMO: 0.36 –0.73 –0.03 0.58

E HOMO –16.6 eV HOMO: 0.36 0.23 –0.73 –0.53
H2C4=CH–C(CH3)=C1H2 C-1 C-2 C-3 C-4
E LUMO 0.5 eV LUMO: 0.57 –0.43 –0.37 0.51

E HOMO –9.2 eV HOMO: 0.60 0.45 –0.41 –0.55
H2C4=CH–C(OCH3)=C1H2
E LUMO 0.4 eV LUMO: 0.51 –0.41 –0.44 0.58

E HOMO –9.1 eV HOMO: 0.67 0.42 –0.28 –0.41
H2C2=CH–OCH3 C-1 C-2 OCH3
E LUMO 1.4 eV LUMO: 0.72 –0.66 0.21

E HOMO –9.5 eV HOMO: 0.48 0.69 –0.51
224
Dale L. Boger
AM1 π-MO's
Thermal reaction Model for Lewis acid-catalyzed reaction
H H
H
O O
2.2 eV 1.9 eV 2.2 eV
0.5 eV 0.5 eV
E 0.0 eV E
–4.0 eV
9.2 eV 11.4 eV
2.2 eV –7.0 eV
–9.2 eV –9.2 eV
–10.9 eV
–14.3 eV –14.3 eV
–14.6 eV
–16.6 eV
HOMOdiene – LUMOdienophile energy difference is

controlling factor for normal Diels-Alder reaction -
making this E difference smaller will increase rate
of reaction. For uncatalyzed reaction, ∆E = 9.2 eV For catalyzed reaction, ∆E = 2.2 eV –21.6 eV
Rate:
-Lewis acids catalyze reaction by lowering energy of π MO's of dienophile.
-Importantly, the LUMO of the dienophile becomes much lower in energy.
Rate increase by Lewis acid catalysis due to lowering of E of LUMOdieneophile.
225
Regioselectivity:
Thermal Lewis acid-catalyzed
HOMO LUMO HOMO LUMO
0.51 0.43 0.51 0.03 H

CHO O
0.60 0.63 0.60 0.58
∆ = 0.09 ∆ = 0.20 ∆ = 0.09 ∆ = 0.55!
Enhanced polarization of dienophile

leads to enhanced regioselectivity.
Diastereoselectivity (endo cycloaddition):
Thermal Lewis acid-catalyzed
0.41 H 0.50 0.41 H 0.73

stabilizing 1° (bonding) orbital
2° orbital interactions O O
interactions
HOMOdiene
HOMOdiene LUMOdienophile HOMOdiene LUMOdienophile
LUMOdienophile
increase in
greater endo gives coefficient at
stereoselectivity rise to complexed
carbonyl carbon
NOTE comparison of
vs.
MeO Me
HOMO–LUMO
rate of reaction, >
MeO Me ∆E difference
regioselectivity, >
MeO Me
stereoselectivity,
<
MeO Me
due to smaller (relative) coefficient at C3 of diene.
226
Dale L. Boger
AM1 Results
Lewis acid-catalyzed
HOMOdiene-controlled HOMOdiene-controlled
Diels–Alder reaction Diels–Alder reaction
H H
H
O O
CH3O CH3O
2.2 eV 1.9 eV 2.2 eV
0.4 eV 0.4 eV
E 0.0 eV E
9.1 eV 17.0 eV
–4.0 eV
HOMO
11.3 eV 2.1 eV –7.0 eV
–9.1 eV –9.1 eV
–10.9 eV
–12.7 eV –12.7 eV
–14.6 eV
–16.6 eV
–21.6 eV
Note: 1 eV = 23.06 kcal/mol, so difference of 0.1 eV is 2.3 kcal/mol and is significant in ∆∆G‡.
227
∆E (E LUMOdienophile – E HOMOdiene) = 9.1 eV

Rate: versus
∆E (E LUMOdiene – E HOMOdienophile) = 11.3 eV
0.42 0.67
MeO
HOMOdiene
–0.28
0.42 –0.41 0.63

O
LUMOdienophile
–0.50 –0.43
stabilizing secondary orbital dominant HOMOdiene–LUMOdienophile

interaction: endo selectivity orbital interaction: regioselectivity
0.42 0.67
MeO
HOMOdiene
–0.28
0.36 –0.41 0.58

+
H O
LUMOdienophile
–0.03
–0.73

Rate: versus
Thermal and (Lewis) acid-catalyzed HOMOdiene-controlled

Diels–Alder reaction of acrolein and 2-methoxybutadiene, AM1 results
228
Dale L. Boger
AM1 Results
Lewis acid-catalyzed
LUMOdiene-controlled LUMOdiene-controlled
Diels–Alder reaction Diels–Alder reaction
H H
OCH3 OCH3 H
O O
1.9 eV
1.4 eV 1.4 eV
E 0.0 eV E
9.5 eV 18.0 eV
–4.0 eV
HOMO
12.3 eV 2.5 eV –7.0 eV
–9.5 eV –9.5 eV
–10.9 eV
–14.6 eV
–16.6 eV
–21.6 eV
229

Rate: versus
–0.43 0.63
LUMOdiene
–0.50 O
0.42 0.69
Me HOMOdienophile
O
–0.51 –0.48
stabilizing secondary orbital dominant LUMOdiene–HOMOdienophile

interaction: endo selectivity orbital interaction: regioselectivity
–0.03 0.58
LUMOdiene
–0.73 O
0.36 +
H 0.69
Me HOMOdienophile
O
–0.51 –0.48

Rate: versus
Thermal and (Lewis) acid-catalyzed LUMOdiene-controlled

Diels–Alder reaction of acrolein and methyl vinyl ether, AM1 results
230
Strained Olefins Participate in Accelerated Normal or Inverse Electron Demand Diels–Alder Reactions: FMO
Basis
HOMOdiene-controlled Neutral LUMOdiene-controlled
Diels–Alder reaction Diels–Alder reaction Diels–Alder reaction
CH3CO2
CH3O
CH3O
H
2.3eV O 2.3eV
1.9 eV 1.4 eV 1.4 eV 1.3 eV
1.0eV 1.0eV
0.5 eV 0.5 eV
0.0 eV
E
–0.5 eV
∆E = 9.8 eV ∆E = 8.8 eV ∆E = 11.0 eV ∆E = 10.8 eV ∆E = 11.4 eV ∆E = 10.9 eV
∆E = 10.3 eV ∆E = 11.4 eV ∆E = 9.0 eV ∆E = 9.3 eV
–8.8 eV
HOMO
–9.4 eV –9.5 eV
–9.8 eV –9.9 eV –9.8 eV
HOMO
HOMO
–10.5 eV
HOMO
HOMO
HOMO
–10.9 eV
HOMO

HOMO
–11.4 eV
–12.0 eV
–12.4 eV
Dale L. Boger
–14.6 eV
231
8. Cation–Radical Diels–Alder Reaction
Me H
cat. H
H
Br N SbCl6–
3 20% 40%
CH2Cl2, 0 °C, 0.25 h
SPh
SPh
SPh SPh
reaction via radical cation
Bauld J. Am. Chem. Soc. 1981, 103, 718; 1982, 104, 2665; 1983, 105, 2378.
9. Ionic Diels–Alder Reaction
O H+ O much more reactive,

O OH much more electron
deficient
O cat. CF3SO3H
+
O CH2Cl2
67% O O
Gassman J. Am. Chem. Soc. 1987, 109, 2182.

J. Chem. Soc., Chem. Commun. 1989, 837.
10. Dienophiles
a. Effect of electron-withdrawing group
X
X
X
X
X = COCl > PhSO2 > PhCO > COCH3 > CN ~ COOCH3
relative rates: 6700 155 18 4 1.1 1.0
b. Alkyl groups on dienophile can slow Diels-Alder reaction (steric effect)
c. Strain in dienophile
~ >
232
Dale L. Boger
PhS
O
benzyne bridgehead olefins Wiberg Corey Kraus
Keese, Krebs Angew. J. Am. Chem. Soc. J. Am. Chem. Soc. J. Org. Chem.
Chem., Int. Ed. Eng. 1960, 82, 6375. 1965, 87, 934. 1988, 53, 1397.
1972, 11, 518.
O O
H H
hν H
H
O H
H
Photochemical isomerization to strained trans enone (7-membered: Corey J. Am.

Chem. Soc. 1965, 87, 2051. 8-membered rings: Eaton J. Am. Chem. Soc. 1965,
87, 2052) followed by inter- or intramolecular Diels−Alder reaction.
intermolecular: Eaton Acc. Chem. Res. 1968, 1, 50.
intramolecular: Rawal J. Am. Chem. Soc. 1999, 121, 10229.
-Normal and inverse electron demand Diels–Alder reactions of cyclopropenone ketals

exo adduct due to destabilizing steric
R O R
interactions in preferred endo T.S.
O
O
25 oC O
72% R = OMe
69% R = H
65% R = CO2Me
Boger Tetrahedron 1986, 42, 2777.
OMe OMe OMe OMe

MeO MeO MeO MeO
O
N N N N
MeO MeO MeO MeO
O
O
O OH O OMe
O OMe O
Grandirubrine Imerubrine Isoimerubrine
O
MeO OMe MeO OMe O
N H O
O N N
25 °C O OH
96% H
O O O
O O
OH
Boger J. Am. Chem. Soc. 2000, 122, 12169. Rubrolone aglycon
233
d. Quinones are outstanding dienophiles
O
O
e. Number and position of electron-withdrawing groups
Diels–Alder
dienophile + or
Reaction
Dienophile Relative Rates
NC CN
1.3 x 109 4.3 x 107
NC CN
NC CN
5.9 x 105 4.8 x 105
CN
NC CN
1.3 x 104 4.5 x 104 NOTE: large increase in
rate by addition of one
CN more complementary EWG
0.09 1
NOT as large an increase
upon addition of one more
COOCH3
noncomplementary EWG
215 74
CH3OOC
CH3OOC COOCH3 140 31
f. cis vs. trans Dienophiles
-In polar (or radical) processes, cis isomer reacts faster than trans, but in Diels–Alder reaction:
COOCH3 COOCH3
CH3OOC COOCH3
Due to
E
E
E E
one additional destabilizing

steric interaction
-The relative rates of such cis vs. trans reactions are sometimes used to distinguish between concerted
cycloadditions vs. nonconcerted stepwise reactions.
234
Dale L. Boger
g. Heterodienophiles: typically electron-deficient
e.g. O
HOMOdiene-controlled
CH3OOC COOCH3 Diels–Alder reaction.
2π component
h. Heterodienes: typically electron-deficient

e.g.
H O
LUMOdiene-controlled
Diels–Alder reaction.
4π component
introduction of heteroatom
makes diene electron-deficient.
Note: Dienophiles can also be generated in situ:
OCH3
OCH3
CH3O OCH3
OCH3 CH3O OCH3
Boger J. Org. Chem. 1984, 49, 4050.

catalytic amount electron-deficient diene
N N
O N
N N N N N
H
N
–N2, retro
Diels–Alder reaction
N N N
H
Catalytic Diels–Alder reaction

Boger J. Org. Chem. 1982, 47, 895.
i. Dienophiles which are not electron-deficient
(1) Participate in inverse electron demand Diels–Alder reactions:
Cl O
Cl
Cl
O
Cl O
Cl
Cl O
krel = 12 2 1
McBee J. Am. Chem. Soc. 1954, 77, 385.

Jung J. Am. Chem. Soc. 1977, 99, 5508.
(2) Can be used in cation–radical Diels–Alder reactions.

(3) Also include the behavior of strained olefins.
235
j. Dienophile equivalents
-Many specialized dienophiles have been developed which react well in the Diels–Alder reaction and
which serve to indirectly introduce functionality not otherwise directly achievable.
inaccessible equivalent
OH O OCH2Ph OCH3
O OsO4 AgOAc/I2
OH O OAc OCH3
acetylene acetylene
J. Am. Chem. Soc. 1958, 80, 209.

J. Org. Chem. 1988, 53, 5793.
J. Org. Chem. 1984, 49, 4033.
OH m-CPBA; OCH2Ph BR2

Chem. Ber. 1964, 97, 443.
H+, H2O
J. Org. Chem. 1988, 53, 5793, 3373.
HO acetylene AcO R2B Tetrahedron Lett. 1994, 35, 509.
O OH
AcO CN Cl COCl Me3Si OMe MeO OMe PPh3 BR2
or + OH– + NaN3/
CH2 HOAc, H2O
J. Am. Chem. Soc. 1956, 78, 2473.

J. Am. Chem. Soc. 1971, 93, 4326.
J. Org. Chem. 1977, 42, 4095.
Review: Synthesis 1977, 289.
Review: Tetrahedron 1999, 55, 293.
O OH
MeO OMe
or
J. Org. Chem. 1984, 49, 4033.
OH OMe
OH
COCH3
NH2 N
O Tetrahedron Lett. 1981, 2063.
NH2 N
COCH3
R
NH2 N
O Tetrahedron Lett. 1977, 3115.
O Ann. 1976, 1319.
OH
R = H, COCH3
O
Br CHO Br CHO
+ BH4–; + BH4–; J. Am. Chem. Soc. 1972, 94, 2549.
MeO– TsCl; HO–
236
Dale L. Boger
inaccessible equivalent
O O O
RS
or
O J. Am. Chem. Soc. 1977, 99, 7079.
COOR
CH2
O
O
Cl O MeO OMe
J. Am. Chem. Soc. 1977, 99, 7079.
O
Cl O MeO OMe
O
O Me
O + m-CPBA + PCl5; HO– Chem. Ber. 1964, 97, 443.
O CO2H J. Org. Chem. 1973, 38, 1173.
O
O O H
O + H2O; S + (RO)3P + nBuLi
Pb(OAc)4 O O Ph
O
SO2Ph
N SO2Ph
OR NR2
O SO2Ph
R = Et, Ac enamines
J. Am. Chem. Soc. 1973, 95, 7161.

J. Org. Chem. 1984, 49, 4033.
R BR2 SO2Ph
J. Am. Chem. Soc. 1980, 102, 853.
J. Am. Chem. Soc. 1990, 112, 7423.
R = H, R
J. Am. Chem. Soc. 1978, 100, 2918.
COR COR SO2Ph Tetrahedron Lett. 1981, 22, 603.
J. Org. Chem. 1979, 44, 1180.
O2N O2N J. Org. Chem. 1977, 42, 2179.
reversed regioselectivity J. Am. Chem. Soc. 1978, 100, 1597.
COR
PhS COR PhO2S COR
J. Org. Chem. 1981, 46, 624.
J. Am. Chem. Soc. 1978, 100, 1597.
R
PPh3 CH3 SOPh J. Org. Chem. 1977, 42, 4095.
J. Chem. Soc., Chem. Commun. 1991,
1672.
O
EtO2C CO2Et J. Org. Chem. 1977, 42, 4095.
O O
237
11. Diene
-Dienes must adopt an s-cisoid (s-Z) conformation to react.
H
H H
H H
H (~2.3 kcal/mol)
s-E (transoid) s-Z (cisoid)
Cisoid conformation of diene is favored with:
(a) 2- and/or 3-substitution
CH3 CH3
H
H
CH3 CH3
H
H
CH3 CH3
(b) 1-Substituted dienes R R
E-diene
But
R R
not very reactive
H
Z-diene
R
105 rate difference for cis and trans
can be used to separate cis and trans isomers of dienes
(c) And, by locking the diene into cisoid conformation
> >
reaction rates for cyclic dienes are faster
O :
MeO Cl
O
krel = 1348 110 12 5 3.3 2.2 2 1 0.1
238
Dale L. Boger
12. Functionalized Dienes
Review: Petrzilka, Grayson Synthesis 1981, 753.
-Diels–Alder reaction with introduction of useful functionality
O O
O
RO H3O+
160 oC
RO O
-Danishefsky:
OCH3 H
CHO OCH3
H3O+ CHO
CHO
TMSO Si O (–CH3OH) O
So an alternative disconnection for α,β-unsaturated enones looks like a Robinson

annulation product
R
Y Y R
O O
OCH3
Y R
TMSO
Example:
OCH3 O O
R R = Me
TMSO i) 200 °C O
2 h, xylene H
ii) H3O+
47% compare to
Wieland–Miescher Ketone
see also: Danishefsky J. Am. Chem. Soc. 1979, 101, 6996, 7001, 7008, 7013.
239
Companion Strategy: Woodward J. Am. Chem. Soc. 1952, 74, 4223;
Bloom J. Org. Chem. 1959, 24, 278.
regioselectivity: ortho adduct
diastereoselectivity: 2o orbital
interaction of endo addition
O O
CH3 110 oC
5.5 d
CH3O (endo) CH3O

CH3
O 50% H
O
vinylogous ester,
not as reactive
Al2O3 (epimerization)
O O
NaBH4
CH3O CH3O
H H
OH O
i) MsCl, Et3N, CH2Cl2 vinylogous ester, so this

ii) Zn/HOAc carbonyl not reduced by NaBH4
(reductive elimination)
OH O
CH3O CH3O
H H
See also: Robinson J. Am. Chem. Soc. 1961, 83, 249. very useful
Orchin, Butz J. Org. Chem. 1943, 8, 509.
Kishi Tetrahedron Lett. 1970, 5127.
Kakushima Can. J. Chem. 1976, 54, 3304.
Can also add nucleophiles (RLi, H–) to the "vinylogous ester" carbonyl:
H
O
i) R'Li (R' = H O R'
alkyl, H, etc.)
CH3O ii) H3O+ CH3O

H H
R R
H3O+
as above
O R'
CH3
CH3O O
H
O R R
240
Dale L. Boger
-Aromatic Annulation
CH3O CO2CH3
+ O
CO2CH3 OR
O
O
CO2CH3
any oxygenated aromatic
substitution pattern using
different electron-rich olefins.
OCH3 OCH3
OCH3 OCH3 CH3O OCH3 CH3O OCH3
Boger J. Org. Chem. 1984, 49, 4033, 4045 and 4050.
Use of aromatic annulation in total synthesis:
CH3 OCH3
OH CH3O
N
CH3O
Rufuscine, Imelutine
HO X Norrufuscine
CH3 Juncusol X = H, OR
OR
Heteroatom Substituted Dienes:
CO2CH3
O O O
LICA
THF 90%
CO2CH3
Diels–Alder or Michael–Michael Reaction

Lee Tetrahedron Lett. 1973, 3333.
OLi OR
CO2CH3 60% CO2CH3
Kraus Tetrahedron Lett. 1977, 3929.
O
O O
CH3O CH3O HCl [O] O
PhS H2O –PhSOH

PhS
5:1 complement to
RS > OR Danishefsky diene
Diels–Alder product.
241
Danishefsky Diene: (see summary list)
OCH3
OCH3 W
W W
HCl
TMSO O
TMSO
CO2CH3 O
OCH3 CO2CH3 O
1) KOH
2) KI3 O I
TMSO O
H H
Iodolactonization
OH
O
O
H
O
O
Vernolepin
OSiR3 OR
O
•
OR
,
Note the dienophile and diene equivalency list

O O
i. 80–140 °C
OMe ii. HCl, aq.
Cl THF
OSiR3 O OH OH O OH
Brassard Tetrahedron Lett. 1979, 4911.

Danishefsky Applications
Reviews: Danishefsky Chemtracts: Org. Chem. 1989, 2, 273.

Danishefsky Acc. Chem. Res. 1981, 14, 400.
dienes J. Am. Chem. Soc. 1979, 101, 6996, 7001 and 7008.
tatettine J. Am. Chem. Soc. 1980, 102, 2838.
coriolin J. Am. Chem. Soc. 1980, 102, 2097.
prephenate J. Am. Chem. Soc. 1979, 101, 7013.
griseofulvin J. Am. Chem. Soc. 1979, 101, 7018.
pentalenolactone J. Am. Chem. Soc. 1979, 101, 7020.
vernolepin J. Am. Chem. Soc. 1977, 99, 6066.
lasiodiplodin J. Org. Chem. 1979, 44, 4716.
papulacandin aglycon Carbohydr. Res. 1987, 171, 317.
vineomycinone J. Am. Chem. Soc. 1985, 107, 1285.

242
Dale L. Boger
methyllincosaminide J. Am. Chem. Soc. 1985, 107, 1274.
KDO and N-acetylneuraminic acid J. Am. Chem. Soc. 1988, 110, 3929.
tunicaminyluracil J. Am. Chem. Soc. 1985, 107, 7761.
mevinolin J. Am. Chem. Soc. 1989, 111, 2596.

Pure App. Chem. 1988, 60, 1555.
compactin J. Am. Chem. Soc. 1989, 111, 2599.
avermectin A1a J. Am. Chem. Soc. 1987, 109, 8119.

J. Am. Chem. Soc. 1987, 109, 8117.
J. Am. Chem. Soc. 1989, 111, 2967.
octosyl acid J. Am. Chem. Soc. 1988, 110, 7434.
methyl-α-peracetylhikosanamide J. Am. Chem. Soc. 1989, 111, 2193.
zincophorin J. Am. Chem. Soc. 1988, 110, 4368.
6a-deoxyerythronolide Silicon Chem. 1988, 25 (Ellis Horwood Ltd.)
-Unactivated dienes
O O O
CO2CH3 CO2CH3
CO2CH3 HBr
double activation permits reaction even with deactivated dienes

Boger J. Org. Chem. 1985, 50, 1904.
N N
OR
intramolecular reaction permits use of unactivated diene or dienophile

Boger Tetrahedron Lett. 1991, 32, 7643.
-Deslongchamps: Tetrahedron Lett. 1990, 31, 3969; Synlett 1990, 516.

R1 1. Cs2CO3, O R1
O E
R2 CH2Cl2 R2
CO2CH3
+
O 2. TsOH
O
CO2 But H
via [4 + 2] Diels–Alder reaction E = CO2CH3

R1
R2
OH
CO2tBu
243
-Compilation of Representative Functionalized Dienes
Review: Petrzilka, Grayson Synthesis 1981, 753.
diene reference
R = SiMe3 Tetrahedron Lett. 1976, 2935.

RO R = Et J. Chem. Soc., Chem. Commun. 1966, 1152.
J. Am. Chem. Soc. 1980, 102, 3270.
R = Ac J. Am. Chem. Soc. 1976, 98, 1967.
R = P(O)(OEt)2 Helv. Chim. Acta 1979, 62, 442; Synthesis 1981, 753.
R = CH3, Ac Tetrahedron Lett. 1976, 3869, 3873.

R = Ac J. Am. Chem. Soc. 1977, 99, 8116.
R = CH3, 3-Me Tetrahedron Lett. 1978, 1387.
OR R = CH3, 4-Me Tetrahedron Lett. 1978, 3869.
R = Ac, 3-Me J. Chem. Soc., Chem. Commun. 1980, 197.
Syn. Commun. 1980, 233.
J. Org. Chem. 1980, 45, 4825.
OMe J. Am. Chem. Soc. 1974, 96, 7807.

J. Org. Chem. 1975, 40, 538.
Danishefsky's diene J. Am. Chem. Soc. 1977, 99, 5810.
Me3SiO J. Am. Chem. Soc. 1979, 101, 6996, 7001.
See Danishefsky reference list.
see also: J. Chem. Soc., Perkin Trans. 1 1979, 3132.
OR R = Me J. Org. Chem. 1982, 47, 4774.

R = Et J. Am. Chem. Soc. 1978, 100, 7098.
R = SiMe3 Syn. Commun. 1977, 7, 131.
RO Chem. Lett. 1978, 649.
Chem. Pharm. Bull. 1978, 26, 2442.
Synthesis 1981, 30.
OR R = SiMe3 Tetrahedron Lett. 1979, 4437.

Chem. Lett. 1978, 649.
OMe
R = Me J. Chem. Soc., Perkin Trans. 1 1976, 1852.
Me3SiO J. Org. Chem. 1978, 43, 379.
J. Am. Chem. Soc. 1979, 101, 7001.
OMe See Danishefsky reference list.
J. Org. Chem. 1977, 42, 1819.

Me3SiO
SePh
244
Dale L. Boger
diene reference
OR R = CH3 J. Am. Chem. Soc. 1978, 100, 7098.

R = Ac, 2-Me J. Org. Chem. 1976, 41, 2625.
R = SiMe3 J. Org. Chem. 1976, 41, 1799.
OR R = Ac J. Org. Chem. 1965, 30, 2414.
Org. Syn. 1970, 50, 24.
Angew. Chem., Int. Ed. Eng. 1979, 18, 304.
J. Chem. Soc., Dalton Trans. 1974, 956.
Chem. Ber. 1957, 90, 187.
J. Org. Chem. 1976, 41, 1655, 2625.
J. Org. Chem. 1978, 43, 4559.
RO R = SiMe3 J. Org. Chem. 1978, 43, 2726.

Chem. Lett. 1977, 1219; 1978, 649.
RO Synthesis 1971, 236.
Others J. Org. Chem. 1960, 25, 1279.
J. Am. Chem. Soc. 1957, 79, 3878.
J. Am. Chem. Soc. 1941, 63, 131.
OR R = CH3 Recl. Trav. Chim. Pays-Bas 1975, 94, 196.

R = SiMe3 Tetrahedron Lett. 1979, 4911.
OMe
R = CH3, 3-Me Tetrahedron Lett. 1979, 4912.
J. Org. Chem. 1976, 41, 3018.
Can. J. Chem. 1974, 52, 80.
J. Org. Chem. 1978, 43, 1435.
OEt
EtO
Me3SiO
OEt

Me3SiO
OEt
OMe
OMe
R = H, OSiMe3 J. Chem. Soc., Perkin Trans. 1 1979, 3132.
R J. Org. Chem. 1978, 43, 1435.
OMe
245
diene reference
J. Org. Chem. 1976, 41, 3218.

J. Org. Chem. 1978, 43, 1208.
RS Angew. Chem., Int. Ed. Eng. 1966, 5, 668.
J. Org. Chem. 1976, 41, 3218.

J. Am. Chem. Soc. 1972, 94, 2891.
(also reports corresponding sulfoxides).
SR J. Org. Chem. 1978, 43, 1208.
OR
R = CH3, R1 = H J. Chem. Soc. 1964, 2932, 2941.
R1 R = SiMe3, R1 = H, Me Tetrahedron Lett. 1976, 3169.
RO R1
R
R = H, R1 = Me Tetrahedron Lett. 1970, 4427.
R R = H, R1 = Ac J. Am. Chem. Soc. 1968, 90, 113.
R1O R R = Me, R1 = SiMe3 Tetrahedron Lett. 1977, 611.
OR R = SiMe3 Tetrahedron Lett. 1981, 22, 645.

J. Am. Chem. Soc. 1980, 102, 3654 and 5983.
R = CH3 J. Chem. Soc. 1964, 2932 and 2941.
J. Chem. Soc., Perkin Trans. 1 1973, 3132; 1976, 2057.
Tetrahedron Lett. 1970, 3467 and 4427.
OR
J. Org. Chem. 1978, 43, 4559.
J. Am. Chem. Soc. 1977, 99, 8116.
SR
RO J. Am. Chem. Soc. 1976, 98, 5017.
J. Am. Chem. Soc. 1977, 99, 8116.
RS J. Am. Chem. Soc. 1980, 102, 3548 and 3554.
J. Org. Chem. 1982, 47, 4005.

J. Org. Chem. 1978, 43, 4052.
RO J. Org. Chem. 1976, 41, 3218.
SR Org. Syn. 1979, 59, 202.
SR
SR
J. Org. Chem. 1976, 41, 2934.
RO
SR
SR J. Org. Chem. 1972, 37, 4474.

R
246
Dale L. Boger
diene reference
OSiR3
R Tetrahedron Lett. 1980, 21, 3423.
O J. Chem. Soc., Chem. Commun. 1981, 211.
R
OSiR3
NR2 = NEt2 J. Org. Chem. 1966, 31, 2885.
NR2 = NHCOX J. Am. Chem. Soc. 1976, 98, 2352 and 8295.
R2N
NR2 = NHCOX Tetrahedron Lett. 1976, 3089.

NR2 = NHCO2R J. Org. Chem. 1979, 44, 4183.
NR2 J. Am. Chem. Soc. 1976, 98, 2352.
J. Org. Chem. 1978, 43, 2164.
Helv. Chim. Acta 1975, 58, 587.
NR2 = NEt2 Chem. Ber. 1957, 90, 238.
Chem. Ber. 1942, 75, 232.
NR2 (comparison) J. Liebigs Ann. Chem. 1969, 728, 64.
O
Me3Si •
J. Org. Chem. 1980, 45, 4810.
CO2Et
J. Org. Chem. 1970, 35, 3851.

EtO
SiR3
J. Chem. Soc., Chem. Commun. 1976, 679, 681.

R3Si

R3X
X = Si, Sn
13. Heterodienes
-Typically, heterodienes are electron-deficient and participate in inverse electron demand Diels–Alder reactions
Reviews: Boger Tetrahedron 1983, 34, 2869.
Comprehensive Org. Syn., Vol. 5, 451.
Behforouz Tetrahedron 2000, 56, 5259.
247
-Acyclic azadienes, N-sulfonyl-1-azadienes:
R OR R SO2Ph
SO2Ph SO2Ph N
R N R N OR R
R * Regiospecific and endo
R Diastereospecific R
Boat TS
R R R RO
R
R R
R
* Secondary orbital interaction (C-2 diene/OR) * Pressure-induced endo diastereoselectivity
* n–σ* stabilization (T.S. anomeric effect) * k (trans) > k (cis)
* Solvent independent rate * C-3 EWG accelerates reaction (25 °C)
* Dienophile geometry conserved * And C-2 or C-4 EWG accelerate reaction
* C-3 > C-2 or C-4 (25 °C)
O OH O O
O
MeO MeO N
H
N O N CH3
H2N N
O OH O O X = OH, H X
HO H2N CH3
X=O
OH
O N
H
OMe (–)-Mappicine
Fredericamycin A Streptonigrone OMe Nothapodytine B
Boger J. Am. Chem. Soc. Boger J. Am. Chem. Soc. Boger J. Am. Chem. Soc.
1995, 117, 11839. 1993, 115, 10733. 1998, 120, 1218.
-Representative heteroaromatic azadiene Diels–Alder reactions taken from the work of Boger
CO2CH3 R1
N R
O N
N NH R
2
R
R CO2CH3
R N R R = CO2CH3
R=H R = H, Cl
N N R = CO2Et R = CO2CH3 R1
R = SCH3 N N
R R = CO2CH3 R N R
R = SCH3 R = CO2CH3 O
O EDG R = OMe N R = SCH3 R2
N R1
R
R R N N
N N
R N N N R
N R=H R = CO2CH3
O
N N R = CO2Et R = SCH3
R R2
R R = OMe, SMe R = SO2CH3
R R = SMe, NHCOR
R1
R
N
O N
N N
R2
R
Reviews: Boger Tetrahedron 1983, 34, 2869. Prog. Heterocycl. Chem. 1989, 1, 30.
Chem. Rev. 1986, 86, 781. Bull. Chim. Soc. Belg. 1990, 99, 599.
Chemtracts: Org. Chem. 1996, 9, 149.
248
Dale L. Boger
-Heterocyclic azadiene Diels–Alder reaction total synthesis applications taken from the work of Boger
O O
MeO
N CO2H N CO2H
H2N N H2N N
O O
H2N CH3 CH3
HN
OH
OMe
OMe
Streptonigrin Lavendamycin
J. Am. Chem. Soc. 1985, 107, 5745. J. Org. Chem. 1985, 50, 5782 and 5790.
OH HO
C5H11 HO OH
OH HO
HO OH
N CH3
MeO
NH O
O O N
O
N
NH O H O
Prodigiosin Ningalin A Nigalin B

J. Org. Chem. 1988, 53, 1405. J. Am. Chem. Soc. 1999, 121, 54. OH
J. Org. Chem. 2000, 65, 2479. OH
HO
MeO CO2Me
MeO
N Me
HO
N
H MeO2C N O
O
Me
cis-Trikentrin A Isochrysohermidin
O OH
n
Bu OH
N
NH HN MeO N CO2H
OH O
N
Phomazarin
J. Am. Chem. Soc. 1999, 121, 2471.
OMP
Richard M. Willstatter received the 1915 Nobel
J. Org. Chem. 1984, 49, 4405. Prize in Chemistry for his investigations of plant
pigments, particularly chlorophyll. His use of
H. Fischer received the 1930 Nobel Prize in chromatography to isolate natural products
Chemistry on the structure of haemin and first popularized the technique introduced in
chlorophyll and the subsequent synthesis of haemin. 1906 by M. Tswett and his synthesis of cocaine
By many, this is regarded as a milestone is considered by many as the launch of
accomplishment for the field of organic synthesis. modern day natural products total synthesis.
249
H2N
O
N
Me OH R
N
HN OMe HO2C O
NH N OH
H
O N N OMe
O
PDE-I R = NH2
O N OH PDE-II R = CH3
H
OMe
(+)-CC-1065
Me
H
S N O
Me
H2N O
NH2
H
N N
H2N O CONH2 O S
NH2 H
H HO N
N N N O NH N
CONH2 H
N O S
H2N N HO
N N O Me H H
H Me O
N O N
H2N N CO2H OH
H HO O N
O N O H
OH
N OH O
OH
H OCONH2
OH
(+)-P-3A Bleomycin A2
J. Am. Chem. Soc. 1994, 116, 82. J. Am. Chem. Soc. 1994, 116,
5607, 5619, 5631, 5647.
OMe OMe
HO OH MeO OMe
HO OH
MeO OMe
H H
O N N
CO2Me N
N N
O O O O
MeO OMe
OMe OH OMe
Lamellarin O Lukianol A Permethyl Storniamide A

250
Dale L. Boger
O
N OMe O N
O
O
Cl
HN
ent-(−)-Roseophilin Anhydrolycorinone
14. Intramolecular Diels–Alder Reactions

Review: Ciganek Org. React. 1984, 32, 1.
Jung Synlett 1990, 186.
Thomas Acc. Chem. Res. 1991, 24, 229.
Weinreb Acc. Chem. Res. 1985, 18, 16.
Oppolzer Comprehensive Org. Syn., Vol. 5; pp 315.
A. General Considerations:
-less negative ∆S , which accelerates reaction and results in milder reaction conditions.
-naturally affects regioselectivity and diastereoselectivity.
-extends Diels–Alder reaction to include systems which are normally unreactive.
no activating groups
160 °C
95% H
Wilson J. Am. Chem. Soc. 1978, 100, 6289.

B. Notable applications in synthesis:
-tethered intramolecular Diels–Alder reactions
Ph Ph OiPr Ph OH
B(OiPr)2 1. BHT, PhCH3, B
150 °C, 0.5 h OH
+ OH O
Me Me
2. H2O2, NaOH
Me Me Me
Me Me
74% (major
Me Me
diastereomer)
Batey J. Am. Chem. Soc. 1999, 121, 450.
-metal-catalyzed intramolecular Diels–Alder reactions
An emerging group of transition-metal mediated [4 + 2] cycloadditions are under development.
Ni-catalyzed
Ni(COD)2 (0.1 equiv)
O O
TMS TMS
98%
Wender J. Am. Chem. Soc. 1989, 111, 6432.
Rh-catalyzed
[(C8H14)2RhCl]2
(0.013 equiv)
TBSO TBSO
98%
Livinghouse J. Am. Chem. Soc. 1990, 112, 4965.
251
-applications in total synthesis
CO2Me CO2Me
CO2Me 1,2,4-trichlorobenzene
H
NOMe
NOMe 200 °C, 67% NOMe H
HN HN HN
Oppolzer Helv. Chim. Acta 1981, 64, 478. for lysergic acid
t
t t
Me O Bu Me O Bu
Me O Bu
o-dichlorobenzene H
180 °C H H H
H
MeO MeO MeO
Kametani J. Am. Chem. Soc. 1978, 100, 6218. for estrone
O O H
toluene, sealed tube
NPiv NPiv
N 140 °C, 24 h N H
Ac Ac
Merour Synlett 1998, 1051.
H H
NHAlloc
O O O NHAlloc
O
TESO 0.2 mM in dodecane TESO
O O
70 °C H
O O CO2tBu
O CO2tBu O
H H
H O H O
OTBS OTBS
Kishi J. Am. Chem. Soc. 1998, 120, 7647. for pinnatoxin A
OTBS OTBS
Me O
O
t
Bu
O O
O O O tBu
toluene, BHT O
Me 70 °C, 20 h Me CO2All
40–45%
Me3Si OMOM Me3Si OMOM

Roush J. Am. Chem. Soc. 1998, 120, 7411. for chlorothricolide
252
Dale L. Boger
15. Asymmetric Diels–Alder Reaction
Catalytic Asymmetric Diels–Alder Reactions: Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007.
Asymmetric Hetero Diels–Alder Reaction: Waldermann, H. Synthesis 1994, 535.
A. General considerations
-Unsymmetrically substituted dienes or dienophiles have enantiotopic faces. Even with exclusive cis-endo
addition and regioselectivity, products occur as a pair of enantiomers.
RO2C H
Si
Re Si
Re +
CO2R
CO2R
-There are three possible ways to obtain one of the enantiomers in excess:
a) using chiral dienes.

b) using chiral dienophiles.
c) using chiral Lewis acid catalysts.
In addition, double stereoselection can be realized in many situations.
-Comparison of chiral substrate vs. chiral catalyst
use of a chiral substrate (chiral diene or dienophile): a stoichiometric amount of chiral auxiliary R* is
needed and its introduction before and removal after the Diels–Alder reaction are neccessary.
R*O2C H TiCl4
Si + +
–60 °C CO2R*
Re CO2R*
use of a chiral catalyst: usually 0.1 equiv. is enough to introduce chirality and the catalyst can be
recovered from the reaction mixture and reused.
CHO ML*n
+ +
CHO
CHO
B. Chiral dienophiles
Review: Oppolzer Angew. Chem., Int. Ed. Eng. 1984, 23, 876.
Ager and East Asymmetric Synthetic Methodology; CRC Press: New York, 1996.
-Chiral dienophiles provide the vast majority of the examples of asymmetric Diels–Alder reactions.
Type I Type II
O O
XR* R*
X = O, NR*
253
First example:
O
TiCl4 COOR*
OR*
+
R*O toluene COOR*
25 °C
O R* = (–)-menthyl
78% de 80% yield
Walborsky Tetrahedron 1963, 19, 2333.
COOMe COOMe
R*OOC
O AlCl4
+
O
O CH2Cl2
R
–30 °C
R = CH2Ph, CONHPh 99% de
Helmchen Angew. Chem., Int. Ed. Eng. 1981, 20, 205.
tBu
OH +
tBu
O O
OH
conditions endo de yield
–20 °C, 24 h 89% 99% 90%
ZnCl2, –43 °C, 1 h 94% >99% 95%
Masamune J. Org. Chem. 1983, 48, 1137, 4441.
O O
Et2AlCl
R N O + R
–100 °C
O N
O O
>86% de
O O
Et2AlCl
+ R
R N O
–100 °C CH3
CH3 Ph O N Ph
O
O
>98% de
Evans J. Am. Chem. Soc. 1984, 106, 4261; 1988, 110, 1238.
254
Dale L. Boger
other notable chiral dienophiles:
O
OH N
S O O
O
R
N R1
CH3
O
Arai J. Org. Chem. 1991, 56, 1983. Boeckman J. Am. Chem. Soc. 1992, 114, 2258.
R O O
O
O Ph O TolS
N N O
R O
SO2 H
SO2
Oppolzer Helv. Chim. Acta 1989, 72, 123. Inverse electron demand Diels–Alder reaction
Oppolzer Tetrahedron Lett. 1990, 31, 5015. Posner J. Am. Chem. Soc. 1986, 108, 7373.
O
COOMe
O OR* R* = l-menthyl
O
Liu Tetrahedron Lett. 1991, 32, 2005. Feringa Tetrahedron: Asymmetry 1991, 2, 1247.
Boger J. Org. Chem. 1985, 50, 1904.
O O
X
R
R' N CO2Me
O
X = O, NAc O
Roush Tetrahedron Lett. 1989, 30, 7305 and 7309. Meyers Tetrahedron Lett. 1989, 30, 6977.
Kneer Synthesis 1990, 599.
O O
Me OBn
O H
Tol S CO2Et O Et
CH3
O

Koizumi Tetrahedron Lett. 1984, 25, 87. Danishefsky J. Am. Chem. Soc. 1984, 106, 2455.
O R1 Ph3CO
N
R N
R2 O O
Ghosez Tetrahedron Lett. 1989, 30, 5891. Koga J. Chem. Soc., Perkin Trans. 1 1990, 426.
255
C. Chiral dienes
-These have been much less extensively studied.
O O
(S)
Ph O MeO
O O
BF3•OEt2 Ph
H OMe + H H CHO 64% de

Ph
O O O O COR*
H
15 kbar
+ 50% de
23 h, 20 °C
62% H
O O
Dauben Tetrahedron Lett. 1982, 23, 4875.
O
EtO2C N O EtO2C N O
15 kbar H O
+ O
23 h, 20 °C
O
O 62%
H O
Smith Tetrahedron Lett. 1989, 30, 3295.
TMSO
Me O O
H
O TMSO
OAc + N Ph N Ph 90% de
Me
O H O
OAc R*O
OAc OAc
Stoodley J. Chem. Soc., Perkin Trans. 1 1990, 1339.
OMOM MOMO
O H O
Toluene
+ N Ph N Ph
25 °C, 48 h
(S) H O
Me O
OTBS Me H
H OTBS
O MOMO O
OMOM H
THF
+ N Ph N Ph
25 °C, 0.5 h
O H O
(R)
PhS H
H SPh
Me Me
McDougal Tetrahedron Lett. 1989, 30, 3897.
256
Dale L. Boger
R
R
NO2
1. Ar NO2
N
2. HOAc
26−76%, 95−99% ee O Ar
OMe
Enders Synthesis 1992, 1242; 1994, 66.
Barluenga J. Am. Chem. Soc. 1993, 115, 4403; 1998, 120, 2514.
TBSO TBSO
OTBS
Ph O
N R'
+ CHO
R' CHO Ph OHC R'
R N R R N R
R' CHO
R = CH2OMe, Ph 86%, 88% ee

Rawal J. Am. Chem. Soc. 1999, 121, 9562.
D. Chiral Lewis acid catalysts
Review: Oh Org. Prep. Proced. Int. 1994, 26, 129.

Age and East Asymmetric Synthetic Methodology; CRC Press: New York, 1996.
-Pioneer work
catalyst
CHO toluene CHO
+
–78 °C
catalyst: R yield ee
Cl 56% 57%
O Et 57% 35%
ClAl iBu
R 67% 23%
Koga J. Chem. Soc., Chem. Commun. 1979, 437.

a. Boron-based Lewis acids
O
Me catalyst
H Me CHO
+ Me +
Me Me
CHO Me
catalyst: endo exo
CH3O O COOH 3:97 (endo:exo)

O O 90% yield
BH 91% ee
OCH3 O O
Yamamoto J. Org. Chem. 1989, 54, 1481.
257
O
O O
H
BH3, HOAc
Ph
O O H
OH O B OH O OCH3
OH Ph O O Ph
OH OCH3 70–90% yield
98% ee
Ph
Kelly J. Am. Chem. Soc. 1986, 108, 3510.
O
O O
H
B(OMe)3
HO NHAr O O H
OH O B OH O OSiR3
O O
HO NHAr OSiR3 73% yield
NHAr
ArHN 92% ee
Yamamoto Tetrahedron Lett. 1986, 27, 4895.
other boron-based catalysts
SO2Ar
N R
HB
O O
O R = Et
O
R = iPr
O BB O R = 3-indole
O O
Yamamoto Synlett 1990, 194.

Helmchen Synlett 1990, 197.
Mukaiyama Chem. Lett. 1991, 1341.
C3-symmetric Corey J. Am. Chem. Soc. 1991, 113, 8966.
Kaufmann Angew. Chem., Int. Ed. Eng. 1990, 29, 545.
See also: Yamamoto J. Am. Chem. Soc. 1998, 120, 6920.
tBuCH
2 CH3 Br CH3
BBr2•SMe2 B
Cl2B
Kaufmann Tetrahedron Lett. 1987, 28, 777.
Hawkins J. Am. Chem. Soc. 1991, 113, 7794. Kaufmann J. Organomet. Chem. 1990, 390, 1.
258
Dale L. Boger
b. Aluminum-based Lewis acids
BnO
O O
catalyst O
+ CH2OBn
N O O N
–78 °C O
CH2Cl2
94% yield
catalyst: 95% ee
Ph Ph
CF3O2SHN NHSO2CF3 Corey J. Am. Chem. Soc. 1989, 111, 5493.

Al
CH3
OMe Me
O
Me O
1) (R)-catalyst
+ H
O Ph
TMSO 2) CF3COOH
Me
Me
95–97% ee
catalyst:
SiAr3
O
Al Me
O
SiAr3 Yamamoto J. Am. Chem. Soc. 1988, 110, 310.

Ar = Ph, 3,5-xylyl
other chiral ligands used for chiral aluminum-based Lewis acids:
CH3 H Ph Ph CH3 H Ph Ph
CH3O OH HO OH
Ph OH Ph OH Kagan Tetrahedron: Asymmetry 1990, 1, 199.

Ph OH Ph OH
OH OBn
OBn NH
BnO
OBn OH SO2
Wulff, Rheingold J. Am. Chem. Soc. 1993, 115, 3814. Chapuis Helv. Chim. Acta 1987, 70, 436.
259
c. Titanium-based Lewis acids
O Cl R O
O R* Ti
Cl O O
R N O + + R N
O N O O
endo exo
catalyst: Cl
R* Ti
Cl
R* = endo:exo (90:10)
Ph Ph endo 92% ee
Ph O OH
Me O OH
Ph Ph
Narasaka J. Am. Chem. Soc. 1989, 111, 5340.
Seebach Helv. Chim. Acta 1987, 70, 954.
Other Titanium catalysts:
O
Ph O
O O TiCl2
TiCl2 Ph O
O O
Oh J. Org. Chem. 1992, 57, 396.
O
Chapuis Helv. Chim. Acta 1987, 70, 436. CH3
X
Ph
OH X = Ph, SiPh3,
OH
O O SitBuPh2,
TiCl2 TiCl2 OH
OH SiiPr3,
O O Si(o-tolyl)3
X
Ph
CH3
Mikami Tetrahedron: Asymmetry 1991, 2, 643.
Chapuis Helv. Chim. Acta 1987, 70, 436. Yamamoto J. Org. Chem. 1993, 58, 2938.
d. Copper-based Lewis acids
O R
O R = H, CH3, Ph, CO2Me
Cu(OTf)2 O
R N O +
bis(oxazoline) O N 90–97% ee
O
85–92% yield
260
Dale L. Boger
bis(oxazoline):
CH3 CH3
R = Ph
O O iPr
N N tBu
R R

Evans Tetrahedron Lett. 1993, 34, 7027.
Review: Evans Acc. Chem. Res. 2000, 33, 325.
Me Me Me
catalyst H+
+
MeO2C CHO
(MeO)2P O OEt (MeO)2P O OEt
O O
94–99% ee
catalyst:
CH3 CH3 2+ CH3 CH3 2+

O O O O
or
N N 2 –OTf N N 2 –OTf
Cu Cu
Me3C CMe3 Ph Ph
Evans J. Am. Chem. Soc. 1998, 120, 4895; 1999, 121, 7559 and 7582.
e. Iron, Magnesium-based Lewis Acids
CH3 CH3 + CH3 CH3

O O CH3 O O CH3
N N CH3 N N CH3
Fe Mg
Ph I I Ph Ph I I Ph
Corey J. Am. Chem. Soc. 1991, 113, 728. Corey Tetrahedron Lett. 1992, 33, 6807.
f. Miscellaneous chiral Lewis acids
C3F7
O O
Yb(OTf)
O O Eu
3
Eu(hfc)3
Kobayashi Tetrahedron Lett. 1993, 34, 4535. Danishefsky J. Am. Chem. Soc. 1986, 108, 7060.
261
E. Biological catalysts
COOR Baker's yeast

COOR
+
COOR
COOR
100% exo, against
R = Me, Et the Alder endo rule
Rao Tetrahedron Lett. 1990, 31, 5959.
Catalytic antibodies (abzymes):

O O
abzyme
+ N NHAc N NHAc
O O
O O NH O
HN O –
O
O–
O O
Schultz J. Am. Chem. Soc. 1990, 112, 7430.
Schultz Science 1998, 279, 1929.
Review: Schultz, Lerner Science 1995, 269, 1835.
CONMe2
IgG 4D5
(endo)
NHCO2R
+
CONMe2 IgG 13D5 CONMe2
NHCO2R
(exo)
R = 4-carboxybenzyl NHCO2R
Houk, Janda, Lerner Science 1993, 262, 204.
Janda J. Am. Chem. Soc. 1995, 117, 7041.
Houk, Janda, Wilson Science 1998, 279, 1934.
Cl O O S O Cl O
Cl Cl
abzyme Cl Cl
SO2 + N Et N Et
Cl Cl O
Cl Cl
Cl O N O
Cl
O Et
Hilvert J. Am. Chem. Soc. 1989, 111, 9261.

F. Double asymmetric induction
O O
(S)
Ph O MeO
O O O
BF3•OEt2 Ph
H OMe +
OH
H OH
t
Bu t
Bu
ds > 130:1
O O
(R)
Ph O MeO
O O O
BF3•OEt2 H
MeO H +
OH
Ph OH
tBu tBu
ds 35:1
Masamune J. Org. Chem. 1983, 48, 4441.
262
Dale L. Boger
S O
catalyst H
O N Ph + Ph S conversion 72%
–20 °C, 36 h endo:exo > 97:3
Bn O N O endo1:endo2 97:3
Bn
matched
S O
catalyst H
O N Ph + Ph S conversion 7%
–20 °C, 36 h endo:exo 97:3
Bn O N O endo1:endo2 57:43
Bn
catalyst:
2+
mismatched
H H
Cl N N Cl
Cu 2 –OTf
Cl Cl
Evans Tetrahedron Lett. 1993, 34, 7027.
G. Intramolecular Diels–Alder reactions
CH3
CO2R* CO2R*
O (l-bornyloxy)AlCl2
R R
R +
O
(CH3)2Ph
82 : 18
64% ee
Roush J. Am. Chem. Soc. 1982, 104, 2269.
CH3
S
O O O O
catalyst S H
N O N O
H
S S CH3
catalyst: 70% yield

Ph Ph 87% ee
Ph O O
TiCl2
Me O O
Ph Ph
Narasaka Chem. Lett. 1989, 1947.
263
16. Some Classic and Favorite Total Synthesis Applications
OH
N HO
MeO N OH
H H
O CH3 N
H
MeO OMe
O
O OMe
OMe Pyridoxol
OMe Harris J. Org. Chem. 1962, 27, 2705.
Reserpine Doktorova Tetrahedron 1969, 25, 3527.
Woodward Tetrahedron 1958, 2, 1.
O
N
O
N
H
H O
H
Fraxinellone
Ibogamine
Fukuyama Tetrahedron Lett. 1972, 3401.
Sallay J. Am. Chem. Soc. 1967, 89, 6762.
OH OH O
OH OH OH
HO HO OH
OH
OH OH
OH
α-Damascone
Cookson J. Chem. Soc., Chem. Commun.
allo-Inositol myo-Inositol
1973, 161, 742.
Kowarski J. Org. Chem. 1973, 38, 117.
HO COOH
HO
O
O
HO OH
O OH
O Quinic acid
Raphael J. Chem. Soc. 1960, 1560.
Cantharidin Smissman J. Am. Chem. Soc. 1963, 85, 2184.
Stork, Burgstahler J. Am. Chem. Soc. 1953, 75, 384. Wolinsky J. Org. Chem. 1964, 29, 3596.
Grieco J. Am. Chem. Soc. 1990, 112, 4595. Raphael Tetrahedron Lett. 1968, 1847.
Newkome Tetrahedron Lett. 1968, 1851.
O–
O
HO OH
HO OH
HN N OH
NH H
OH
Tetrodotoxin Patchouli alcohol

Kishi J. Am. Chem. Soc. 1972, 94, 9217. Naf, Ohloff Helv. Chim. Acta 1974, 57, 1868.
264
Dale L. Boger
COOH MeO
O NHAc
MeO
MeO
HO O
OH
OMe
Prostaglandins Colchicine
Corey J. Am. Chem. Soc. 1970, 92, 397. Eschenmoser Helv. Chim. Acta 1961, 44, 540.
Taub Tetrahedron Lett. 1975, 3667. Boger J. Am. Chem. Soc. 1986, 108, 6713.
Nootkatone α-Copaene
Dastur J. Am. Chem. Soc. 1974, 96, 2605. Corey J. Am. Chem. Soc. 1973, 95, 2303.
O O
O R O
N
H
O
H
O O OH
Steroids
Sarett J. Am. Chem. Soc. 1952, 74, 4974. Chelidonine
Sarett J. Am. Chem. Soc. 1954, 76, 5026. Oppolzer J. Am. Chem. Soc. 1971, 93, 3836.
OH Me
HO H Me
Me
O O
O
N N
O
Me
Dendrobine
Lycorine Kende J. Am. Chem. Soc. 1974, 96, 4332.
Torssell Tetrahedron Lett. 1974, 623. Roush J. Am. Chem. Soc. 1980, 102, 1390.
N
HO
H
N N
H
CH3 CO2CH3
Minovine
Hasubanan Derivative Spitzner J. Am. Chem. Soc. 1973, 95, 7146.
Evans J. Am. Chem. Soc. 1972, 94, 2891. Spitzner J. Am. Chem. Soc. 1970, 92, 3492.
265
COOH
HO OH N
OH H
Shikimic acid Pumilotoxin

Raphael J. Chem. Soc., Chem. Commun. 1960, 1560. Oppolzer Helv. Chim. Acta 1977, 60, 48, 204.
Raphael Tetrahedron Lett. 1968, 1847. Inubushi Chem. Pharm. Bull. 1978, 26, 2442.
Newkome Tetrahedron Lett. 1968, 1851. Inubushi Tetrahedron Lett. 1976, 3169.
Smissman J. Am. Chem. Soc. 1962, 84, 1040. Overman Tetrahedron Lett. 1977, 1253.
Smissman J. Am. Chem. Soc. 1959, 81, 2909. Overman J. Am. Chem. Soc. 1978, 100, 5179.
Wolinsky, Vasileff J. Org. Chem. 1964, 29, 3596.
COOH NMe2
HO Me OH
H H
OH
CONH2
HO
HO OH OH O OH O
Prostaglandins (−)-Tetracycline
Sakai, Kobori Tetrahedron Lett. 1981, 115. Tatsuta Chem. Lett. 2000, 646.
O OH O
OH O
CH2R2
HO HO OH
O
R1 O OH OR3
H CH3 O
OH R3 =
HO NH2
Illudol Fomannosin Anthraquinone antibiotics (aglycon)

Semmelhack J. Am. Chem. Soc. 1980, 102, 7567. Kelly J. Am. Chem. Soc. 1980, 102, 5983.
Semmelhack J. Am. Chem. Soc. 1981, 103, 2427. Cava J. Am. Chem. Soc. 1981, 103, 1992.
Semmelhack J. Am. Chem. Soc. 1982, 104, 747. Vogel Tetrahedron Lett. 1979, 4533.
Brassard Tetrahedron Lett. 1979, 4911.
Gesson Tetrahedron Lett. 1981, 22, 1337.
Rapoport Tetrahedron Lett. 1980, 21, 4777.
O Gesson Tetrahedron Lett. 1980, 21, 3351.
H H N
HO
N
Estrone (orthoquinodimethide) H
CO2CH3
Grieco J. Org. Chem. 1980, 45, 2247.
Saegusa J. Am. Chem. Soc. 1981, 103, 476.
Vollhardt J. Am. Chem. Soc. 1980, 102, 5245 and 5253. Vinca alkaloids and related analogs
Nicolaou J. Org. Chem. 1980, 45, 1463. Kuehne J. Org. Chem. 1980, 45, 3259.
266
Dale L. Boger
CH3 O
CH3 N
CH3 O
O
H H
Seychellene Stemoamide
Yoshkoshi J. Chem. Soc., Perkin Trans. Jacobi J. Am. Chem. Soc. 2000, 122, 4295.
1 1973, 1843.
Jung Tetrahedron Lett. 1980, 21, 3127.
HOOC O
O O
OC O
HO OH CH3O
O
CH3 CO2H
Gibberellic acid
Corey Tetrahedron Lett. 1973, 4477. Fumagillin
Corey J. Am. Chem. Soc. 1978, 100, 8031, 8034. Corey J. Am. Chem. Soc. 1972, 94, 2549.
O
OMe MeO
MeO H
N O
N H2N N
MeO O
H2N CH3
OH
OMe OMe
OMe
Rufescine Streptonigrone
Boger J. Org. Chem. 1984, 49, 4050. Boger J. Am. Chem. Soc. 1993, 115, 10733.
Me
H
S N O
Me
H2N O
NH2 H2N O
H NH2
N N H
CONH2 O S N
H CONH2
HO N
N N O NH N
H N N O CH3
N O S H
H2N N HO N
H H H2N N COOH
Me O N H H
O O
OH N
HO O N
O H
OH N
OH O H
OH
OCONH2
OH
Bleomycin A2 (+)-P-3A
Boger J. Am. Chem. Soc. 1994, 116, Boger J. Am. Chem. Soc. 1994, 116, 82.
5607, 5619, 5631, 5647.
267
MeO2C OH
MeO Me
N
MeO
N O
H
MeO2C O
N
HO
cis-Trikentrin A Me
Isochrysohermidin
O Boger J. Am. Chem. Soc. 1993, 115, 11418.
MeO
O
N CO2H
H2N N
O N CO2Me
H2N Me H2N N
HO O
Me
HN
MeO
OMe
Streptonigrin
Boger J. Am. Chem. Soc. 1985, 107, 5745. Lavendamycin methyl ester
Weinreb J. Am. Chem. Soc. 1980, 102, 3962. Boger J. Org. Chem. 1985, 50, 5790.
H
O O
N
NH HN H OH
N Trichodermol
H2N
Octamethylporphin
O
Boger J. Org. Chem. 1984, 49, 4405.
N
Me OH
MeO
C5H11 HN OMe
N OMe
NH N NH
Me O N N
O
O
NH
O N OH
Cl H
HN
OMe
Prodigiosin Roseophilin (+)-CC-1065/PDE-I and PDE-II
Boger J. Org. Chem. Boger J. Am. Chem. Soc. Boger J. Am. Chem. Soc. 1987, 109, 2717.
1988, 53, 1405. 2001, 123, 8515. Boger J. Am. Chem. Soc. 1988, 110, 4796.
CH3
OH
MeO OMe
HO N
HO
CH3
Juncusol Sendaverine
Boger J. Org. Chem. 1984, 49, 4045. Boger J. Org. Chem. 1984, 49, 4033.
268
Dale L. Boger
H H
H H
Ph
Ph COOH
H n HOOC H
n
n = 0: Endiandric acid E n = 0: Endiandric acid D

n = 1: Endiandric acid F n = 1: Endiandric acid G
Nicolaou J. Am. Chem. Soc. 1982, 104, Nicolaou J. Am. Chem. Soc. 1982, 104,
5555, 5557, 5558, 5560. 5555, 5557, 5558, 5560.
OMe
O
O
N
MeO
N
H O O
CO2Me
Catharanthine Quassin and Quassinoids

Trost J. Org. Chem. 1979, 44, 2052. Grieco J. Am. Chem. Soc. 1980, 102, 7586.
HO O HO
H
O
N HO
H CO2H
O
Indicine N-oxide Retigeranic acid

Keck J. Am. Chem. Soc. 1980, 102, 3632. Corey J. Am. Chem. Soc. 1985, 107, 4339.
OH
NH
Dodecahedrane Perhydrohistrionicotoxin
Paquette J. Am. Chem. Soc. 1982, 104, 4503. Keck J. Org. Chem. 1982, 47, 3590.
NC O
9-Isocyanopupukeanone 9-Pupukeanone Sativene

Yamamoto J. Am. Chem. Soc. 1979, 101, 1609. Snowden Tetrahedron Lett. 1981, 22, 97, 101.
White J. Org. Chem. 1980, 45, 1864.
269
O OMe OMe
MeO MeO
H
O N N
MeO2C MeO MeO
O Me
O
OH O
O OMe
Phyllanthocin Grandirubrine Imerubrine

Burke Tetrahedron Lett. 1986, 27, 4237. Boger J. Am. Chem. Soc. 1995, 117, 12452.
O OH O
MeO O
N
N CH3
O OH O
HO X = OH, H2 X
X=O
O N
H
Fredericamycin A (–)-Mappicine and Nothapodytine B

Boger J. Am. Chem. Soc. 1995, 117, 11839. Boger J. Am. Chem. Soc. 1998, 120, 1218.
OH HO
HO OH
OH HO
HO OH
O
N
O
O O
N
O H O
OH
OH
Ningalin A Nigalin B
J. Am. Chem. Soc. 1999, 121, 54. J. Org. Chem. 2000, 65, 2479
O
O
O N
N
OH O
O
OH
Rubrolone Anhydrolycorinone
270
Dale L. Boger
B. Robinson Annulation
R. Robinson was awarded the 1947 Nobel Prize in Chemistry
Reviews for his work on the synthesis of natural products, especially
M. Jung, Tetrahedron 1976, 32, 3. steroids and alkaloids. Notably, he was also the first to
Org. React. 1959, 10, 179. address the issue of reaction mechanisms with applications
Org. React. 1968, 16, 3. of valence theory to reaction mechanisms, and is credited
Synthesis 1976, 777. with the first use of the curved arrow to indicate electron
Synthesis 1969, 49. movement. His synthesis of tropinone (1917) is viewed by
many to represent the first natural product total synthesis
from simple precursors (succindialdehyde, acetone, and
methylamine).
Robinson J. Chem. Soc. 1917, 762. (tropinone)
Ph
O NaNH2
+
Ph NH3-Et2O
O
O
43%
Robinson J. Chem. Soc. 1935, 1285.
Generated a great deal of interest and subsequent work

because of relationship to steroid synthesis.
1. Scope
- Formally, a [4 + 2] condensation approach
1 O O O
2 Michael Reaction
+
O HO
O 3
4 O O O
H. Wieland received the 1927 Nobel Prize in Aldol Condensation

Chemistry for his work in isolating and
deducing the structures of bile acids/steroids
including cholic acid. He concluded his Nobel O O
Lecture with the statement that he had a
"duty" to synthesize the bile acids even though
the task was insurmountable at the time.
O O
OH
Wieland–Miescher ketone
Wieland and Miescher Helv. Chim. Acta 1950, 33, 2215.
- Alternative "[3 + 3] Robinson Annulation"

–
Both the [4 + 2] and [3 + 3] approaches
+ were first generalized by Robinson
O O J. Chem. Soc. 1937, 53.
O
- Org. Synth., Coll. Vol. 5, 486.

O O O
N
cat. 0.01 N KOH H
+
CH3OH O benzene
O reflux
O O O
60–65%
271
- With stronger base, other reactions are observed:
O O– OCH3
CH3O– –O
O O
O OCH3
irreversible step
O O
O O
- Double addition of methyl vinyl ketone (MVK) sometimes a problem, especially at more acidic
sites. O
O
O
O O
-Solutions
O
NaH CH3O2C NaH R

O O
O CH3O OCH3 O
O R = CO2CH3
- For the preparation of the useful starting octalone derivatives, the low yield has been considered acceptable
since it is prepared from readily available materials.
tBuOK
tBuOH
O
+
O 35% O
At low temperature, MVK Gaspert J. Chem. Soc. 1958, 624.
polymerization is slow and But, many variations on
Michael reaction OK, the reaction have provided
but, the conditions are not MVK, NaOEt (CO2H)2, H2O general improvements.
sufficiently vigorous for
H2O elimination, so the EtOH–Et2O O steam distill
reaction is conducted in –10 °C, 54% OH 86%
two steps.
Marshall J. Org. Chem. 1964, 25, 2501.
MVK, cat. H2SO4 Reaction simple to set

Acid-catalyzed up, but, conversion still
variant of reaction. modest.
O C6H6, reflux, 16 h
49–55% O
Heathcock and McMurry Tetrahedron Lett. 1971, 4995.
O
Lewis acid OTMS O O
NaOMe Superb
catalyzed conversions
variant of Bu2Sn(OTf)2 MeOH possible.
reaction. 89% overall O
CH2Cl2
based on MVK
Nozaki Tetrahedron 1991, 47, 9773.
J. Am. Chem. Soc. 1992, 113, 4028.
272
Dale L. Boger
- Alternatives to methyl vinyl ketone: MVK difficult to employ due to tendency to polymerize
X O + CH2O + HNR2
X = NR2
X = N+R3 Robinson J. Chem. Soc. 1937, 53.
X = Cl Theobald Tetrahedron 1966, 22, 2869.
O Halsall J. Chem. Soc. 1964, 1029.
- Other equivalents
Julia Bull. Soc. Chim., Fr. 1954, 5, 780.

Cl Cl
OEt
I
R
Cl Stork J. Am. Chem. Soc. 1967, 89, 5461 and 5463.
O
N
Stork Tetrahedron Lett. 1972, 2755.

O Wenkert J. Am. Chem. Soc. 1964, 86, 2038.
CO2CH3
Fried J. Am. Chem. Soc. 1968, 90, 5926.
O –
+ + CO2R
Li P(OR)2
O OCH3 O O O
O
Li P(OR)2
O
O –
O
(RO)2P O
SiMe3
I
(allylic alkylation reaction is rapid and yield is high)
CO2tBu
I Stotter J. Am. Chem. Soc. 1974, 96, 6524.
TMS

O
Boeckman J. Am. Chem. Soc. 1973, 95, 6867.
273
Enamine Annulations
O
N +
O
O O
+ N
N
H

J. Am. Chem. Soc. 1963, 85, 207.
Henderickson J. Am. Chem. Soc. 1971, 93, 1307.
O O
O
O
O
+
N N O
Bn Bn
Stevens J. Chem. Soc., Chem. Commun. 1970, 1585.
Evans Tetrahedron Lett. 1969, 1573.
Evans J. Org. Chem. 1970, 35, 4122.
O
O O
+
CHO
(Wichterle annulation) CHO
- The bridged annulation
+
O reversible O
O O O OH
aldol
reversible irreversible
aldol
irreversible
O O O
OH
slow, difficult –H2O: requires usually kinetic aldol product elimination especially effective
vigorous H+conditions but formed reversibly under basic conditions
274
Dale L. Boger
- Helminthosporal synthesis, Corey J. Am. Chem. Soc. 1963, 85, 3527.
O 1. HCO2Et O
2. MVK, Et3N BF3•OEt2 O
3. K2CO3, EtOH-H2O CH2Cl2
O O
6 steps OHC
CHO
H
Aromatic Annulation
H O S Ph
syn-sulfoxide
PhOS
elimination
+
O O O HO
Boger J. Org. Chem. 1980, 45, 5002.
OH
t
BuOK
CH3OS OBn tBuOH OBn
+
O O 61% HO HO
Boger J. Org. Chem. 1984, 49, 4045. Juncusol
R When R = H, also subject to

equilibration to most stable isomer.
O
Substituents at these positions subject to
thermodynamic equilibration to most stable product.
allylic strain substituents adopt

H
R1 equatorial positions
R R1
R2 R2
General Observations: H R O−
3 axial attack
O R
R4 O
275
3. Tandem Robinson Annulation
(Incorporation of more than four carbons from MVK for more convergent syntheses)
- Examples
O
CH3O2C
Karady Tetrahedron Lett. 1976, 2401.

Velluz Angew. Chem., Int. Ed. Eng. 1965, 4, 181.
O
N O
via Michael addition to vinyl pyridine

Birch reduction to dihydropyridine, and hydrolysis to diketone

Elements of three sequential Robinson annulations

(3) (2) (1)
O O
CH3O O
via Birch reduction of aromatic ring, followed by hydrolysis
OH
MeO
Poirier Tetrahedron 1989, 45, 4191.
Cl
O
CO2tBu
276
Dale L. Boger
4. Robinson Annulation: Key Synthetic Transformations of the Robinson Annulation Product
R R R
m-CPBA Claisen
HO HO Rearrangement
O H(R')
CHO
NaBH4
reduction (R'Li)
Simmons–Smith R R
R R cyclopropanation R BH3, H2O2
CrO3 CuLi
2 oxidation
Li/NH3 O O
LiO HO O
Key Intermediate Derived CHO
From Robinson Annulation
R R
R R
NaOH
Li/NH3 cyclopropanation hν O O
LiO O
R O
R
Li/NH3 DDQ
O RX
H O
R
R
R
LDA, MeI KOtBu, MeI
O
O
R 0.95 equiv R
Ph3CLi R2AlCN
O MeI O
CN
R R R
NH2NH2 H2O2, NaOH R'2CuLi
base
O O O
O R'
R R
Li/NH3 H2, Pd–C
O
tBuOH cat. H+ O
H H
R R R
R'2CuLi Li/NH3 O3
R Ph2P(O)O Ph2P(O)Cl HO2C

H H O
R R R
HO R R OsO4
BH3, H2O2 OH Ph3P=CH2
O O cat. H+
O H O O OH
X HO
[O] X = OH, H
X=O
277
R R R
NaBH4 LisBu3BH
or THF
HO LiAlH4 O HO
axial H–delivery equatorial H– delivery
equatorial –OH axial –OH
- Deconjugation with ketalization or reduction

R R R R
ethylene glycol Ac2O NaBH4
O EtOH
TsOH, C6H6
O O AcO HO
Marshall J. Org. Chem. 1972, 37, 982.
- Reductive deoxygenation:
- without double bond migration
R R 1. BF3•OEt2
1. LiAlH4, Ac2O R
ethanedithiol
2. Li, EtNH2 2. Raney–Ni
O
EtOH
- with double bond migration

1. Li, NH3 R R
R R
ClPO(NMe2)2 NaCNBH3
2. Li, EtNH2 TsHNN HCl, DMF

O
via enol phosphate
via
N
N H
Hydrogenation: McMurry J. Am. Chem. Soc. 1968, 90, 6821; Can. J. Chem. 1972, 50, 336.
Birch reduction: For exceptions to generalizations which can exist, see: Boger Tetrahedron Lett. 1978, 17.
HO2C HO2C HO2C

Pb(OAc)4 H2 Pb(OAc)4
Li/NH3
Pd–C
O Cu+2 O O O Cu+2 O
H H H H
cis trans
5. Asymmetric Robinson Annulation and Related Reactions
Taber J. Org. Chem. 1989, 54, 3831.
H3CO
O
H Ar
O O CO2R*
O O
278
Dale L. Boger
Asymmetric Michael
Revial Tetrahedron Lett. 1989, 30, 4121.

d'Angelo J. Am. Chem. Soc. 1985, 107, 273.
Guingant Tetrahedron: Asymmetry 1993, 4, 25.
R R
R
EWG EWG
N HN
O O
H Ph H
Ph 90%, 90% ee
O
O 1. H2O, HOAc
N
N 2. NaOMe
Ph H O
Ph
Revial Org. Syn. 1992, 70, 35.
Review: d'Angelo Tetrahedron: Asymmetry 1992, 3, 456.
Asymmetric Aldol
O
(MeO)2P O O
O O O
HO 64–80%
CO2R*
91–98% de Mandai J. Org. Chem. 1994, 59, 5847.
O O D-proline O
DMSO
82%
O O
69% ee Harada Synthesis 1990, 53.
O O L-proline O
TsOH, benzene
69%
O O
63% ee Swaminathan Tetrahedron: Asymm. 1996, 7, 2189.
O O O
L-proline
93%
O O
88% ee Hajos J. Org. Chem. 1974, 39, 1615.
O O O
ab 38C2
O O
>95% ee Lerner J. Am. Chem. Soc. 1998, 120, 2768.
279
6. Steroid Synthesis
Steroid synthesis: Woodward (Nobel 1965), Robinson (Nobel 1947) Adolf Windaus received the
Isolation methods: Chromatography 1928 Nobel prize in Chemistry
Conformational analysis: Barton (Nobel 1969) for his work in the sterol area
UV spectroscopy: Woodward, Fieser contributing to the structure
ORD: Djerassi determination of cholesterol,
Biosynthesis theory: Bloch and Lynen (Nobel in Medicine 1964), ergosterol, vitamin D, and
Cornforth (Nobel 1975) vitamin B1.
1. Cholesterol
Isolation: 1812
Structure, wrong!, Windaus (Nobel 1928) and Wieland (Nobel 1927) H
1932, correct planar connectivity (Wieland)
1947, stereochemistry (Hodgkin, X-ray, Nobel 1964) H H
1952, absolute stereochemistry (Ruzicka, Nobel 1939) HO
Leopold Ruzicka received the 1939 Nobel Prize in Chemistry that recognized his contribution in three areas:
macrocyclic compounds, higher terpenes, and steroids including the male sex hormones. He was the first to
use Wallach's isoprene rule (1887) and defined monoterpenes as naturally occurring compounds composed
of two isoprene units, sesquiterpenes (three), and diterpenes (four). His biogenetic isoprene rule and the
complete structure elucidation of cholesterol are among his greatest achievements.
2. Sex Hormones
OH The hormone responsible for female development and maintenance of reproductive
organs and secondary sex characteristics.
H Pure material isolated 1929, E. Doisy (St. Louis Univ. Medicine Nobel 1943) and A.
Butenandt (Gottingen, Nobel 1939)
H H 4 tons of sow ovaries: 25 mg
HO
Estradiol Adolf Butenandt, a student of A. Windaus, received the 1939 Nobel Prize in
Chemistry for his work on the isolation and structure elucidation of sex hormones.
In 1929, he isolated estrone simultaneously with E. Doisy, the hormone that
determines sexual development in females in pure crystalline form. Within a few
years, he isolated androsterone (1931), a male sex hormone, and progesterone
(1934), a hormone involved in pregnancy.
OH
H The male sex hormone

1931, Butenandt isolated androsterone (metabolite of testosterone)
H H 15,000 L of men's urine: 15 mg
1935, testosterone isolated from 100 kg bull testicles: 10 mg, E. Laquer
O 1939, planar structure elucidated by Butenandt, Ruzicka (Nobel 1939)
Testosterone
O
The pregnancy hormone: maintains proper uterine environment for development of
H fetus, inhibits further ovulation, nature's contraceptive.
1934, isolation and planar structure, Butenandt
H H 50,000 sows to provide 625 kg ovaries: 20 mg
O
Progesterone
3. Cortisone Structure: 1935–38, Kendall, Reichstein, Wintersteiner
OH from adrenal cortex of 1.25 million cattle
1952, 36 step synthesis via degradation of bile acids (Sarett, Merck)
O 1949, Hench and Kendall (Mayo Clinic), 1950 Nobel with Reichstein for anti-arthritic
O OH activity
1951, Djerassi (Syntex), synthesis from Mexican yam steroid
H
1951, Upjohn microbial process for C11 oxidation of progesterone
H H
Tadeus Reichstein received the 1950 Nobel Prize in
O Medicine for the isolation and structural characterization
of pituitary hormones, including cortisone.
280
Dale L. Boger
Natural steroid hormones are present in such trace amounts in mammals that it is not a practical source.
Synthetic steroids, e.g. 19-nor steroids, became commercially important.
Russell E. Marker (Syntex, Penn. State)

Degradation of sapogenins and other plant products
J. Am. Chem. Soc. 1947, 69, 2167.
Diosgenin is obtained from the Mexican diocorea plant (Mexican yams).
H (1) Ac2O/C7H11CO2H H (1) Ac2O/pyr

O 2 h, 240 °C OH 0.5 h, 150 °C
O H O
H
(2) KOH, MeOH (2) CrO3, 90% aq. HOAc
H H reflux, 0.5 h H H 1.5 h, 30 °C, 75%
HO 85–90% HO
Diosgenin Pseudodiosgenin
O
O
Testosterone
H O O HOAc, 2 h, reflux Estrone
Estradiol
H H H
95% Progesterone
AcO H H
AcO
OAc
Diosone 16-Dehydropregnen-3(β)-ol-20-one acetate
(> 60% overall)
Dehydropregnenolone is easily transformed to progesterone in 3 steps:

(1) H2, Pd–C (2) hydrolysis (3) Oppenauer oxidation: cyclohexanone, Al(OiPr)3
Upjohn avoided attempted monopoly by use of stigmasterol obtained from soybeans:
H 1. Oppenauer H
CHO HN
oxidation
H H
2. O3 benzene, reflux
H H H H
HO O
Stigmasterol
H H
O
N O3
H H
H H H H
O O
Progesterone
281
O
NHAc O
1. NH2OH, HCl, pyr
H 1. H3O+ 1. H2
H
H
2. SOCl2 2. NaOH 2. Jones
H H H H
H H
AcO HO
AcO
16-Dehydropregnenolone acetate Beckmann Rearrangement Dehydroepiandrosterone
(5 steps from diosgenin)
O
O O
H 530 °C
H Br2, HOAc Br collidine H
H H with mineral oil
H H H H
O
O H O
H Br
1. CH3I
O OH
2. acetylene
KOtAm H
H
H H H H
HO MeO
Estrone Mestranol (16 steps from diosgenin)
CH3I
O O O
HC(OEt)3
1. Li, NH3 HCl
H H H H H
2. HOAc, CrO3
H H H H selective protection of H H
enone carbonyl
MeO O EtO
2-O-Methyl Estrone more stable isomer
1. acetylene OH
KOtAm
H
2. HCl H H
O
Norethindrone (20 steps from diosgenin)
There are more stories told about Russell Marker (1902−1995) than perhaps any other chemist. Marker
achieved the first practical synthesis of progesterone which led to the creation of Syntex S.A. in Mexico. Marker
received not only his B.Sc. (1923), but also a M.S. degree in physical chemistry from the Univ. of Maryland
(1924) and subsequently completed enough work in 1 year for his doctoral degree with M. Kharasch at
Maryland. However, he did not receive his Ph.D. because he refused to complete his physical chemistry
coursework, which he considered a waste of time. In 1925, he joined Ethyl Corp. where he invented the gasoline
"octane number" rating system. Following a subsequent position at Rockefeller Univ. with P. A. Levene, he
joined Penn State College in a position funded by Parke−Davis. After discovering an economical source of a
steroid starting material (diosgenin) in a Mexican yam, Marker developed a degradation synthesis of
progesterone producing 3 kg at a time it was selling for $80/g. Marker commercialized his process in 1944 at
Syntex in Mexico which he cofounded. After a dispute in 1945, Marker left Syntex and took with him the details of
the synthesis, the key operations which only he had conducted. He founded another company Botanica-Mex
which became Hormonosynth and subsequently Diosynth.
Syntex did not fade into the background. After a few months, it was back up a running recruiting C. Djerassi and
entrepreneur A. Zaffaroni. Using Syntex progesterone, Djerassi focused on the discovery of a mimic that would
not only prevent ovulation like progesterone, but would also be orally active. His group prepared norethindrone,
the active ingredient of the first birth control pill.
282
Dale L. Boger
The Total Synthesis Of Steroids
Representative strategies employing the Robinson and related annulations
The Velluz Approach (Roussel–Uclaf, Paris)

Compt. rend. 1960, 250, 1084, 1511.
Cl
O
Stork isoxazoles, J. Am. Chem. Soc. 1967, 89, 5464.
N
O O
S. Danishefsky vinyl pyridines, J. Am. Chem. Soc. 1975, 97, 380.

N
J. Tsuji via Wacker oxidation of terminal double bonds, J. Am. Chem. Soc. 1979, 101, 5070. O
Comparison of strategies employing the intramolecular Diels–Alder reaction:

First applications of this strategy were developed independently in laboratories of
T. Kametani and W. Oppolzer.
Examples
T. Kametani, Tetrahedron Lett. 1978, 2425.

J. Am. Chem. Soc. 1976, 98, 3378.
J. Am. Chem. Soc. 1977, 99, 3461.
J. Am. Chem. Soc. 1978, 100, 6218.
O OtBu OtBu
17 steps
12% DMF, 1 h, 40 °C Na/THF/NH3
I 49% EtOH, 1 h, –78 oC
O 85%
MeO
optically pure NaH, DMF
CN NC 10 min, 25 oC
Br 3 h, 180 °C 84%
NaNH2/NH3 (o-Cl2C6H4), N2
2 h, –33 °C OtBu
65%
OMe OMe exo transition state
MeO
OtBu HCl/H2O HCl, pyr OH

dioxane 45 min, 240 °C
7 h, reflux, 84% 81%
H H
H H H H
MeO HO
(+)-Estradiol
Oppolzer Helv. Chim. Acta 1977, 60, 2964.
Oppolzer Angew. Chem., Int. Ed. Eng. 1977, 16, 10.
Oppolzer Helv. Chim. Acta 1980, 63, 1703.
283
O 1. NaBH4, MeOH OTBS
O 2. TBSCl
CuLi MeO2C
2
3. LiAlH4 I
Br CO2Me
4. TsCl, pyr
5. NaI, acetone 77% NaH
6:1 OTBS
95% THF, HMPA
82%
SO2
NC
1. I2, AgSO4 1:1
H2SO4
SO2 SO2
2. NaCN, (Ph3P)4Pd NC Cl
toluene (–SO2) Cl
213 oC
Cl
OH OTBS
1. MeLi
2. CF3CO3H
H H
3. HCl, THF, MeOH
H H H H
HO NC
(+)-Estradiol 80%
retro-cheletropic cycloaddition
followed by Diels–Alder reaction
T. Saegusa J. Am. Chem. Soc. 1981, 103, 476.
O
O
Me3Si CsF
>86% H
H H
MeO
MeO
NMe3+I–
Estrone
K. P. C. Vollhardt and R. Funk J. Am. Chem. Soc. 1977, 99, 5483.
MgBr(CuI)
OSiMe3 1. LiNH2, NH3, THF O
THF, 45 min neat TMSC≡CTMS
O
–60 to –40 oC 0.5 h, –33 oC CpCo(CO)2
TMSCl, Et3N (HMPA) 2. alkylation, THF N2, 35 h, 140 oC

0.5 h, –40 to 25 oC 25 oC, 64%
I
89%
284
Dale L. Boger
O O
TFA, Et2O, CCl4
∇ 20 h, 25 °C
Me3Si H
Me3Si
4πe– electrocyclic 100%
ring opening followed H H
Me3Si by Diels–Alder reaction Me3Si
O
H H
(±)-Estra-1,3,5(10)-trien-17-one
K. Vollhardt J. Am. Chem. Soc. 1979, 101, 215.
O O O
TFA, CHCl3, CCl4
H –30 °C H Pb(OAc)4 H
Me3Si
H H H H H H
Me3Si Me3Si HO
90%, 9:1 regioselectivity Estrone
Total Synthesis of Cortisone
R. B. Woodward received the 1965 Nobel Prize in Chemistry for "Contributions to the Art of Organic Synthesis"
and the award preceded the total synthesis of vitamin B12 carried out in collaboration with A. Eschenmoser, the
principles of orbital symmetry conservation (Hoffmann Nobel Prize in 1981), the Wilkinson structure
determination of ferrocene (Nobel 1973) carried out with Woodward, and the collaborative delineation of the
steroidal biosynthesis involving stereoselective cation–olefin cyclizations in collaboration with Bloch (Nobel
1964). Woodward changed synthesis from the application of empirical reactions to a mechanistic foundation for
predicting reactions and substrate reactivity (rates, stereoselectivity) and designed this rationale into the
preplanned synthesis. The results were stunning with unattainable objectives falling one after another: quinine
(1944), patulin (1950), cholesterol (1951), cortisone (1951), lanosterol (1954), lysergic acid (1954), strychnine
(1954), reserpine (1956), chlorophyll (1960), tetracyclines (1962), colchicine (1963), cephalosporin C (1966),
most before the wide spread usage of 1H NMR. Breathtaking natural product structure determinations: penicillin
(1945), strychnine (1948), patulin (1949), terramycin (1952), aureomycin (1952), cervine (1954), magnamycin
(1956), gliotoxin (1958), oleandomycin (1960), streptonigrin (1963), and tetrodotoxin (1964) also preceded the
reliance on 1H NMR. The formal total synthesis of vitamin B12 was completed in 1972 in collaboration with A.
Eschenmoser (>100 postdoctoral fellows) and synthetic cobyric acid was converted to vitamin B12 in 1976.
R. B. Woodward The chemical publication with the most coauthors (49) is the
J. Am. Chem. Soc. 1951, 73, 2403, 3547, 4057. posthumous account of the total synthesis of erythromycin by
J. Am. Chem. Soc. 1952, 74, 4223. Woodward (J. Am. Chem. Soc. 1981, 103, 3210). Physics holds
the record with 406 coauthors: Phys. Rev. Lett. 1993, 70, 2515.
O O
1. benzene
100 °C, 96 h 1. LiAlH4 1. Ac2O, pyr
+
MeO 2. NaOH; H+MeO 2. 2 N H2SO4 O 2. Zn
H H
O O OH
1. EVK
tBuOK
NaOMe
tBuOH
HCO2Et H 1. OsO4
O O 2. KOH H 2. acetone, CuSO4

H H
HOHC O
285
1. NaOMe O
O H2 O
HCO2Et H
H Pd–SrCO3 H O
O O H
H H 2. C6H5NHMe
O
O O MeOH
CHNMeC6H5
OsO4
H
O O
CH2=CHCN Ac2O, NaOAc
H H
O O
Triton B H
tBuOH H
HO2C
O O O
CHO
O
1. MeMgBr H 1. HIO4•2H2O
H
+
O
2. KOH; H H 2. HOAc
H
piperidine
O benzene O
CO2Me CO2Me
1. Na2Cr2O7•2H2O 1. NaBH4, EtOH
H O
2. CH2N2 2. Ac2O, pyr
H 3. PhCO3H H
3. H2, Pd–SrCO3
O AcO
H H
CO2Me Br CO2Me
O O
1. NaOMe HBr
H H
2. Na2Cr2O7 O H H H
CrO3–H2O HO O
H H
1. NaBH4, 0 oC O
CO2Me CH2OAc
O 2. Ac2O, pyr
3. KOH O
Zn–HOAc H
H
4. SOCl2
H H 5. CH2N2; HOAc H H
O
H HO
H
NC O
CH2OAc CH2OAc
1. KMnO4
O O OH
1. HCN, Et3N CH3COCH3
H
H
2. POCl3, pyr 2. TsOH
H H H H
CH3COCH3
HO O
H H
1. HBr O
CH2OH
2. 2,4-dinitrophenyl
hydrazone O OH Tadeus Reichstein received the 1950
H Nobel Prize in Medicine for the isolation
3. pyruvic acid and structural characterization of pituitary
4. hydrolysis H H hormones, including cortisone.
O
Cortisone
286
Dale L. Boger
C. Birch Reduction
Li/NH3 H3O+
MeO MeO O
Robinson annulation-
type product
- See the discussion in the sections on the Birch reduction and the Robinson annulation.
- Allows an aromatic ring to be incorporated into a synthesis and converted into a useful, nonaromatic
ring system.
D. Dieckmann Condensation
- An intramolecular Claisen condensation, see enolate section for a more detailed discussion.
O
CO2Et
CO2Et
CO2Et
E. Intramolecular Nucleophilic Alkylation
- Powerful approach to closure of rings
Examples:
- Kinetic enolate generation (Note: O-alkylation may compete).
O O
LDA - Gem dimethyl effect

facilitates cyclization
Br 55–66%
House J. Org. Chem. 1978, 43, 700.
O O
LDA
52–63%
Br
- Versus thermodynamic enolate generation (Note: O-alkylation may compete).
O O O
tBu
KO O O
tBuOH
Br
∆
7–19% 58–72% 5–7% 5%
- Closure subject to stereoelectronic control.
X
180° / SN2 displacement - Note Baldwins Rules
Preceded by Eschenmoser
Helv. Chim. Acta 1970, 53, 2059.
O O
X
LDA
O
Et2O Not possible
Br 25 °C 70% Not formed
O H
287
- Examples
O OMs
KOtBu O
Gibberelic Acid, Corey
O toluene O J. Am. Chem. Soc. 1979, 101, 1038.
Cl O 53% O
N R N CC-1065, Boger
NaH
J. Am. Chem. Soc. 1988, 110, 4796.
N O
N
H H
OH O Duocarmycin SA, Boger
OMs
O J. Am. Chem. Soc. 1992, 114, 10056.
O NaH N J. Am. Chem. Soc. 1993, 115, 9025.
MeO2C
MeO2C N
83% O
N Duocarmycin A, Boger
N O H
H O J. Am. Chem. Soc. 1996, 118, 2301.
OH J. Am. Chem. Soc. 1997, 119, 311.
F. Intramolecular Aldol Condensation

- The intramolecular aldol condensation has been used extensively to close or form rings.
Representative Examples:
- Two aldol closures possible:
Robinson Annulation
O
R Base or
O BF3•OEt2
O H2SO4 O
R R
OR O OR O
NaOCH3
CHO
OR OR OH OR
RO
Fredericamycin A
Boger J. Org. Chem. 1991, 56, 2115.
J. Am. Chem. Soc. 1995, 117, 11839.
G. Intramolecular Michael Reaction
Michael J. Prakt. Chem. 1887, 36, 113.
Majetich
TMS
EtAlCl2 J. Org. Chem. 1985, 50, 3615.
1 h, 0 °C Tetrahedron Lett. 1988, 29, 2773.
O O
toluene
50%
H H
House
J. Org. Chem. 1965, 30, 2513.
O O
50%
O
O
288
Dale L. Boger
Mander
MeO2C MeO2C
MeO2C NaOMe MeO2C J. Am. Chem. Soc. 1979, 101, 3373.
MeOH
100%
O O O O
H. Cation–Olefin Cyclization
1. Reviews
Johnson Acc. Chem. Res. 1968, 1, 1.
Bioorg. Chem. 1976, 5, 51.
van Tamelen Acc. Chem. Res. 1968, 1, 111.
Harding Bioorg. Chem. 1973, 2, 248.
Goldsmith Fortschr. Chem. Org. Nat. 1972, 29, 363.
Lansbury Acc. Chem. Res. 1972, 5, 311.
Speckamp Recl. Trav. Chim. Pays-Bas. 1981, 100, 345.
Sutherland Comprehensive Org. Syn. Vol 3, pp 341−377.
2. Representative Cation–Olefin Cyclizations
COOH SnCl4
Cl Cl
Monti J. Org. Chem. 1975, 40, 215. O O
SnCl4 O
benzene
O O
Grieco Tetrahedron Lett. 1974, 527.
OAc H+
O
BF3
Money J. Chem. Soc., Chem. Commun. 1969, 1196.

Goldsmith J. Org. Chem. 1970, 35, 3573.
Cl
OAc BF3
O
Cl
Money J. Chem. Soc., Chem. Commun. 1971, 766.
HCO2H
O
Cl
Lansbury J. Am. Chem. Soc. 1966, 88, 4290.
J. Am. Chem. Soc. 1970, 92, 5649.
289
COCl SnCl4
O
Marvell J. Org. Chem. 1970, 35, 391.
OTs
OCH2CF3
Baldwin Tetrahedron Lett. 1975, 1055.
TsO HOAc
OAc
NaOAc
Bartlett J. Am. Chem. Soc. 1965, 87, 1288.

OH
HCO2H OR
Marshall J. Am. Chem. Soc. 1965, 87, 2773.

J. Am. Chem. Soc. 1966, 88, 3408.
H
SnCl4
H H
MeNO2, –23 °C
HO 3 h, 70% Progesterone total synthesis
O H
O H
O
H H
CF3CO2H
HO 70%
Progesterone total synthesis
J. Am. Chem. Soc. 1980, 102, 7800.
290
Dale L. Boger
O O
H
CF3CO2H
70%
MeO MeO Shionone total synthesis
Ireland J. Am. Chem. Soc. 1974, 96, 3333.
J. Org. Chem. 1975, 40, 973.
J. Am. Chem. Soc. 1970, 92, 2568.
OH
HCO2H
Cedrene
OH
J. Am. Chem. Soc. 1961, 83, 3114.
OH
O
Cl
H
Lansbury J. Am. Chem. Soc. 1966, 88, 4290.
O
N2
O
BF3•OEt2
CH2Cl2
MeO MeO
Mander J. Chem. Soc., Chem. Commun. 1971, 773.

Erman J. Am. Chem. Soc. 1971, 93, 2821.
O O
Nazarov cyclization
Hiyama J. Am. Chem. Soc. 1974, 96, 3713.

OH
CHO SnCl4
MeNO2, 0 °C
10 min, 30–40%
Ireland J. Am. Chem. Soc. 1974, 96, 3333.

J. Org. Chem. 1975, 40, 973.
J. Am. Chem. Soc. 1970, 92, 2568.
291
H H
CHO
OH
H H
PCC
CHO
O
Naves Helv. Chim. Acta 1964, 47, 51.

Corey J. Org. Chem. 1976, 41, 380.
OH O
PCC
OH PCC O
Corey, Boger Tetrahedron Lett. 1978, 2461.

H+
O O
OMe
and aldehyde
J. Am. Chem. Soc. 1973, 95, 2656.
SnCl4
β-Vetivone and
CH2Cl2 Vetispirene
OHC 1.5 min, 90% total syntheses
HO
McCurry, Jr. Tetrahedron Lett. 1973, 3325.
CO2Me CO2Me
OPO(OEt)2 Hg(OCOCF3)2 O Aphidicolin
NaCl total syntheses
ClHg
H
TBDMSO
TBDMSO
Corey, Tius J. Am. Chem. Soc. 1980, 102, 1742. (Aphidicolin)

J. Am. Chem. Soc. 1980, 102, 7612. (Stemodinone)
J. Am. Chem. Soc. 1982, 104, 5551. (K-76)
Tf2O
OR OR
H
HO H
Corey J. Am. Chem. Soc. 1987, 109, 6187. (Atractyligenin)
J. Am. Chem. Soc. 1987, 109, 4717. (Cafestol)
292
Dale L. Boger
3. Background
Squalene cyclization first suggested as a biosynthetic precursor to cholesterol
Heilbron, Kamm, and Owens J. Chem. Soc. 1926, 1630. J. L. Goldstein and M. S. Brown received
the 1985 Nobel Prize in Medicine for their
Robinson Chem. Ind. 1934, 53, 1062. discoveries concerning the regulation of
cholesterol metabolism.
- Robinson's proposal
Cholesterol
HO
- Correct cyclization scheme
Lanosterol
HO
H
- Lanosterol was proposed in 1953 by Woodward and Bloch.
- Experimental verification that cholesterol is biosynthesized from squalene was developed
independently by
Bloch J. Biol. Chem. 1953, 200, 129.
Cornforth Biochem. J. 1954, 58, 403.
Biochem. J. 1957, 65, 94.
K. Bloch received the 1964 Nobel J. W. Cornforth received the 1975 Nobel
Prize in Medicine for his discoveries Prize in Chemistry jointly with V. Prelog
concerning the mechanism and for outstanding intellectual achievement
regulation of the cholesterol and on the stereochemistry of reactions
fatty acid metabolism. catalyzed by enzymes.
- Stork–Eschenmoser hypothesis: the trans-anti-trans stereochemistry of the steroids and many

terpenoids is a consequence of a concerted polyene cyclization.
Cyclization
Y Y
about a trans
olefin R OH R OH
H H
H H
Cyclization H H
R R
about a cis OH OH
olefin
Y Y
- Anti addition of a carbocation and nucleophilic olefin on opposite faces of a π-bond analogous to
trans electrophilic addition to alkenes. Therefore, cyclization of a trans olefin leads to a trans ring
fusion and cyclization of a cis olefin leads to a cis ring fusion.
293
O
Squalene
Squalene
monooxygenase
H
HO
Squalene-2,3-oxide
O
H+
2,3-Oxidosqualene
–H+ lanosterol cyclase
H
H
H
H
HO
HO
H
Dammaradienol
8 chiral centers with 256 possible stereoisomers - Two methyl migrations and two
hydride transfers
–H+
HO Lanosterol
H
Twenty enzymatic
reactions
Cholesterol
294
Dale L. Boger
4. Key Publications
- Initial experimental demonstrations of multiple cascade cyclizations and the Stork-Eschenmosher

steroid-type cyclizations:
Stork and Burgstahler J. Am. Chem. Soc. 1955, 77, 5068.
Eschenmoser, Ruzicka, Jeger, and Arigoni Helv. Chim. Acta 1955, 38, 1890.
First disclosed in lectures and proposals as early as 1950, but experimental verification was difficult.
- A clear verification of Stork–Eschenmoser hypothesis:

J. Am. Chem. Soc. 1964, 86, 2085.
trans only
HCO2H OH
12%
H Only bicyclic products
ONs isolated or generated
cis only
HCO2H OH
16%
ONs
5. Three Stages of Reaction
- Initiation
- Cyclization and Propagation
- Termination
- Mechanistically all three may take place simultaneously or stepwise paths may be involved.
- Depends on the nature of the substrate and the reaction medium.
- Without careful control, the formation of many products will result in a complex mixture.
- For example: Johnson verification of Stork–Eschenmoser hypothesis.
OH HO
HCO2H NaOH
HCO2Na H2O
H2O to hydrolyze
ONs the formates
75 °C, 1 h
51.2% 13.5%
OH
H H
OH
6.7% 5.4% 3.3% 2.9%
OH
total trans = 12%

H OH total cis = 0%
2.2% 1.6%
- Much effort expended to control the reaction through mild, selective and efficient initiation and termination.
295
A. Initiation
- Alkenes
O O
75% H2SO4
OH
25 °C, 25 min
66%
β-Ionone Vitamin A
used in perfumes Isler Helv. Chim. Acta 1949, 32, 489.
- Alcohols and Derivatives
HO HCO2H OCHO
25 °C, 5 min Johnson J. Am. Chem. Soc. 1964, 86, 1972.

tertiary allylic alcohols have been extensively used
- Epoxides
OAc OAc
85:15 β:α
BF3•OEt2
C6H6
HO
O H van Tamelen J. Am. Chem. Soc. 1963, 85, 3295.
- Aldehydes and Ketones
MeAlCl2 OH
CHO
CH2Cl2
0 °C, 24 h
76% Snider J. Am. Chem. Soc. 1980, 102, 7951.
- Aldehyde or Ketone Derivatives
SnCl4 OEt HCO2H O

O N N
H
C6H6 O 25 °C, 18 h
O O
25 °C, 5 min 100% OCHO
OH
Johnson J. Am. Chem. Soc. 1968, 90, 5277; 1974, 96, 3979. Speckamp Tetrahedron Lett. 1975, 4047.
MeO TsOH MeO

25 °C, CH3CN
MeS SMe Me SMe

- Carboxylic Acids and Derivatives

O
AlCl3 Cl O O
COCl 74% SR SeR
Kemp J. Chem. Soc., Chem. Commun. 1973, 84. also extensively studied
296
Dale L. Boger
- Ketene Acetals and Thioacetals
CF3
O
CH3SO3H
heptane S
S S CF3CH2OH
0 °C, 15 min H S Andersen, Yamamoto Tetrahedron Lett. 1975, 4547.
- α,β-Unsaturated Ketones, Esters,......
OAc
HClO4
HOAc−Ac2O
O 25 °C, 1.5 h OAc
50% Harding Tetrahedron Lett. 1977, 3321.
B. Cyclization and Propagation
a. Alkenes
5-exo 6-endo
6-exo 7-endo
4-exo 5-endo
In the absence of olefin substituent directing effects:

• 5-endo >> 4-exo, the latter violates Baldwin's rules
• 6-endo > 5-exo
• 6-exo > 7-endo
b. Alkynes
R 5-exo 6-endo
R = alkyl R = H, R3Si
R
R
but can further rearrange to 6-endo product
6-exo 7-endo
R R = alkyl R=H
R
297
c. Allenes
R 5-exo 6-endo
R = alkyl R=H
R
C. Termination
- Alkenes and Arenes
Elimination of H+ reintroduces double bond or aromatic system.

Can result in complex mixture of products.
SnCl4
+ + H
H H
C6H6 O O O
O O 25 °C
OH 84% OH 6% OH 4%
Allylsilanes can be enlisted to direct the termination.
X−
E+ SiMe3 E SiMe3 E
SiMe3
MeO OMe OMe
Fleming J. Chem. Soc., Chem. Commun. 1976, 182.
SiMe3
SnCl4
H H
pentane
O O 0−15 °C, 34% H
O
OH
Substitution on alkene can also alter regioselectivity (5-exo vs 6-endo)
- Substituted Alkenes
X X
Allows regiocontrol, but need to select substituents that avoid complications with initiation.
298
Dale L. Boger
Vinyl chlorides and fluorides
OH
HCO2H
Cl
40% CO2H
Cl
Landsbury Acc. Chem. Res. 1972, 5, 311.
OBs
CH3CN
Et3N, ∆
O
OMe
Felkin J. Chem. Soc., Chem. Commun. 1968, 60.
- Acetylenes
R
Cl
R = Me R=H Cl
TiCl4 TiCl4
O
CH2Cl2 CH2Cl2
OH 94% 60% OH
O O O
Sutherland J. Chem. Soc., Chem. Commun. 1978, 526.
- Allenes see: Harding J. Am. Chem. Soc. 1978, 100, 993.
- Organostannanes
SnBu3 O
TiCl4 TiCl4 O
CH2Cl2, 25 °C SnBu3 82%

OH 72%
Macdonald J. Am. Chem. Soc. 1980, 102, 2113; 1981, 103, 6767.
6. Synthesis of Estrone
1. TsNCl2
SnCl4 H2O−DME
H
2. Me4NOH
OH H H
MeO MeO
O O
H BF3•OEt2 H
H H H H
MeO MeO
Bartlett and Johnson J. Am. Chem. Soc. 1973, 95, 7501.
299
7. Synthesis of Progesterone
Johnson
J. Am. Chem. Soc. 1971, 93, 4332.
J. Am. Chem. Soc. 1978, 100, 4274.
O
O
CF3CO2H
O
0 °C, 2 h
O H H
O
HO O
- Tertiary allylic alcohol for initiation Efficient trap of vinyl cation

- Substituted alkyne for termination
- 5-exo-dig vs. 6-endo-dig
CF3CO2H, pentane, ClCH2CH2Cl 10% aq. K2CO3

1 h, 0 °C, 78% CH3OH, 70%
OCOCF3 O
Ring expansion
via diketone and
aldol 13% cis-α Me
epimer
H H H H
1
1. O3, CH3OH–CH2Cl2, 0.5 h, –70 °C 1. O3, CH3OH–CH2Cl2,

2. Zn–HOAc, 1 h, 25 °C, 84% (2 steps) 2 min, –70 °C
3. KOH, CH3OH, 20 h, 25 °C, 70% 2. Zn–HOAc, 1 h, 25 °C
3. KOH, CH3OH,
20 h, 25 °C
O O
49% overall
H H H H
O O
(± )-4-Androstene-3,17-dione ( ± )-Progesterone
F O
O
but
gave
also gave 78% 1
H
H
10%
Johnson J. Am. Chem. Soc. 1980, 102, 7800. and only 3.5% cis-α Me epimer
- More recent efforts have reduced this to the synthesis of optically active agents.
- How would you imagine doing this?
- Remember chair-like transition states for the cyclization.
300
Dale L. Boger
8. Enantioselective Synthesis of 11-Hydroxyprogesterone
enantioselective ketone reduction
O O
H
HO HO
HO TFA 13
H H
50%
H H H H
HO + 20% 13α isomer O
I. Free Radical Cyclizations

1. Reviews
Acyloin Condensation: Bloomfield, J. J.; Owsley, D. C.; Nelke, J. M. Org. React. 1976, 23, 259.
McMurry Coupling: McMurry, J. E. Acc. Chem. Res. 1983, 16, 405.
Julia Free Radical Cyclization: Julia, M. Acc. Chem. Res. 1971, 4, 386.
Pure App. Chem. 1967, 15, 167.
- General Reviews
Beckwith, A. L. J.; Ingold, K. U. Rearrangements in Ground State and Excited States, Vol. 1; de Mayo, P.,
Ed.; Academic: NY, 1980, pp 182–220.
Beckwith, A. L. J. Tetrahedron 1981, 37, 3073. (Regioselectivity of ring cyclization)
Giese, B. Radicals in Organic Synthesis: Formation of Carbon–Carbon Bonds, Pergamon: Oxford, 1986.
Symposium-in-print: Tetrahedron 1985, 41, no. 19.
Curran, D. P. Synthesis 1988, 417 and 489.
Hart, D. J. Science 1984, 223, 883.
Ramaiah, M. Tetrahedron 1987, 43, 3541.
Comprehensive Org. Syn., Vol. 4, Chapter 4.1 and 4.2, pp 715–831.
Laird, E. R.; Jorgensen, W. L. J. Org. Chem. 1990, 55, 9.
Giese, B. Org. React. 1996, 48, pp 301–856.
2. Reductive Coupling of Carbonyl Compounds
a. Acyloin Condensation
Na O
CO2CH3
CO2CH3 toluene OH
57%
Sheehan J. Am. Chem. Soc. 1950, 72, 3376.
- Mechanism
O
2e OCH3 O O
radical coupling 2e
•
•
OCH3 O O
O
- Alternative
OCH3 OCH3
O • •
OCH3
e • O O
CO2CH3 OCH3
O O
OCH3 OCH3 O
•
e O
O
• O O
O
2e O First report: Freund Justus Liebigs Ann. Chem. 1861, 118, 33.
Macrocyclization: Finley Chem. Rev. 1964, 64, 573.
O Review: Comprehensive Org. Syn. Vol. 3, 613.
301
b. Rühlmann Modification with Me3SiCl
CO2CH3
Na–K OSi(CH3)3
Et2O, Me3SiCl OSi(CH3)3

CO2CH3
Bloomfield Tetrahedron Lett. 1968, 591.
Ruhlmann Synthesis 1971, 236.
3. Reductive Coupling of Ketones and Aldehydes (Pinacol Coupling and McMurry Reaction)
- Low valent Ti reagents used to generate ketyl radicals and chosen to permit generation of either
the pinacol or olefin product.
Ti OH
CHO
n CHO n n
OH
Mg–Hg OH
CHO
CHO TiCl4 OH
THF
32%
Corey, Danheiser J. Org. Chem. 1976, 41, 260.
Mg–Hg
OH
O TiCl4
THF OH
43%
O
Zn–Cu
O
TiCl3
O DME
79%
McMurry J. Org. Chem. 1977, 42, 2655.
LiAlH4
O CO2Et TiCl3
DME OEt
80%
McMurry J. Am. Chem. Soc. 1983, 105, 1660.
CHO O O
Zn–Ag
O
TiCl3
H DME H
CH3O CH3O
Estrone Synthesis: Ziegler J. Org. Chem. 1982, 47, 5229.
302
Dale L. Boger
- Other Functional Groups: Corey Tetrahedron Lett. 1983, 24, 2821.
O OH
Zn
(CH3)SiCl
CO2CH3 77% CO2CH3
O OH O
CN 83%
CO2CH3 CO2CH3
O OH NHOCH3
NOCH3
84%
CO2CH3 CO2CH3
4. SmI2 Promoted Reductive Coupling Reactions (Radical Mechanisms)

- Lanthanide chemistry reviews
Molander Chem. Rev. 1992, 92, 29.
Molander in Chemistry of the Carbon Metal Bond, Hartley, F. R.; Patai, S., Eds.; Wiley: NY, 1989, Vol. 5.
Molander in Comprehensive Org. Syn., Vol. 1, 262.
Kagan New. J. Chem. 1990, 14, 453.

Kagan Tetrahedron 1986, 42, 6573.
Soderquist Aldrichim. Acta 1991, 24, 15.
a. Ketyl–Olefin Coupling Reactions

- Intermolecular (Only effective for activated olefins)
2 SmI2 Ph O
CHO O
Ph THF–HMPA
CO2CH3 1.5 equiv iPrOH
78%
SmI2 e–, H+
–OCH3
Sm(III) (III)Sm
O O
Ph • H CO2CH3 Ph • CO2CH3
Inanaga Tetrahedron Lett. 1986, 27, 5763.

O 2 SmI2 OH
Ph THF–HMPA Ph Si(CH3)3
Si(CH3)3 tBuOH
93%
303
- Intramolecular
O O HO COY
2 SmI2 R R'
R Y
R' THF–MeOH
60–80%
Molander
Y = OR", NR2" Tetrahedron Lett. 1987, 28, 4367.
O O HO CO2Et J. Am. Chem. Soc. 1989, 111, 8236.
2 SmI2 R R'
J. Org. Chem. 1991, 56, 1439.
R OEt
R' THF–MeOH J. Org. Chem. 1993, 58, 7216.
EtO2C
90% CO2Et J. Org. Chem. 1994, 59, 3186.
OH
O HO O
O 2 SmI2
O THF–acetone O
85%
2 e– Sm(III) H+
O O
O (III)Sm
O
1. 2 SmI2 OH
O THF–HMPA SePh
O 2. (PhSe)2 O
81%
1. 4 SmI2
O THF–HMPA
HO
I OEt 2. H +
61%
H+
2 e–
2 e–
O O
I2Sm OEt
CHO OH
TBSO 2 SmI2
TBSO
CO2CH3 CO2CH3
O O 73%
O O
Enholm J. Am. Chem. Soc. 1989, 111, 6463.
304
Dale L. Boger
OH
CHO O SmI2 H ( ± )-Coriolin
O
THF–HMPA
O
91% H O
Curran J. Am. Chem. Soc. 1988, 110, 5064.
O 8-endo OH
2 SmI2
OAc THF–HMPA
81%
Molander J. Org. Chem. 1994, 59, 3186.
- Imminium ion generated in situ
2 SmI2
CH3CN N
ClO4– N H
Ph
Ph
Martin Tetrahedron Lett. 1988, 29, 6685.
- Hydrazone (5-exo hydrazone >> 5-exo alkene; 6-exo hydrazone > 5-exo alkene)
Ph2N Ph2N NPh2

N O SmI2 NH N
OH
H THF–HMPA H
n n OH
n = 1: 72% : 0%
e– Ph2N Sm(III)
n = 2: 4.2 : 1
N O
H •
n
Fallis J. Am. Chem. Soc. 1994, 116, 7447.
J. Org. Chem. 1994, 59, 6514.
- Fragmentation–cyclization
O O
SmI2
THF–HMPA
MeOH TMS
TMS
79%
e– 5-exo-dig
Sm(III) (III)Sm TMS

O O
• •
TMS
Motherwall Tetrahedron Lett. 1991, 32, 6649.
305
b. Alkyl/Aryl Radical Cyclizations
Br OAc 2 SmI2
CH3CN
O O
HMPA–tBuOH
61%
Inanaga Tetrahedron Lett. 1991, 32, 1737.
Br
O SmI2 O
THF
HMPA–tBuOH
31%
Br SmI2
THF
N N
HMPA–tBuOH
Ac Ac
88%
OH
O 2 SmI2
O
I THF–HMPA
57% O
I O HO
O
2 SmI2
THF–HMPA
81% O
Curran Synlett 1990, 773.
c. Pinacol-type Coupling Reactions

- Intermolecular
O 1. 2 SmI2 HO R' R
2
R R' 2. H3O+ OH
R R'
aldehydes or 80–95%
ketones
Kagan Tetrahedron Lett. 1983, 24, 765.
- Intramolecular
O O HO
2 SmI2 iPr
iPr OEt CO2CH3
THF–tBuOH >200 : 1
HO
73%
OHC
306
Dale L. Boger
O O O O O OH
N 2 SmI2 N
O O OH
CHO THF–tBuOH
52%
O O HO CO2Et
2 SmI2
OEt
THF–tBuOH >200 : 1
O
45%
NC
CO2CH3
CO2CH3
COCH3 2 SmI2
81%
92% de TBDPSO OH
TBDPSO CHO
OH
Hanessian Tetrahedron Lett. 1991, 32, 1125.
OTBDPS OTBDPS OTBDPS
O O OH O OH
CHO 2 SmI2
O CHO THF–tBuOH O O
OH OH
OTBDPS 86% OTBDPS OTBDPS
Chiara Tetrahedron Lett. 1994, 35, 2969. 92 : 8
- A recent total synthesis of (–)-Grayanotoxin III incorporated two ketyl–olefin cyclization reactions and a
pinacol coupling reaction (SmI2-promoted).
- Shirahama J. Org. Chem. 1994, 59, 5532.
H OH
HO
OH
HO
OH OH
SPh
(–)-Grayanotoxin III
2 SmI2 CHO
O O
THF–HMPA OMOM
OH
O OH 86% O TBSO MOMO
OH
2 SmI2
O
THF–HMPA, 78%
H OMOM H
HO TBSO
O OMOM OMOM
OHC HO
MOMO MOMO
SmI2
THF–HMPA, 54%
H OMOM H OH
HO HO
OMOM OH
HO HO
OH MOMO OH OH
307
5. Radical–Olefin Cyclizations
a. Representative Examples
- Concurrent with Johnson's investigation of cation–olefin cyclizations, Julia initiated
radical–olefin cyclization studies.
CH3O2C BzOOBz CH3O2C
NC NC
cyclohexane
∆
57% Reversible,
Julia Compt. rend. 1960, 251, 1030. thermodynamically
controlled reactions.
CH3O2C CH3O2C
NC NC 6-endo-trig
88%
b. Reactivity and Regioselectivity

- Relative rates of addition to PO(OEt)2 : typical electron-deficient olefin.
CH3• CH3CH2• CH3OCH2• (CH3)2CH• (CH3)3C•
krel = 1 1 2.7 4.8 24
- Alkyl radicals are regarded as nucleophilic.
Steric Effects on Addition Regioselectivity

olefin % addition to: krel
Ca Cb
>95 <5 1.16
a b
a b
>95 <5 18.4
a b >95 <5 2 × 136
a b
50 50 2 × 0.50
50 50 2 × 0.63
a b
a b >95 5 15
<5 >95 13.9

a b
CO2CH3 krel
C6H11•
R R=H 1 β-substitution strongly
decelerates intermolecular
R = tBu 0.24 addition with activated
acceptors
CO2CH3
tBu
5 × 10–5
H
308
Dale L. Boger
I Bu3SnH CN
CN
95%
Nucleophilic Electrophilic
radical acceptor alkene
• Bu Cl Ph CO2CH3 CHO
krel 1.0 8.4 84 3000 8500
Note the substantial effect

of two geminal vs vicinal
electron-withdrawing groups
• CO2CH3 CO2CH3 CO2CH3 CO2CH3
CO2CH3 CH3O2C
krel 1.0 (3000) 150 (450000) 5 (15000) 0.01 (30)
( ), relative to
Bu
Note the substantial
deceleration of the
reaction rate by
β-substitution (100×)
EtO2C
Bu3SnH EtO2C OtBu
Cl OtBu
EtO2C 60% CO2Et
Electrophilic Nucleophilic
radical acceptor alkene
EtO2C Ph Ph Ph
•
EtO2C N CO2CH3
O
krel 23 3.5 1
309
c. Cyclization Rates, Regioselectivity, and Diastereoselectivity
1° < 2° Stability
•
•
•
but
5-exo > 6-endo
98% 2%
Beckwith J. Chem. Soc., Chem. Commun. 1974, 472.
Beckwith J. Chem. Soc., Chem. Commun. 1980, 484.
• •
•
6-exo > 7-endo
90% 10%
- Chair-like transition state subject to stereoelectronic and kinetic control rather than
thermodynamic control.
• 5-exo
Stereochemical features of substitution can be

rationalized and predicted based on these models.
• 6-exo
•
•
•
Product
krel exo krel endo ratio
1.0 0.02 (98 : 2)
•
1.4 0.02 (99 : 1)
• (>200:1)
2.4 <0.01
•
0.022 0.04 (36 : 64) endo
predominates
•
0.16 <0.002 exo >> endo
(>80:1)
- Linker chain effects
• kexo/kendo
X = CH2 0.55 endo > exo
X X=O 38.6 exo >> endo
• krel
R=H 1 gem dimethyl effect
R
R = CH3 10
R
310
Dale L. Boger
• ring size k krel
n=1 5 ~105 s-1 1
n n=2 6 ~104 s-1 0.1 exo >> endo
n=3 7 ~102 s-1 0.001 7-membered ring
closure so slow that
reduction competes.
- Stabilized radicals participate in reversible cyclizations and the thermodynamic product is observed.
CO2Et • CO2Et CO2Et

• CO2Et •
CO2Et CO2Et
3:2
•
only
NC •
CO2Et NC CO2Et
- Alkynyl radicals give 5-exo closure (stereoelectronic) even with stabilized radicals.
R R
•
CN CN
• CO2Et CO2Et
- Note effect of additional sp2 centers in the linking chain: 5-exo closure takes precedence over the overall
stability of the resulting free radical. • 1° vs 3°
• •
not
O O O
more stable
• 1° vs stabilized 2°
• •
O not
O O
more stable
- Closure onto carbonyls possible OH
CHO
6-exo HCO > 5-exo C=C
Ph • Ph
- Macrocyclizations are very facile
O O
- Requires unsubstituted and
O O activated acceptor alkene
n n to compete with reduction.
•
Porter J. Am. Chem. Soc. 1987, 109, 4976.
311
d. Initiator Groups SnBu3
S Bu3Sn• S
R OH R R R•
O X O • X
X = SR, OR, SeR Barton deoxygenation reaction
Bu3Sn•
R X R• Bu3SnX X = Br, I
Bu3Sn•
R SePh R• Bu3SnSePh
Bu3Sn• R OSnBu3
R NO2 N R•
O
•
Bu3Sn•
R SO2R R•
Hg(OAc)2 NaBH(OR)3
HgOAc
NHCBZ N N •
CBZ CBZ
- Different Initiators
Special reagent that increases reactivity of Si–H
M–H Bond so it may be used effectively in synthesis.
strength (kcal/mol) 74 79 84 90
nBu Sn (Me3Si)3Si H n H
3 H Bu3Ge Et3Si H
weakest Sn-H < Ge-H < Si-H
More competitive reduction by H• abstraction from reagent
Giese Tetrahedron Lett. 1989, 30, 681.
Ingold Int. J. Chem. Kinet. 1969, 7, 315.
- Initiation Conditions
In situ generation of Bu3SnH (catalytic amount of Sn)
Me
(Bu3Sn)2O + Si O n Bu3SnH
H
PMSH (polymethylsiloxane), readily avaible

Green J. Org. Chem. 1967, 32, 882.
e. Rearrangements are possible

• •
•
•
O O•
R R=H
• •
O Ph R = Ph
312
Dale L. Boger
f. Functionalized Free Radicals
Stork, vinyl radicals

•
Br
SPh
•
N Me N Me
Hart J. Am. Chem. Soc. 1997, 119, 6226.
O O
O O O O
•
• O N SePh O N
O SePh O
review: Chatgilialoglu, Crich, Ryu Chem. Rev. 1999, 99, 1991. Keck Synlett 1999, 1657.
Boger, acyl radicals J. Am. Chem. Soc. 1990, 112, 4008. Macrocyclization
J. Org. Chem. 1988, 53, 3377. Intramolecular J. Org. Chem. 1990, 55, 5442. Ring expansion
J. Org. Chem. 1989, 54, 1777. Intermolecular J. Org. Chem. 1992, 57, 1429. Full description
J. Am. Chem. Soc. 1990, 112, 4003. Tandem cyclization Israel J. Chem. 1997, 37, 119. Review
- Examples
Bu3SnH
COX X = SePh, 84% O
X = SPh, 0%
X = Cl, 59%
COSePh 86%
O
COSePh
69%
O
H
COSePh 82%
O
O
COSePh
X
n X
n
ring size
X=H n=0 81% 5
n=1 76% 6
n=2 74% 7
X = CO2CH3 n=0 88% 5
n=1 84% 6
n=2 92% 7
313
COSePh
CO2CH3 O
n
n
CO2CH3
ring size
n=0 83% 6
n=1 71% 7
O
COSePh
58%
Note: Alkyl and vinyl radicals are subject to faster reduction. Cyclizations such as the above example or
those for the formation of 7-membered rings are not very successful, but acyl radicals are much more
stable and not subject to competitive reduction.
O
Strong CH Weak CH
R H bond R H bond
- Tandem Cyclizations
Ph
X
O O
PhSe
X = CHPh
O3
77% X=O
H
> 98% cis
Ph
X
X = CHPh
O3
O 72% X=O
H
PhSe O
> 97% cis
Ph X
X = CHPh
O3
O 82% X=O
H
PhSe O
6 : 4 cis : trans
- Cyclization–Addition Reactions
Bu3SnH
CO2CH3
O SePh
63% O
CO2CH3
314
Dale L. Boger
- Addition–Cyclization Reactions
CO2CH3 CO2CH3
O
SePh
CO2CH3 2.4 : 1 diastereomers
61%
Ph
CO2CH3 O
SePh Bu3SnH O
O CO2CH3
Ph 71% Ph CO2CH3
- Macrocyclization Reactions
O O
n SePh
O O - decarbonylation very slow
O - reduction very slow
n - macrocyclization proceeds
activated, unsubstituted ring size exceptionally well
O
acceptor alkene
n = 15 20 57%
n = 11 16 68%
n=9 14 55%
n=7 12 46%
n=6 11 47%
- Macrocyclization onto activated acceptor is faster than 6-exo, 7-exo or 6-endo closure.
- Competitive with 5-exo closure.
O O
O O
R R = H, 30% R
R = CH3, 74% O
O SePh
- Rearrangement/Ring Enlargement Cyclization

O O O
Br H H
Bu3SnH O3
Ph O
Ph
5-exo-dig
cyclization
O O• O Ph
H
•
More stable 3°
• radical
315
- Applications
N OMe
N COSePh N O
SEM SEM
O
Cl
HN
Hong, Boger J. Am. Chem. Soc. 2001, 123, 8515. ent-(−)-Roseophilin
Remarkabley, ent-(−)-roseophilin was found to be 10-fold more potent

than the natural enantiomer in cytotoxic assays. To our knowledge,
this is the first example of an unnatural enantiomer of a naturally
occurring antitumor agent diaplaying more potent activity although Table. In vitro cytotoxic activity
several instances of comparable activity have been disclosed.
(+)- and ent-(−)-CC-1065: IC50 (µM)
compound
Kelly J. Am. Chem. Soc. 1987, 109, 6837. L1210 CCRF-CEM
Boger and Coleman J. Am. Chem. Soc. 1988, 110, 4796. ent-(−)-roseophilin 0.02 0.1
Natural and ent-fredericamycin A
Boger J. Am. Chem. Soc. 1995, 117, 11839. nat-(+)-roseophilin 0.2 1.5
Natural and ent-mitomycin C
Fukuyama and Tomasz J. Am. Chem. Soc. 1995, 117, 9388.
g. A case study comparison of cyclization approaches
Br
N Bu3SnH N BH3•THF
SO2Ph SO2Ph
N 77% N H2O2
H 5-exo-dig H
OBn OBn
OH N NH2
N O
N N N OH
SO2Ph O H
N OH OBn
O H
N N OBn
H H
OBn O
(+)-CC-1065
Boger and Coleman J. Am. Chem. Soc. 1988, 110, 1321.

J. Am. Chem. Soc. 1988, 110, 4796.
- A useful comparison series employed in the preparation of analogs of CC-1065

and the duocarmycins (Boger)
316
Dale L. Boger
H OH
Br 5-exo-dig
NBOC 1. Bu3SnH NBOC
2. BH3•THF
OBn 60% overall OBn

J. Am. Chem. Soc. 1989, 111, 6461.
J. Org. Chem. 1989, 54, 1238. 1. NaIO4, OsO4
J. Am. Chem. Soc. 1990, 112, 5230.
2. NaBH4
SPh
Br
NBOC Bu3SnH, 75% NBOC
self terminating
5-exo-trig
OBn cyclization OBn
J. Org. Chem. 1990, 55, 5823.
OTHP OTHP
Br
NBOC NBOC
Bu3SnH
97%
OBn OBn
J. Org. Chem. 1992, 57, 2873.
N
O
I
NBOC Bu3SnH NBOC
TEMPO
97%
OBn OBn
J. Org. Chem. 1995, 60, 1271.
THPO THPO
OBn BnO
Br
NBOC Bu3SnH NBOC
5-exo-trig
cyclization
OBn OBn
J. Am. Chem. Soc. 1992, 114, 9318.
Cl Cl
I
NBOC Bu3SnH NBOC
90%
OBn OBn
317
h. Further Notable Examples
CO2CH3
HgClOAc O CO2CH3
O
C5H11 HgCl
OOH
C5H11
Bu3SnH O CO2CH3
O
O2 H
Biomimetic approach to PGG2 and PGH2
HOO C5H11
For a more successful alternative see
CO2CH3 CO2CH3
CO2CH3 H
∆
•
N •
N H
Hirsutene synthesis diyl
Little J. Am. Chem. Soc. 1981, 103, 2744.
i. Selected Notable Free Radical Reactions
Barton Nitrite Photolysis

OAc OAc
O O
HON
HO H 1) NOCl HO H
H H
2) hν
H H H H
O O 21%
OAc O
O H HO
O N
ONO HO
H H • NO
H
H H
H H H H
H H H H
O
Barton J. Am. Chem. Soc. 1960, 82, 2640.
This process was used to produce 60 g of aldosterone at a time the world supply was in mg quantities. The
aldosterone synthesis ("a good problem") was achieved in 1961 by J. M. Beaton ("a good experimentalist")
through a nitrite photolysis ("a good idea"), quotes from D. H. R. Barton, 1991 ACS autobiography.
Barton Decarboxylation Barton J. Chem. Soc., Chem. Commun. 1983, 939.

S
NaON S
S
O
PhSSPh
CH3(CH2)14COCl CH3(CH2)14CO N S CH3(CH2)14SPh 74%
∆
Barton Tetrahedron Lett. 1984, 25, 5777.
318
Dale L. Boger
S
O
S N
COCl N BrCCl3 Br
OH O
75%
AIBN
130 °C
Barton Tetrahedron Lett. 1985, 26, 5939.
Barton−McCombie Deoxygenation
O O O
O O O
S
NaH, CS2 Bu3SnH
O OH O O SMe ∆ O
MeI
O O O
Barton, McCombie J. Chem. Soc., Perkin 1

Hunsdiecker Reaction 1975, 1574.
Br2
R CO2Ag R Br
Br•
Hunsdiecker, H.; Hunsdiecker, C. Ber. 1942,
O −Br• O −CO2 75, 291.
R•
R O Br R O•
CO2H HgO Br tBuLi

Wiberg Acc. Chem. Res. 1984, 17, 379.
Br2
HO2C Br
Kochi Reaction
Pb(OAc)4
RCO2H RCl Kochi J. Org. Chem. 1965, 30, 3265.
LiCl Org. React. 1972, 19, 279.
Bergman Cyclization
H-atom
abstraction
enediyne
Bergman J. Am. Chem. Soc. 1972, 94, 660.
Acc. Chem. Res. 1973, 6, 25.
Calicheamicin and esperamicin derive their biological properties through DNA binding and trisulfide
cleavage which initiates a reaction cascade which culminates in a Bergman cyclization which results in
DNA H-atom abstraction and DNA cleavage.
Ellestad J. Am. Chem. Soc. 1987, 109, 3466.
Nicolaou Angew. Chem., Int. Ed. Eng. 1991, 30, 1387.
calicheamicin R = OH OMe
R O O
esperamicin R = MeO HO O
HO NHCO2Me Me
MeSSS
H NH O
MeO
OSugar
O
319
R O R O
Bergman
HO NHCO2Me HO NHCO2Me cyclization
MeSS S S
Nu− OSugar OSugar
R O R O
HO NHCO2Me DNA HO NHCO2Me
S DNA cleavage S
OSugar OSugar
Myers Cyclization
H-atom
abstraction
Myers J. Am. Chem. Soc. 1988, 110, 7212; 1992, 114, 9369.
Neocarzinostatin is activated for DNA cleavage by thiol addition generating the reactive enyne allene.
O O
O
HO O
Me O
O Me
MeO MeHN
HO
OH
neocarzinostatin chromophore
R' R'
+
OH OH
MeO2CCH2SH MeO2CH2CS
Myers
RO RO cyclization
O O
O Me O Me
MeHN MeHN
HO HO
OH OH
MeO2CH2CS R' OH MeO2CH2CS R' OH
RO DNA RO
O O
DNA cleavage
O Me O Me
MeHN MeHN
HO HO
OH OH
320
Dale L. Boger
J. Anionic Cyclizations
Li Li
stable at –78 °C
t1/2 = 5.5 min at 25 °C
Bailey J. Am. Chem. Soc. 1992, 114, 8053. Intramolecular carbometalation, review:
J. Am. Chem. Soc. 1991, 113, 5720. Comprehensive Org. Syn., Vol. 4, 871.
J. Am. Chem. Soc. 1987, 109, 2442.
1. tBuLi
I
2. E+
E
63–91%
tandem
I
cyclizations
E
65–90%
H
tandem E
cyclizations
I H
65–87%
Stereochemistry and comparison with radical cyclizations: Cooke J. Org. Chem. 1992, 57, 1495.
Br 1) 2.2 equiv tBuLi E

2) (−)-sparteine R = CH2CH=CH2
R = CH3
N 3) E+ (H+) N R = Bn
R 60−90% ee R
Bailey J. Am. Chem. Soc. 2000, 122, 6787.
Groth J. Am. Chem. Soc. 2000, 122, 6789.
Funk J. Am. Chem. Soc. 1993, 115, 7023.

OR
5-endo-dig cyclization 120°
SO2Ph
line of attack
OEt OEt
SO2Ph
SO2Ph R
RX
OEt OEt OEt

Li SO2Ph
Li SO2Ph
SO2Ph Li
Synthetic aspects of magnesium (Grignard) carbometalation have been studied in detail.

For a review see: Oppolzer Angew. Chem., Int. Ed. Eng. 1989, 28, 38.
321
1) Mg powder
1) Li 2) 60 °C, 23 h
O 2) SOCl2, 25 °C Cl 3) OH
O H
76% 57%
SOCl2
Et2O 72%
H 1) Mg powder
*
2) 25 °C, 20 h
* OH 3) O2
H H H H
Cl
∆9(12)Capnellene 70% (3 : 2)
Oppolzer Tetrahedron Lett. 1982, 23, 4669.
K. 1,3-Dipolar Cycloadditions
Review: 1,3-Dipolar Cycloaddition Chemistry, Padwa, A., Ed., Wiley: New York, 1984.
- 2πs + 4πs Cycloaddition
- Subject to FMO control: can predict regioselectivity and reactivity.
- FMO Control:
(a) Reactivity: ∆E (HOMO/LUMO) and the reactivity of the system is related to the
magnitude of the smallest energy gap of the pair of HOMO–LUMO combinations.
(b) Regioselectivity: depends on the magnitude of the orbital coefficients and is
determined by the orbital coefficients on the predominant HOMO–LUMO interaction.
The largest coefficient on the 1,3-dipole binds to the largest coefficient on the
dipolarophile.
(c) Diastereoselectivity: influenced by stabilizing secondary orbital interactions and
subject to an endo effect.
(d) Olefin geometry is maintained in the course of the cycloaddition reaction, they are
concerted reactions.
(e) No solvent effect on the reaction rate: concerted reactions.
(f) No rearrangement products from postulated zwitterion or biradical.
(g) Trans-1,2-disubstituted olefins react faster than cis-1,2-disubstituted olefins.
Cis olefins are generally more reactive than trans olefins in ionic or radical
addition reactions.
1. Azomethine Ylides Ar
R N R'
+
Ar R R' Ar
N R' ∆ R N R'
R
R R'
R R'
Ar R''O2C CO2R'' R''O2C CO2R''
R N R'
+
R R'
H H H H
H ∆ +
RO2C N Ar RO2C N Ar
H
1,3-dipole
322
Dale L. Boger
2. Azomethine Imines
R'
R N R''
+ N
H
3. Nitrones
R' HgO R' R'CHO
N Oxidation of N +
R OH R + O
hydroxylamine
RNHOH
- Symmetrical precursor or a precusor with one adjacent oxidizable center.
X X
R' R' R'
X +
N N O N O
R + O R R
X = Ph, CO2R, OEt X = NO2

- The regioselectivity depends on X and the substitution pattern of the nitrone.
- Review: Confalone Org. React. 1988, 36, 1.
4. Diazoalkanes R' R
R R ∆ or hν
R
N2 N
R=H N R' − N2 R'
R R
R R
N N N N
+ +
R R
5. Azides
Ph
CO2Me N
PhN3 N
N
25 °C
5 days, 77% CO2Me
PhN3 Ph N N N Ph N N N
∆ − N2
N N N R
N N H
N N
R R H
R = Ph (160 °C) R = Ph, 49%
R = COPh (40 °C)
Ph Ph Ph
OTMS OTMS OTMS
BnO OBn OBn
SEt SEt SEt
MeO O MeO O MeO O
O 110 °C
O − N2 O
Me N3 toluene Me N Me N
OMe OMe N N OMe
Fukuyama J. Am. Chem. Soc. 1989, 111, 8303. Mitomycins
323
6. Nitrile Oxides
R
R X − HX ∆
N N N O
N O
OH
O
X=H
X = Cl, Br, I
O O R N C O
N
RCH2NO2
R H
R R
CO2R
N N CO2R
O
O
7. O3 / Carbonyl Oxides
O 1,3-dipolar
O + primary
O cycloaddition O O ozonide
O
O
1,3-dipolar
cycloreversion O
1,3-dipolar
final H
ozonide O O +
cycloaddition O O
O O
O O
8. Nitrile Ylides
Ar N Ar' Ar C N
Ar'
Et3N Ar N Ar' CN N
Ar N Ar' Ar Ar'
(–HCl)
Cl
CN
N ∆ or hν
Ar N H
Ar
H
R' O
–CO2 R' N R
N O
R
R R
9. Carbonyl Ylides
R O R O CO2R
O CO2R
R' C R'
R R'
- problem: collapse of the carbonyl ylide to the epoxide
324
Dale L. Boger
10. Methylene Cyclopropanone Ketals
CN
∆ O O
O O O O
4π three carbon CN
1,3-dipole
Nakamura J. Am. Chem. Soc. 1989, 111, 7285.
J. Am. Chem. Soc. 1991, 113, 3183.
Key: reversible ring opening generation of the 4π component
11. Cyclopropenone Ketal (CPK) Diels–Alder/Dipolar Cycloadditions
CO2CH3
H H
OR OR O OR
OR OR OR
H H O
R CO2CH3 OCH3
O
R OCH3
Boger, Brotherton–Pleiss:
O OCH3 Advances in Cycloaddition Chemistry, Vol. 2,
JAI: Greenwich, 1990, 147.
O OCH3 Boger:
J. Am. Chem. Soc. 1995, 117, 12452.
75 °C 75 °C J. Org. Chem. 1994, 59, 3453.
J. Org. Chem. 1988, 53, 3408.
Org. Syn. 1987, 65, 98.
J. Org. Chem. 1985, 50, 3425.
O O CH3O OCH3
J. Am. Chem. Soc. 1986, 108, 6695 and 6713.
J. Am. Chem. Soc. 1984, 106, 805.
Tetrahedron Lett. 1984, 25, 5611 and 5615.
CO2CH3 O CO2CH3 O
RO2C CO2R
O R H
R
H
CO2CH3
OR
RO2C CO2R
CH3O2C O OR O OR
OR R R
CO H
OR OR
OR
RO OR OR
325
L. 1,3-Sigmatropic Rearrangement
1. Vinylcyclobutane rearrangement
∆
350–600 °C
Overberger J. Am. Chem. Soc 1960, 82, 1007.

H3C CH3
KH, THF, ∆
NCH3 91% NCH3
H H
H3C CH3
Bauld J. Am. Chem. Soc. 1988, 110, 8111.
O nBu O
4NF, 20 °C
N N
OH 66% OH
CO2Et CO2Et
OH
O
Sano Chem. Pharm. Bull. 1992, 40, 873.
2. Vinylcyclopropane rearrangement
First report: Neureiter J. Org. Chem. 1959, 24, 2044.
Review: Hudlicky Chem. Rev. 1989, 89, 165.
500–600 °C
Org. React. 1985 33, 247.

Mechanism:
concerted diradical
TMS
570 °C
TMS
80%
Paquette Tetrahedron Lett. 1982, 23, 263.

R CO2Me
R
CO2Me Et2AlCl, CH2Cl2
RO
85−95% RO
Davies Tetrahedron Lett. 1992, 33, 453.
SPh toluene, 250 °C hydrolysis

94% 73%
SPh O
MeO MeO MeO
326
Dale L. Boger
MeO MeO2C OMe MeO2C
AlMe3, Et2O, ∆ (–MeOH)
48%
nPr
MeO2C
Prn Prn
Harvey Tetrahedron Lett. 1991, 32, 2871.
O O O
hν, benzene
+
H
Wood, Smith J. Am. Chem. Soc. 1992, 114, 10075.
3. Carbonyl/Imine cyclopropane rearrangement
OMe OMe
OMe OMe
aldimine hydrobromide
76%
NMe NMe
Stevens J. Am. Chem. Soc. 1968, 90, 5580.
O O
hν
N 100% N
BOC BOC
Boger, Garbaccio J. Org. Chem. 1997, 62, 8875.
Note: The di-π-methane rearrangement produces substrates that may be used in the vinylcyclopropane
rearrangement.
R R R R R R
hν R R
Zimmerman, Grunewald J. Am. Chem. Soc. 1966, 88, 183.

Zimmerman Chem. Rev. 1973, 73, 531; 1996, 96, 3065.
327
M. Electrocyclic Reactions
C8H17
Calciferol
(Vitamin D)
C8H17 C8H17
HO
∆, <100 °C
1,7 H-shift H
HO C8H17 HO
Lumisterol hν hν Ergosterol
HO
Precalciferol
(Previtamin D)
C8H17 C8H17
heat
100-200 °C
H
HO disrotatory ring closure HO
6π e–
Isopyrocalciferol Havinga Tetrahedron 1960, 11, 276. Pyrocalciferol
Provided the impetus for the Woodward–Hoffmann rules
Ph
H
Total Synthesis of
H Endiandric Acids
CO2R H
CO2R
H
8π e– 2πs + 4πs
conrotatory Diels–Alder reaction
Ph closure
6π e– H H
disrotatory
Ph
CO2R
closure
CO2R Ph H
Nicolaou J. Am. Chem. Soc. 1982, 104, 5555, 5557, 5558 and 5560.
N. Nazarov Cyclization
4π e– Conrotatory electrocyclic ring closure
Review: Santelli–Rouvier, C.; Santelli, M. Synthesis 1983, 4295.
Nazarov Usp. Khim. 1949, 18, 377.; Usp. Khim. 1951, 20, 71.
Denmark Org. React. 1994, 45, 1–158.
Denmark Comprehensive Org. Syn., Vol. 5, pp 751–784.
328
Dale L. Boger
O OH+ OH OH
4π e–
H+
conrotatory
R1 R2 R1 R2 R1 R2 electrocyclic R1 R2
ring closure
–H+
O OH
Nazarov Bull. Acad. Sci., USSR 1946, 633.
J. Gen. Chim., USSR 1950, 20, 2009, 2079, 2091.
Woodward, Hoffmann Angew. Chem. 1969, 81, 797.

R1 R2 R1 R2
O O O
HCO2H
70%
H3PO4
90 °C, 7 h
Nazarov Chem. Abstr. 1948, 42, 7731a, 7731h, 7732g, 7733e, 7734a, 7734.
O O
H3PO4
Me Me
Braude J. Chem. Soc. 1953, 2202.
- Silicon-directed Nazarov cyclization.
O OH
O
FeCl3
95% via:
CH2Cl2
TMS TMS Cl–
Denmark J. Am. Chem. Soc. 1982, 104, 2642.
O
under usual Nazarov conditions: isomerization to
CN Li O O O
1. Br2 PPA
+
2. LiBr, Li2CO3 100 °C
62%
Eaton J. Org. Chem. 1976, 41, 2238.
- Extensions to annulation procedures.
OH OH O
O OLi
Li H2SO4
70%
88%
Raphael J. Chem. Soc. 1953, 2247.

329
- Stereochemical course of the reaction: via Nazarov cyclization.
OH O O O
OH
conrotatory 4π e– electrocyclization 67% 10%
Hiyama J. Am. Chem. Soc. 1979, 101, 1599.

Bull. Chem. Soc. Jpn. 1981, 54, 2747.
- Lewis acid-catalyzed reactions.
O O O
MeO2C MeO2C MeO2C
GaCl3
+
MeO2C MeO2C MeO2C
H
Also: FeCl3
49% 40%
BF3•Et2O
Tsuge Bull. Chem. Soc. Jpn. 1987, 60, 325.
- Tin-directed Nazarov cyclization.
O O
R BF3•Et2O R
Bu3Sn R' 44–93%

R'
Johnson Tetrahedron Lett. 1986, 27, 5947.
O. Divinylcyclopropane Rearrangement
Org. React. 1992, 41, 1.
(2σs + 2πs + 2πs)
- Mechanism:
H H H H H H
boat-like
transition state
H
∆
H H H
- Synthesis of functionalized 7-membered rings:
silyl enol ether
O OTMS O O
O O O OTMS
H TMSCl, Et3N H 210 °C KF
MeO MeO
MeO MeO
Et2O benzene MeOH
H 100% H 96%
Marino J. Org. Chem. 1981, 46, 1912.
330
Dale L. Boger
- Fused ring systems:
α,β-unsaturated enone
OEt Li O
O
1. H 170–180 °C
n n
2. HCl, H2O benzene n
O H
n=1 n=1 n = 1, 72%
n=2 n=2 n = 2, 74%
Wender J. Org. Chem. 1976, 41, 3490.
P. Carbene Cycloaddition to Alkenes

1. Halocabenes
Parman, Schweizer Org. React. 1963, 13, 55.
Moss Acc. Chem. Res. 1989, 22, 15.
Acc. Chem. Res. 1980, 13, 58.
Kostikov, Molchanov, Khlebnikov Russ. Chem. Rev. 1989, 58, 654.
2πs + 2ωa
cycloaddition
CH2
Addition of a singlet carbene X X

Triplet carbene behaves
proceeds by a concerted
as a diradical.
process in a syn fashion.
X X
- Methods for generating halocarbenes:

For a comprehensive list see: Kirmse Carbene Chemistry, 1971, 313.
CHCl3 + KOtBu CCl2

BrCCl3 + nBuLi CCl2
CH2Cl2 + RLi CHCl reactivity of carbenes
N2CHBr CHBr CH2 > CHCl > CCl2 > CBr2 > CF2
Cl3CO2R + RO– CCl2

∆
PhHgCCl2Br CCl2
- Reaction with alkenes:

Br
CBr2
H H H Br
H
Stereospecific
H Br
H
CBr2
H Br
H
Doering J. Am. Chem. Soc. 1956, 78, 5447.
- Reaction with aromatic C=C bonds (cyclopropanation followed by rearrangement):
Cl Cl
OMe Cl
CCl2 OMe
O
Parman, Schweizer J. Am. Chem. Soc. 1961, 83, 603.
331
Cl
H
MeLi
N CH2Cl2 N N
H
Li
Closs, Schwartz J. Org. Chem. 1961, 26, 2609.
2. Simmons–Smith Reaction
Simmons Org. React. 1973, 20, 1.
Simmons, Smith J. Am. Chem. Soc. 1958, 80, 5323; 1959, 81, 4256.
+ CH2I2 + Zn(Cu) + ZnI2 + Cu
- Mechanism:
C ZnI C ZnI C
H2C C CH2 + ZnI2
I H2 I
C C C
1) concerted mechanism likely (above)

2) reaction is stereospecifically syn
3) alkenes with higher alkyl substitution react faster
4) electron donating substituents accelerate reaction
i.e., enol ethers, enamines...
- Addition can be directed by a hydroxyl group or ether functionality:
OH CH2I2 OH
Zn(Cu) H
60%, 100% cis
H
OMe CH2I2 OMe
Zn(Cu) H
70%, 100% cis
H
Rickborn J. Am. Chem. Soc. 1968, 90, 6406.
J. Org. Chem. 1972, 37, 738.
- Examples:
enone
CO2Et CH2I2 CO2Et
MeO Zn(Cu) MeO
N N
H H
Shen Chem. Abstr. 1967, 67, 108559m.
HO HO HO
OMe OMe O
enol ether 91%
Wenkert, Berges J. Am. Chem. Soc. 1967, 89, 2507.
332
Dale L. Boger
3. Diazocarbene Addition and Rearrangement
Review: Burke and Grieco Org. React. 1979, 26, 361.
O O O O
CH2N2 N2 Cu HCO2H
Cl
Re
∆ H2O
Re Re Rz OH
Rz R z
R e Rz
Li/NH3
OLi
regioselective
enolate generation
Rz
Re
1. NaH O
O O O O O O
Cu CO(OMe)2 H HCl
C6H6 2. NaBH4 THF
N2
O MeO2C OH2+ HO2C
O
Deslongchamps Can. J. Chem. 1970, 48, 3273.

Can. J. Chem. 1980, 58, 2460.
Agarospirol
HO
dianion
alkylation
OLi O O
CO2Et
Li CO2Et CO2Et
TsN3 Cu
+ N2
Et3N Toluene
C5H11 C5H11
Br
O O O
CO2H CO2Et PhSH CO2Et
C5H11 C5H11
t
C5H11 KO Bu
H
PGA2 OH H
PhS
sulfoxide [2,3]-sigmatropic Taber J. Am. Chem. Soc. 1977, 99, 3513.
rearrangement used to install
Nu– Nu– CO2R

CO2R homoconjugate addition vs. conjugate addition
CO2R CO2R
333
4. Metal Carbene Cycloaddition Reactions E. O. Fischer received the 1973 Nobel Prize
Comprehensive Org. Syn., Vol. 5, 1065. in Chemistry for his work in organometallic
- Three-membered ring [2 + 1] chemistry with transition metal complexes
Bookhart, Studabaker Chem. Rev. 1987, 87, 411. including metallocenes and his stabilized
Doyle Chem. Rev. 1986, 86, 919. carbene complexes.
Reaction works well for electron-rich, electron-poor and unactivated C=C bonds.
Ph OMe Ph OMe
OMe OEt neat, 50 °C
(CO)5Cr + +
Ph 100 atm CO OEt OEt
enol ether 61% (76 : 24)
Ph OMe Ph OMe
OMe CO2Me neat, 90 °C
(CO)5Cr + +
Ph 60% CO2Me CO2Me
enone (29 : 71)
Fischer, Dötz Chem. Ber. 1972, 105, 3966.
Chem. Ber. 1972, 105, 1356.
- Four-membered rings [2 + 1 + 1]
OMe hν O
OMe R1 = H, R2 = OEt, 85%
(CO)5Cr +
R1 R2 CH3CN R1 = R2 = Me, 61%
R1 R2 R1 = H, R2 = Ph, 30%
hν
(CO)5Cr OMe
Hegedus J. Am. Chem. Soc. 1989, 111, 2335.
O
- Fischer carbene addition to alkynes typically leads to 6-membered ring , 4- and 5-membered rings form
only under special circumstances.
tBu
O Ph
OMe 65 °C OMe 4-membered ring formation is a
(CO)5Cr +
Ph THF tBu
result of the large tbutyl group.
CO2Et CO2Et
93%
Cr leads to 6- Yamashita Tetrahedron Lett. 1986, 27, 3471.
membered ring Ph Ph
OMe Ph
100 °C
(CO)5W +
Ph
toluene Ph
Ph 90% OMe OMe
Foly J. Am. Chem. Soc. 1983, 105, 3064.
N required for O Et
5-membered ring Et
N 100 °C Et
(CO)5Cr +
DMF N
Et 96%
O
Yamashita Tetrahedron Lett. 1986, 27, 5915.
334
Dale L. Boger
- Six-membered rings [3 + 2 + 1] (Fischer carbene addition to alkynes)
Dötz, Fischer Transition Metal Carbene Complexes, VCH: Deerfield Beach, FL, 1983.
Dötz Angew. Chem., Int. Ed. Eng. 1984, 23, 587.
Casey in Transition Metal Organometallics in Organic Synthesis, Academic Press: New York, 1976, Vol. 1.
Dötz Pure Appl. Chem. 1983, 55, 1689.
Casey in Reactive Intermediates, Wiley Interscience: New York, 1982, Vol. 2, and 1985, Vol. 3.
Hegedus Principles and Applications of Organotransition Metal Chemistry, University Science Books: Mill
Valley, CA, 1987, 783.
Brown Prog. Inorg. Chem. 1980, 27, 1.
Wulff in Advances in Metal-Organic Chemistry, JAI Press: Greenwich, CT, 1989, Vol. 1.
- General scheme
OH O
RL R2 RL
R2 R3 R2 R3 C RL
L +
M(CO)4
R1 R1 RS R1 RS
R2 or R3 = H
RS OMe
XR XR
- Most widely studied after cyclopropanation of Fischer carbenes. Extensively applied in natural product
synthesis. Examples:
OH OH
OMe H 1) THF, 45 °C iPr
(CO)4Cr + +
2) FeCl3–DMF
iPr
iPr THF, 25 °C
55% OMe 99.6 : 0.4 OMe
Wulff in Advances in Metal-Organic Chemistry, JAI Press: Greenwich, CT, 1989, Vol. 1.
OMe 1. PhH, 75 °C O
O O O
(CO)4Cr 2. air, 10 min
+ O 11-Deoxydaunomycinone
MeO 3. (CF3CO)2O
NaOAc
CO2tBu 4. TFA OMe O OH
5. aq. NaOH
Wulff Tetrahedron 1985, 41, 5797.

OH
OMe CO2Me Sphondin
(CO)4Cr 85 °C
+ and
THF O
O
OMe Angelicin
CO2Me
Wulff J. Am. Chem. Soc. 1988, 110, 7419.
OTBS MOMO OMe OTBS

MOMO OMe MeO
MeO Ac2O
Cr(CO)5 Fredericamycin A
TBSO heptane
+ MOMO OH OTBS
MOMO
EtO N EtO N
J. Org. Chem. 1991, 56, 2115.
J. Org. Chem. 1990, 55, 1919.
335
Q. [2 + 3] Cycloadditions for 5-Membered Ring Formation
Review: Comprehensive Org. Syn., Vol. 5, 239.
1. (2π + 2π)
- Noyori reaction: J. Am. Chem. Soc. 1972, 94, 1772.

J. Am. Chem. Soc. 1973, 95, 2722.
J. Am. Chem. Soc. 1977, 99, 5196.
J. Am. Chem. Soc. 1978, 100, 1793.
R R
Br Fe2(CO)4
+ O O via O–Fe2+
D Br benzene D
R ∆ R stepwise process
OFe
D
Br
O
Ph Br Ph
O
70%
Ph Ph
O n = 5, 75%
n N n = 6, 100%
n
O
N
70%
O
Cuparenone
Noyori Tetrahedron Lett. 1978, 493.
- Intramolecular version: Yamamoto J. Am. Chem. Soc. 1979, 101, 220.
Br
+
O O 2:1 O
Br 58%
- Reviews: Acc. Chem. Res. 1979, 12, 61.

Org. React. 1983, 29, 163.
336
Dale L. Boger
Cl
ZnCl2
Cl
+ 21%
Cl
Cl
Miller Tetrahedron Lett. 1980, 577.
Cl
Cl + Ph 50%
Ph
Cl
ZnCl2, HCl
Cl 70%
+
CH2Cl2
OEt
+ OEt 81%
Cl
Mayr Angew. Chem., Int. Ed. Eng. 1981, 20, 1027.
2. (2π + 4π)
Ph
Ph LDA, THF
41%
Ph
Ph Ph
Ph
Kauffman Angew. Chem., Int. Ed. Eng. 1972, 11, 292.
CN
CN 25 °C, 2 h
Ph Ph Ph
Ph Ph +
65%
Ph
Martens Angew. Chem., Int. Ed. Eng. 1972, 11, 724.
337
- Trost trimethylenemethane equivalent:
J. Am. Chem. Soc. 1979, 101, 6429.
J. Am. Chem. Soc. 1983, 105, 2315.
OAc
EWG Pd(PPh3)4 EWG L
+ via:
Pd
TMS L
Stepwise mechanism:
CO2Me MeO2C CO2Me MeO2C
MeO2C MeO2C CO2Me MeO2C

32% 60%
cis : trans
1 : 1.3
Related equivalents:
O Cl O O
TiCl4 Cl KOtBu
+
TMS
1,4-addition of allylsilane: Knapp Tetrahedron Lett. 1980, 4557.
I TMS SO2Ph
SO2Ph SO2Ph
KH Bu4NF
+
Et2O THF
O TMS O OH
O
CO2Me MeO2C O
+
O
O
O
Nakamura J. Am. Chem. Soc. 1989, 111, 7285.
J. Am. Chem. Soc. 1991, 113, 3183.
338
Dale L. Boger
R. Cyclopropenone Ketal Cycloadditions
Review: Boger Adv. Cycloaddition Chem., JAI Press: Greenwich, CT, Vol. 2, 1990, pp 147–219.
1. [2 + 1] Cycloaddition
O
O O
CO2Me CO2Me CO2Me
O cis : trans
H O H O 20 : 1
80 °C H H
[1 + 2] OH
endo diastereoselectivity
- Carbene addition: 2πs + 2ωa suprafacial antarafacial

H H
OMe
H H OMe
O O
H H OMe
H H H OMe
R
R H
endo stabilization
H H
OMe
H H OMe
R R
H H OMe
H H H OMe
O
H
O
- Carbene angle of attack: Jorgensen J. Am. Chem. Soc. 1989, 111, 1919.
O O
O O
117 o O O
O 75 oC O O
OMe 75 oC MeO OMe
OMe
339
- Substrates that contain two geminal electron-withdrawing groups.
EWG EWG O 70–80 °C O O

+ EWG
R O EWG
R
[4 + 2] Tetrahedron 1986, 42, 2777. J. Am. Chem. Soc. 1984, 106, 805.
[1 + 2] Tetrahedron Lett. 1984, 25, 5611. J. Am. Chem. Soc. 1986, 108, 6695.
[3 + 4] J. Org. Chem. 1985, 50, 3425. J. Org. Chem. 1988, 53, 3408.
J. Am. Chem. Soc. 1986, 108, 6713. O Advances in Cycloaddition Chemistry Vol. 2, JAI:
O
(total synthesis of Colchicine) Greenwich, CT, 1990, pp 147–219.
single e– transfer
Note: For substrates that may react

EWG EWG O O O O via this pathway (e– transfer),
EWG
+ [3 + 2] > [1 + 2], [4 + 2], or [3 + 4]
EWG cycloadditions
R
radical radical R
anion cation
MeO2C CO2Me O O
95% MeO2C
1. Solvent independent rate.
MeO2C
MeO
2. No addition–elimination or
Unusual polarity that uniquely MeO
addition–rearrangement products.
stabilized radical anion.
3. No inhibition by free radical traps. O O
NC CN 89% NC
4. Putative carbene addition product NC
(a cyclopropane ketene acetal)
does not undergo vinylcyclopropane
rearrangement to the product. Cycloaddition faster than cyclopropyl-
carbinyl radical rearrangement.
5. Little or no loss of olefin stereo-
chemistry and this diastereospecific
nature of the reaction increases, not NC CO2Me O O
decreases, in polar solvents. NC
58% MeO2C
- (2πs + 2πa) Cycloaddition
CO2R
MeO R
MeO MeO H H CO2R'
MeO H
H
H 3π e– bond, little loss of
– stereochemistry due to
bond rotation
340
Dale L. Boger
Tear Gas, CS Used as an antiriot agent, the tear gas CS, named after its two developers B.
Cl Corson and R. Stoughton who introduced it in 1928, causes pain and burning
in the eyes and skin within seconds. It acts as a sulfhydryl alkylating agent
resulting in a copious flow of tears, coughing, sneezing, chest tightening, and
dizziness which subside within 30 min. No carcinogenic activity was found in
mice exposed to CS for up to 2 years.
NC CN
O O O
O O O O
O
+
O + − O
O O + H
− O
O H
MP2/6-31++G(d)//6-31++G(d)
H O H H O H
O O O O
O O + H + H
O + − O + - – H
–
O H O H H singlet
anti H
π-delocalized 0.00 kcal 1.40 kcal
singlet vinylcarbene
H O H H O H
O O O O
O O H H
O + H O + H H
O − O - H triplet
syn H 9.22 kcal 8.73 kcal
Singlet carbene stabilized by two alkoxy electron-donating substituents
- 2πs + 4πs Cycloaddition or Diels–Alder reaction but via a 2π three carbon dienophile.
MeO
80 °C
73% MeO
MeO O
CO
MeO MeO
O O
NHCOMe
O
MeO MeO
MeO O
MeO O
O O
OMe MeO
Colchicine
88% MeO H
O O
25 °C MeO CO
6.2 kbar
Boger J. Am. Chem. Soc. 1986, 108, 6713. H O
341
4. [4 + 2] Cycloaddition (standard Diels–Alder reaction)
O
O
O
R R R O
25 °C O
[4 + 2]
O
O
O R
R R O
O 25 °C
6–13 kbar O O
[4 + 2]
R R
O O R = CO2CH3, 56–65%
+ R = H, 69%
O O R = OCH3, 56–72%
Participates in normal, neutral, or inverse electron demand

Diels–Alder reactions, high lying HOMO and low lying LUMO.
O VS O
O O
Exclusive exo addition
Note: cyclopropene itself
is endo selective.
CO2CH3 O CO2CH3 CO2CH3 CH3O2C

O KOtBu, 25 °C
O O 25 °C
X
O O
25 °C –CH3OH
OCH3 80% OCH3
6πe– disrotatory electrocyclic O
ring opening referred to as a X=
norcaradiene rearrangement O
X=O
OMe OMe
MeO MeO
O
N N Grandirubrine
MeO O MeO
Imerubrine
Granditropone
O
O O
342
Dale L. Boger
S. [2 + 2] Cycloadditions
1. Ketene [2 + 2] cycloadditions
Org. React. 1995, 45, 159. H
O O 2πs + 2πa
Cycloaddition
Et3N Hermann Staudinger, noted for his

pioneering studies of ketenes, received
hexanes the 1953 Nobel Prize in Chemistry for
O his pioneering work in macromolecular
COCl
chemistry.
Baldwin J. Chem. Soc., Chem. Commun. 1972, 1337.
2. Photochemical [2 + 2] cycloaddition Ronald Norrish received the 1967 Nobel Prize

Comprehensive Org. Syn., Vol. 5, 123. in Chemistry for his work on photochemistry
Org. React. 1993, 44, 297. and flash photolysis. The latter was developed
with George Porter with whom he shared the
1967 Nobel Prize and is used for the production
and spectroscopic determination of short-lived
reaction intermediates.
O O
Norrish Type I Fragmentation Reaction
hν O hν O
+ R'
92% H
R R' R
OH
Norrish Type II Reaction
Cargill Tetrahedron Lett. 1978, 4465.
H hν H
O O
OH
+
Norrish Trans. Faraday Soc. 1937, 33, 1521.
OEt O O
1. LDA, MeI hν 1. Ph3P=CH2
2. 2. TsOH
O
MgBr
Isocomene
Pirrung J. Am. Chem. Soc. 1979, 101, 7130.
J. Am. Chem. Soc. 1981, 103, 82.
O O O O
MgBr
1. CuI OH 1. TsCl hν
2. CH2O 2. base 67%
Panasinene
C. R. Johnson J. Am. Chem. Soc. 1981, 103, 7667.
343
CHO O
I O O
EtO O 1. LDA O
hν O3
2. LiAlH4
O
O O
Hibiscone C
O O
CO2Me CO2Me
MeO2C Ph3P=CH2
hν
+
H H
Note: regioselectivity of
cycloaddition in excited state. 210 °C, 2 h
- Mechanism:
CO2Me H CO2Me
retro CO2Me ene reaction
H [2 + 2]
H
CHO
- Ene reaction:
OH
CHO
H H Warburganal
H
Wender Tetrahedron Lett. 1982, 23, 1871.
- Note regioselectivity:
O O
hν
+
OMe
MeO OMe
OMe
O O
excited state reversed polarity VS.
344
Dale L. Boger
3. Paterno–Buchi Reaction
Dermuth Synthesis 1989, 152.
First studied in detail by Buchi J. Am. Chem. Soc. 1954, 76, 4327.
R6
O R5 R6 hν O R5
+
R1 R2 R1 R4
R3 R4
R2 R3
hν
* R5 R6 R5
O R6 R4
O
R3
R1 R2 R3 R4 R1
R2 a diradical intermediate
has been observed
-Addition to enol ether occurs with only moderate selectivity ...

OEt
O hν O O
+ +
OEt Ph Ph
Ph Ph
Ph OEt Ph
(75 : 25)
Schroeten J. Org. Chem. 1969, 34, 1181.
... while addition of the carbonyl to a furan occurs with high selectivity.
O hν O O
O
+ +
Ph Ph
Ph Ph O O
Ph Ph
(1 : 99)
Schenk Chem. Ber. 1963, 96, 498.
- Intramolecular variant:
O hν
O Thromboxane A2
O cat. Na2CO3 O
benzene
Carless J. Chem. Soc., Chem. Commun. 1984, 667.

- Diastereoselectivity:
R R R
H
fast H
hν O O O
R CHO O O H O
H H
R R H not
hν
formed
slow O
O H
O O R
O O O H
H H
Aoyoma J. Org. Chem. 1984, 49, 396.
Pattenden J. Chem. Soc., Chem Commun. 1980, 1195.
J. Chem. Soc., Chem Commun. 1979, 235.
345
T. Arene–Olefin Photoadditions
- Discovery in 1966: Wilzbach J. Am. Chem. Soc. 1966, 88, 2066.
Bryce–Smith J. Chem. Soc., Chem. Commun. 1966, 512.
LiO OMe
H
O Li/NH3
+ H
Li
OMe
MeO
hν
65%
OMe OMe
H KOH, N2H4 H 1. Br2, CH2Cl2 H H
O +
diethylene 2. Bu3SnH
glycol (1 : 1)
α-Cedrene 200 °C
hν 244 °C
+
72% toluene
50–60%
(1 : 1)
Isocomene
Wender Tetrahedron 1981, 37, 4445.
OAc
hν H 1. KOH, MeOH KOtBu, MeI
O O
21% OAc 2. BaMnO4
THF
82% 68%
1. Li, Et2NH 1. Me2CuLi

THF, 0 °C THF, –78 °C
Modhephene OPO(NMe2)2
2. H2, PtO2 2. then Cl2PO(NMe2)
93% 3. Et2NH
76%
346
Dale L. Boger
U. Intramolecular Ene Reaction

Review: H. M. R. Hoffmann Angew. Chem., Int. Ed. Eng. 1969, 8, 556.
H H
concerted thermal
[4 + 2] cycloaddition
ene eneophile
- First systematic study by Alder:
O O
∆
+ O O
H Ph
Ph O O
Alder Chem. Ber. 1943, 76, 27.
- First intramolecular versions: review: Oppolzer Angew. Chem., Int. Ed. Eng. 1978, 17, 476.
∆
O OH
H
Treibs, Schmidt Chem. Ber. 1927, 60, 2335.
300 °C
CO2Me 14 h CO2Me
65%
cis
AlCl3, 0 °C
H
BnO 69% BnO
O Me OR

R
N R AlCl3, 25 °C N
CH3 91%
H H OH
O CH3
Overman Tetrahedron Lett. 1985, 35, 4167.
Note the Sharpless mechanism for SeO2 oxidation of olefins: allylic oxidation involves an ene reaction.
H O OH
or
O ene reaction O Se Nu–
Se Se
[2,3]-sigmatropic OH
O OH rearrangement
Sharpless J. Am. Chem. Soc. 1972, 94, 7154.

J. Am. Chem. Soc. 1973, 95, 7917.
347
Chugaev (Tschugaeff) Reaction syn elimination
R
1) NaOH, CS2 R
RCH2CH2OH H O
2) CH3I S 100−250 °C
SMe
Tschugaeff Ber. 1899, 32, 3332.
Review: Nace Org. React. 1962, 12, 57.
DePuy Chem. Rev. 1960, 60, 431.
Amine Oxide Elimination (Cope Elimination) Me2

N –
Org. React. 1960, 11, 361. + O
Org. Syn. 1963, 4. 612. 90%
Cope J. Am. Chem. Soc. 1954, 81, 2799.
Zutter J. Am. Chem. Soc. 1986, 108, 1039. Cope J. Am. Chem. Soc. 1949, 71, 3929.
O ∆
H N + N OH
syn
elimination
Sulfoxide Elimination
Trost Chem. Rev. 1978, 78, 363. Ziegler J. Am. Chem. Soc. 1984, 106, 721.
Acc. Chem. Res. 1977, 11, 453. Schreiber J. Am. Chem. Soc. 1984, 106, 4038.
J. Am. Chem. Soc. 1973, 95, 6840. Agosta J. Am. Chem. Soc. 1986, 108, 3385.
J. Am. Chem. Soc. 1976, 98, 4887.
O
R ∆
H S +
syn RSOH
elimination
H 220 °C
O
S syn
elimination
Ph
H 110 °C H 80 °C
O O
S syn S syn
elimination elimination
Me O O Ph O O
R R
R
O O O HO
O
O
O O O O
SPh SPh SPh
PhS
25 °C
O O O HO
O
Boger, Mullican J. Org. Chem. 1980, 45, 5002.

J. Org. Chem. 1984, 49, 4045.
348
Dale L. Boger
- Selenoxide Elimination
Clive Tetrahedron 1978, 34, 1049.
Reich Acc. Chem. Res. 1979, 12, 22.
H 25 °C
Selenoxide elimination occurs
O at lower temperature.
Se syn
elimination
Ph O O
O
Br NaSePh SeAr [ox.] SeAr ∆
R R R R
Bu3P
OH
R
NO2
CN
Se
V. Oxy–Ene Reaction: Conia Reaction

Review: J. M. Conia Synthesis 1975, 1.
O O O
H
Conia Tetrahedron Lett. 1965, 3305, 3319.
O 350–370 °C O 85%
30 min Epimerized to more
stable trans isomer.
O 350–370 °C O cis
30 min
Conia Bull. Chim. Soc., Fr. 1969, 818.
O
O 335 °C
60 h
50%
tandem Conia reactions: Conia Tetrahedron Lett. 1974, 2931.
349
W. Cyclopentenone Annulation Methodology
Br
1.
O
O OLi 2. O2, PdCl2, CuCl2
1 3. NaOH, EtOH 2
Wacker oxidation, review:Tsuji Synthesis 1984, 369.

Wayner J. Org. Chem. 1990, 55, 2924.
Br
1.
1 2
2. NaIO4, OsO4
3. NaOH, EtOH
McMurry J. Am. Chem. Soc. 1979, 101, 1330.
Br
1. Br
1 2
2. H2SO4
3. NaOH, EtOH
1. TMSCl
1 2
2. SnCl4,
CH2=C(Me)NO2
3. NaOH, EtOH
1. Br TMS
2. KOH, MeOH (–TMS)
1 2
3. Hg(OAc)2, H+
4. NaOH, EtOH
OMe
Br CO2Me
1.
O
OLi 2. H2SO4, H2O
3. NaOH, EtOH CO2Me
OEt O Used in Quadrone total synthesis:

Br PO(OMe)2 Br PPh3 Helquist J. Am. Chem. Soc. 1981, 103, 4647.
Piers Tetrahedron Lett. 1979, 3279. Altenbach Angew. Chem., Int. Ed. Eng. 1979, 18, 940.
350
Dale L. Boger
- Flemming–Greene Annulation:
1. Cl3CCOCl
Zn–Cu
O O
62%
2. CH2N2
Cl Cl 3. Zn, HOAc
2πs + 2πa
cycloaddition Zn, HOAc
O
O
CH2N2
O O
Cl 59%
Cl Cl Cl
olefin–ketene
cycloaddition
Loganin: Flemming J. Chem. Soc., Chem. Commun. 1977, 81.

Hirsutene: Greene Tetrahedron Lett. 1980, 3059.
Hirsutic Acid: Greene J. Am. Chem. Soc. 1983,105, 2435.
O R SiR3 O R
TiCl4
+
SiR3
Cl3Ti OTiCl3 OTiCl3

R SiR3
O R SiR3 R
SiR3
Danheiser J. Am. Chem. Soc. 1981, 103, 1604.

- Cyclopropylphosphonium salts:
CO2Me
CO2Me PPh3 NaH
+
THF
O CO2Et 90%
CO2Et
Fuchs J. Am. Chem. Soc. 1974, 96, 1607.
PPh3
Marino Tetrahedron Lett. 1975, 4531.
SPh
351
- β-Vetivone synthesis:
O O
CHO PPh3 NaH CO2Et
+
CO2Et HMPA
EtO EtO
38%
H
PPh3
O
+
O
PPh3
Burgstahler, Boger Tetrahedron 1976, 32, 309.
- Benzothiazoles as carbonyl equivalents:
N Li OEt N
E E E
1. (MeO)2SO2 CHO
S S
E+ 2. NaBH4
3. H+, Ag(I) O
O O
Corey, Boger Tetrahedron Lett. 1978, 5, 9, 13 and 4597.
I Br
H H
i) LDA, I PCC
BuLi
O
Me2NN ii) CuCl2, H2O O
OH
Piers Tetrahedron Lett. 1993, 35, 8573.
- Additional reviews: Denmark Org. React. 1994, 45, 1.

Hudlicky Chem. Rev. 1989, 89, 1467.
Sehore Chem. Rev. 1988, 88, 1085.
Ramarah Synthesis 1984, 529.
352
Dale L. Boger
X. Pauson–Khand Reaction
[2 + 2 + 1]
Org. React. 1991, 40, 1.
Pauson Tetrahedron 1978, 41, 5855.
Schore Chem. Rev. 1988, 88, 1081.
Brummond Tetrahedron 2000, 56, 3263.
First detailed study: Khand J. Chem. Soc., Perkin Trans. 1 1973, 977.
Co2(CO)6
CO O
- Mechanism: large
H Me small
OMe H Me MeO MeO
CO Me
H
+ H Co Co(CO)3 H
(CO)3Co Co(CO)3 – CO (CO)2
H Co
(CO)3 Co(CO)3
less hindered
exo face
CO
large
Co(CO)3
MeO Me
MeO H MeO H H
Co(CO)3 H
O
– Co2(CO)6 reductive Co(CO)3
elimination Co
H H O H H O (CO)3
60% CO inserted
only isomer
1. Regio- and stereochemistry are controlled by steric factors.
2. Complexation of alkene and insertion into Co–C bond occurs from less hindered face.
3. Insertion of the alkene carbon bearing the largest allylic substituent to form the first C–C bond occurs
at the alkyne carbon bearing the smallest substituent.
4. Subsequent CO insertion occurs next to the largest alkyne substituent.
5. Reductive elimination followed by decomplexation gives the final product.
- Intermolecular:
HO HC CH HO H H
Co2(CO)6 6 steps
DME, 65 °C
OMe MeO H O H OTBDPS
4 days O
65%
entry into guaianolide and pseudo-
Schore J. Org. Chem. 1987, 52, 3595. guaianolide natural products
- Intramolecular
RO RO H RO H
Co2(CO)8
O + O
heptane
TMS
80–90 °C TMS TMS
The dimethyl and R = H, 18% R = H, 7%
alkyne substituents R = MOM, 69% R = MOM, 0%
accelerate the reaction.
Magnus J. Am. Chem. Soc. 1983, 105, 2477.
353
Co2(CO)8 H H
O + O
heptane
110 °C, 20 h
45% 6%
Schore J. Am. Chem. Soc. 1988, 110, 5224.
TMS
OTBDMS TMS OTBDMS Epimerization occurs
Co2(CO)8 via the Co-stabilized
O propargyl cation.
isooctane
H H H
OTBDMS 160 °C
OTBDMS
76%
Serratosa Tetrahedron Lett. 1985, 26, 2475.

OH
Mo(CO)6
O
H DMSO−toluene
HO 110 °C, 10 min HO HO
OTBS OTBS O
69%
hyrdoxymethylacylfulvene
Brummond J. Am. Chem. Soc. 2000, 122, 4915.
-Heterosubstituted systems:
H
O benzene O
60 °C, 4 h
H
CO2(CO)6
O
85%
Schreiber J. Am. Chem. Soc. 1986, 108, 3128.
O O
Co2(CO)8
hexane O O
60 °C, 4 h
O
45%
Smith Tetrahedron Lett. 1986, 27, 1241.
354
Dale L. Boger
Y. Carbonylation Cyclizations
Alper Acc. Chem. Res. 1995, 28, 414.
- Pd mediated carbonylation
O O
CO2Me PdCl2(PPh3)2 Pd(PPh3)4
R1 Et3N, CO R1 I CO R1
MeOH R2 (not catalytic)

R2 (catalytic) R2
PdCl2(PPh3)2 O CO2Me
I Et3N, CO
65%
O CO2Me
I PdCl2(PPh3)2
Et3N, CO
66%
Negishi J. Am. Chem. Soc. 1985, 107, 8289.
- Formation of lactones
OH PdCl2, PPh3
SnCl2, CO O
O
93%
Norton J. Am. Chem. Soc. 1981, 103, 7520.
- Formation of amides
Heck J. Org. Chem. 1975, 40, 2667.
Pd(OAc)2
NHBn PPh3, CO
NBn
Br 63%
O
Mori J. Org. Chem. 1978, 43, 1684.
Boc Pd2(dba)3 Boc Boc O

N PPh3, CO N Pd N
BnO BnO
51%
OBn
Nakanishi Synlett 1991, 91.
- Alternative carbonylation method: Hydroboration/Carbonylation
1. CO, H2O H O
BH2 H
B 1000 psi
2. NaOAc, H2O2
H H
60%
Brown, Negishi J. Chem. Soc., Chem. Commun. 1967, 594.
J. Am. Chem. Soc. 1967, 89, 5477.
355
Z. Olefin Ring Closing Metathesis K. Ziegler and G. Natta shared the 1963 Nobel
Grubbs Comprehensive Org. Syn., Vol. 5, 1115. Prize in Chemistry for their discovery and
Acc. Chem. Res. 1995, 28, 446. development of transition metal catalyzed
Tetrahedron 1998, 54, 4413. preparation of polyethylene and stereoregular
Schrock J. Am. Chem. Soc. 1990, 112, 3875 and 8378. polymers including polypropylene.
J. Am. Chem. Soc. 1991, 113, 6899.
-General concept:
Ring
Opening
n
Metathesis
Ring
Closing
X Metathesis X
Acyclic
Cross
R1 + R2 R2
Metathesis R1
- Mechanism: R1
R1
M M
R2 The mechanism appears

R1
to be the same regardless
of transition metal used.
R1
M
R1 M
R2 R2
Grubbs Comprehensive Organometallic Chem., Vol. 8, 1982, 499.
Sehrer J. Sci. Ind. Res. 1983, 42, 250.
- Defined Catalysts
1. Early catalysts were poorly defined and incompatible with basic functionality.
2. Development of well-defined catalysts lead to high catalytic activity and compatibility with a
wide variety of funtionalities.
3. Catalysts are based on variety of transition metals including: Mo, Ru, W, Re, Ti and Ta.
4. The mechanism appears the same for all transition metals.
5. The most widely used catalysts are:
PCy3 PCy3
iPr iPr
Cl Ru Ph Cl Ru
N Ph
Cl Cl Ph
Mo
(CF3)2MeCO PCy3 Ph PCy3
(CF3)2MeCO
1 2 3
Schrock Grubbs Grubbs
356
Dale L. Boger
- Applications to organic synthesis Review: Phillips, Abell Aldrichim. Acta 1999, 32, 75.
Ring closing metathesis is rapidly becoming one of the more powerful methods for preparing
medium and large rings.
Modern use of ring closing metathesis traced back to:
M=CHR
n n
X X
X = O, NR, CHR
n = 1, 2, 3
Grubbs, R. H.; Fu, G. C. J. Am. Chem. Soc. 1992, 114, 5426, 7324.
J. Am. Chem. Soc. 1993, 115, 3800.
Recent examples:
OH O O HO O O
N O N O HO
3 (1 mol%)
CH2Cl2 HO
30 min
Ph Ph carbocyclic nucleosides
97%
Crimmins J. Org. Chem. 1996, 61, 4192.

Jacobsen J. Org. Chem. 1996, 61, 7963.
H H
O R1 1 (13 mol%) O R1
R1 = H, n = 1, 2 >90%
R1 = Et, n = 1, 2 42-73%
O n
C5H12, 25 °C O n R2
H H
R2
n R1 R2 conc (M) Yield
R1R2
H R1 H
O R1 1 (25 mol%) 1 H Et 0.008 97%
O O
2 H Et 0.003 86%
PMP O C6H6, 60 °C PMP O 2 Et H 0.003 14%
n
H H n
2 H H 0.003 58%
note dependence on conformation
between two diastereomers.
Clark, Kettle Tetrahedron Lett. 1997, 38, 123 and 127.
OAc OAc OAc OAc

O O
NHCOCF3 NHCOCF3
O O
1 (20 mol%)
O O 90% Sch 38516
C6H6, 60 °C
HN HN
Hoveyda J. Am. Chem. Soc. 1995, 117, 2943.

J. Am. Chem. Soc. 1996, 118, 10926.
357
- Danishefsky, Nicolaou and Schinzer have all prepared Epothilone A using ring closing metathesis as
the key cyclization step.
S S
N N
H H
O O O O
X ring closing X
metathesis Epothilone A
Y Y
OR OR

Nicolaou Angew. Chem., Int. Ed. Eng. 1997, 36, 166.
Schinzer Angew. Chem., Int. Ed. Eng. 1997, 36, 523.
- Application to ring closing metathesis of enynes:
R R
H
O O O
N N O N
H H H
O
H
R = Me: 2 (5 mol%), C6H6, 50 °C, 73% (–)-Stemoamide
R = CO2Me: 3 (4 mol%), CH2Cl2, 25 °C, 87%
Kinoshita, Mori J. Org. Chem. 1996, 61, 8356.
- Application to the synthesis of fused nitrogen heterocycles:
O O
x n = 0, R = Me a (68%)
x R 1, benzene n = 1, R = H a (92%); b (91%)
N n
N
n = 2, R = H a (81%); b (84%)
25 or 50 °C n = 3, R = H a (47%); b (50%)
n
a) x = 1 a) x = 1
b) x = 2 b) x = 2
CO2Me CO2Me
H H
H 1 H
BnN BnN Manzamine A
O benzene
O 50 °C O
N 64% N O
H
Martin Tetrahedron 1996, 52, 7251.
358
Olefin Synthesis
Dale L. Boger
XI. Olefin Synthesis

A. Wittig Reaction
G. Wittig received the 1979 Nobel Prize in Chemistry for "many significant contributions
to Organic Chemistry" which included not only the Wittig reaction, but also PhLi
prepared by metal–halogen exchange, benzyne, and the Wittig rearrangement.
Reviews: Comprehensive Org. Syn., Vol. 1, 755.

Org. React. 1965, 14, 270.
Top. Stereochem. 1970, 5, 1.
Pure. Appl. Chem. 1979, 51, 515.
Chem. Rev. 1989, 89, 863.
1. Formation of Ylides
+ PhLi, nBuLi, LDA +
ether Ph3P CH2R X Ph3P CHR
Ph3P + X CH2R
or MeS(O)CH2Na
strong electron-withdrawing group pKa ~ 18–20

(R = alkyl, H)
Ph3P CHR
ylide
- Unstabilized ylides are sensitive to H2O, O2
2. Reaction of Ylides with Ketones

+
PPh3
O
O CH-R
+
+ Ph3P CHR
Ylide Betaine
Ph
R Ph P Ph
O R
+ Ph3P O
Oxaphosphetane
Strong bond formation is part of the driving
force for the collapse of the oxaphosphetane.
Wittig and Schöllkopf Chem. Ber. 1954, 87, 1318.
359
3. Mechanism and Stereoselectivity of the Wittig Reaction
RCHO
Ph3P CHCH3 CH3 R
cis olefin from nonstabilized ylides
- Stereoselectivity increases as the size of the R group increases.

- Accepted mechanism today: irreversible and concerted [2 + 2] cycloaddition.
P Ph3
H π2a + π2s cycloaddition
slow (–Ph3P=O) Ph3P O O
H H R
CH3 R suprafacial
CH3 R
cis CH3 H
antarafacial
Orientation such that the R groups on the aldehyde

and on the ylide are as far apart as possible.
- The three alternative [2 + 2] cycloaddition transition states suffer destabilizing steric interactions:
Ph Ph Ph Ph Ph Ph
Ph P Ph P Ph P
R R H
O O O
H H R
CH3 H H CH3 H CH3
trans cis trans

Not bad, probably gives
rise to trans product
- So, the mechanism involves fast, irreversible [2 + 2] cycloaddition (at –78 °C) followed by slow
decomposition of oxaphosphetane (frequently requires warming to 0–25 °C).
- Nonpolar solvents facilitate the initial addition.
- Polar solvents facilitate the final elimination reaction.
4. Representative Examples
+ 1) NaN(SiMe3)2
PPh3 CO2CH3
2) OHC(CH2)8CO2CH3
–78 °C, THF 80%, >98% cis
Besterman Chem. Ber. 1976, 109, 1694.
6.5 equiv CH3PPh3Br

5 equiv nBuLi
H H
Et2O, 25 °C, 1 h
O reflux, 3 h, 56% vitamin D3
OH OH
Inhoffen Chem. Ber. 1958, 91, 2309.
360
Olefin Synthesis
Dale L. Boger
OTs O
HO H H
Al2O3 Ph3P CH2
79%
H H H
O
–
NaH O Ph3PCH3Br
DMSO Ph3P CH2
70 °C S+ Na DMSO 50–55 °C
25 °C 73%
Corey J. Org. Chem. 1963, 28, 1128.
H H H
S S
1) SOCl2 90 °C S
O O
N N 48 h, PhMe N
O OH 2) Ph3P, iPr2NEt O PPh3
89% O
RO2C 51% RO2C CO2R
Woodward J. Am. Chem. Soc. 1979, 101, 6301.
- α-oxygenated substrates
PPh3 O 1) addition
+ O OMe - trisubstituted
2) H3O+ Z-alkene
OH
85%, >99% Z
Still J. Org. Chem. 1980, 45, 4260.
- Schlösser modification: allows the preparation of trans vs. cis olefins.
+
PhLi, Et2O R1CHO O PPh3 PhLi, –30 °C
Ph3P CHR H H
Ph3P CH2R
25 °C, 10 min –70 °C, 5 min R1 R 5 min
+
O– PPh3 1 equiv HCl O– PPh3 KOtBu/tBuOH R1
H H R
R1 R R1 H Et2O, 25 °C R
2h
R R1 % yield trans:cis
CH3 C5H11 70 99:1
C5H11 CH3 60 96:4
C3H7 C3H7 72 98:2
CH3 Ph 69 99:1
C2H5 Ph 72 97:3
Schlösser Angew. Chem., Int. Ed. Eng. 1966, 5, 126.
361
- β-Oxido Phosphonium Ylide Reaction: adaptation of the Schlösser modification for the stereoselective
preparation of trisubstituted allylic alcohols.
O PPh3 sBuLi
OLi
Ph3P THF
+ R'CHO H H PPh3
R –78 °C –78 °C R'
R' R
R
CH2O, 0 °C
O PPh3 –O
+
H R PPh3
H R
H R
R' R'
R' OH – –
O O
Only 2° alkoxide forms oxaphosphetane

that eliminates to form the olefin.
Corey, Katzenellenbogen and Posner J. Am. Chem. Soc. 1967, 89, 4245.
Corey and Yamamoto J. Am. Chem. Soc. 1970, 92, 226.
C. J. Pedersen (DuPont) received the

I 18-crown-6 1987 Nobel Prize in Chemistry for his
+
Ph3P Ar1 + Ar2CHO Ar1 Ar2 (Z)-alkene discovery and development of crown
KOH ethers.
(I– > Cl– > Br–) > 98:2 Z :E
Jean-Marie Lehn received the 1987
Ar2
Nobel Prize in Chemistry along with D.
Br Cl 18-crown-6
+ J. Cram and C. J. Pedersen for their
Ph2P Ar1 + Ar2CHO Ar1 (E)-alkene
KOH development and use of molecules
with structure-specific interactions of
> 96:4 E : Z high selectivity.
Chiappe Tetrahedron Lett. 1996, 37, 4225.
5. Stabilized Ylides
O PPh3 O Na2CO3 O
+ +
Br Ph3P Ph3P
OR ether OR OR
or H2O
benzene
Has two electron-withdrawing

groups so the pKa is very low. Ph3P CHCOOR
- Stabilized ylides are solid; stable to storage, not particularly sensitive to moisture, and can even be
purified by chromatography.
- Because they are stabilized, they are much less reactive than alkyl ylides. They react well with
aldehydes, but only slowly with ketones.
- The first step, involving the addition to the aldehyde, is slow and reversible with stabilized ylides.
362
Olefin Synthesis
Dale L. Boger
R'CHO Ph3P O Ph3P O
Ph3PCHCOOR H R' H H
+
ROOC H ROOC R'
rotation available before elimination minor kinetic product major kinetic product
+
Ph3P O faster slower
H H
ROOC R'
R'
+
ROOC ROOC R'
+ thermodynamically more stable,
Ph3P O and is predominant or exclusive
ROOC H product of the reaction.
H R'
- It is also possible that elimination occurs in a stepwise manner via stabilized zwitterionic
intermediate that may simply afford the more stable product.
- α-Oxygenated substrates
- The exception to the generation of E-alkenes with stabilized ylides is their reaction with α-alkoxy aldehydes.
O
O O (EtO)2P CO2Me O O Ph3P CHCO2Me O O
MeO2C CO2Me
NaH, DME OHC CHO CH3OH
MeO2C CO2Me –78 to 25 °C –78 to 25 °C
trans (E)-olefin cis (Z)-olefin!

Krief Tetrahedron Lett. 1988, 29, 1083.
- And, this departure is solvent dependent CO2Et
O O
OHC O O
Ph3P CHCO2Et
MeO O MeO O
DMF 14 : 86 Z:E trans

CHCl3 60 : 40 Z:E
MeOH 92 : 9 Z:E cis
Tronchet, Gentile Helv. Chim. Acta 1979, 62, 2091.
- Reaction with esters, lactones, and activated lactams
CN CN
O
Ph3P
N BOC 79−92% N BOC
CN
CN O CN
Ph3P CN Ph3P
C7H15CO2Me O O
100 °C C7H15 OMe 25 °C
83% 93%
Tsunoda Tetrahedron Lett. 2000, 41, 235.
363
6. Annulation Applications of the Wittig Reaction
OH a) NaH O O
O 75%
+
b) + PPh3 PPh3 2 carbon unit
PPh3 O
O O
O a) NaH O PPh3 [O]
S
b) + S O2
SH S
PPh3
(–SO2)
chelotropic ∆
extrusion
2 carbon unit
4 carbon unit
O NaH
+
+ PPh3
COOEt
CO2Et
- Homoconjugate addition:
OH O 3 carbon unit
NaH
+ +
PPh3
O
- Modest yields because one electron-withdrawing group is not sufficient to activate the cyclopropane ring to
nucleophilic ring opening.
So: 1) O O
+ N 1) ClCOOEt +
PPh3 SPh PPh3
PPh3
SPh 2) NaBF4 2) NaBF4 COOEt

- Applications:
EtOOC
NaH
O + COOEt
PPh3
COOEt
COOEt
90% PhS O
NaH H+ (Hg2+)
H
+
PPh3 COOEt COOEt
SPh
82%
364
Olefin Synthesis
Dale L. Boger
B. Wadsworth–Horner–Emmons Reaction
Horner Chem. Ber. 1958, 91, 61; 1959, 92, 2499.
Wadsworth, Emmons J. Am. Chem. Soc. 1961, 83, 1733.
Reviews: Org. React. 1977, 25, 73–253.
1. Arbuzov (Michaelis−Arbuzov) Reaction: Preparation of Phosphonate Esters

Arbuzov J. Russ. Phys. Chem. Soc. 1906, 38, 687. Michaelis Ber. 1898, 31, 1048.
O OEt
O O O
P OEt –EtCl
(EtO)3P: + Cl EtO P(OEt)2
OEt O EtO
CH2CH3
Arbuzov Pure Appl. Chem. 1964, 9, 307. Cl

- The same approach to the preparation of β-ketophosphonates is not successful:
O O
(RO)3P
(RO)2P
R'
O
O
Cl
R' Perkow reaction P(OR)2
O
R'
- But can use variation on Claisen conditions:
OEt O
EtI O LDA or nBuLi,
P(OEt)3 EtO P+ CH2CH3 (EtO)2P CH3
(EtO)2P CH3
O –78 °C
Li
CH3CH2
Unstable at higher temperatures or O
I under prolonged reaction times.
EtO R'
Can also use: O O
O
(EtO)2P Cu +
Cl R (EtO)2P CH3
Savignac Tetrahedron Lett. 1976, 2829.
R' O
2. Mechanism and Stereoselectivity
O O O O O O
NaH RCHO (EtO)2P ONa
P(OEt)2 P(OEt)2 + (EtO)2P ONa
EtO EtO H H
THF H R
Na+ EtOOC R EtOOC H
O O
OH H R
EtO P O (EtO)2P O (EtO)2P O
+
H R H R
EtO EtOOC H
EtOOC H EtOOC H
E-selective
Note possibility of C–C bond rotation
(trans)
(may or may not be discrete intermediate)
Water soluble (easily removed through aqueous workup)
EtO W = CN, COOR, C(O)R, CHO, SO2Ph, Ph
Good reactions for: EtO P W
But not W = alkyl, H
O
365
3. Modifications and Scope
- LiCl/tertiary amines (DBU, iPr2NEt, Et3N)
Masamune, Roush Tetrahedron Lett. 1984, 25, 2183.

Can substitute for conventional conditions and is especially good for base sensitive substrates
(epimerization, elimination).
O O OMTM LiCl, iPr2NEt O

P(OEt)2 +
CH3 O O H CH3CN CH3 O OMTM
80%
subject to β-elimination
Keck J. Org. Chem. 1989, 54, 896. (thioester was also stable to these conditions)
-Hindered phosphonates and hindered aldehydes increase E-selectivity (trans).
CH3 CH3
BnO BnO
CHO CO2R
Ph3P=CHCO2Et, CH2Cl2, 0 °C 7:1 E:Z
(iPrO)2POCH2CO2Et, KOtBu, THF, –78 °C 95 : 5 E:Z
(MeO)2POCH2CO2Me, KOtBu, THF, –78 °C 1:3 E:Z
Kishi Tetrahedron 1981, 37, 3873.

- The use of a nonhindered phosphonate, low temperatures, and a strongly dissociating base (KOtBu) can
give increased or high Z-selectivity (cis).
- Coordinating countercations slow the rate of elimination relative to equilibration.
Ph CHO Ph CO2R Ph CH3

+
CH3 CH3 CH3 CH3 CO2R
Stabilized Ph3P=C(Me)CO2Et, CH2Cl2, 25 °C 95 : 5

Wittig reagent Ph3P=C(Me)CO2Et, MeOH, 25 °C 85 : 15
(MeO)2POCH(Me)CO2Me, KOtBu, THF, –78 °C 5 : 95
(MeO)2POCH(Me)CO2Et, KOtBu, THF, –78 °C 10 : 90
Wadsworth–Horner–
Emmons reagent (EtO)2POCH(Me)CO2Et, KOtBu, THF, –78 °C 40 : 60
(iPrO)2POCH(Me)CO2Et, KOtBu, THF, –78 °C 90 : 10
(iPrO)2POCH(Me)CO2iPr, KOtBu, THF, –78 °C 95 : 5
- Still–Gennari modification selective for Z-alkenes (cis):

O
KHMDS R
R'CHO + (CF3CH2O)2P CO2Me R'
18-c-6 CO2Me
R THF
R = H, Me Z selective
Z : E > 10 : 1
Still Tetrahedron Lett. 1983, 24, 4405.

R = Br, Kogen Org. Lett. 2000, 2, 1975. (Trisubstituted olefins via Suzuki or Stille coupling)
366
Olefin Synthesis
Dale L. Boger
CH3 CO2Me (CF3CH2O)2POCH2CO2Me CH3 (EtO)2POCH2CO2Et CH3
BnO KH, THF BnO CHO NaH, THF BnO CO2Me

84% 11 : 1 Z : E 83% 12 : 1 E : Z
Cinquini Tetrahedron 1987, 43, 2369.
OH
I O
I (CF3CH2O)2POCH2CO2Me
CHO KHMDS, 18-c-6

–78 °C, 30 min MeO2C O
97%, >25:1 Z : E
O
Boger J. Org. Chem. 1991, 56, 4204. Combretastatin D-2
- Additional Z-selective stabilized phosphonates.

R CO2Et
RCHO R CO2Et RCHO
(PhO)2P(O)CH2CO2Et (PhO)2P(O)CH(R')CO2Et
R'
Ando J. Org. Chem. 1997, 62, 1934. Selected diarylphosphonates provide high Z-selectivity
Ando J. Org. Chem. 2000, 65, 4745. (NaI/DBU vs NaH) Ando J. Org. Chem. 1998, 63, 8411.
- Other useful reactions of functionalized phosphonates.
H
O
(MeO)2P H - Direct production of alkynes.
CHO
N2 Provide a mechanism
for this transformation
tBuOK, THF
OMe OMe
–78 °C
OTIPS 95% OTIPS
Schreiber J. Am. Chem. Soc. 1990, 112, 5583.
O
OR
O (MeO)2P H - Synthesis of enol ethers
R = Me, 58% and enamines.
N2 R = tBu, 56%
t
BuOK, ROH
or NiPr2
i
Pr2NH
59%
Gilbert Tetrahedron Lett. 1980, 21, 2041, 5003; 1984, 25, 2303.
J. Org. Chem. 1983, 48, 448.
C. Peterson Olefination
Peterson J. Org. Chem. 1968, 33, 780.

J. Org. Chem. 1967, 32, 1717.
J. Am. Chem. Soc. 1975, 97, 1464.
Reviews: Org. React. 1990, 38, 1.
367
1. Nonstabilized Peterson Reagents
- Me3SiCH2Met, Met = Li, Mg, offer an alternative to Wittig or Tebbe procedures. They are more reactive
and sterically less demanding than a Wittig reagent and the volatile byproduct (Me3SiOH/ Me3SiOSiMe3)
is simpler to remove than Ph3PO. It does, however, require a second step to promote elimination of the
β-hydroxysilane.
- Example
Et3SiO O O
MeO OMe 1) LiCH2SiMe3 MeO OMe
CH3 N NMe 2) DDQ, THF CH3 N NMe

OMe O
Danishefsky J. Org. Chem. 1988, 53, 3391.
- TMS eliminates in preference to Ph3P or P(O)(OR)2:
Ph Ph
O + Ph3P SiMe3 +
Ph Ph PPh3
Peterson. J. Org. Chem. 1968, 33, 780. Note: this is the origin of its discovery
- Modifications include: Me3SiCH2MgBr/ TiCl4 (direct production of olefin), and Me3SiCH2Li/ CeCl3
(enolizable ketones and aldehydes, while esters and acid chlorides give allylsilanes via addition 2x).
- The elimination is stereospecific: acid-promoted being anti and base-promoted being syn.
Pr Pr
Acid Base
(anti) (syn)
Me3Si OH Me3Si OH
Pr Pr Pr Pr
Base Acid
(syn) (anti)
Pr
Pr
Hudrlik, Peterson J. Am. Chem. Soc. 1975, 97, 1464.
- Unstabilized Peterson reagents add to ketones and aldehydes irreversibly with little diastereoselectivity.
Therefore, mixtures of cis and trans olefins are obtained and the reactions are not yet as useful as the
Wittig reaction.
2. Stabilized Peterson Reagents

- The stabilized Peterson reagents give predominantly the most stable trans olefins (E) although this has
been studied far less than the Wittig or Wadsworth–Horner–Emmons reactions. The origin of this
diastereoselection has not been extensively explored with regard to enolate geometry, reversible/
irreversible addition, or mechanism of elimination. In this case, the elimination takes place under the
reaction conditions.
368
Olefin Synthesis
Dale L. Boger
O a) LDA, –78 °C OtBu OSiMe3
SiMe3
CH3 OtBu b) Me3SiCl O OtBu
LDA
OtBu
R
RCHO
LiO
CO2tBu
SiMe3
trans predominates
Rathke Tetrahedron Lett. 1974, 1403.

Yamamota J. Am. Chem. Soc. 1974, 96, 1620.
- via:
Me3Si OLi Me3Si O t
BuO2C
t tBuO
BuO2C H 2C H
H R H R R
major
+
Me3Si O tBuO
2C
H R
Me3Si OLi Me3Si O t R
t BuO2C H major
t BuO2C R
BuO2C R
H H H H
t
Can be trapped BuO2C R
minor
- Both single step and two-step elimination via an equilibration have been proposed.
- Additional examples:
OHC CH3
Cl CH3 Cl CH3
NtBu
CH3O NCOCF3 OHC CH3 CH3O NCOCF3 CH3
CH3
H
SiMe3
OMEM Li OMEM
maytansine
S S
S 82% S
CH3 OMe CH3 OMe
Corey, Weigel, Chamberlin, Lipshutz J. Am. Chem. Soc. 1980, 102, 1439.
Corey, Enders, Bock Tetrahedron Lett. 1976, 3 and 7.
N SiMe3
N
+ O
S Li 92% S
Corey and Boger Tetrahedron Lett. 1978, 5.
369
D. The Tebbe Reaction and Related Titanium-stabilized Methylenations
reviews: Org. React. 1993, 43, 1.
- The Wittig, Wadsworth–Horner–Emmons, and Peterson olefination do not convert esters or amides to the
corresponding olefin, but rather fail to react or result in the cleavage of the ester or amide bond.
- Schrock discovered that Ta and Nb tert-butyl alkylidene complexes behave analogous to phosphorous ylides
and, notably, react with esters and amides to provide the corresponding tbutylalkenes.
Schrock J. Am. Chem. Soc. 1976, 98, 5399.
- The Tebbe reagent was introduced in 1978 and was shown to react with aldehydes, ketones, esters, and
lactones to produce the methylene derivatives.
O
Cp2Ti AlMe2
X X Cl
X = H, R, OR, NR2 Tebbe reagent
65%
Tebbe J. Am. Chem. Soc. 1978, 100, 3611.
- Tolerates ketal and alkene derivatives.
Scope defined by Evans and Grubbs J. Am. Chem. Soc. 1980, 102, 3270.
Extended to tertiary amides by Pine J. Org. Chem. 1985, 50, 1212.
O 81% O 90%
Ph Ph
Ph OCH3 Ph OCH3 OEt OEt
O
87% Ph 96% Ph
O O O
O O O O
OEt OEt
O
80%
Ph N Ph N
For an analogous use of Cp2TiMe2: Petasis J. Am. Chem. Soc. 1990, 112, 6392.
370
Olefin Synthesis
Dale L. Boger
E. Representative Other Methods for Terminal Methylene Formation
Reagents References
R2CO, CH2CI2, Mg Cainelli Tetrahedron Lett. 1967, 5153.
R2CO, LiCH2PO(NMe2)2 Corey J. Am. Chem. Soc. 1966, 88, 5653.
R2CO, LiCH2SPh; CH3SO2Cl; Li/NH3 Coates J. Am. Chem. Soc. 1972, 94, 4758.
R2CO, LiCH2SPh; (RO)2PCl; heat Kuwajima Tetrahedron Lett. 1972, 737.
R2CO, LiCH2S(O)Ph Kuwajima Tetrahedron Lett. 1972, 649.
- Julia Olefination
Review: Comprehensive Org. Syn., Vol. 1, 792.
OR''
1) R'CHO Na–Hg
R SO2Ar R R
R' R'
2) PhCOCl
SO2Ar
R'' = Ms, Ts, Ac, COPh exclusively or predominantly
the more stable trans isomer
- Example:
CHO
1) addition Na–Hg
+ H H
2) BzCl BzO
Ts MeOH–THF
H TBSO OTBS 2 h, –20 °C
Li Ts 80%
TBSO OTBS TBSO OTBS

Julia Tetrahedron Lett. 1973, 4833.
Julia developed a more recent, single-step variant that avoids the reductive elimination
ArCHO
S N S N S N Li S N
OLi Ar
O SO2
Li SO2 SO2 54% 98:2 E:Z OLi
Ar
Ar
Julia Bull. Soc. Chim., Fr. 1993, 130, 336.
R2CO, LiCH2S(O)tBu; SOCl2–CH2Cl2 Durst J. Am. Chem. Soc. 1973, 95, 3420.
–CH(OH)CH2CO2H, HC(OMe)2NMe2, heat Hara Tetrahedron Lett. 1975, 1545.
RC CH, RCu R2C=CH2 Normant Tetrahedron Lett. 1971, 2583.
RCO2CH3, Ph3P=CH2 R(CH3)C=CH2 van der Gen Tetrahedron Lett. 1975, 1439.
R2CO, PhS(O)(NCH3)CH2Li Johnson J. Am. Chem. Soc. 1973, 95, 6462.
RCH2SO2CH2Cl, HO– Doomes and Corfield J. Am. Chem. Soc. 1970, 92, 2581.
- Ramberg–Backlund reaction
R R R
R S Cl S R
O2 O2 R
Org. React. 1977, 25, 1.
371
Reagents References
RC CH, H2/ Lindlar catalyst Org. Syn. 1969, 46, 89.

R2CHCH2OAc, ∆ (pyrolysis) Org. React. 1961, 12, 57.
Also: xanthates Chem Rev. 1960, 60, 431.
R2CHCH2NMe2, H2O2, ∆ Org. React. 1960, 11, 317.
- Cope Elimination
+
- it is related to the Hofmann elimination reaction (–NMe3)
- Both the acetate pyrolysis and the Cope elimination have been superceeded by the related syn
elimination reactions of sulfoxides and selenoxides.
R2C(Hal)CH3, tBuOK J. Chem. Soc., Chem. Commun. 1968, 305.
F. Olefin Inversion Reactions

Vedejs J. Am. Chem. Soc. 1971, 93, 4070. OLi
m-CPBA H OLi H Ph
O Ph
Ph
Ph Ph
Ph Ph Ph2PLi Ph2P H Ph H
PPh2
Li
Ph2PCl
THF
MeI
Ph OLi
H Ph H Ph
–Ph2MeP O
Ph Ph H
Ph + H
99% yield Ph2P O PPh2
>98% cis CH3
CH3
-Other examples:
m-CPBA 1) Ph2PLi
Ph Ph Ph
Ph
2) MeI
95%; > 99% trans
m-CPBA 1) Ph2PLi
2) MeI OTHP
OTHP
85%; >98% Z
m-CPBA 1) Ph2PLi
2) MeI
90%; >99% trans
372
Olefin Synthesis
Dale L. Boger
-Deoxygenation of epoxides (with retention of geometry)
O
R'
R
R R'
–SCN van Tamelen J. Am. Chem. Soc. 1951, 73, 3444.
Ph3P S , H+ Chan J. Am. Chem. Soc. 1972, 94, 2880.

S
S Stojnac Can. J. Chem. 1975, 621.
N
–SeCN Johnstone J. Chem. Soc., Perkin Trans. 1 1975, 1216.

Ph3P Se Clive J. Chem. Soc., Chem. Commun. 1973, 253.
S
Se Chan Tetrahedron Lett. 1974, 2091.
N
Calo Synthesis 1976, 200.
-Deoxygenation of epoxides (with inversion of geometry)

O
R'
R
R R'
Me3SiK Dervan J. Am. Chem. Soc. 1976, 98, 1265.
PhMe2SiLi Reetz Synthesis 1976, 199.
-Diol Alkene
HO OH
R R'
R R'
S
HO OH (RO)3P
H H O O R R'
R R' H H cis elimination
R R'
Corey–Winter Olefin Synthesis Corey J. Am. Chem. Soc. 1963, 85, 2677.
OEt
HO OH H+, EtOH
H H O O R R'
R R' H H (–CO2)
R R' cis elimination
Eastwood Aust. J. Chem. 1964, 17, 1392.

Eastwood Tetrahedron Lett. 1970, 5223.
HC(OEt)3 H
OH O H+ R
OH O OEt
RR RR R
Burgstahler, Boger Tetrahedron 1976, 32, 309.
373
G. [3,3]-Sigmatropic Rearrangements
1. Claisen and Cope Rearrangement
Org. React. 1975, 22, 1.
Acc. Chem. Res. 1977, 10, 227.
D D
Cope Rearrangement
HO HO
Oxy-Cope Rearrangement
O Claisen Rearrangement
O
Introduction of C=O is the driving force of the reaction
- Originally conducted on aryl allyl ethers.
- Most useful variant established when extended to nonaromatic substrates.
- First example of an acyclic Claisen rearrangement:
CH3 CH3 CH3

OEt 200 °C
cat. Hg(OAc)2 12 h
HO O 85%
CHO
Burgstahler J. Am. Chem. Soc. 1961, 83, 198.

2. Amino-Claisen Rearrangement
Me2SO4 ∆ H2O
+ +
N N N O
- This reaction occurs best when nitrogen is converted to the ammonium salt.
Gilbert Tetrahedron Lett. 1984, 25, 2303.
Stille J. Org. Chem. 1991, 56, 5578.
3. Thio-Claisen Rearrangement
∆ H3O+
S S O
- This reaction is often run with a reagent that will convert sulfur to oxygen following the reaction.
- An advantage of the thio-Claisen rearrangement is that the precursor can be deprotonated and alkylated.
1) nBuLi R R R
∆
S S S O
2) RX
trans C=C bond
Yamamoto J. Am. Chem. Soc. 1973, 95, 2693 and 4446.
374
Olefin Synthesis
Dale L. Boger
- Also can be conducted with the corresponding sulfoxide.
S
O
Block J. Am. Chem. Soc. 1985, 107, 6731.
4. The Carroll Reaction

R R
R esterification ∆
O R' O R'
OH HO R' Base
O O O O
O O
Carroll J. Chem. Soc. 1940, 704, 1266. R R

H3O+
Hartung J. Chem. Soc. 1941, 507. O
R' R'
Cope J. Am. Chem. Soc. 1943, 65, 1992. –CO2
Tanabe J. Am. Chem. Soc. 1980, 102, 862. O O O
5. Eschenmoser–Claisen Rearrangement
MeO OMe
1
CO2Me NMe2 CO2Me CO2Me
O
Me2N
OMe xylene, 140 °C

OH O
14 h, 70%
NMe2 NMe2
+ MeOH
Eschenmoser Helv. Chim. Acta 1964, 47, 2425; 1969, 52, 1030.
1 O NMe2
OH H xylene Me2N H Me O
17 h H H
- Chair-like transition state, substituents in equatorial positions lead
to trans double bond with transfer of chirality.
Hill J. Org. Chem. 1972, 37, 3737.
6. Ireland Ester Enolate Claisen Rearrangement
- The most useful of all Claisen rearrangements. The enolate may be trapped with TMSCl or the
enolate may be used directly.
- The reaction works well with the free enolate and actually allows for a faster rearrangement that will
occur at 25 °C (anion accelerated).
OSiMe3 OSiMe3
R' R'
O O
O
R R
R'
R OH O
OSiMe3 OSiMe3
R R'
O O
Ireland J. Am. Chem. Soc. 1972, 94, 5897. R'
Larock Comprehensive Org. Trans., 935. R R
375
7. Oxy-Cope Rearrangement
HO HO O
H
relatively slow
250 °C
+ +
KO KO H3O+
1010–1017fold rate acceleration,

occurs at 25 °C
H H
250 °C OH O
OH (slow)
H H
KH
H H
OK O
25 °C H3O+
OK
H H
H K
Li Li NBn
N –40 °C N –60 °C
R R NBn
toluene THF
R K R
PhS PhS H
Macdonald Tetrahedron Lett. 1993, 34, 247.
- For a review of anion accelerated sigmatropic rearrangements: Org. React. 1993, 43, 93.
376
Olefin Synthesis
Dale L. Boger
8. Representative [3,3]-Sigmatropic Rearrangement Routes to Olefins
X
OH ∆
O RHC • CHCH2COX
R
R
Lumbroso–Bader Tetrahedron Lett. 1968, 4139; 1966, 3203.
O NaNH2 O
R OH R
R NH2
Br
Katzenellenbogen Tetrahedron Lett. 1975, 3275.
O
Zn O
R OH R O
R OH
Br
Baldwin J. Chem. Soc., Chem. Commun. 1973, 117.
O R2NLi, Me3SiCl
OH O
O 60 °C OH
SPh
SPh
Lythgoe Tetrahedron Lett. 1975, 2593.
CHO
O ∆
CHO
Carnduff J. Chem. Soc., Chem. Commun. 1967, 606.
Me3SiO O O OSiMe3 O O
Me3SiO CH3
∆ O OSiMe3
O
CH3
CH3 H3C
Coates J. Am. Chem. Soc. 1975, 97, 1619.
∆
O S O S
OPh OPh
Faulkner J. Am. Chem. Soc. 1973, 95, 553.
377
H. [2,3]-Sigmatropic Rearrangements
Review: Comprehensive Org. Syn., Vol. 6, pp 834, 873–908.
Org. React. 1994, 46, 105–209.
- Analogous to [3,3]-sigmatropic rearrangement except it enlists a localized charge (anion) in place of a
double bond.
- Often times the reaction is referred to as a Wittig [2,3]-rearrangement in honor of Wittig's discovery of the
related 1,2-alkyl shift of oxycarbanions (Wittig Rearrangement). The reacton is simply a [2,3]-sigmatropic
version of the Wittig rearrangement.
- Examples: R R R
R R R R
R CN R
CN
O O O
more stable anion

Julia Tetrahedron Lett. 1974, 2077.
S
S
+ S - reaction facilitated by loss of positive charge on sulfur
S
ylide zwitterion
Lythgoe J. Chem. Soc., Chem. Commun. 1972, 757.
O R OH
S
:PR3
S
R O
R
S
O
Cl O S :PR3
R O
Cl
Evans Acc. Chem. Res. 1974, 7, 147.
- Still's use of the [2,3]-sigmatropic rearrangement:
OH O SnBu3 O R
nBuLi
Bu3SnCH2I [2,3] O
R R R H
base
CH3
no 1,3-diaxial interactions A 1,2-strain

CH3
R H O
R
H H R H R
O O vs. O
CH3 CH3 H CH3
H H
Li Z-transition state E-transition state one isomer, Z
- R prefers the axial versus equatorial position:
- Selectivity is lost when A 1,2-strain is removed
H
R OH
R R
+ OH
O
H H
Li 40:60
378
Olefin Synthesis
Dale L. Boger
O Ph3P OH
O + O
R S R S S
R Ph R
Ph Ph trans olefin
H H
H H
R H
via the transition state: S O vs. S O
Ph Ph
H H R H
OH (EtO)2PCl R1
O
R2
R1 (EtO)2P
R2
Bodalski Synthesis 1990, 799.
- Ring expansion:
Br + +
S B– S
S S
65%
Vedejs J. Am. Chem. Soc. 1975, 97, 6878.

Vedejs J. Org. Chem. 1978, 43, 1185.
Vedejs Tetrahedron Lett. 1978, 523, 519.
+
N N
Ph 90% 83%
CO2R N+ N
RO2C Ph
Jones J. Org. Chem. 1962, 27, 3572.
- Diastereoselectivity:
tBu +
S Ph SPh 97:3
H2O tBu
Cl
Cl 53% O
tBu +
S Ph SPh
tBu
91:9
59%
CO2Et CO2Et
379
S
S
Br N
Ts(H)N SMe SMe

NC NMe2 CHO
R + R Base H3O+
N R R
Br
∆
NC
Mander J. Org. Chem. 1973, 38, 2915.
CH3 CH3
R2NLi
S R SH R
Kreiser Tetrahedron Lett. 1975, 1669.
Stork J. Am. Chem. Soc. 1974, 96, 6774. Prostaglandin synthesis; sulfenate/sulfoxide rearrangement.
o-formylation of anilines: note olefin inversion.
H
N NH2
NH2 +
S
SMe
X X
+
RS N
SR CH3 O CH3 CH3
OMe OMe OMe OH
R2N
MeO MeO MeO MeO

CH3 CH3 CH3 CH3
Juncusol
Boger J. Org. Chem. 1984, 49, 4045.
H CH3
Me3SiOTf CH3
+
N CO2CH3 Et3N HN CO2Me
CH3 CH2Cl2, 25 °C HN CO2Me
CH3 CH3
81:19
Nakai Chem. Lett. 1990, 2069.
CH3 O
CH3
H N+
TMS H OCH3
H H
See Also:
Sato J. Am. Chem. Soc. 1990, 112, 1999.

CH3 NaNH2
N
N+ NH3
di- and trisubstituted olefins

380
Olefin Synthesis
Dale L. Boger
I. Olefin Synthesis Exemplified with Juvenile Hormone
1. Trost Synthesis: J. Am. Chem. Soc. 1967, 89, 5292.

Wadsworth–Horner–Emmons Reaction
Me
O
2. Syntex Synthesis: J. Am. Chem. Soc. 1968, 90, 6224. Me CO2Me
Robinson Annulation H
Alkylation Diastereoselectivity
Fragmentation Reaction
Directed Epoxidation Reaction
3. Corey Synthesis: J. Am. Chem. Soc. 1968, 90, 5618.

Dissolving Metal Reductions: Cyclic Precursors to Trisubstituted Olefins
Oxidative Cleavage of Enol Ethers
LiAlH4 Reduction of Propargyl Alcohols
Cuprate Coupling Reactions
Allylic Alcohol Oxidation
4. Johnson Synthesis: J. Am. Chem. Soc. 1968, 90, 6225.

Julia Olefin Synthesis
Cornforth Nucleophilic Addition
5. Corey Synthesis: J. Am. Chem. Soc. 1970, 92, 6635, 6636, 6637.
Lindlar Catalyst Alkyne Reduction
1,5-Hydrogen Migration
β-Oxido Ylide Reaction
Diimide Reduction

[3,3]-Sigmatropic Rearrangements
Claisen Reaction
Cope Reaction
Oxy-Cope Reaction
7. Stotter–Kondo Synthesis: J. Am. Chem. Soc. 1973, 95, 4444.

Dihydrothiopyran Strategy: Cyclic Precursors to Trisubstituted Olefins

Stabilized Allylic Anions, Desulfurization (Benkeser Dissolving Metal Reduction)
Sulfur Ylides
Cyclopropane Synthesis
Epoxide Synthesis
8. Still Synthesis: Tetrahedron Lett. 1979, 593.

[2,3]-Sigmatropic Rearrangement
9. Other Syntheses:
Beltsville Synthesis: J. Econ. Entomol. 1968, 61, 866.
Mori Synthesis: Tetrahedron 1969, 25, 1667.
MacKay Synthesis: J. Chem. Soc., Chem. Commun. 1969, 733.
Schering Synthesis: Angew. Chem., Int. Ed. Eng. 1969, 8, 271. (Farnesol -> C-18 JH)
Zoecon Synthesis: J. Am. Chem. Soc. 1970, 92, 735.
van Tamelen Synthesis: J. Am. Chem. Soc. 1970, 92, 737.
381
1. Trost Synthesis: J. Am. Chem. Soc. 1967, 89, 5292. Wadsworth–Horner–Emmons Reaction
O
(MeO)2P CO2Me
1. LiAlH4, 86% alkylation
+ 2. PBr3, 45% +
spinning-band CO2Me NaOH;
O distillation Br O
H+, –CO2
CO2Me CO2Et
Wadsworth–Horner– 73%
Emmons reaction 37% 17%
O
(MeO)2P CO2Me 1. LiAlH4
2. PBr3
+
CO2Me 3. CH3COCH2CO2Me
O 4. NaOH
Wadsworth–Horner– 39% CO2Me 30% 5. H+, –CO2
Emmons reaction
O
(MeO)2P CO2Me
Me Me Me
+ CO2Me
O
CO2Me
Wadsworth–Horner– 18% 30%
Emmons reaction
Me 40% C-18 JH
m-CPBA
O 10% internal epoxide
CO2Me
10% diepoxide
Relative Activity
nat. C-18 JH 1 Synthesis was relatively non-stereoselective
syn. C-18 JH 1 - structural assignment
t-t-t (epoxide) 0.4 - structure–activity studies
c-t-t (triene) 0.1 - prevents adult development from pupa
t-t-t (triene) 0.04 - more potent analog found
c-t-t (epoxide) 8
ethyl ester
H Stereoselectivity
Me H - not much difference between Me and H
H (second atom steric effect)
O - both isomers obtained from the Wadsworth–
HH Horner–Emmons reaction (Modern
improvements now available)
Me
Retrosynthetic Analysis
CO2Me - repeating subunits recognized
- repeating reactions utilized
382
Olefin Synthesis
Dale L. Boger
2. Syntex Synthesis: J. Am. Chem. Soc. 1968, 90, 6224. Robinson Annulation
Alkylation Diastereoselectivity
Directed Epoxidation Reaction
O Et O Et OTHP
1. KOH, MeOH 1. NaBH4, 5 °C 1. KOtBu, MeI
Et + O
2. TsOH, C6H6 2. DHP, H+ 2. H+, H2O
O O
O 67% 54% (4 steps )(95% d.e.)
Et Et
Robinson annulation Selective reduction Thermodynamic enolate:
THP protecting group alkylation diastereoselectivty
Et OH Et OH Et OH
LiAlH(OtBu)3 m-CPBA LiAlH4
74% CH2Cl2 dioxane
O HO HO
50% O 65%
Et Me Et Me Et Me
Reduction diastereoselectivity Directed epoxidation Reduction
Et2O gives exclusively regioselectivity
the isomeric epoxide
Et OH Et OH
TsCl, pyr NaH 1. DHP, H+
–5 °C THF, 25 °C Et OH
2. MeLi
HO 89% TsO 50% 3. H+, H2O
OH OH
Et Me Et Me 57%
Selective equatorial O
Fragmentation reaction Stereochemistry
OTs formation of Nu– addition
100% stereospecific
TsCl, pyr NaH

Et OH Et OTs
25 °C THF, 25 °C O
95% 80%
HO HO
Me 2° vs. 3° TsCl selectivity Me Fragmentation reaction C-18 JH
Et O Et OH Selective Reduction
NaBH4 - saturated vs. α,β-unsaturated carbonyl
- ring strain associated with 5-membered
5 °C ring carbonyl released on reduction
O O
- attack from least hindered face
Et Et
THP Protecting Group

H+ ROH
- if R group contains chiral centers,
O O O OR diastereomers result
DHP THP - removed by mild acid
383
Thermodynamic Enolate
OTHP - severe 1,3-diaxial interaction in chair-like
OTHP – T.S. axial alkylation
O
vs.
- no steric incumberance to axial alkylation on
–
O least hindered face of twist boat T.S.
LiAlH(OtBu)3 Reduction
H - large reagent, usually equatorial H– delivery
Dunitz angle
OTHP - 1,2-interaction (torsional strain) relatively
O invariant to Nu– size
- 1,3-steric interaction highly dependent on
O H 109°
Nu– size
H– - due to absence of axial C(3)–H, large reagent
H– now gives axial delivery
Et OH Et OH Et OH Epoxidation
- in Et2O, coordination of peracid to solvent
m-CPBA +
gives delivery from the least hindered α-face
HO HO HO - in CH2Cl2, H-bonding of OH to peracid
O O
Et Me Et Me Et Me provides delivery to the less accessible β-face
Solvent - Teranishi J. Am. Chem. Soc. 1979, 101, 159.
CH2Cl2 50% 0%
Et2O 0% 100%
OH 1st Fragmentation
- utilized to control C=C bond
OH NaH stereochemistry
TsO O H - trans periplanar orientation of breaking
O bonds
- dictates Z olefin geometry in product
2nd Fragmentation
OTs - utilized to control C=C bond
stereochemistry
O NaH
H - trans periplanar orientation of breaking
H R R O bonds
H H - dictates E olefin geometry in product
Fragmentation Reactions Grob Angew. Chem., Int. Ed. Eng. 1969, 8, 535.
Interannular LG
LG
P
P
- Trans periplanar LG
arrangement of Intraannular
LG
participating bond
P
orbital and departing
P
bond orbital
Extraannular LG
LG
P O
P
384
Olefin Synthesis
Dale L. Boger
- Wharton J. Org. Chem. 1965, 30, 3254.
- Fuchs J. Am. Chem. Soc. 1979, 101, 3567.
- Case A
OTs
H H
KOtBu
+
OH OH OH
H H
KOtBu
E2 elimination, no fragmentation
O OTs
H
- Case B
OTs
H
KOtBu
trans olefin only
90%
OH O
H H
OTs
KOtBu
O H O H
H
- Case C
OTs
H
KOtBu
90% trans olefin only
OH O
OTs
H H OH
OTs
KOtBu less stable conformation
O O H and not set up for
H
H H fragmentation
most stable conformation
- Case D
OTs
H
KOtBu
cis olefin only
95%
OH
O
H H O
OH
KOtBu
TsO H
H
385
- Other groups at "promoter" site can be used
OTs
O O
KOtBu
O O
95%
H
CO2CH3 CO2CH3
Me
CO2CH3 Me
O O CO2CH3
OTs
O KOtBu O
H H H
H H
- Many other types of fragmentation reactions
CH3 O
OCH3 CH3O
1 N OH
O2 < 5 °C CH3O2C
HO2C O O
N CO2CH3 N
[4 + 2] O oxidative HO
CH3 Cycloaddition CH3O CO CH decarboxylation CH3
2 3
Boger J. Org. Chem. 1991, 96, 6942.

J. Am. Chem. Soc. 1993, 115, 11418.
CO2CH3
CH3O HO CO2CH3
CH3O
N CH3 N CH3
CH3O 1O CH3O
2
CO2H CH3O2C O
CH3O2C CO2H O
N HO N
CH3 CH3
Isochrysohermidin
What is
mechanism?
CH3O2C
CH3O OCH3 N
N N CH3O N 1. Zn–HOAc
CH3O2C CO2CH3 + CH3O
N N 2. CH3I, NaH
CO2CH3
CH3O OCH3 CH3O2C CO2CH3
N N
CO2CH3 CO2CH3
CH3O CH3O
1. LiOH
N CH3 2. TFAA N CH3
CH3O CH3O
3. CH2N2
CO2CH3 CO2H
CH3O2C CO2CH3 4. H2O CH3O2C CO2H
N N
CH3 Intramolecular cyclic anhydride CH3
formation utilized to differentiate
internal acids of tetraacid.
386
Olefin Synthesis
Dale L. Boger
3. Corey Synthesis: J. Am. Chem. Soc. 1968, 90, 5618. Dissolving Metal Reductions
Cyclic Precursors to Trisubstituted Olefins
Oxidative Cleavage of Enol Ethers
LiAlH4 Reduction of Propargyl Alcohols
Cuprate Coupling Reactions
Cyclic precursor to stereochemically Allylic Alcohol Oxidation
defined trisubstituted olefin
1. O3 , –78 °C CO2Me
MeO MeO Me2S/MeOH
Li, THF/tAmOH 1. TsCl, pyr
NH3, –33 °C 2. NaBH4, –78 °C 2. LiAlH4, Et2O
HO
53% 65%
Birch reduction
note regioselectivity Mechanism
1. TsCl, pyr I
OH
OH
THPO 1. LiAlH4, NaOMe OH Et2CuLi, Et2O
2. Li THF, ∆ –30 °C
3. TsOH, MeOH 2. I2, –60 °C EtI, 0 °C
30% 65% 78%
Directed hydroalumination Cuprate

of alkyne substitution
1. LiAlH4, NaOMe
OH 1. PBr3, 0 °C THF, ∆ Me2CuLi, 0 °C
Li 2. I2, –60 °C I 53% for 3
2. steps
TMS
80% OH
3. AgNO3, KCN OH
4. nBuLi, (CH2O)n
1. MnO2, hexane 1. NBS, DME/H2O

2. MnO2, NaCN 2. NaOiPr, iPrOH
O
HOAc, MeOH, 70% CO2Me CO2Me
OH
MnO2 oxidation
MeO
Ozonolysis
O - reacts preferentially with more electron-rich C=C
O - ring (cleavage) enlisted to control olefin stereochemistry
O
- addition of MeOH gives methyl ester
Me2S:
Stereospecific Synthesis of Trisubstituted Olefins

- propargylic alcohols can be reduced with LiAlH4 to give an allylic alcohol
R H R R
OH LiAlH4 (1.0) I2 R'2CuLi
R NaOMe (2.0) Al I OH R' OH
O
R R I R R'
OH LiAlH4 I2 R'2CuLi
R AlCl3 (cat.) H OAl H OH H OH
60:1 ratio
387
- Cuprate Mechanism
I I I
Et2CuLi
+ Et2CuLi
OH O– O–
H H H
O– + Et2CuLi + I–
H
Et
Et CuIII
+ Li+ + I–
O– reductive
elimination
- Posner Org. React. 1975, 22, 253. H
Org. React. 1972, 19, 1.
Et
+ EtCu +
O–
H
CuI Cu O
origin for requirement
Et–Et + for use of EtI
O–
H H
EtI
competitive reductive
elimination product Et
O–
H
MnO2
hexane
OH O MnO2 Oxidation
- mild oxidation of allylic alcohols
- direct, mild method for oxidation
to a methyl ester
MnO2
NaCN
MeOH
O NC OH NC O MeO O
Epoxidation
1. NBS electron
deficient - selective
DME/H2O
and less - in polar solvent the molecule folds up such
2. iPrONa reactive that the terminal C=C is more accessible
O
CO2Me CO2Me
388
Olefin Synthesis
Dale L. Boger
4. Johnson Synthesis: J. Am. Chem. Soc. 1968, 90, 6225. Julia Olefin Synthesis
1. Ba(OH)2
R
NaH, THF MeOH
CO2Me CO2R
R 2. H+, H2O
Br CO2Me
O O O
NaH R=H R = CO2Me CH2N2 R=H

(MeO)2CO R = CO2Me 65% R = Me
NaBH4 ZnBr2
CO2Me Et2O, 0 °C CO2Me
MeOH Br
R
Cyclopropylcarbinyl– 95:5 (t,t:t,c)
PBr3, LiBr R = OH
collidine homoallylic alcohol
Et2O, 0 °C R = Br rearrangement
1. NaI, HMPA
25 °C Ba(OH)2
2. LDA, THF CO2Me EtOH, 0 °C CO2Me
5% HMPA O O
R
Cl
O
CuCl2–LiCl R=H
O O DMF, 45% R = Cl
MeMgCl Me K2CO3
CO2Me O
THF, –75 °C HO MeOH, 25 °C Me CO2Me
H Cl
H
Cornforth nucleophilic diastereoselective
92:8
addition
O O O O
Na, EtI HCl KOH 1. NBS
CO2H CO2Me
O O 2. MeOH
O O cat. H2SO4 Br
Cl
Br Et Cyclopropylcarbinyl Bromide Rearrangement

Et Br - highly stereoselective modification of Julia olefin synthesis
vs. - Johnson J. Am. Chem. Soc. 1968, 90, 2882
H R H R - Julia Bull. Soc. Chim., Fr. 1960, 1072.
- ring opening concomitant with ionization
- antiperiplanar arrangement of the C–Br and cleaved
cyclopropane bond is necessary
Br Br
Cl
O Et
R H - J. Chem. Soc. 1959, 112, 2539.
- earliest generalization of the Felkin model of
nucleophilic addition to a carbonyl group in
MeMgBr acyclic systems
389
5. Corey Synthesis: J. Am. Chem. Soc. 1970, 92, 6635, 6636. Lindlar Catalyst Alkyne Reduction
1,5-Hydrogen Migration
β-Oxido Ylide Reaction
Diimide Reduction
1. nBuLi OH
H H 2. (CH2O)n
H2SO4 3. Ac2O CH2I2, Cu–Ag
4. H2/Pd-BaSO4
5. NaOH
Allylic alcohol directed
OH Lindlar catalyst hydrogenation
OH Simmons–Smith
H OHC NaBH4
350 °C HO
65% 96%
H
1,5-H Shift dictates olefin stereochemistry
- Alternatively
OTHP 1. PPh3 OTHP PBr3 OTHP Me2CuLi

n
2. BuLi or
CHO Me3FeLi
3. (CH2O)n OH Br
β-Oxido ylide modification

of Wittig reaction
OTHP OTHP 1. H3O+ PPh3I

2. TsCl
+ 3. NaI/acetone
4. Ph3P
(50:50) with Cu
(100:0) with Fe
1. nBuLi HO
Me Me
PPh3I
OH OTHP
1. H+, DHP 2. 1. MnO2
H
2. O3, Zn, HOAc 3. sBuLi Me 2. Ph3P=CH2
O 4. (CH2O)n
OTHP
β-Oxido ylide Wittig reaction
1. H+
HN=NH 2. [O] (c.f. 1968)
Me Me 3. epoxidation Me
O
CO2Me
OTHP OTHP
Diimide reduction
–O O PPh3 H R
Ph3P O PPh3 sBuLi –O PPh3 (CH2O)n PPh3
+ R H H R H R
+ R'CHO R' R R' R R' – R' R'
O –O
β-Oxido Ylide Modification HO
OH OH 1,5-H Shift Diimide Reduction

H N N N N
H - less substituted C=C
H H
reduced more rapidly H H
- generated in-situ H H H H
H
R R R R
390
Olefin Synthesis
Dale L. Boger
6. Johnson Synthesis: J. Am. Chem. Soc. 1970, 92, 4463. [3,3]-Sigmatropic Rearrangements
Claisen Reaction
Cope Reaction
Oxy-Cope Reaction
CO2Me + H+, toluene NaBH4

CO2Me CO2Me
100 °C MeOH, 0 °C
OH MeO OMe O OH
1 cis (13%) removed
Olefinic ketal 87:13 trans:cis 51%
after reduction
Claisen reaction
1. 1, H+, toluene
100 °C SOCl2
CO2Me CO2Me
2. NaBH4 hexane, 0 °C
MeOH, 0 °C OH 85% Cl
70%
SN2' reaction and 12%
Olefinic ketal
Claisen reaction Cl
1. NBS
NaBH4, DMSO H2O/THF
O
CO2Me CO2Me
1,5-hexadiyne 2. K2CO3, Me
50 °C MeOH, 35% H
and chlorine impurity
CO2Me CH3CO2H K2CO3

CO2Me CO2Me
O (CH3CO)2O MeOH, 0 °C
OAc 81% OH
H+ H+, tol
+ CO2Me
100 °C
MeO OMe OMe OH
Olefinic Ketal Claisen Reaction
- selectivity dependent on
1,3-interaction in chair-like T.S.
CO2Me CO2Me - second Claisen more selective
H+ due to larger R group vs. CO2Me
O O
OMe –MeOH
Me Me
O CO2Me vs. O H
R H R H
H CO2Me
CO2Me
O O CO2Me
87 : 13
391
7. Stotter–Kondo Synthesis: J. Am. Chem. Soc. 1973, 95, 4444. Dihydrothiopyran Strategy:
J. Chem. Soc., Chem. Commun. 1972, 1311. Cyclic Precursors to Trisub. Olefins
Stabilized Allylic Anions
Desulfurization, Benkeser Red.
Sulfur Ylides
Cyclopropane Synthesis
Epoxide Synthesis
S 1. MeMgBr S
2. POCl3, C6H6
O Me
pyr, 90% sBuLi S S SOCl2, pyr S S
DABCO 75–90%
–20 °C, THF Me overall Me
S Me2S+(O)CH2– S OH
75%
O O
Sulfur ylide epoxidation
cyclic precursors dictate trisubstituted olefin stereochemistry
sBuLi S S Me Li/EtNH2 SH SH Me
1 or 2 –78 °C
DABCO Me OR Me OH
R = THP, 60% Benkeser reduction
R = Li, 90% dissolving metal reduction
R=H
Ra–Ni Me [O], see Corey 1968 Me

55–70% CO2Me
Me OH Me
Trost Intermediate
Me HOCl HOCl Me
Cl nBuLi DHP, H+ Cl
OLi OTHP
2 1
thermodynamic E product
Cl
S Convergent Route
- symmetrical intermediate
O
O Cl
DABCO
N DABCO - accelerates slow deprotonation
N - breaks up Li aggregates
* Site of Deprotonation
** S - at carbon activated by both S
** *** and vinyl
Sulfur Ylides: Trost, Melvin Sulfur Ylides: Emerging Synthetic Intermediates, Academic Press, 1975.
Benkeser Reduction Synthesis 1972, 391.

392
Olefin Synthesis
Dale L. Boger
Use of Cyclic Precursors

S S - control olefin geometry
Me - insert S, remove with Ra–Ni
Specific Deprotonation Site

S S - kinetically preferred site due to sterics
- the thermodynamic and kinetic product
Me - alkylation occurs cleanly α, not γ, to
heteroatom (a well established trend)
- Li/NH3 Birch Reduction (blue solution), –33 °C at refluxing NH3 temperatures

- Li/EtNH2 or MeNH2 Benkeser Reduction, more strongly reducing because of higher reaction temperature
S e– S e– S
EtNH2 S H3O+ SH
H H
protonation
no protonation,
more hindered,
olefin geometry maintained
restricted rotation of allyl
anion π-system
- 1,4-Addition of sulfur ylides -> cyclopropanes
Ph2S + EtI Ph2S-CH2CH3 ICH2CH3
I–
AgBF4
AgI + Ph2S-EtBF4
Me
O O
Ph2S - This reaction is sensitive
Me Me to substitution pattern on
R' = H the α,β-unsaturated carbonyl
R' Me
Me Me
O O
Ph2S Me - In addition, a substituted sulfur
Me ylide increases propensity for
R' = Me epoxide formation over
R' R' cyclopropane formation
393
8. Still Synthesis: Tetrahedron Lett. 1979, 593. [2,3]-Sigmatropic Rearrangement
tBuLi,Et2O
THF, –78 °C –78 to 0 °C
+
OHC Br Li 93% Br OR
OH OHC OR OH OH
OH OH
KH, THF nBuLi, THF
OR
Bu3SnCH2Cl O O –78 to –20 °C
88% 79% OR
SnBu3 SnBu3
[2,3]-Sigmatropic
rearrangement
OTs OTs
TsCl, pyr LiAlH4
0 °C, 93% Et2O, 0 °C
OR
OR 98%
H2O–HOAc R = CH(CH3)OCH2CH3
45 °C, 92% R=H
Me Me
R
J. Am. Chem. Soc. 1978, 100, 1927.
O R
OLi
Li
one isomer, Z
Note: Me substitution on olefin
provides Z selectivity.
R
H H R
O H O–
Me H Me
vs.
H
R R H
O H O–
Me H Me
severe allylic 1,2-strain
394
Organocuprate and Conjugate Addition Reactions
Dale L. Boger
XII. Conjugate Additions: Organocuprate 1,4-Additions
Reviews: House Acc Chem Res., 1976, 9, 59. Review: Lipshutz Org. React. 1992, 41,135.
Ashby Chem Rev., 1975, 75, 521. Posner Org. React. 1975, 22, 253.
Comprehensive Org. Syn., Vol. 4, 169. Posner Org. React. 1972, 19, 1.
O RMgX HO R
or
RLi
1,2-addition
- But Kharasch observed 1,4-addition with added Cu(I) salt:

O OM O
RMgX
cat. Cu(I)
1,4-addition R R
Kharasch J. Am. Chem. Soc. 1941, 63, 2308.
- This led to the development of stoichiometric organocuprate reagents:

ether or MeLi (1.0 equiv)
MeLi + CuI Me-Cu + LiI Me-Cu-Me Li
THF "ate" complex
(1 equiv) insoluble,
bright yellow colorless, soluble,
organocopper stable even at 25 °C
reagent
House, Whitesides J. Org. Chem. 1966, 31, 3128.

- "ate" complexes incorporating Li+ were first described by Gilman (J. Org. Chem. 1952, 17, 1630) and
consequently such reagents are often referred to as "Gilman reagents".
- Most organometallics, including organocuprates, are susceptible to β-elimination:
H R H R
CH –40 to
R Cu H +
CH2 –20 °C CH2
R Cu
Li
- So most organocuprates are best handled at temperatures lower than ca. –40 °C.
1. Scope
- Relative ease of ligand transfer from Cu follows the order:
, Ph > Me > Et > iPr > tBu >> PhS, R2N, RC C

Dummy ligands for
mixed cuprates
- In addition, the size of the migrating group also affects the conversion:
R=H Me2CuLi 60–80%

R R=H Ph2CuLi 25%
R = CH3 Et2CuLi 55–65%
iPr CuLi
R = CH3 2 58%
O R = CH3 t
Bu2CuLi 40%
R = CH3 Ph2CuLi 0%
R = CH3 CuLi 0% 1,2-addition observed
2
395
- Effect of substrates:
O O O O
> CN >>
OR O– RO OR
O
Me2CuLi
Me
t O 96% tBu
Bu
- Unsaturated esters are less reactive than enones.

- β,β-Disubstitution slows reaction.
O
OCH3
OCH3
Me2CuLi
// Me
tBu O tBu
δ BF
3
BF3•OEt2 53%
δ O OCH3
tBu
- unreactive substrates will react - also note the alternative
if Lewis acids are added to activate use of higher order cuprates
substrate toward nucleophilic addition. [R2CuCN]Li2.
Maruyama J. Am. Chem. Soc. 1977, 99, 5652.

Yamamoto J. Am. Chem. Soc. 1978, 100, 3240.
RCu•BF3
Yamamoto J. Am. Chem. Soc. 1980, 102, 2318.
Yamamoto J. Org. Chem. 1979, 44, 1745.
MeCu•BF3
88%
O O
Me2CuLi Review: Yamamoto Angew. Chem.,
// Int. Ed. Eng. 1986, 25, 947.
Me2CuLi•BF3
70%
Me2CuLi−TMSCl
O O O
Me2CuLi Me2CuLi
TMSCl
O O O
396
Dale L. Boger
- Conjugate addition to α,β-unsaturated aldehydes is typically problematic but
successful examples have been reported.
O Me3CuLi2 Me O
H 81% H
Still Tetrahedron Lett. 1976, 2659.

Meyer Org. Prep. Proceed. 1979, 11, 97.
Clive J. Chem. Soc., Chem. Commun. 1981, 643. (Me5Cu3Li2)
Clive J. Org. Chem. 1982, 47, 2572.
Conjugate Addition/Alkylation (stereochemistry)

Posner J. Org. Chem. 1979, 44, 3661.
Review: Comprehensive Org. Syn., Vol. 4, pp 237–268.
Conjugate Addition/Aldol
Heng Tetrahedron 1979, 35, 425.
- Cuprates can also be prepared from other organometallic reagents which

have greater compatibility with reactive groups:
e.g. activated Cu(o)/RBr, RZnI, RSnBu3/Me2Cu(CN)Li2, RCH=CH2/ Cp2Zr(H)Cl then CuBr•SMe2
O
O
H 1.
Cp2Zr 2. CuBr•SMe2
Cl
ZrCp2
25 °C, 1h
hydrozirconation Cl 79%
Lipshutz Tetrahedron Lett. 1992, 33, 5857.
- Useful in the regiospecific trap and subsequent generation of enolates.
R2CuLi TMSCl MeLi
O LiO TMSO LiO

R R R
Horiguchi Tetrahedron Lett. 1989, 30, 7087.
- Asymmetric 1,4-addition
O O
cat. Cu(OTf)2
+ R2Zn
> 95% ee
cat.
Ph
O
P N
O
Ph
Feringa Acc. Chem. Res. 2000, 33, 346.
397
- Additions to acetylenes
R2CuLi R' CO2CH3

R' CO2CH3 cis addition of "RCu"
R Cu
R' = Et R = CH3
THF at –100 °C 97:3 cis:trans

THF at –78 °C 92:8 lower stereoselectivity
due to configurational
toluene (3 h) 92.5:7.5
instability of alkenyl copper
ether (3 h) 24:76 reagent
see also: Alexakis Bull. Chim. Soc., Fr. 1977, 693.

Cahiez Synthesis 1976, 245.
Alexakis Tetrahedron Lett. 1976, 2313.
Truce J. Org. Chem. 1978, 43, 2252.
Marfat J. Am. Chem. Soc. 1977, 99, 253.
R' CO2CH3 R' Cu 25 °C rapid

–30 °C to 0 °C 0 °C slow
R Cu R CO2CH3 –30 °C observable
Corey, Katzenellenbogen J. Am. Chem. Soc. 1969, 91, 1851.

Fried J. Am. Chem. Soc. 1969, 91, 1853.
Klein J. Chem. Soc., Perkin Trans. 2 1973, 1971.
- Alkenyl copper intermediates can be subsequently trapped:
R' CO2CH3 E+ R' CO2CH3
R Cu E+= H+ (H2O), R E
Br+ (NBS)
- Also, used in displacement of leaving groups (addition/elimination reactions).
R2CuLi via β-elimination

from intermediate enolate
X CO2CH3 R CO2CH3
X = SPh, Br, OAc (good leaving group)
CO2CH3 CO2CH3 net retention of

stereochemistry
X R
cis addition trans elimination
CO2CH3 X CO2CH3
X H H
R Cu R Cu
X = SPh
Casey Tetrahedron Lett. 1974, 925.
Mukaiyama Chem Lett. 1974, 705.
398
Dale L. Boger
- Examples:
CO2CH3 CO2CH3
R2CuLi
Coates J. Org. Chem. 1974, 39, 275.
AcO R
Coates J. Am. Chem. Soc. 1971, 93, 1027.
AcO CO2CH3 R CO2CH3
R2CuLi
X = SPh, Cl, Br, OAc

(but not for OCH3)
X
O OLi Me O
Me2CuLi –PhS
SPh SPh Me
OLi Me O Me
R
Me2CuLi RX
Me Me
O
Li0 1. CuSPh
Cl Li
Cl Li
Et2O –78 to –15 °C
0 °C O
2.
Wender Org. Syn. 1992, 70, 204.
Cl
- Selective preparation of ketones from carboxylic acid derivatives.

O R2CuLi O OLi
no overaddition
// R' R to give 3° alcohol
R' Cl R' R R
O Cl (tBu)2CuLi O tBu
tBu tBu
60%
Et2O, 0 °C
no epimerization of axial
carbonyl group
- Additions to terminal alkynes.

R
R H+
R'Cu
R H R'
cis addition Cu R' E+ R
E R'
399
- Alkylation reactions
Br Me
2 Me2CuLi
H Br H Me
H H
H H
Me2CuLi substitution reactions proceed
H Br H Me with retention of configuration
H H
O
Me P OR a) Li/NH3
H
Me2CuLi O OR
b) H+
- Mechanism:
O O–
H
P OR P OR
O OR O OR
e– e– H
- Also can be conducted with aryl and enol triflates
OSO2CF3 Me
Me2CuLi
functional group reactivity~ RCOCl > CHO > tosylates > epoxides > bromides > ketones > esters > nitriles
400
Dale L. Boger
2. Mechanism
reversible
oxidative
π-complex addition
a) Me Cu Me O O
(I)
Me Cu(III) Li
Me Cu Me Me
(I)
reductive
Me-Cu(I) + OLi OLi
elimination
Me Me Cu(III)
Me
or
Me2Cu + Li O
electron
b) Me2CuLi + O
transfer radical anion
Me2CuLi
O
-Evidence for mechanism b)
i. Isomerization and recovery of substrates without 1,4-addition

tBu
CO2tBu CO2tBu CO2tBu Me

< 1 equiv
MeLi OH
vs.
tBu Me2CuLi tBu tBu tBu
no isomerization of
via recovered starting material
OLi
tBu
tBu
evidence for
electron transfer
mechanism
401
ii. Cation is essential for the reaction Me2Cu Li

- if crown ethers are added to reaction mixture, reaction is slowed or prevented
- Li+ complexes with carbonyl oxygen and activates substrate to conjugate addition
(Ouannes Tetrahedron Lett. 1977, 815.)
iii. Retention of stereochemistry of cuprate alkyl group that is transferred
e.g.
O
tBu O
Cu
//
retention of configuration
//
tBu
Cu
O
O
Whitesides J. Org. Chem. 1972, 37, 3718.
Whitesides J. Am. Chem. Soc. 1969, 91, 6542.
- So reaction cannot be proceeding through a free-radical
tBu
Cu
O
would get mixture
- Retention also observed for alkenyl cuprates:

0.5 equiv O
Br Li CuLi
CuI
2
O
CH3 CH3 CH3
Casey Tetrahedron Lett. 1971, 2455.
Configurationally stable
- Not true for free radical

H H
H H
402
Dale L. Boger
- Additional evidence for radical anion mechanism:
Me
Me2CuLi
+
O O O
Marshall Tetrahedron Lett. 1971, 2875. 55% 39%
may be formed via intermediate

radical anion
Me2CuLi
+
O O O
43% 49%
- but
Me2CuLi OtBu
CO2tBu // OtBu
k = 10–2 s–1
OLi OLi
not observed
Me2CuLi
CO2tBu
tBu tBu
//
tBu
O OLi
LiO
- So half-life of intermediate radical anion is very short.
- Subsequent coupling with cuprate reagent (after e– transfer) is faster
than other radical reactions in some cases.
- However, competitive single electron reductions with cuprates have been observed
and they may be used to effect reductive elimination reactions in manner analogous to
dissolving metal or Zn reductions.
403
iv. Trap of intermediate radical anion
OTs
Me2CuLi, –78 °C H+
H2O
O MO O
96%
Ac2O
AcO
- no conjugate or homo-conjugate addition observed, only intramolecular trap of intermediate radical anion
Hannah Tetrahedron Lett. 1975, 187.
OTs OTs
LiO O O
e–
Ac2O
- Key piece of evidence for
electron transfer mechanism. AcO LiO
v. House J. Am. Chem. Soc. 1972, 94, 5495.

- Rate and ease of conjugate addition to the substrate correlate with the polarographic reduction
potential while they do not always correlate with propensities for Michael addition.
Eo
Me2CuLi Me2CuLi + e– –2.35 v
CuLi CuLi + e– –2.1 v But these are not

2 2
experimentally determined
Eo values.
Ph2CuLi Ph2CuLi + e– –2.3 v
CuLi CuLi + e– –2.4 v

2 2
404
Dale L. Boger
- And for conjugate addition with Me2CuLi
Ered Ered
O
–1.63 v nPr –2.26 v
CO2Me
Ph
CO2Et O
–2.13 v
CO2Et –2.25 v
tBu
MeO2C
–2.14 v
COMe
O
–2.33 v
OCH3
tBu
–2.12 v
O
O –2.35 v
–2.20 v
OCH3
O All can accept an e–
(undergo reduction)
by Me2CuLi.
Eo = –2.35 v
- But these substrates do not react with Me2CuLi:
OBu CO2CH3
–2.43 v –2.50 v
t
Bu
O
CO2CH3 CN
–2.54 v –2.55 v
tBu tBu
Note that for the ease of organocuprate conjugate addition

E
decreases in the order:
E = COR > CO2R > CN House Acc. Chem. Res. 1976, 9, 59.
405
-House estimation of
O
O
R3 R1 base value = –1.9 v R2 base value = –1.8 v
R4 R2 R1
substituent R1 R2 R3/R4 substituent R1 R2
alkyl –0.1 –0.1 –0.1 alkyl –0.1 –0.1

alkoxy –0.3 0 –0.3 alkoxy –0.3 ---
phenyl +0.4 +0.1 +0.4
R CN
base value = –2.3 v
R R
vi. Kinetic preference for 1,2-addition for standard organometallic (and other) nucleophiles suggests
something unique about 1,4-addition of organocuprates
O O
//
R-M //
R-CuX
13C
vii. NMR detection of reaction intermediates
- Mechanism of organocuprate conjugate addition: observation of cuprate–olefin complexes
and Li-coordinated intermediates in the reaction of lithium dimethyl cuprate with 10-methyl-
∆1,9-2-octalone. Robin and Smith J. Am. Chem. Soc, 1989, 111, 8276.
Cu(III) intermediate
observed directly
O O Li O
1 3 (CuMe2)nLin 5 CuMe2
The intermediates 1–5
were observed at –78 °C
in Et2O-d6 by 13C NMR
O O M O
XLi (CuMe2)nLin
LiX
2 4 6
See also: Corey Tetrahedron Lett. 1990, 31, 1393.
viii. Isolation of the π-complex and conversion on to product

406
Dale L. Boger
3. Homoconjugate Addition
CO2Et Me2CuLi Me CO2Et

CO2Et CO2Et
- Can also use

O O -These reactions work well with Me2CuLi, and
probably vinyl cuprates and aryl cuprates
O (no problem with β elimination) but
not as well for simple alkyl cuprates (less
O stable, must keep < –30 °C)
- Application to prostaglandin synthesis:
O O
O
CO2CH3
CuLi O CO2CH3
O O CO2CH3 2
N2
OTHP
OTHP OTHP
Corey J. Am Chem. Soc. 1972, 94, 4013.
and
CO2CH3 CO2CH3 Me
O CO2CH3
N2 O
O
OSiMe2tBu OSiMe2tBu
R R
– CuLi
2Cu 2
R
O O
407
4. Competitive Reduction and Rearrangement
a) Interception of radical–anion intermediate

OTs
Me2CuLi
O O
b) Reduction e–
OLi O OLi
//
Me
CH3O OCH3 CH3O OCH3 OCH3
Also observed with γ-acyloxy enones:
OLi O OLi
R = Ac Me2CuLi
R = CH3
OR R = THP OR
Note: This is cited as further

Ruden Tetrahedron Lett. 1975, 2043. poorer leaving groups support of the electron
transfer mechanism.
via
OLi OLi
OAc
OLi O OLi
X R2CuLi X
R2CuLi
X = Cl X = OCH3 R
reduction
conjugate
addition
408
Dale L. Boger
5. Mixed Organocuprates
- For dialkylcuprates, one alkyl substituent (ligand) is lost:

O
R O
2RI R2CuLi + RCu lost
- Mixed cuprates have been developed in which one ligand will not transfer:
Corey J. Org. Chem. 1978, 43, 3418.
Cu Cu RS Cu R2N Cu C5H11 Cu
CH3O
- With these reagents, only the non-transferable reagent is lost
Cu + MeLi Cu Me Li
CH3O CH3O
- Also: addition of Li salts forms cuprate reagents from alkyl copper reagents ("ate" complexes)
MeCu No reaction
O
MeCu
LiI
1,4-addition
(MeCuILi)
MeCu
LiCN
1,4-addition
(MeCuCNLi)
House J. Org. Chem. 1966, 31, 3128.
These are more reactive and also

Higher Order Cuprates very good for sluggish reactions
e.g., epoxide openings, alkylations.
R2CuLi LiCN R2Cu(CN)Li2
2RLi + CuCN R2Cu(CN)Li2
See: Lipshutz Org. React. 1992, 41, 135.

Lipshutz Synthesis 1987, 325.
Lipshutz Tetrahedron 1984, 40, 5005.
409
- Representative Mixed Cuprates
RLi, CuI, R3P (1:1:2) Suzuki Tetrahedron Lett. 1980, 1247.
(COD)RCuMgX Leyendecker Tetrahedron Lett. 1980, 1311.
RCu(SPh)Li, RCu(OtBu)Li, RCu(NMe2)Li Posner J. Am. Chem. Soc. 1973, 95, 7788.
RCu(SPh)Li Alexakis Tetrahedron Lett. 1976, 3461.

Org. Prep. Proc. Int. 1976, 8, 13
RCu(C CtBu)Li and RCu(CN)Li Boeckman J. Org. Chem. 1977, 42, 1581.
Marino J. Org. Chem. 1976, 41, 3213.
RCu(CN)Li Acker Tetrahedron Lett. 1977, 3407.

Miyaura Tetrahedron Lett. 1977, 3369.
RCu(C CPr)Li Corey J. Am. Chem. Soc. 1972, 94, 7210.
RCu(C CC(OMe)Me2)Li Corey J. Org. Chem. 1978, 43, 3418.
6. Functionalized Organocuprate Reagents
- Examples
O O CO2Et O O
Cu•TMEDA•LiI TMSCl, CO2Et

H H –78 °C, 3 h H H
92%
Configurationally stable (better than higher order cyano cuprate):

prepared from the corresponding Bu3Sn reagent/nBuLi then CuI/TMEDA.
Linderman J. Org. Chem. 1991, 56, 5491.
410
Dale L. Boger
- Other representative functionalized organocuprate reagents
)2CuLi
Kojima, Wakita and Kato Tetrahedron Lett. 1979, 4577.
O
Doyle and West J. Org. Chem. 1975, 40, 3821.

Nordlander and Haky J. Org. Chem. 1979, 45, 4780.
EtO )2CuLi Me3Si
)2CuLi Schollkopf and Haenssle Justus Liebigs Ann. Chem. 1972, 763, 208.
Baldwin, Hoefle and Lever J. Am. Chem. Soc. 1974, 96, 7125.
Huynh and LinstrumelleTetrahedron Lett. 1979, 1073.
R2CuLi
R = nBu, Ph, CH2=CH, sBu House and Wilkins J. Org. Chem. 1978, 43, 2443.
R = tBu, Me, CH2=CHCH2
X X Corey and Enders Tetrahedron Lett. 1976, 11.

N N Corey and Boger Tetrahedron Lett. 1978, 4597.
Cu(SPh)Li Gawley, Termine, and Aube Tetrahedron Lett. 1980, 21, 3115.
R ) CuLi
2
R
X = NMe2, OCH3
(RCH=CHCH2)2CuLi Miginiac, Daviaud and Gerard Tetrahedron Lett. 1979, 1811.
Depezay and Le Merrer Tetrahedron Lett. 1974, 2751.

Boeckman and Rammaiah J. Org. Chem. 1977, 42, 1581.
(MeO)2CH Cu(C CtBu)Li
Cyano cuprate: Marino and Farina J. Org. Chem. 1976, 41, 3213.
Thiophenyl cuprate: Grieco, Wang, and Majetich
J. Org. Chem. 1976, 41, 726.
Savignac and Mathey Tetrahedron Lett. 1976, 2829.

[(EtO)2P(O)CH2]2CuLi
Mathey and Savignac Synthesis 1976, 766.
Wender and Filosa J. Org. Chem. 1976, 3490.

Marino and Browne J. Org. Chem. 1976, 3629.
) CuLi )2CuLi Piers, Lau and Nagakura Tetrahedron Lett. 1976, 3233.
Piers and Nagakura Tetrahedron Lett. 1976, 3237.
2
Marino and Browne Tetrahedron Lett. 1976, 3241.
Marino and Browne Tetrahedron Lett. 1976, 3245.
PhSCu(Li)CH2(CH2)nCH2Cu(Li)SPh Wender and Eck Tetrahedron Lett. 1977, 1245.
411
Y
((RO)2PCH2)2CuLi, Y= O, S Savignac and Mathey Tetrahedron Lett. 1976, 2829.
)2CuLi Fargeas Tetrahedron 1996, 52, 6613; 1994, 35, 7767.
Bu3Sn
Me2NCH2 ) 2CuLi Corey, Cane and Libit J. Am. Chem. Soc. 1971, 93, 7016.
O
Ireland J. Org. Chem. 1975, 40, 973.
CuLi
)2CuLi Wollenberg J. Am. Chem. Soc. 1977, 99, 7365

Schlosser, M. J. Org. Chem. 1978, 43, 1595.
OEt
) 2CuLi Linstrumelle Tetrahedron Lett. 1979, 1073.

Me3Si
Cu(Li)C CPr (n = 1, R = THP) Corey J. Am. Chem. Soc. 1976, 98, 222.
OR (n = 3, R = TBDMS) Corey Tetrahedron Lett. 1976, 4701 and 4705 .
Me Cu(Li)C C(Me)2OMe Corey Tetrahedron Lett. 1978, 1051.

THPO
R(Li)Cu C5H11 Corey J. Am. Chem. Soc. 1972, 94, 7210.

OR Corey Tetrahedron Lett. 1986, 27, 2199 and 3585.
412
Dale L. Boger
7. Stereochemistry of Organocuprate Conjugate Addition Reactions
A. Cyclic Substrates
Cyclic enones: intraannular diastereoselectivity

Ref. 2,3-diastereoselectivity
O O
1 Me Me2CuLi Me condition dependent:
cis preferred, but isomerization
Me to trans is facile.
O O
H
Me2CuLi
Me
3,4-diastereoselectivity
O O R1 R trans:cis R1 R trans:cis
R2CuLi Me Me 72:28 Et Me 77:23
2
Et 78:22 Ph 89:11
iPr iPr
R 88:12 Me 89:11
R1 R1 Ph 96:4 Et 92:8
(87:13)
3-substituted enones
O O
3 R2CuLi
R
R
R
O O R1 R trans:cis
4 Me Me 98:2
R2CuLi (99:1)
(93:7)
R1 R1 R
Me CH2Ph trans only
3,4-diastereoselectivity vs 3,5-diastereoselectivity
O O
Ph2CuLi
4
Ph Ph Ph
Ph Ph
This will be dependent on the relative size
O O of the C-3 and C-4 substituents.
CuLi
2
Me Me Me Me
CO2Et CO2Et 80 : 20
O OSiMe3
5 Me2CuLi
R R
Me
413
Exocyclic enones and esters
Ref. CHCOMe
CHCOMe
Me
96%
6
Me2CuLi
tBu tBu
O O
Me
Me2CuLi
7
tBu tBu
Bicyclic enones and related substrates
R R
Me2CuLi
8 R = H, Me
O O
Me
Me R
Me2CuLi
9
O O
H MeMe H
Me
H H
N Me2CuLi N
O O
Me
OTHP OTHP
Me Me
Me2CuLi
O O
Me
H H
CuLi
2
10
O O
R R1 R1 R
Me Me
R2CuLi N R2CuLi N
11
O O O O
H H
414
Dale L. Boger
ref. Me Me Me Me
H H H H
12 Me2CuLi Me2CuLi
O O O O
Me Me
1 2
rate: 2 > 1 (>20:1)
R trans:cis
Me Me
1,6-addition Me 93:7
13 98:2
Et
R2CuLi
O O R iPr 100:0
tBu 100:0
Medium-sized rings
Me O Me O
Me2CuLi
14
> 100:1 Me
Me Me Me
O Me2CuLi O Me2CuLi O
14 O
96:4 99:1
Me Me Me
BUT
Me Me Me
14 O Me2CuLi O O Me2CuLi O
96:4 96:4
Me Me Me
415
B. Acyclic Substrates
O O H Me
Ph Me2CuLi
Ph
12 Ph Ph
> 30:1
H OMOM H OMOM
Bu H H Bu
CO2Et Bu2CuLi CO2Et CO2Et
15 Ph Ph + Ph
(Bn)2N H H > 30:1 (Bn)2N H H (Bn)2N H H
> 95: <5
Bu H H Bu
CO2Et Bu2CuLi CO2Et CO2Et
15 Ph Ph + Ph
(Bn)2N H CO2Et > 30:1 (Bn)2N H CO2Et (Bn)2N H CO2Et
< 5: >95
OBOM R2CuLi OBOM 73–93%

TBDPSO TBDPSO > 50:1
16 CO2Me TMSCl, THF CO2Me R = Me
–78 °C, 3 h R = Et
R R = Bu
- favorable interaction between alkoxy and π system.

CO2Et - free of 1,2-allylic strain.
H OR
H - increased stabilization of the α,β-unsaturated system via
H interaction between low-level π* orbital and high-level σR'–C
R' orbital.
R2CuLi 70–90% yield

NCO2R NCO2R > 50:1
O TMSCl, THF O R = Me
CO2Me –78 °C, 3 h CO2Me R = Et
R R = Bu
R O O
CO2Et - favorable interaction between parallel σC–R and σ*C–Cu orbitals.
N H - possibility of chelation between carbamate and ester may overide
H
1,2-allylic strain as well as bulk of γ-substituent.
O H
416
Dale L. Boger
Stereochemistry of Organocuprate Conjugate Addition Reactions (References)
Books and Reviews

Kozlowski, J. A. in Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 4, pp 169–198.
Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–631.
Posner, G. H. Org. React. 1972, 19, 1–113.
March, J. Asymmetric Synthesis, Vol. 4, Academic: New York, New York, 1983.
Taylor, R. J. K. Synthesis 1985, 4, 364.
Kharasch, M. S.; Reinmuth, O. Grignard Rections of Nonmetallic Substances, Prentice-Hall: Englewood Cliffs, NJ,
1954, pp. 196–239.
Endocyclic enones
1. Pesaro, M.; Bozzato, G.; Schudel, P. J. Chem. Soc., Chem. Commun. 1968, 1152.
Siscovic, E.; Rao, A. S. Curr. Sci. 1968, 37, 286.
Boeckman, R. K. J. Org. Chem. 1973, 38, 4450.
Coates, R. M.; Sandefur, L. O. J. Org. Chem. 1974, 39, 275.
Posner, G. H.; Sterling, J. J.; Whitten, C. E.; Leutz, C. M.; Brunelle, D. J. J. Am. Chem. Soc. 1975, 97, 107.
Posner, G. H. Isr. J. Chem. 1984, 24, 88.
Piers, E.; Karunaratne, V. J. Chem. Soc., Chem. Commun. 1983, 935.
2. Luong-Thi, N. T.; Riviere, H. Compt. rend. 1968, 267, 776.

Riviere, H.; Tostain, J. Bull. Soc. Chim., Fr. 1959, 568.
Zimmerman, H. E.; Morse, R. L. J. Am. Chem. Soc. 1968, 90, 954.
Luong-Thi, N. T.; Riviere, H. Tetrahedron Lett. 1971, 587.
3-substituted enones
3. Buchi, G.; Jeger, O.; Ruzicka, L. Helv. Chim. Acta 1948, 31, 241.
House, H. O.; Fischer, W. F. J. Org. Chem. 1968, 33, 949.
Stotter, P. L.; Hill, K. A. J. Org. Chem. 1973, 38, 2576.
4. House, H. O.; Fischer, W. F. J. Org. Chem. 1968, 33, 949.

Allinger, N. L.; Riew, C. K. Tetrahedron Lett. 1966, 1269.
Wheeler, O. H.; de Rodriguez, E. G. J. Org. Chem. 1964, 29, 718.
Eliel, E. L.; Biros, F. J. J. Am. Chem. Soc. 1966, 88, 3334.
Ellis, J. W. J. Chem. Soc., D 1970, 406.
Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308.
House, H. O.; Giese, R. W.; Kronberger, K.; Kaplan, J. P.; Simeone, J. F. J. Am. Chem. Soc. 1970, 92, 2800.
Siscovic, E.; Rao, A. S. Curr. Sci. 1968, 37, 286.
Cacchi, S.; Caputo, A.; Misiti, D. Indian J. Chem. 1974, 12, 325.
Hoye, T. R.; Magee, A. S.; Rosen, R. E. J. Org. Chem. 1984, 44, 3224.
Posner, G. H.; Sterling, J. J.; Whitten, C. E.; Leutz, C. M.; Brunelle, D. J. J. Am. Chem. Soc. 1975, 97, 107.
417
5. Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462.

Stork, G. Pure Appl. Chem. 1968, 17, 383.
Exocyclic enones and esters

6. House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128.
Coates, R. M.; Sowerby, R. L. J. Am. Chem. Soc. 1971, 93, 1027.
Foulon, J. P. J. Organometal. Chem. 1982, 228, 321.
7. House, H. O.; Chu, C. Y.; Wilkins, J. M.; Umen, J. J. Org. Chem. 1975, 40, 1460.
Corey, E. J.; Boger, D. L. Tetrahedron Lett. 1978, 9 and 13.
Bicyclic enones and polyenones

8. Birch, A. J.; Robinson, R. J. Chem. Soc. 1943, 501.
Ireland, R. E.; Pfister, G. Tetrahedron Lett. 1969, 2145.
Piers, E.; Keziere, R. J. Tetrahedron Lett. 1968, 583.
Marshall, J. A.; Roebke, H. J. Org. Chem. 1968, 33, 840.
Birch, A. J.; Smith, M. Proc. Chem. Soc. 1962, 356.
Marshall, J. A.; Fanta, W. I.; Roebke, H. J. Org. Chem. 1966, 31, 1016.
Filler, R.; Rao, Y. S. J. Org. Chem. 1962, 27, 3348.
Settepani, J. A.; Torigoe, M.; Fishman, J. Tetrahedron 1965, 21, 3661.
Piers, E.; Britton, R. W.; deWaal, W. J. Chem. Soc., D 1969, 1069.
Piers, E.; deWaal, W.; Britton, R. W. J. Am. Chem. Soc. 1971, 93, 5113.
Piers, E.; Keziere, R. J. Can. J. Chem. 1969, 47, 137.
Corey, E. J.; Carney, R. L. J. Am. Chem. Soc. 1971, 93, 7318.
11. Marshall, J. A.; Brady, S. F. Tetrahedron Lett. 1969, 1387.

Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068.
Wechter, W. J. Tetrahedron 1965, 21, 1625.
Marshall, J. A. Tetrahedron Lett. 1971, 3795.
Piers, E.; deWaal, W.; Britton, R. W. Can J. Chem. 1969, 47, 4299.
Marshall, J. A.; Andersen, N. H. J. Org. Chem. 1966, 31, 667.
Piers, E.; deWaal, W.; Britton, R. W. Can J. Chem. 1969, 47, 4307.
Wiechert, R.; Kerb, U.; Kieslich, K. Chem. Ber. 1963, 96, 2765.
Marshall, J. A.; Warne, T. M. J. Org. Chem. 1971, 36, 178.
Slosse, P.; Hootelé, C. Tetrahedron Lett. 1979, 4587.
12. Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1990, 1393.
1,6-addition
13. Marshall, J. A.; Roebke, H. J. Org. Chem. 1966, 31, 3109.
Campbell, J. A.; Babcock, J. C. J. Am. Chem. Soc. 1959, 81, 4069.
Atwater, N. W. J. Org. Chem. 1961, 26, 3077.
Birch, A. J.; Smith, M. Proc. Chem. Soc. 1962, 356.
Marshall, J. A. Tetrahedron Lett. 1971, 3795.
Medium-sized Rings
14. Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
Acyclic Substrates
15. Reetz, M. T.; Röhrig, D. Angew. Chem., Int. Ed. Eng. 1989, 28, 1706.
16. Hanessian, S.; Sumi, K. Synthesis 1991, 1083.

418
Dale L. Boger
8. Origin of Diastereoselectivity
A. 2,3-Diastereoselection determined by protonation of enolate Destabilizing 1,3-diaxial

interaction developing.
H+
H
H
pseudo equatorial pseudo axial
R
R
Li H
O R O
H R Li
H
H
H+ this is preferred
axial protonation, axial protonation,

chair-like transition state, chair-like transition state,
cis to C3 R-substituent. trans to C3 R-substituent.
O O
R R
readily epimerizes
R' to more stable product. R'
most stable product observed
- Examples:
O O
Me2CuLi axial, through chair-like
1:1 transition state
H
H
H
Li
O O O
H
Me2CuLi
//
Me
H H
Me equatorial, through boat-like
transition state
Posner J. Org. Chem. 1973, 38, 4459.
419
B. 3,4-Diastereoselection
O O O
R'2CuLi
+
R' R'
R R R
R'MgX + cat. CuI major (trans) minor (cis)
R = Me R' Ratio
Me 72:28
Et 78:22 increasing size of R'
iPr
increasing amount of trans
88:12
Ph 87:13 (75%)
96:4 (PhCu)
R = Et R' Ratio
Me 77:23
increasing size of R
Et 89:11 increasing amount of trans
R = iPr R' Ratio
Me 89:11
Et 92:8
equatorial delivery, boat-like transition axial delivery, chair-like transition state;

state; cis to C4 R-substituent cis to C4 R-substituent
H H
//
R
vs. R
O
O
H
preferred H //
H H
axial delivery, chair-like transition state;
trans to C4 R-substituent
but remember: reactive intermediate may be radical anion
H
//
R H
O
H
420
Dale L. Boger
C. 3,5-Diastereoselectivity
O O O
R2CuLi
+
Me Me R Me R
trans (major) cis (minor)
House J. Org. Chem. 1968, 33, 949.
R = Me 93 : 7 (MeMgI, cat, CuI) >90%
98 : 2 (Me2CuLi)
99 : 1 (Me2CuLi + LiI)
Posner J. Am. Chem. Soc. 1975, 97, 107.
R = CH2Ar trans only
unaffected by C3 substitution
Posner J. Am. Chem. Soc. 1975, 97, 107.
O O
Me
Me2CuLi
Br
4 Me
- equatorial delivery of group, no destabilizing interactions in the

grows into boat conformation of enolate. ground state for axial Me group but
cannot achieve axial delivery of Nu–
through chair-like transition state:
two nearly CH3 severe Me/Me1,3-diaxial interaction.
//
H equally populated
//
H
conformations
H O
O
CH3
H ~ H
A = B
axial delivery of group
grows into chair form of enolate equatorial delivery but would grow
into boat conformation of enolate
Me
R O
enone with alkyl substituent in the equatorial

position is the reactive conformation.
421
D. 3,4- vs 3,5-Diastereoselectivity
3,4 > 3,5

O O
Ph2CuLi
Ph Ph Ph
Ph Ph
equatorial delivery axial delivery, chair-like transition state

boat-like transition state but destabilizing 1,2-steric interaction
//
//
Ph Ph
Ph
O O
H H
1,2-interaction > 1,3-interaction
Ph
axial delivery, 1,3-destabilizing steric interactions equatorial delivery requires
but chair-like transition state. boat-like transition state
preferred
again, it may be viewed as a radical anion intermediate

equatorial axial
//
//
H
Ph Ph
O Li Ph
OLi
H
H H
Ph
axial equatorial
E. 3,6-Diastereoselectivity
O O
R R
equatorial delivery, boat-like transition state axial delivery, chair-like transition state
H H
//
H R H
O
O
H H
more stable ground state
//
H R
axial delivery, chair-like transition state equatorial delivery, boat-like transition state
cis product predominates
422
Dale L. Boger
F. Exocyclic enones
O O
t
tBu Bu CH3
equatorial attack would require

boat-like transition state
//
O
tBu tBu
O
H
axial attack proceeds through
chair-like transition state
axial protonation (observed even when tBu replaced with H,

see alkylation section).
H
OLi H+
tBu tBu
H O
R R
G. Fused enones
relative to B ring this is equatorial
delivery of the nucleophile.
R
decelerates conjugate addition
CH3 this steric interaction is a
H 1,2-interaction or torsional strain (eclipsing interaction)
H
O Cuprate behaves as large nucleophile preferring
H equatorial attack (1,2-interactions) to axial attack
H (1,3-interactions) on the exocyclic olefin.
H
//
R
axial delivery of nucleophile suffers
severe steric interactions (1,3-diaxial interactions)
-May really want to consider radical-anion conformation

1,2-torsional interaction
large reagent (Cuprate)
Me
H
LiO
H
H
small reagent (H+)

(e.g., Birch reduction)
1,3-steric interactions
423
Me Me
O Me O
H H Me
Me
- cis ring fusion. Piers Can. J. Chem. 1969, 47, 137.
- protonation from least hindered
face of enolate, also most stable product.
Me
O O
Me2CuLi cis fusion
N N
H H
OTHP OTHP
Me2CuLi
O O
Me
H H
CuLi
2
O O
Corey J. Am Chem. Soc. 1971, 93, 7318.
- but
1,6-addition
H
O R2CuLi O R O
R
R = Me 93:7
Et 98:2
iPr
100:0 axial delivery
tBu of nucleophile
100:0
Me2CuLi
–78 oC
O O
CuLi
2
O O
96%
H H H
1. CuLi O
2 1. O3, 1 equiv.
O Me3SiO
2. Me3SiCl 2. BH4– O
74% 80%
Clark Tetrahedron Lett. 1974, 1713. [for vernolepin]
424
Dale L. Boger
H. Exocyclic enones
Me
96%
O tBu O
tBu
steric 1,3-diaxial interaction
//
O
H H
H H
tBu O tBu Me
H H
H H
torsional strain Cuprate behaves as a large reagent

eclipsing 1,2-interaction preferring equatorial attack
i) Acyclic systems Felkin model
H Bn
NBn2 CO2Et
CO2Et CO2Et
Ph Ph
H
NBn2 NBn2 Bn H
> 95:5
H Bn NBn2 CO2Et
CO2Et CO2Et
Ph Ph Ph
NBn2 CO2Et NBn2 CO2Et H CO2Et
minimizes
A 1,3-strain
425
426
Synthetic Analysis and Design
Dale L. Boger
XIII. Synthetic Analysis and Design

Design:
Corey The Logic of Chemical Synthesis, Wiley: New York, 1989.

Warren Organic Synthesis: The Disconnection Approach, Wiley: New York, 1982.
Fuhrhop, Penzlin Organic Synthesis: Concepts, Methods, Starting Materials, VCH: Weinheim, 1994.
Total Synthesis:
Nicolaou, Sorensen Classics in Total Synthesis, VCH: Weinheim, 1996.
Hanessian Total Synthesis of Natural Products: The Chiron Approach, Pergamon: Oxford, 1983.
Lindberg Strategies and Tactics in Organic Synthesis, Vol. 1-3; Academic: San Diego.
ApSimon The Total Synthesis of Natural Products, Vol. 1-9; Wiley: New York.
Turner The Design of Organic Synthesis, Elsevier: Amsterdam, 1976.
Fleming Selected Organic Syntheses, Wiley: New York, 1973.
Bindra Creativity in Organic Synthesis, Academic: New York, 1975.
Bindra Art in Organic Synthesis, Wiley: New York, 1988.
Lednicer, Mitscher, Georg The Organic Chemistry of Drug Synthesis, Vol. 1-4; Wiley: New York.
Nakanishi Natural Products Chemistry, Vol. 1-3; Academic: New York.
Koskinen Asymmetric Synthesis of Natural Products, Wiley: New York, 1993.
Danishefsky and Danishefsky Progress in Total Synthesis, Meredith: New York, 1971.
Key Reviews:
Corey Science 1969, 166, 178; 1985, 228, 408.

Chem. Soc. Rev. 1988, 17, 111.
Pure. App. Chem. 1967, 14, 19; 1990, 62, 1209.
Angew. Chem., Int. Ed. Eng. 1991, 30, 455. (Nobel Prize Lecture)
E. J. Corey received the 1990 Nobel Prize in Chemistry for his development of the theory and
methodology of organic synthesis. His development and systemization of retrosynthetic analysis
transformed organic synthesis from inspired recognition of a route into a precise and logical
science. As the modern techniques of structure determination emerged (NMR, IR, X-ray), Corey
applied his retrosynthetic analysis to some of the most challenging syntheses of the time. The
application of computer analysis with LHASA (Logic and Heuristics Applied to Synthetic Analysis),
the development of practical synthetic methodology for individual transformations based on
clear mechanistic rationales, and the more than 100 natural product total syntheses that followed
transformed modern organic synthesis.
Corey, Cheng The Logic of Chemical Synthesis, Wiley: New York, 1989.
Corey, Wipke Science 1969, 166, 178-192.
Protecting Groups:
Greene, Wuts Protecting Groups in Organic Synthesis, 3rd Ed., Wiley: New York, 1999.
Note: The material in this book was first assembled in conjunction with the LHASA project
(Corey) and composed the Ph.D. dissertation for T. W. Greene.
Computer Assisted Analysis:
Corey, Wipke (LHASA: Logic and Heuristics Applied to Synthetic Analysis), Science 1969, 166, 178.
Corey, Long J. Org. Chem. 1978, 43, 2208.
Jorgensen (CAMEO: Computer Assisted Mechanistic Evaluation of Organic Reactions):
Pure App. Chem. 1990, 62, 1921.
Hendrickson J. Chem. Inf. Comput. Sci. 1992, 32, 209.
Acc. Chem. Res. 1986, 19, 274.
427
A. Classifications
1. Linear Synthesis
- The target compound is made through a series of linear transformations.
A B 5 steps overall yield
90%/step 59%
70%/step 17%
2. Convergent Synthesis
- Individually prepared compounds are convergently brought together to make the target compound.
5 steps overall yield

C D
B 90%/step 73%
E F 70%/step 34%
Advantages of a convergent synthesis

- shorter
- simpler to execute
- higher overall yields
- better material balance and supply
- Triply Convergent Synthesis

-three major components are brought together in a single step to make the target compound.
C D
E F I
G H
3. Divergent Synthesis
- For a class of compounds, it is advantageous to prepare a common intermediate and

use this common intermediate to prepare all members of the class of agents.
- Examples: prostaglandins
O OH
O PGF1α
R2
PGF2α
R2
RO CHO PGF3α HO
OH
Variations lie only
in the side chains
- Rather than use a linear synthesis for all agents, a divergent synthesis allows the use of a
common intermediate to prepare structurally related products.
- The divergent synthesis is a very good strategy if structure–activity studies are the ultimate goal.
428
Dale L. Boger
Note: Though widely used, the discussion of this strategy was first formally presented in the literature
along with a disclosure of a strategy for divergent aromatic annulation in conjunction with the total
synthesis of a series of azafluoranthene alkaloids. Today, the divergent introduction of diversity is
the basis of most combinatorial chemistry methods.
Boger J. Org. Chem. 1984, 49, 4050; see also J. Org. Chem. 1984, 49, 4033 and 4045.
OMe OMe
MeO OMe MeO
MeO
N N
MeO MeO
N
MeO
R1
O
O OR
OMe 1
R = CH3, R = H Rufescine
Imerubrine R = H, R1 = H Norrafescine
R = CH3, R1 = OCH3 Imeluteine
Boger J. Am. Chem. Soc. 1995, 117, 12452. Boger J. Org. Chem. 1984, 49, 4050.
4. Total Synthesis
- Start with readily available materials and build up to the target molecule from simple, common materials.
5. Partial Synthesis
- This is technically not a total synthesis.
- Start with a naturally occurring compound or an advanced intermediate and independently convert that
to the target molecule.
- Examples
partial synthesis
HO
HO OH
Previtamin D3
- For commercialization, it would be hard to match the synthesis starting with cholesterol.
R H
H2N H N H
S S
O Anne S. Miller, the first
N N OAc person to be saved by
partial synthesis
O O penicillin in the US (1942)
CO2H CO2H died on May 27, 1999 at
the age of 90.
Penicillins, available by fermentation Cephalosporins - not as accessible Hospitalized, sometimes
at Lilly, as an inexpensive bulk chemical through fermentation delirious, with a tempera-
ture that spiked at 107 °F,
Eduard Buchner, who worked in the laboratories of both E. Erlenmeyer and and having not responded
A. von Baeyer, received the 1907 Nobel Prize in Chemistry for his to treatment with sulfa
biochemical research and discovery of cell-free fermentation. Not only drugs, blood transfusions,
did this mark the beginning of the modern era of biochemistry but his or surgery, a dose of the
greatest legacy might be the development of today's fermentation industry experimental drug penicillin
which provides us with not only foods and beverages, but also antibiotics provided a quick cure and
and other important biological products. recovery.
429
6. Formal Total Synthesis vs. Total Synthesis
O O
O(CH2)8CO2H O(CH2)8CO2H
HO HO
O m-CPBA O
HO known HO
transformation
O
Pseudomonic Acid Pseudomonic Acid A
Rogers Tetrahedron Lett. 1980, 21, 881.

Kozikowski J. Am. Chem. Soc. 1980, 102, 6577.
H H
HO OH
OR
Me
Formal Total O
HO Synthesis CO2H
O
intermediate Gibberellic acid
Independent synthesis of this precursor would constitute a formal total synthesis of gibberellic acid
since the conversions have been previously accomplished. In this case, the key intermediate is so
far from the final target that most would not "claim" such an accomplishment unless the final
conversions were also developed within their own laboratories.
7. Biomimetic (Total) Synthesis
- Presumably, nature will not be using a process that is intrinsically difficult or impossible.
It is believed that one can effectively mimic the conditions provided by nature, and conduct the same
reaction in a flask.
- Two important considerations

1 - The reaction must be capable of occurring
2 - The biogenetic process is under a great deal of control (enzymatic) and a similar level of contro
in lab may be difficult, but necessary
- Classic example : Steroid synthesis

Extensively studied and many good chemists failed before the experimental parameters were
sufficiently defined to mimic the cation–olefin cyclization.
Steroids
Biomimetic
Synthesis
O
430
Dale L. Boger
B. Retrosynthetic Analysis
- Work backwards from the target compound to generate a set of intermediates which can
be made from available starting materials.
T11
T1 T12 antithetic direction
working backwards
T13
Target Structure T2 synthetic direction
building up materials
T3 toward the target
These less complicated building blocks

in organic synthesis were called synthons
in the early years. Now they are referred
to as retrons.
Objectives:
1. Generate a large number of potential approaches in order to obtain an optimal route.
2. Strive to generate simpler, less complex intermediates which can be obtained from
readily available materials.
3. All steps are subject to reevaluation - this allows for design of a better or optimized synthesis.
Steps in Design and Execution of a Synthesis

1. Selection of a problem more time is or should be devoted to
2. Selection of goals to be achieved through synthesis steps 1 and 2 than most may realize
3. Simplification
4. Generation of synthetic pathways steps 3 and 4 constitute
5. Evaluation of synthetic pathways --> assignment of merit retrosynthetic analysis
6. Selection of specific reactions and reagents for each step
7. Selection of specific reaction conditions and design of experiments
8. Execution and analysis of results
Because of the amount of time and effort involved in the execution, it is
important to be meticulous in evaluating the potential synthetic pathways.
1. Selection of a problem
- One of the most important considerations.
- Should be the first consideration, independent of all others. This assures that it
is a problem that you want to address.
- Recognize the time and effort involved in the actual conduct of the synthesis.
- This will depend on the setting, circumstances and interests of the individual.
2. Selection of goals
OH
CO2H
SRS-A (Slow Reacting
SR Substance of Anaphylaxis)
a. Structure determination of SRS-A: the initial intent. The R group on the thiol was not known,
so the first synthesis was designed to facilitate the introduction of different R groups permitting
a comparison with the endogenous product to confirm the structure.
b. Once the structure was determined, objectives included providing sufficient material for
biological testing.
c. Determination of absolute configuration - the chiral centers were unambiguously established
through synthesis.
d. Development of a route amenable to analogue preparation: want to inhibit the action of
SRS-A (an antagonist development).
e. Biomimetic synthesis (follows the biosynthetic generation of materials) - might constitute a
simplification.
431
f. Development of commercially viable processes.
g. Demonstration of improvements in current methodology.
h. Novel, interesting structures.
i. Common intermediate for a class of structures (divergent synthesis).
j. Mechanism of action of a class of compounds - devise partial structures of the parent
compound to define the mechanism of action.
k. Chemistry of a class of compounds.
l. Properties of a class of compounds.
The specific goals are established prior to the generation of the

retrosynthetic pathway. The goals will play an important role in
the assignment of relative merit of each potential pathway in the
retrosynthetic analysis.
3. Simplification and Background Chemistry

a. Recognition of symmetry elements present in a structure.
i.e, Squalene
CHO
CHO
- two identical halves

- build out from a central core by conducting each of the steps twice and simultaneously
- Johnson J. Am. Chem. Soc. 1970, 92, 741.
SO2Ar Br OH
- combines two halves prepared from a common intermediate at the end of the synthesis.
- Grieco J. Org. Chem. 1974, 39, 2135.
CH3O2C CO2CH3 N N
CH3O OH CH3O CH3O2C CO2CH3
N CH3 N N
N CH3 CH3O
CH3O
CH3O OCH3
CH3O2C O CO2H
O CH3O2C CO2H
N N
HO
CH3 CH3
CH3O OCH3
Isochrysohermidin Boger J. Am. Chem. Soc. 1993, 115, 11418.
432
Dale L. Boger
- The recognition of symmetry elements is not always so obvious by initial examination of the agent.
e.g., Juncusol
Me Me
OH OH
X
HO
HO HO Me
Me Me Kende J. Am. Chem. Soc. 1979, 101, 1857.
now symmetrical - simplification
of the synthetic problem
O
or start with the central ring and build out in a similar symmetrical fashion
Boger J. Org. Chem. 1984, 49, 4045.
O
e.g., Carpanone
Me Me
Me Me Me
H H
O O O O O
Dimerize
O O O O O OH
O O
O O
Chapman J. Am. Chem. Soc. 1971, 93, 6696.
- biomimetic synthesis of this agent allows for simplification.

- this is a very good example where the symmetry elements
are not obvious by looking at the agent.
e.g., Rifamycin Me H
O
RO
Me Me Me Me
AcO H
Me Me Me Me
OAc OH OH
RO S C
OH O
H O
Me N Me OR1 OR2 OR3 S
O H Me
O
O S
Me
O O - this agent does not contain symmetry in the entire
O molecule but a subunit is symmetrical. H S
Me
433
e.g., Usnic Acid
COMe COMe
HO O O HO OH
Oxidative
Me COMe Dimerization Me
Me OH
OH OH
Barton J. Chem. Soc. 1956, 530.
e.g., Porantherine
H H
N N N
Me Me
Me Me
H H H
O O
O
O Me H O H
H
HN
O Me
Me
N Me NH2 Me
H O O
O Me
- the symmetry elements are tucked more deeply into the structure
b. Background Chemistry
- Information available in the literature will provide very important insights required to
effectively design a synthesis.
e.g., Quassin
OMe
O Me
O
Me Me
MeO
H H Grieco J. Am. Chem. Soc. 1980, 102, 7586.
O O
H H
Me
- 7 stereocenters but 3 are epimerizable centers and the natural product possesses the
most stable configuration, so a synthesis without stereocontrol of these 3 centers can
be used (epimerize later). Need only worry about control of 4 of the 7 stereocenters.
434
Dale L. Boger
c. Recognize and Remove Reactive Functionality
- Another key to simplification derived from background chemistry
e.g., Vernolepin
OH OH
O O
O O
H H
O O
O O
remove as well
- α-Methylene lactone in a trans fused 5-membered ring
This is extraordinarily reactive to nucleophiles (Michael).
It will not stand up to many synthetic steps/reagents.
- the final step should be introduction of the reactive group.

Grieco J. Am. Chem. Soc. 1976, 98, 1612.
e.g., Precursor to aromatic amino acids
OCH3
CO2H O CO2– CO2CH3
O
H+ O OH–
O O O
decarboxylation
loss of the OH
HO H
HO H
+
H
- acid sensitive (derived from background chemistry).
- a successful approach must involve generation
under basic conditions.
e.g., PGI2 (prostacyclin)
CO2H
H H+, H2O OH
O
CO2H
C5H11 O C5H11
HO HO
OH OH
- enol ether sensitive to acid-catalyzed hydrolysis.
U. von Euler, B. Katz, and Julius Axelrod received S. K. Bergstrom, Bengt I. Samuelsson,
the 1970 Nobel Prize in Medicine for the discovery and J. R. Vane shared the 1982 Nobel
of hormonal transmitters in the nerve terminals Prize in Medicine for their discovery of
and the mechanism for their storage, release, and the prostaglandins and related
inactivation. biologically active substances.
435
e.g., Thromboxane A2 (TXA2)
OH
CO2H pH = 7.0 CO2H

O
C5H11 t1/2 = 32 sec C5H11
O HO O
OH OH
The strained acetal should be
introduced late in the synthesis TXB2
e.g., PGH2 (R = H)
PGG2 (R = OH) Still J. Am. Chem. Soc. 1985, 107, 6372.
O CO2H pH = 7.0
Reduction / Acid-catalyzed Rearrangement
O C5H11 t1/2 = 4–5 min
OR
Reactive cyclic peroxide is sensitive
to nucleophilic attack - introduce late
in the synthesis
Porter J. Am. Chem. Soc. 1980, 102, 1183.
Salomon J. Am. Chem. Soc. 1979, 101, 4290.
e.g., Mitomycin C - stable as the quinone Porter J. Am. Chem. Soc. 1979, 101, 4319.
O CH2OCONH2 OH CH2OCONH2 OH CH2OCONH2

H2N OCH3 H2 H2N OCH3 H2N Nu–
reduction
CH3 N NH CH3 N NH CH3 N NH
O OH OH
note vinylogous amide hydroquinone - basic, nucleophilic steer clear of such synthetic
free amine - intermediate less stable intermediates
There are only two total syntheses of mitomycin C to date
Kishi J. Am. Chem. Soc. 1977, 99, 8115.
Fukuyama J. Am. Chem. Soc. 1989, 111, 8303.
Absolute configuration established in J. Am. Chem. Soc. 1967, 89, 2905
by a single crystal X-ray structure (INCORRECT).
But in the early 1980's, additional X-ray structures on related agents gave
the opposite and correct absolute configuration. Take home message:
Evaluate the quality of the background chemistry and assess the level of
confidence and committment you want to place on it. The earlier X-ray
was not on a heavy atom derivative and preceded the advances in direct
methods we take for granted today.
Hirayama J. Am. Chem. Soc. 1983, 105, 7199.
A number of Nobel Prizes have chronicled the achievements of X-ray

crystallography including the contributions of:
J. Kendrew and M. Perutz (1962, heavy atoms and structure of hemoglobin).

D Hodgkin (1964, X-ray structure determinations including vitamin B-12, penicillin and insulin).
O. Hassel (1969, chair conformation of cyclohexane reported in 1930).
W. N. Lipscomb (1976, borane structures and chemical bonding, structure of carboxypeptidase A in 1967).
A. Klug (1982, elucidation of nucleic acid–protein complexes).
H. A. Hauptman and J. Karle (1985, direct methods).
J. Deisenhofer, R. Huber, and H. Michel (1988, structure of photosynthetic reaction center (> 10,000 atoms)
and first membrane protein structure determination).
436
Dale L. Boger
- The background chemistry can provide keys to the design of a synthetic strategy.
O O OCONH2
OCONH2 O OCONH2 OMe
MeO OMe MeO MeO N H
OMe
H
Me N NH Me N Me N
O O N O H
Isomitomycin was isolated and
Mitomycin Rearrangement characterized and provided the basis
for Fukuyama's total synthesis.
OH
e.g., Thienamycin
H OHH H H
O H O H OH
SR S SR
N N N
O
CO2H NH2
CO2H CO2H
trans preferred cis less favored

must protect the amine throughout the synthesis.
A. Fleming, H. W. Florey, and unusual trans H–H relationship - easily epimerizable center
E. B. Chain received the and fortunately, trans is most stable configuration.
1945 Nobel Prize in Medicine
Grieco J. Am. Chem. Soc. 1984, 106, 6414.
for the discovery of penicillin
Georg J. Am. Chem. Soc. 1987, 109, 1129.
and its curative effects in
various infectious diseases. Yet - almost all the early syntheses went to great
length to control this relative stereochemistry and
it often, unnecessarily, added to their length.
e.g., Coriolin OH OH
O H H
Me Me
O O
Me H Me Me H Me
O OH Me OH
introduce reactive
functionality last Danishefsky J. Am. Chem. Soc. 1981, 103, 3460.
4. Generation of Synthetic Pathways (Retrosynthesis) (General strategies employed in working backwards)

Covered in detail in Corey The Logic of Chemical Synthesis, Wiley: New York, 1989, pp 1–98.
a. Transform-based strategies
- powerful, simplifying transformation that reduces complexity.
- usually very key reactions in the synthesis that dominate the approach - formation
of a key intermediate (i.e., the Diels–Alder transform, the aldol transform).
b. Structure-goal strategies
- oldest approach.
- in working backwards from the target molecule to the various intermediates, an intermediate
may actually be located that is already in the literature or commercially available.
e.g., Prostaglandins
O
O
OH O
HO
CO2H
C5H11 OR
HO
HO OH R'O
abundant
437
c. Topological strategies
- strategic bond disconnections (J. Am. Chem. Soc. 1975, 97, 6116).
- recognize strategic bonds and remove them in the retrosynthetic direction.
d. Stereochemical strategies
- strategies which remove the stereocenters.
- simplifying the stereochemistry of the product may be related to:
1. substrate - features of the substrate will permit you to solve the stereochemical problems.
2. mechanism - reaction mechanism will permit relative or absolute stereocontrol.
e. Functional group strategies

1. Functional group interconversion (FGI)
- don't gain much but it permits you to get from one point to another.
2. Functional group combination (FGC)

- combine pairs of functional groups.
- usually a ring forming reaction in the retrosynthetic direction to give you one FG rather than two.
O
H ozonolysis
H
O
X
fragmentation
O OH
OH O O
O
OH Baeyer–Villiger
3. Functional group addition (FGA)

- hard to recognize while working in the reverse direction.
- for example, introduce a double bond which then may key the recognition of a Diels–Alder reaction.
O O
O O OH
Bromo-lactonization
Br
O
CO2Me CO2Me CO2Me

Diels–Alder
CO2Me CO2Me MeO2C
438
Dale L. Boger
i.e., Diels–Alder reaction
CH2OH FGA CH2OH DA CH2OH

+
cat H2 not optimal
CH2OH CH2OH CH2OH
neutral unreactive
unreactive dienophile
FGI diene
(reduction)
O O
DA
O + O
optimal
O neutral O
unreactive reactive
diene dienophile
O
CH2OH CO2R
O
CH2OH CO2R
O
more reactive due to EWG further enhances reactivity,
reevaluation: isomerization assures stereochemistry.
may occur about the C=C.
But:
There is an alternative and still better Diels–Alder pathway that most would miss without careful consideration.
CH2OH FGA CH2OH FGI CO2R
cat H2 reduction
CH2OH CH2OH CH2OH
FGI hydrolysis
O O
O Intramolecular O
Diels–Alder
439
5. Evaluation of Pathways and Assignment of Merit
a. excellent knowledge of organic chemistry
b. suspect reactions must be recognized - one poor step can ruin the synthesis
c. control of stereochemistry is clear
d. want opportunity for alternatives - reactions that look good on paper aren't always successful in lab
6. Selection of Specific Reactions and Reagents

a. this also requires an excellent knowledge of organic chemistry
b. check the literature for alternative reagents - it is wiser to change reagents than to
change the entire synthesis if problems arise
c. many reference texts are available
Larock Comprehensive Organic Transformations

Fieser and Fieser Reagents for Organic Synthesis Vol. 1–18
Paquette Encyclopedia of Reagents for Organic Synthesis
Handbook of Reagents for Organic Synthesis:
Coates, Denmark Reagents, Auxiliaries and Catalysts for C–C Bonds
Burke, Danheiser Oxidizing and Reducing Agents
Reich, Rigby Acidic and Basic Reagents
Pearson, Roush Activating Agents and Protecting Groups
Computer Databases CLF, Reaccs, Scifinder, Beilstein, Isis
7. Selection of Reaction Conditions

a. reaction temperature
b. solvent
c. knowledge of reaction mechanism
d. consult current and background literature
8. Execution of the synthesis - most difficult and time consuming element of work
a. easy: setting up and conducting the reaction
b. difficult: interpreting the results from the reaction
C. Strategic Bond Analysis

- For bridged ring systems Corey J. Am. Chem. Soc. 1975, 97, 6116.
- Most desirable bond disconnections in the antithetic direction minimize:
1. appendages
2. appendage chiral centers
3. medium or large size rings
4. bridged rings
Rule 1: Because it is easy to form common size rings, a strategic bond must be in a 4–7 membered
primary ring. A primary ring is one which cannot be expressed as an envelope or two or
more smaller rings. This is restricted to primary rings because ring forming reactions are
strongly affected by the size of the smallest ring containing the newly forming bond.
The six membered ring is not primary

because it contains two smaller rings.
Rule 2a: A strategic bond must be directly attached to another ring (i.e. exo to another ring). This
is because a ring disconnection which produces two functionalized appendages is harder
to utilize than one which produces one or no functionalized appendages.
c a
c or d a or b
or or
non-strategic strategic bonds
bonds
d b
two ring appendages - more complicated one ring appendage
440
Dale L. Boger
b a
non-strategic b strategic bond
bond a
Rule 2b: A strategic bond may not be exo to a preexisting 3-membered ring.
non-strategic even though exo to a ring
anion displacement reactions don't work

well on a three-membered ring
X
EWG
Rule 3: Strategic bonds should be in ring(s) which exhibit the greatest degree of bridging. The
maximum bridging ring is selected from the set of synthetically significant rings which is
defined as the set of all primary rings plus all secondary rings which are less than 8-
membered. The maximum ring is that which is bridged, not fused at the greatest number
of sites.
Select the maximum bridging ring and
disconnect the strategic bonds within that ring
bridge point
fusion point
5R-3B 5R-4B 4R-2B
maximum bridging
fusion point
fusion point
5R-2B 6R-3B 7R-2B
Rule 4: To avoid formation of >7-membered rings during the antithetic bond cleavage, any bond
common to a pair of rings whose envelope is >7 is not strategic.
non
10-membered ring
strategic non-strategic
H *
strategic
* H
441
Rule 5: Bonds within aryl rings cannot be strategic.
non-strategic
Rule 6a: If a disconnection leaves chiral atoms on the remaining arc then the disconnections
cannot be strategic.
*
non-strategic
OH
* increased difficulty
H H
OH
The stereochemistry is much harder to control
on the acyclic precursor than on the cyclic precursor
Rule 6b: Chiral atoms may be allowed if they appear directly at the point of attachment.
NO2 b NO2 a
*
* Me NO2
b a
non-strategic strategic * O
* OH HO Me
Me
Rule 7: C–X Bonds (X = heteroatom) in rings will be strategic.
C–X bonds are easier to form than C–C
442
Dale L. Boger
D. Total Synthesis Exemplified with Longifolene
Me Me
1. Strategic Bond and Retrosynthetic Analysis
Me
fusion
point not a fusion point
even though it is in a
a 1,2 relationship
b
fusion
5R, B2 8R, 3B point 7R, B2
8 ring - secondary
- Ho disconnection (a)
- Kuo disconnection (b)
Fusion vs. bridge points:

there must be at least one
carbon (not in the ring in
question) between the
carbon in question and
5R, B4 6R, 3B another carbon in the ring
for it to be a bridgepoint.
H * H
* b a c
** e b
*
c
*
H d H
d 5R, B4 e
H
*
a H *
* *
H *
Me
*
non-strategic gives non-strategic gives
8-membered ring * * 8-membered ring
*
- Oppolzer but via 5-membered ring
H *
much simpler than longifolene!

- Corey and McMurry disconnection
- Schultz disconnection
- Simultaneous or sequential b/d bond disconnection: Brieger, Fallis (Diels–Alder), Johnson (cation–olefin).
- Simultaneous a/e bond disconnection: Schultz (indirect via vinylcyclopropane rearrangement).
443
2. Corey Synthesis: J. Am. Chem. Soc. 1961, 83, 1251; 1964, 86, 478.
Me Me
Intramolecular Michael Addition (Santonin–Santonic Acid)
Robinson Annulation
Wittig Reaction
Pinacol Ring Expansion
Dithiane Reduction
Chromatographic Resolution through Diastereomeric Derivatization (Product) Me
3. McMurry Synthesis: J. Am. Chem. Soc. 1972, 94, 7132.

Intramolecular Enolate–Epoxide Addition (Alkylation)
Dibromocarbene Addition, Ring Expansion
Ethyl Diazoacetate Ring Expansion
Organocuprate 1,4-Additions
Intramolecular Aldol Reaction, Transannular Reactions
4. Brieger Synthesis: (attempted) J. Am. Chem. Soc. 1963, 85, 3783.

Diels–Alder Reaction
Intramolecular Diels–Alder Reaction
1,5-Hydrogen Migration of Cyclopentadienes

Organocuprate 1,4-Addition, Regiospecific Enolate Trap
Cation–Olefin Cyclization
6. Oppolzer Synthesis: J. Am. Chem. Soc. 1978, 100, 2583.

Helv. Chim. Acta 1984, 67, 1154.
Enamine Acylation
Photochemical [2 + 2] Cycloaddition
Retro-Aldol Fragmentation Reaction
Wittig Reaction
Simmons–Smith Cyclopropanation
Hydrogenation of Cyclopropanes
Classical Resolution via Crystallization of Diastereomeric Salts
7. Schultz Synthesis: J. Org. Chem. 1985, 50, 915.

Birch Reductive Alkylation
Retro Cheletropic Cycloaddition
1,3-Dipolar Cycloaddition
Vinylcyclopropane Rearrangement
Asymmetric Synthesis via Substrate Chiral Auxiliary
8. Fallis Synthesis: J. Am. Chem. Soc. 1990, 112, 4609.

J. Org. Chem. 1993, 58, 2186.
Barton Free Radical Deoxygenation Reaction
Acetate Pyrolysis
Chromatographic Resolution through Diastereomeric Derivatization (Starting Material)
9. Kuo Synthesis: Can J. Chem. 1988, 66, 1794.
Intramolecular Aldol Addition

Wagner–Meerwein Rearrangement
10. Ho Synthesis: Can J. Chem. 1992, 70, 1375.

Alkylative Esterification
444
Dale L. Boger
2. Corey Synthesis: J. Am. Chem. Soc. 1961, 83, 1251. Intramolecular Michael Addition
J. Am. Chem. Soc. 1964, 86, 478. Robinson Annulation
Wittig Reaction
Pinacol Ring Expansion
Dithiane Reduction
Chromatographic Resolution through
Diastereomeric Derivatization
(Product)
Wieland–Miescher
ketone
O O O O
Me HO
Me O OH MeCH=PPh3
cat H+,
60% 96%
O O C6H6–H2O O
Robinson Annulation Ketone Reactivities Wittig Reaction
O O O O O O
OsO4 p-TsCl LiClO4
100% pyridine CaCO3, THF
OH OH 50 °C, 2.5 d
Me Dihydroxylation OH OTs Pinacol
Stereochemistry Rearrangement
O O O O O
Me
2 N HCl 2 N HCl
O + Me O
25 °C, 6 h 100 °C, 24 h
Me O Me
41-48% 5%
Me Me Me Me Me
O
Me O O
Et3N 0.95 equiv HS SH
O ethylene glycol O Ph3CLi; CH3I O BF3•OEt2
225 °C 60% SiO2 separation
Me H
Me Me
Intramolecular Thermodynamic Diastereomeric
Michael Addition 10–20% Enolate Derivatization and
Chromatographic
Resolution
Me
Me MeS Me Me Me Me
Me
S 1. LiAlH4 1. MeLi, 93%
O 2. Na, NH2NH2 O 2. SOCl2, pyr
3. RuO4
Me Me Me
Desulfurization
Wolff–Kishner
Reduction
445
Osmylation
- large reagent reacts preferentially
O O O O with more accessible double bond
OsO4 and from the least hindered face.
Typically, this is from the equatorial
100% direction but one 1,3-diaxial H is
OH removed and axial approach now
Me OH observed
Selective Tosylation
- rates: 1° > 2° > 3°
O O O O
- 3° alcohols react very slowly
p-TsCl - MsCl and Et3N generates sulfene
which will react with 1°, 2°, 3° OH
pyridine
to give the mesylate
OH OH O
OH OTs H2C S
O
- Also note the use of DMAP to
acylate 3° alcohols via R
N N
O O O O
O
LiClO4
O
CaCO3 Pinacol Rearrangement
OH 50 °C Me - LiClO4 used as source of free Li+ ion to
OTs accelerate solvolytic loss of TsO group
- migration of unsaturated alkyl group
observed preferentially
O - trans antiperiplanar arrangement
R R
TsO TsO
R' O
O H H O R'
O Me
Me O
Et3N
O HOCH2CH2OH O
Me H 225 °C
Me Intramolecular Michael Addition
10–20% - only cis product undergoes Michael
- side products include the retro-Michael
Me Me product A and the OH– addition and
O O retro aldol product B
O B + A O
CH3 Me
5% 5%
446
Dale L. Boger
Me
Me Me Me Me Me MeS Thio-ketalization (Derivatization)
O
Me - other carbonyl much more hindered
O HS SH S - diastereomers arise that are separable
O by conventional chromatography
BF3•OEt2
SiO2 separation
Me Me
Desulfurization
Me - direct Wolff–Kishner failed
Me MeS Me Me
- LiAlH4 protects ketone from reduction
Me - today: Ra–Ni better for desulfurization
S 1. LiAlH4
O and would avoid need to protect ketone
O 2. Na, NH2NH2 - Wolff–Kishner reduction of dithiane similar
3. RuO4 to Huang–Minlon protocol of Wolff–Kishner
Me Me reduction for carbonyl removal (Huang,
Minlon J. Am. Chem. Soc. 1946, 68, 2487;
H 1949, 71, 3301), van Tamelen J. Am. Chem.
H2NNH2
O NH N NH Soc. 1961, 83, 4302.
(–H2O) N
Wolff–Kishner
Wolff Justus Liebigs Ann. Chem. 1912, 394, 86.
H H H
base Further improvements
N N N NH tBuOK, DMSO, 25 °C
H
Cram J. Am. Chem. Soc. 1962, 84, 1734.
Me Me Me Me Olefination
- Wittig reaction unsuccessful,
1. MeLi, 93% ketone too hindered
O
2. SOCl2, pyr - two-step procedure adopted
Me Me
447
3. McMurry Synthesis: J. Am. Chem. Soc. 1972, 94, 7132. Intramolecular Enolate–Epoxide Addition
Dibromocarbene Addition, Ring Expansion
Organocuprate 1,4-Additions
Intramolecular Aldol Reaction
Transannular Reactions
O O O O O
Me
H2, Pd–C 1. MeMgBr 7 m-CPBA
85% 2. H2SO4 6
O O Me 5 H
H
Robinson Catalytic cis 69% Peracid
Annulation Hydrogenation (31% 6,7 olefin) Epoxidation
Me OH Me
O
Me
tBuOK
MeS(O)CH2Na H2SO4
O O
DMSO, 93% 25 °C, 90% CHBr3
Me
O H 5 d, 60 °C 43%
Me Me
Intramolecular Enolate– Carbene Addition
Epoxide Addition to Olefin
Br
Me Me Me
Br
Br
H AgClO4 Na/NH3 CrO3
O O OH O OH
acetone–H2O MeOH, 62% pyr
100%
Me Me Me
Ring Expansion Dissolving
Methodology Metal Reduction
Me Me Me Me Me
Me2CuLi 1. LiAlH4 OTs base

O O O 2. TsCl, pyr H 100%
OH 97% OH
Me Me Me
Cuprate Reaction Fragmentation
Intramolecular Aldol Reaction Reaction
Me Me Me Me Me Me
H2, Pd–C steps

O O
89%
Me Me Me
448
Dale L. Boger
Me Hydrogenation
O O O
H - known conditions to give cis stereochemistry
H2, Pd–C
H - H2 comes in from less hindered face
85% - heteroatoms can also direct H2 to their face
O
O
H
69% O O
Acid-catalyzed Elimination
- cis ring fusion prefers ∆2,3 double bond
O O Me
H - trans ring fusion prefers ∆3,4 double bond
1. MeMgBr
- known from steroid chemistry
2. H2SO4 O O
31%
O
H
Me
H
O H O Epoxidation
Me
- epoxidation from the least hindered face
Me m-CPBA - no competitive Baeyer–Villiger at ketone
- trisubstituted olefin more reactive than
Me ketone
O H
Me
NaO H O Me OH
Intramolecular Epoxide Addition
CH3 S CH2Na
- very slow epoxide opening due to steric
Me O encumbrance of Me group
O
- benefits from irreversible nature of epoxide
O opening
Me
Me
Alternate route attempted:

Me Me
1. BH3•THF O
–OOH
O O Alternate Route
- hydroboration–oxidation gave ketone
2. H2Cr2O7
- methylation conditions specifically
Me Me employed to avoid over-methylation
- ring expansion with CH2N2 did not
Me Me proceed
Ph3CLi O
CH2N2
O failed ring
MeI AlCl3 expansion
Me
449
Diazomethane Ring Expansion
major
A - CH2N2 poor nucleophile
δ+ - AlCl3 added to activate carbonyl
O –O N N
minor - many side reactions possible
+ CH2 N N - CH2N2 explosive, difficult to use
- products equally reactive toward
additional expansions/epoxidations
O - TMSCHN2 is a safe alternative to
O O diazomethane CHN2, a yellow gas,
CH2 N N
which typically is prepared in situ
+
in special apparatus to diminish
the chance of detonation
A δ+ EtO2C Diazoacetate Ring Expansion

O –O N N - improvement over diazomethane
major - product in enol form and will not
+ HC N N further react with reagent
EtO2C - reagent stable, transportable and
readily available
- ultimately employed in the later Ho
O OH synthesis
no
CO2Et CO2Et further
reaction
Carbene Addition and Ring Expansion

+
- singlet carbene has electrophilic
CHBr3 + KOtBu :CBr2 C character, and undergoes stereospecific
reaction with olefins (no scrambling
as observed with triplet carbene)
H Br - Br can donate electrons into the
+ R R ω2a C
empty p-orbital, thus stabilizing
C + Br
the singlet carbene
R R π2s - cheletropic cycloaddition occurs with
H
olefin geometry maintained via a
π2s + ω2a cycloaddition
R R
R
H Disrotatory Ring Opening of
H disrotatory + Halocyclopropanes
H ring opening H - leaving group will influence direction
H
R of ring opening
X extended - departure of LG simultaneous with
vs. R disrotatory ring opening
H
R - substituents syn to the departing
disrotatory R group will move towards one another
H +
ring opening while they move away from each
X R
H other if anti leaving group. Since this
H H compact system is confined to a 7-membered
ring, the R groups must move toward
H H each other to give the compact alkyl
R H2O R cation and it is the syn bromide that
+
or Nuc– is lost
R R
H H OH
450
Dale L. Boger
H Br
In Fused Bicyclic Systems
Br - imposed geometry of ring controls
H H
Br opening and directs leaving group
- nucleophile comes in trans to departing Br–
- exception: bicyclo[5.1.0]octane can give
Nuc H the trans double bond via outward rotation
- Chem. Commun. 1967, 294.
H Br - Chem. Commun. 1968, 1593.
Br - J. Am. Chem. Soc. 1970, 92, 2566.
H
Br
Nuc–
Br
Me Me
Br Br
AgClO4
H O
O acetone–H2O OH
100% H
McMurry Application
Me Me - ring controls geometry of ring opening, thus
only one bromine departs
- nucleophile (OH2) enters trans to leaving Br
Me Me - no trap at other end of allyl cation - possible
Br Br assistance of C=O
O H O H
OH
Me Me
Me Me
Br Dissolving Metal Reduction
Na/NH3 OH - stereochemistry of reduced OH - most
O OH OH stable product
H H - reduction of the vinyl halide
H
Me Me
Me Me Me Me
Cuprate Addition - Intramolecular Aldol Reaction
Me2CuLi - cuprate adds in Michael fashion to generate
O O
OLi enolate
- enolate then attacks carbonyl in
OH intramolecular fashion
Me Me
Me Me Me Me
OTs Fragmentation
base O - reduction occurs from least hindered face
- tosylation selective for 2° > 3°
100%
O
Me H Me
451
4. Brieger Synthesis: (attempted) J. Am. Chem. Soc. 1963, 85, 3783. Diels–Alder Reaction
1,5-Hydrogen Migration of Cyclopentadienes
Me
Me Me MgBr
OAc
OAc HCl(g)–HOAc OAc Et2O, 0 °C 175 °C
0 °C, 50% 28% 48 h, 90%
Me Me
Me Me Me Me Intramolecular
Cl Diels–Alder
CO2Me Reaction
Me Me
O
Me OAc but
Me H H 94%
OAc Me Me CO2Me
Me Me
0% 90%
TMSO
Snowden Tetrahedron Lett. 1981, 22, 97 and 101.
Me
Me MgBr Grignard Addition
OAc - alkylation at 3° center!
OAc Et2O, 0 °C - nonbasic reagent, E2/E1 elimination
not observed
28%
Me Me
Me Me
Cl
R 1,5 H-Shift
H 1,5-H - proceeds at 0 °C
- causes failure of desired [4 + 2]
R shift H cycloaddition for longifolene above
H H
R H
OAc OAc OAc

H H H
H Intramolecular Diels–Alder
- at 175 °C, all three 1,5-H shift products present
Me - provide three different possible products
Me - only one product observed
Me Me Me
90%
Me Me OAc
OAc Me
Me
Me Me
OAc Me
Me Me
452
Dale L. Boger
5. Johnson Synthesis: J. Am. Chem. Soc. 1975, 97, 4777. Organocuprate 1,4-Addition
Regiospecific Enolate Trap
Cation–Olefin Cyclization
Me Me
(Me
CuLi
2 MeLi ArCO2NR4
2. CH3COCl Br2, 1 equiv acetone, 76%
84% Br
O OAc O
Cuprate Conjugate Addition
Regiospecific Enolate Trap
Me Me
Me Me
HO 2 equiv ZnBr2
LiAlH4 CF3CO2H
ether, 0 °C ether, 0 °C NaCNBH3
92% 75% 94%
O HO H Cation–Olefin
Cyclization
Me Me Me Me Me Me
p-TsOH RuO4 (cat.) LDA
25 °C, 0.5 h NaIO4, 72% O MeI
91%
Me Me Me Me
steps
O
Me Me
Me
Me Me
HO Cation–Olefin Cyclization
CF3CO2H - 2° allylic alcohol for initiation site
ether, 0 °C
75%
HO H
Me Me Me Me Me Me
453
6. Oppolzer Synthesis: J. Am. Chem. Soc. 1978, 100, 2583. Enamine Acylation
Helv. Chim. Acta 1984, 67, 1154. Photochemical [2 + 2] Cycloaddition
Retro-Aldol Reaction
Wittig Reaction
Simmons–Smith Cyclopropanation
Hydrogenation of Cyclopropanes
Classical Resolution via Crystallization
of Diastereomeric Salts
O Cl
O HO PhCH2O2CO
O O
N PhCH2OCOCl hν, pyrex
87% pyr 83%

[2 + 2] Photochemical
Enamine Acylation
Cycloaddition
O
OCO2CH2Ph
10% Pd/C , H2 Ph3P=CH2 Zn–Ag

O O O
HOAc, 25 °C, 18 h 88% CH2I2, 78%
Simmons–Smith
Retro-Aldol Cyclopropanation
Me Me Me Me
H2, PtO2 LDA steps

O O O
HOAc, 96% MeI
Cyclopropane Me
Hydrogenation
Me Me
Me
H CO2H
optically active
starting material
H
H2N Me
classical resolution
recrystallization of
diasteromeric salt
454
Dale L. Boger
7. Schultz Synthesis: J. Org. Chem. 1985, 50, 915. Birch Reductive Alkylation
Retro Cheletropic Cycloaddition
1,3-Dipolar Cycloaddition
Vinylcyclopropane Rearrangement
Asymmetric Synthesis
via Substrate Chiral Auxiliary
Me Me
I
CH(OMe)2 OMe OMe 110 °C
OMe CO2Me CH3CONHBr MeO CO2Me DBN, tol
CO2Me Br
2.5 equiv K in NH3 MeOH, 95%
1.0 equiv tBuOH Me Me
–78 to –25 °C Me CH(OMe)2 Me CH(OMe)2
98%
Birch Reduction–Alkylation Ph
H2N N
O O O CO Me
CO2Me CO2Me Ph 2
p-TsOH hν
acetone, 86% toluene, 110 °C 366 nm
Me Me – N2
43% Me
Me CH(OMe)2 Me CHO N N Me
Retro-Cheletropic Cycloaddition
O 1,3-Dipolar Cycloaddition
40% overall
CO2Me Me Me Me Me
O CO Me
2 140 °C H2, Pd/C KOH, 25 °C
xylenes O 92% O MeOH–H2O
Me 85%
Me CO2Me 90% from 1,3- CO2Me
Vinylcyclopropane
Rearrangement dipolar cycloadduct
Me Me Me Me Me Me
110 °C steps
O O
toluene
86%
CO2H H Me
CH(OMe)2
Me Me Me CHO
O I O Me
CH(OMe)2 Me O
N N HCl/MeOH Me H H•HCl
N
O
2.5 equiv K in NH3
O H O H
1.0 equiv tBuOH O
from (S)-proline –78 to –25 °C
98%
CHO MeO CO Me
Me O OMe
2
MeOCOCl O 1. HCl, CH(OMe)3
Me H
N 2. NaOMe, MeOH Me
O
Me CH(OMe)2
O
455
Ph
H2N N Retro Cheletropic Cycloaddition
O O CO Me and Subsequent 1,3-Dipolar Cycloaddition
CO2Me Ph 2
toluene, 110 °C
Me 43% Me
Me CHO N N Me
retro cheletropic
cycloaddition with
loss of stilbene
O O
O CO2Me CO2Me
CO2Me
Me Me
Me Ph
Me Me
Me N N
N N
N
Ph N
Me Me
O CO Me O CO Me Vinylcyclopropane Rearrangement
2 2
- [1,3]-sigmatropic rearrangement
hν 140 °C O
–N2 xylenes
Me Me
N N Me Me CO2Me
Me Me
- This sequence is equivalent to
adding the elements of a carbene
O O 1,4 across a diene
- Is this 4e– + 2e– cycloaddition
possible? Consider the Woodward–
CO2Me CO2Me Hoffmann rules.
456
Dale L. Boger
8. Fallis Synthesis: J. Am. Chem. Soc. 1990, 112, 4609. Intramolecular Diels–Alder Reaction
J. Org. Chem. 1993, 58, 2186. Barton Free Radical Deoxygenation Reaction
Acetate Pyrolysis
Chromatographic Resolution through
Diastereomeric Derivatization (Starting Material)
OMe
H O
O OH O ClCd
MeLi MnO2
65% 81% 73%
resolution via
diastereomeric derivatization
O
Me Me Me Me
O OMe OMe
O
AcO ClC(=S)OPh
MeOH, BF3•OEt2 1. H2, Pd–C, 99%
O OH
heat, toluene 2. LiAlH4, 96% Bu3SnH, 71%
83 x 97% Me 3. Ac2O, 74% Me Barton
Intramolecular Diels–Alder Reaction Free Radical
Deoxygenation
Me Me Me Me Me
Me
OMe
AcO 1. NaI–TMSCl AcO pyrolysis
2. ClC(=S)OPh 525 °C, 56%
Bu3SnH, 50%
Me Me Me
Barton Free Radical Deoxygenation Acetate Pyrolysis
O O OH
MeLi MeLi 3-exo-tet cyclization
65% Me 65%
AIBN
OH O OPh O OPh
Bu3SnH
Barton Free Radical Deoxygenation
S SSnBu3 - mild method for removal of
•SnBu3
alcohols
Bu3SnH
O OPh H
SSnBu3
Acetate Pyrolysis
- a retro ene reaction
CH3 - comparable to the sulfoxide
O syn elimination (Trost) which is
CH3
H O + activated by an adjacent EWG
HO
- comparable to the selenoxide
O syn elimination (Reich) which is
milder, faster and proceeds at
lower temperature
457
O
O - constraints of the 6-membered ring
O
MeOH precludes reaction from the other
O cyclopentadiene isomers and lactone
BF3•OEt2 stereochemistry dictates π-facial
selectivity
OMe
O O
O O
OMe OMe
Me Me Me Me
OMe OMe
O toluene O
O microwave O
Me 2.5 h, 97%
Me
Me Me Me Me
OMe OMe
O O
O O
Me H Me H
H
OH O - MnO2 serves to oxidize cyclopropyl alcohol
MnO2 analogous to allylic alcohol oxidation
81%
"conjugated"
H cyclopropane - Cadmium reagent for α-versus γ-enolate
Me conformation reaction
Me - Diastereoselective addition
Nu– Nu– OMe
O O
9:1 ClCd
SiMe3
NaI–TMSCl deprotection
R O Me R O Me - dealkylative SN2 methyl ether
deprotection
MeI + I–
H3O+
R O SiMe3 R O H
458
Dale L. Boger
9. Kuo Synthesis: Can J. Chem. 1988, 66, 1794. Intramolecular Aldol Addition
Wagner–Meerwein Rearrangement
1. Br2, HBr, HOAc I NC 1. LDA

2. Br2, ClSO3H TMSO Br
O NaCN, DMSO O
O
3. Zn, HOAc O 70 °C O 2. K, HMPA
4. KI, DMSO, 110 °C
5. TMSCl, HOCH2CH2OH
TMSO MeO MeO

LDA, –78 °C TiCl4, –78 °C
O 1. HCl
MeO MeO
2. PDC, CH2Cl2 O TMSCl TMSO
O
3. HC(OMe)3, CeCl3
1. Ca/NH3 1. BBr3, NaI Et2Zn

O 2. Ac2O, DMAP H 2. PDC, CH2Cl2 H CH2I2
MeO MeO OAc 3. Ph3P=CHBr, OH
Intramolecular
Mukaiyama Aldol BuLi, –78 °C
4. LiAlH4
H2/Pt PCC LiAlH4

H HOAc, 2.5 atm H CH2Cl2 O
OH OH
Me Me
MeSO2Cl, pyr
HO DMAP, 100 °C
H Wagner–Meerwein Me
Rearrangement
Me Me
MeSO2Cl, pyr Wagner–Meerwein Rearrangement
HO
DMAP, 100 °C
H Me
Me Me
H
MsO
* *
H Me
459
10. Ho Synthesis: Can J. Chem. 1992, 70, 1375. Ethyl Diazoacetate Ring Expansion
Alkylative Esterification
O
benzene O H2SO4 O H2SO4
+ CO2H
O
80 °C, 67% O 53% MeOH, 100%
O O
O
Eaton's Acid
H2, Pd–C NaOMe O P2O5

O O
CO2Me 98% CO2Me MeOH, reflux Me3SO3H
93% O 65 °C, 82%
O O CO2Me
Acylium ion Cation–
Olefin Cyclization
Me2CuLi N2CHCO2Et LiI, H2O

CO2Et
0 °C, 96% BF3•OEt2, 100% collidine
O O reflux, 90%
CO2Me O
CO2Me CO2Me
Ring Expansion O
both isomers
present
CO2Et
Me Me Me Me Me Me
K2CO3 1. NaBH4, 82% NaI, Zn
MeI, acetone 2. MsCl, Et3N, 85% reflux
O 95% O OMs <50%
CO2H CO2Me CO2Me
both isomers O both isomers O both isomers OMs
present present present
Me Me Me Me Me Me
KOH 1. MeLi. 87%
O longifolene
reflux 2. CF3CO3H. 48%
100% 3. NaOH, 93%
CO2Me CO2H 4. PCC, 86%
Baeyer–Villiger
I– Me Me Me Me
- SN2 Dealkylative
LiI, H2O K2CO3 Deesterification followed
CO2Et by decarboxylation of the
collidine MeI, acetone
β-keto acid
O reflux, 90% O 95% O - Alkylative Esterification
CO2Me HO2C CO2Me
460
Combinatorial Chemistry
Dale L. Boger
XIV. Combinatorial Chemistry

Combinatorial Chemistry Reviews
• A Practical Guide to Combinatorial Chemistry; Czarnik, A. W. and DeWitt, S.
H., Eds.; ACS: Washington, D. C., 1997.
• Molecular Diversity and Combinatorial Chemistry: Libraries and Drug

Discovery; Chaiken, I. N.; Janda, K. D., Eds.; ACS: Washington, D. C., 1996.
• Balkenhohl, F. et al. Combinatorial Synthesis of Small Organic Molecules,

Angew. Chem. Int. Ed. Eng. 1996, 35, 2288.
• Ellman, J. A. et al. Synthesis and Applications of Small Molecule Libraries,

Chem. Rev. 1996, 96, 555.
• Gordon, E. M. et al. Applications of Combinatorial Technologies to Drug

Discovery. 1. Background and Peptide Combinatorial Libraries, J. Med.
Chem. 1994, 37, 1233.
• Gordon, E. M. et al. Applications of Combinatorial Technologies to Drug

Discovery. 2. Combinatorial Organic Synthesis, Library Screening
Strategies, and Future Directions, J. Med. Chem. 1994, 37, 1385.
• Pavia, M. R., Sawyer, T. K. and Moos, W. H., Eds.; The Generation of Molecular
Diversity, Bioorg. Med. Chem. Lett. Symposia-in-print no. 4. 1993, 3, 381. (First
Review Treatment of Field).
• Combinatorial Peptide and Nonpeptide Libraries: a Handbook; Jung, G., Ed.;

VCH: Weinheim, 1996.
• Combinatorial Chemistry; Terrett, N. K.; Oxford Univ. Press: Oxford, UK, 1998.
• Obrecht, D.; Villalgordo, J. M.; Solid-Supported Combinatorial and Parallel

Synthesis of Small-Molecular-Weight Compound Libraries; Pergamon/
Elsevier, 1998.
• Boger, D. L., Ed.; Combinatorial Chemistry, Bioorg. Med. Chem. Lett.

Symposia-in-print no. 14. 1998, 8, 2273.
• An Information Revolution, Science 2000, 287, 1951–1981.
461
Solid Phase Peptide Synthesis

R1
Cl
O • Attach first amino acid to (chloro-
NHCBz
O
methylated) polymer bead
R1 O
O NHCBz • Deprotect (HBr), Couple (DCC),
N
O H R2
Cap (acetic anhydride)
R1 O H R3 O
O N NHCBz
N N
O H R2 O H R4
• Repeat coupling cycle
R1 O H R3 O
HO N NH2
N N
O H R2 O H R4
• Deprotect, Saponify, Purify
• Allows excess use of reagents and reactants to force reaction to completion

• Removal of reagents, reactants and byproducts by filtration
Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.

Nobel Prize, 1984 "for his development of methodology
for chemical synthesis on a solid matrix"
Additional Highlights in Solid Phase Synthesis

• 1965: Letsinger and Khorana, the application of solid supports for the synthesis of oligonucleosides
(J. Am. Chem. Soc. 1965, 87, 3526 and 1966, 88, 3182)
• 1967: J. Frechet, a highly loaded trityl resin (2.0 mmol/g)
• 1967: Wilkinson et al., polymer-bound tris(triphenylphosphine)chlororhodium as hydrogenation catalyst

(J. Chem. Soc. A 1967, 1574)
• 1969: Solid-phase synthesis of Ribonuclease (J. Am. Chem. Soc. 1969, 91, 501)
• 1971: Frechet and Schuerch pioneered solid-phase chemistry in the field of carbohydrate research
(J. Am. Chem. Soc. 1971, 93, 492)
• 1973: Leznoff et al., the use of polymer supports for the mono-deprotection of symmetrical dialdehydes,
describing oxime formation, Wittig reaction, crossed aldol condensation, benzoin condensation, and
Grignard reaction on solid support (Can. J. Chem. 1973, 51, 3756)
• 1974: F. Camps et al., the first synthesis of benzodiazepines on solid support (An. Quim. 1974, 70, 848)
• 1976: Rapoport and Crowley, published a review and raised three important questions
• degree of separation of resin-bound functionalities
• analytical methods to follow reactions on solid support
• nature and kinetics of competing side reactions
(Acc. Chem. Res. 1976, 9, 135)
• 1976–1978: Leznoff et al., the synthesis of insect sex attractants (Can. J. Chem. 1977, 55, 1143)
• 1979: Leznoff et al., a chiral linker for the asymmetric synthesis of (S)-2-methylcyclohexanone in 95% ee
(Angew. Chem. 1979, 91, 255)
462
Dale L. Boger
Tea-Bag Method
.......... Seal • 10 to 20 mg of 248 different

.......... 13-residue peptides
..........
Mesh
..........
Opening • Sequence
..........
..........
.......... 1. Deprotection
.......... Resin 2. Wash Repeat
3. Coupling
XXX Code 4. Wash
5. HF Cleavage
Houghten, R. A. Proc. Natl. Acad. Sci. USA 1985, 82, 5131.
Multipin Peptide Synthesis

Pin
reagents,
reactants
in wells
• Synthesize on polyacrylate-
grafted polyethylene rods
• Utilize conventional solid
phase synthesis methods
growing
peptide
• Preparation of up to
on a pin 10,000 spatially separate
compounds using
inexpensive equipment
and readily available
automation
Individual pins 96-Well Plate

with crowns
(1 to 7 µmol
loading capacity)
Geysen, H. M. et al. Proc. Natl. Acad. Sci. USA 1984, 81, 3998.
Zuckermann, R. N. et al. Bioorg. Med. Chem. Lett. 1993, 3, 463.
463
Split and Mix Solid Phase Synthesis

(Split-Method, Portioning-Mixing Method)
• Solid support is divided before each
A1 A3
A2 coupling cycle
• Equimolar mixtures of peptides
A1 A2 A3
- Mix • Cannot conduct direct mixture
synthesis on solid phase due
B1 B3 - Split to differential reaction rates
B2 - React • One unique peptide on each bead
A1B1 A1B2 A1B3
A2B1 A2B2 A2B3 N = n1 x n2 x n3 x ..... nm
A3B1 A3B2 A3B3 N = number of products
- Mix after each cycle
C1 C3 - Split
C2 n = number of
- React reactants in each cycle
A1B1C1 A1B1C2 A1B1C3
Portion-mixing
A2B1C1 A2B1C2 A2B1C3 Furka, A. et al. Bioorg. Med. Chem. Lett. 1993, 3, 413.
A3B1C1 A3B1C2 A3B1C3 Furka, A. et al. Int. J. Peptide Prot. Res. 1991, 37, 487.
A1B2C1 A1B2C2 A1B2C3 Split synthesis
Hruby, V. J. et al. Nature 1991, 354, 82.
Divide, couple, and recombine
A3B3C1 A3B3C2 A3B3C3 Houghten, R. A. et al. Nature 1991, 354, 84.
Generation of Combinatorial Antibody Libraries
Use of bacteriophage lambda vector to express in E. coli a combinatorial

library of Fab fragments
Sequence:
First step: Separation of heavy and light chain libraries which are constructed
in λHc2 and λLc1
Second Step: Combination of two libraries are combined at the
antisymmetric Eco R sites present in each vector
This results in a library of clones each of which potentially coexpresses a

heavy and a light chain
Lerner, R. A. et al. Science 1989, 246, 1275.
464
Dale L. Boger
Phage Display
• The general concept is one in which a

Helper Phage library of peptides is presented on the surface
of a bacteriophage such that each phage
displays a unique peptide and contains
Infection
Extrusion
within each genome the corresponding DNA
sequence
Outer Membrane
• Introduction of randomized DNA into gene III
Periplasmic of filamentous phage Expression of
Space Peptide-pIII the corresponding peptides at the N
pIII terminus of the absorption peptide (pIII)
Inner Membrane
• Very quick and efficient generation of
large combinatorial libraries of peptide
Peptide- fragments
ssDNA
pIII
• Screen by panning and enrichment
Peptide Library
Phage DNA • Identify by DNA sequence
pIII
Phagemid DNA
Smith, G. P. et al. Science 1990, 249, 386.
Very Large Scale Immobilized Polymer Synthesis

(VLSIPS)
Lithographic
Mask
hν
Photo- X–A • Light-directed spatially addressable
X X X X
Deprotection
X X
Chemical parallel chemical synthesis
NH NH NH NH NH2 NH2 NH NH Coupling
• Nitroveratryloxycarbonyl (NVOC)
as a photolabile protecting group
hν
X X X X O OMe
X–B O
A A X X A A X X X= OMe
Chemical
NH NH NH NH NH NH NH NH Coupling O2N
• Binary masking yields 2n compounds

E F E F
in n chemical steps
X X X X
C D C D
A A B B
A A B B
Repeat
NH NH NH NH NH NH NH NH Fodor, S. P. A.; Pirrung, M. C. et al.
Science 1991, 251, 767.
465
Solid Phase Synthesis of 1,4-Benzodiazepines

• Application of solid-phase combinatorial synthesis to non-oligomeric compounds
O R1
: solid phase Si SnMe3 Si
attached to 1) R1 Cl Pd0 O
linker NH2
NHBoc 2) TFA, CH2Cl2
O
1) F NHFmoc
"traceless"
linker R2
2) Piperidine
R1 R1 R1
N Si N Si
R2 HF R2 1) 5% HOAc, 65 °C O
N
Me2S N N
2) Ph NH
O O OLi
R3 R3 O NH2
O
3) R3I, DMF R2
Ellman, J. A. et al. J. Am. Chem. Soc. 1992, 114, 10997.

DeWitt, S. H. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
Resin Release Only of Product

First Example: Rapoport, H.; Crowley, J. I. J. Am. Chem. Soc. 1970, 92, 6363.
(Dieckmann condensation)
R1 R2 R1 R2
R1 R2
O 1. TFA O
NH HCl, ∆ O NH
NHBOC
2. R3 NCO O N
O HN O
R3 O
R3 Hydantoins
The desired products are
• Insures product purity without formed by acid-catalyzed
deliberate purification and
independent of overall conversion cyclization and only with
cleavage off the solid support
R1
R4
O O
R1 N N R3
∆ O TFA, ∆
O R1
NH2 NH NHR4 R2
N
O
R2 R3 NHR4 R2
Benzodiazepines
R3
DeWitt, S. H. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
466
Dale L. Boger
Nucleotide Encoding
1. A1 1. A3
2. N1 1. A2 2. N3 CPG beads
2. N2 Linker Unit
PCR Primer
N1 A1 N2 A2 N3 A3 A1, A2, A3: Amino Acids
mix N1, N2, N3: Encoding Nucleotides
1. A1 1. A3
2. N1 1. A2 2. N3
2. N2
• Tag attached to molecule, not bead
N1N1 A1A1 N2N1 A1A2 N3N1 A1A3 • PCR enrichment: sensitivity and
screening by panning and
enrichment
N1N2 A2A1 N2N2 A2A2 N3N2 A2A3
• Bonus: nucleotide tagging could be
used for identification as well
N1N3 A3A1 N2N3 A3A2 N3N3 A3A3
Janda, K. D. et al. J. Am. Chem. Soc. 1993, 115, 9812.

Brenner, S.; Lerner, R. A. Proc. Natl. Acad. Sci. USA 1992, 89, 5381.
Split Synthesis ENCODED with Tagging Molecules ( T1–T4 )

Separate Beads into 3 Groups Tagging Molecules
1. Chemically inert
OH 2. Encoding by attachment to the beads
A+ B+ C+
1%T1 1% T1 + 1% T2 3. After release, analyzed by
1% T2 Capillary Gas Chromatography
T1
T1 OA T2 OB T2 using Electron Capture Detection
OC
(ECGC) on femtomolar scales
Mix Beads and Divide again into 3 Groups from single beads
T1 4. Identity only
T1 OA T2 OB T2 OC (CH2)n
N2CHCO O Clm
O
X+ Y+ Z+ n = 2–11
m = 2–5
1% T3 1% T4 1% T3 + 1% T4 OMe
T O O Ar
T1 T1 T3 1 O ( )n
O-AX O-AY O-AZ HOOC O
T3 T4 T4
NO2
T
T2 T2 T3 2 Linker Electrophoric Tag
O-BX O-BY O-BZ
T3 T4 T4
Cl Cl Cl H Cl H
T1 T
T1
O-CY T2 1 Ar = Cl Cl F
T2 O-CX T2 O-CZ
T3 T4 T3 Cl Cl Cl H Cl H
T4
Still, W. C. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 10922; Acc. Chem. Res. 1996, 29, 155.
467
Peptide Encoding
Fmoc Ddz
B: Fmoc protected, base-labile

Distribute resin into n portions monomers
Deprotect Fmoc C: Ddz-protected, acid-labile
Couple "binding" monomer Bn monomers, which give
reproducibly strong signals upon
B1 Ddz B2 Ddz Bn Ddz Edman sequencing
FmocHN NHMoz
=
O O Resin
Deprotect Moz or Ddz
Couple "coding" monomer Cn HN
MeO
B1 C1 B2 C2 Bn Cn
OMe
Repeat • Identity only
Mix
Zuckermann, R. N. et al. J. Am. Chem. Soc. 1993, 115, 2529.
Electronic Encoding
• Radiofrequency memory chips allow libraries to be tagged in a machine-readable form
• The chips (8 x 1 mm) can be incorporated into various reaction platforms (e.g. beads,
tubes, bags, pins or cans)
Control logic
Transmitter
and receiver
Antenna
Rectifier
Memory encoding
Glass Housing A B C
Nova, M. P.; Nicoloau, K. C. et al. Angew. Chem. Int. Ed. Eng. 1995, 34, 2289.
Armstrong, R. W. et al. J. Am. Chem Soc. 1995, 117, 10787.
468
Dale L. Boger
Noncovalent Color-Coding Strategy
A1 A8
A1B1 A1B12
• 8 different subunits A1–A8 are linked to resin

• each A is then partitioned into 12 Porous • all 96 PCs are
Containers (PCs) with different cap colors combined
• a small amount of colored bead (one color for • subunit C is
each A) is added to each PC added to each
A8B1 A8B12
• the PCs are grouped by cap color and
subunit B is attached
96-well plate
bead color
• compounds are sorted
individually by cap and
bead color
A1B1C A2B1C
• resin is cleaved
• products are filtered into a
separate 96-well plate
cap color
A1B2C A8B12C
Guiles, J. W. et al. Angew. Chem., Int. Ed. 1998, 37, 926.
Fourier Transform Combinatorial Chemistry

• Cotton thread wrapped around a cylinder
• 3 sectors exposed to 3 different reagents Thread library evaluation
Fluorescence
C B Thread length
Screening
and Fourier Transform
A B C A B C A B Evaluation
FT Library Spectrum
Fluorescence
Coupling with 4
other compounds
D
Frequency
G E Reverse F.T.
at a given frequency
F
A B C A B C A B "Fitness Profile" of a sub-molecular unit
D E F G D E F G
Schwabacher, A. W. et al. J. Am. Chem. Soc. 1999, 121, 8669.
469
Toward Larger Chemical Libraries:

Encoding Fluorescent Colloids
Solid support bead • The fluorescent "reporter" is introduced

with numerous silica during the Split & Pool synthesis
particles ("reporter")
• Each particle contains a fluorescent dye
(or a combination) coding for a single
monomer
• "Decoding" the bead (by fluorescence

microscopy) allows identification of the
compound
Trau, M. et al. J. Am. Chem. Soc. 2000, 122, 2138.
Microarray Screening: Immobilized Target or Compound

Membrane Printing: DNA Microarray: Printing small molecules
the SPOT technique 1 Printing oligonucleotide2 on a glass surface3
• Peptide synthesis on Fluorophore

probe
paper using "Fmoc/tBu"
scheme
• The molecule or synthesis • Covalent immobilization of

is arrayed by dispensing the compound on the glass
small droplets in pre-defined surface support
areas
• Covalent immobilization of • Incubation with the target
• Automation of the technique oligonucleotides on support • Detection by fluorescence
allows miniaturization of the with high-density arrays
process and creates • Detection of DNA/DNA
high-through put systems or DNA/RNA interactions for
expression analysis,
genomics, and cellular
response to small molecules > 1000 spots per cm2
1 Frank,R. et al. in Peptide and Nonpeptide Libraries, Jung, G., Ed., 1996, 363.
2
Niemeyer, C. M. et. al. Angew. Chem. Int. Ed. 1999, 38, 2865.
3 Schreiber, S. L. et. al. J. Am. Chem. Soc. 1999, 121, 7967.
470
Dale L. Boger
Screening Mixtures of Beads (Compounds)
• Super permeable resin for organic combinatorial

HO
chemistry (SPOCC) fully compatible with organic
O O chemistry and enzyme assays (polyether polymer)
O
n
O O Meldal, M. et al. J. Am. Chem. Soc. 1999, 121, 5459.
O OH
O
n • Peptide substrates contain a fluorescent dye and
O O
a quencher for use in fluorescent resonance energy
O O transfer (FRET) assay
O
n
• Cleavage of the resin bound substrates leads to
formation of strongly fluorescent beads
• Identification of active compounds by MALDI-MS

of fluorescent beads
Meldal, M. Tetrahedron Lett. 1992, 33, 3077.

Meldal, M. et al. Proc. Natl. Acad. Sci. USA 1994, 91,
3314.
Meldal, M. et al. Biochem. J. 1997, 323, 427.
One-Step Mixture Synthesis and Deconvolution

"Activated Core Approach"
Core molecules: Building blocks: Library size:

3 Tetraacid chlorides 19 amino acids A1: 11,191
A2: 65,341
A3: 1,330
Deconvolution by Omission Resynthesis
1. Libraries A1–A3 to find best core molecule
2. Sublibraries B1–B6 to find best 9 building block amino acids (AA)
3. Sublibraries C1–C7 to check if the selected 9 AA are the best combination
4. Sublibraries D1–D9 to find the best 5 AA
5. Sublibraries E1–E7 to find the best 3 or 4 groupings of the 5 AA
6. Sublibraries F1–F6 to find the best relative position of the 4 AA on the core
7. Single compounds G1–G3 synthesized and the best inhibitor of trypsin determined
Rebek, J. Jr., et al. Chem. Biol . 1995, 2, 171.
471
Multicomponent One-Step Mixture Synthesis
removal from
O resin affords pure
O R1
O O R1
R1 OH compounds O
NH2 N R3
N N R3
R2 CHO CN R3 2 H H N
solid support R
R2
H
resin capture
• Libraries of single compounds excess/unreacted starting O R1
O
materials and byproducts
N
• 4 components removed by filtration H N
H
R2
20 structural variants/input
resin OH
• 160,000 compounds generated capture
AcCl
O
H
new synthesis R1 N
O
O R2
Armstrong, R.W. et al. Acc. Chem. Res. 1996, 29, 123.

Ugi, I. et al. Endeavour 1994, 18, 115.
Multistep Solution Phase Synthesis of Combinatorial Libraries

Purification via Liquid/Liquid or Liquid/Solid Extraction
O
CO2H
• Solvent, reagent byproducts,
BOC N EDCI excess reagents and reactants
BOC N O
CO2H removed through extraction
O
with acid and/or base
1st diversification R1NH2 CO2H • Liquid/solid extraction using

BOC N ion exchange resins
CONHR1
• Products pure irrespective of

2nd diversification R2NH2 CONHR 2 yield
BOC N
PyBOP CONHR1
• 25–50 mg of products
HCl CONHR2 • Multistep synthesis in format of:

HCl•HN
CONHR1
- individual compounds
- small mixtures
3rd diversification R3CO2H O CONHR2
N - large mixture synthesis
PyBOP R3 CONHR1
Boger, D. L. et al. J. Am. Chem. Soc. 1996, 118, 2567.
472
Dale L. Boger
Multistep Convergent Solution Phase Combinatorial Synthesis
O
CO2H EDCI R1NH2 CONHR1 R2NH2 CONHR1
BOC N BOC N O BOC N BOC N
CO2H CO2H PyBOP CONHR2
O
(1) HCl R1HNOC O O CONHR1 • The synthesis of large molecules is possible

N N in only a few steps
(2) PyBrOP R2HNOC N CONHR2
CO2H BOC
BOC N • Purification at each step by acid/base
CO2H extractions or solid/liquid extractions
R1HNOC O O CONHR1
N N • Solution phase only
R2HNOC N CONHR2
X • Multiplication of diversity
R3HNOC N CONHR3
N N • Final dimerization has been achieved via
R4HNOC O O CONHR4 peptide coupling with diacids or olefin
metathesis
Boger, D. L. et al. Tetrahedron 1998, 54, 3955.

Boger, D. L. et al. Bioorg. Med. Chem. 1998, 6, 1347.
Linear, divergent synthesis with mutiplication of diversity

(solid or solution phase)
Sequential, linear oligomer synthesis

Sequential, linear template functionalization
FG3 FG4 FG3 FG4 FG3 FG4 FG4
FG2 FG1 FG2
Convergent synthesis with multiplication of diversity

(solution phase only)
FG3 FG3 FG3 receptor activation
antagonists agonists
FG2 FG1 FG2
FG3 FG3 FG3
FG2 FG1 FG2
Boger, D. L. et al. Tetrahedron 1998, 54, 3955; J. Am. Chem. Soc. 1998, 120, 7220.
473
10 compounds 100 compounds
O
CO2H EDCI A1−A10 CONHA1-n B1−B10 CONHA1-n
BOC N BOC N O BOC N BOC N
CO2H CO2H PyBOP CONHB1-n
O 86%
CONHA1-n CONHA1-n
1) HCl−dioxane
O ( )n B1-nHNOC N N CONHB1-n
2) CH2=CH(CH2)nCON(CH2CO2H)2 O O N
PyBrOP RuCl2(PCy3)2CHPh O O
N ( )n O
A1-nHNOC N N CONHA1-n
n = 3, 4, 7, 8 (C1−C4) 55%
CONHB1-n CONHB1-n
63% ( )n
O
20,200 compounds O O
N
A1-nHNOC N N CONHA1-n
CONHB1-n CONHB1-n
• Multistep, convergent, mixture synthesis
TsNHNH2/NaOAc or H2, Pd−C, 98%
• Deletion synthesis deconvolution provided identity
of active constituent
CONHA1-n CONHA1-n
• Positional scanning not suitable for identification
B1-nHNOC N N CONHB1-n
of unsymmetrical combinations N
O O
( )n O
O ( )n
O O
N
114,783,975 compounds A1-nHNOC N N CONHA1-n
CONHB1-n CONHB1-n
Identification of Potent Inhibitors of Angiogenesis via

Inhibition of MMP2 Binding to Integrin αVβ3
60 mixtures of 10 compounds O O
screen for inhibition of
R1HN O O NHR1 MMP2 binding to αVβ3 R R
O O
H
N R3 N N CO2H
N
R2HN NHR2 deconvolute and H
O O NH
evaluate analogs to R=
O
600-member O optimize binding and O
mixture library improve properties
MMP2 disruption of CF3

angiogenesis
• Blocks angiogenesis and tumor growth
on the chick chorioallantoic membrane
small molecule (CAM) without directly inhibiting αVβ3
α V β3 antagonist α V β3 or MMP2
474
Dale L. Boger
Application of Multistep Solution Phase Synthesis of
Libraries via Liquid−Liquid and Liquid−Solid Extraction
8 step total synthesis of
H distamycin A: 40% overall
Distamycin A: Naturally occurring
H N A subunit >95% purity at each step
polyamide composed of repeating
heterocyclic amino acids and a H
O N B subunit
basic side chain N H
Solution phase combinatorial chemistry Me O N C subunit
using 10–12 different heterocyclic amino N
H
acids and liquid−liquid acid/base extraction for purification Me O N NH2
N
Comparison of results from testing in different formats: Me O NH
Small mixture libraries Large mixture scanning libraries
1320 compounds (10 x 11 x 12) 1000 compounds (10 x 10 x 10)
(132 mixtures of 10 compounds each) (30 scanning library mixtures of 100
compounds each)
First generation libraries of potential DNA binding agents
2640 analogs in
Derivatization of mixture libraries with a basic side-chain prototype library
Second generation libraries of potential DNA binding agents with increased affinity
Boger, D. L.; Fink, B. E.; Hedrick, M. P. J. Am. Chem. Soc. 2000, 122, 6382.
Rapid, High Throughput Screen for DNA Binding Affinity

and Establishment of DNA Binding Selectivity
Identify compounds with
affinity for single sequence
of interest or define
sequence selectivity of a
compound against library
of all sequences
DNA affinity is measured as a decrease in
relative fluorescence indicating binding and
• Establish relative or absolute binding constants displacement of prebound ethidium bromide
• Libraries used at a single concentration during Use of a 96-well fluorescence plate reader
first round of testing or at several concentrations allows screening of 100s of libraries in a
to determine binding constant matter of minutes
• Library of compounds against a single sequence in form of hairpin oligonucleotide
• Single compound assayed against a full library of hairpin oligonucleotide sequences to

establish DNA binding selectivity (Profiling DNA binding selectivity)
• Library of compounds assayed against a library of DNA sequences
Boger, D. L.; Fink, B. E.; Tse, W.; Hedrick, M. P. J. Am. Chem. Soc. 2001, 123, 5878.
475
Rapid, High Throughput Screen for DNA Binding Affinity

and Establishment of DNA Binding Selectivity
A
5'-CGATGCACA
100
90 A
3'-GCTACGTGA
80 A
70
all possible 5
60
base pair sites
50
40
30 DNA affinity is measured as a decrease in

20
relative fluorescence indicating binding and
10
displacement of prebound ethidium bromide
0
1 26 51 76 101 126 151 176 201 226 251 276 301 326 351 376 401 426 451 476 501 512
Use of a 96-well fluorescence plate reader

512 Hairpin Oligonucleotides
allows screening of 100s of libraries in a
90
K = 9.3 x 107 M –1
matter of minutes K = 7.8 x 10 6 M –1 K = 5.4 x 10 6 M –1
aa gc a
aa ctt
ataa g
ac ata
aa ag c
aa ca g
atta g
ac aa a
K = 6.5 x 10 7 M –1 aa ag g
aa aa g
atata
80
aa gta
atctt
aa gtc
ataa a
aa ga c
aa gtt
atttt
aa ta a
atta a
ca ttt
aa ag t
aa ag a
H
aa ga t
ca aa t
atttc
70
aa aa c
aa tta
H N
aa tg t
aa ca a
aa ca t
aa ac a
atttg
aa tg a
60
aa ta g
aa ta c
H
ca att
Distamycin A
aa ta t
O
aa aa t
50
N
aa att
atag t
aa atc
N H
aa ttg
aa aa a
40
aa atg
aa ttc
atatt
Me O
aa ata
N
ataa t
30
aa ttt
20
N H
Me O N NH2
10
N
0
Me O NH
Boger, D. L.; Fink, B. E.; Tse, W.; Hedrick, M. P. J. Am. Chem. Soc. 2001, 123, 5878.
Application of Multistep Solution Phase Synthesis of

Libraries via Liquid−Liquid and Liquid−Solid Extraction
Azatriostin A: cyclic octapeptide, close analogue HUN-7293: cyclic heptadepsipeptide

of the natural occurring depsipeptide Triostin A, potent inhibitor of cell adhesion molecule
an antitumor antibiotic which binds to DNA by expression exhibiting anti-inflammatory
bisintercalation properties
N
R1 = O
CN
O R N O
O N N
N NH
H O NH O
HN R O N R1 O NH
O S O
O
O S O N O
R1 N O R NH H
H N N
HN N O
N O N
R O OMe
Azatriostin A: Boger, D. L.; Lee, J. K. J. Org. Chem. 2000, 65, 5996.

HUN-7293: Boger, D. L.; Chen, Y. Bioorg. Med. Chem. Lett. 2000, 10, 1741.
476
Dale L. Boger
Multistep Solution Phase Synthesis of Nonamide-Based

Libraries with Purification by Liquid–Liquid Extractions
• Isolation and purification by
3 Grignard 5 amines liquid–liquid acid/base extractions
O R1
reagents R2–NH2
BOCN O BOCN O • 25–50 mg of final products
R1–MgX CO2H NaBH(OAc)3
O 87% avg EDCI • >95% purity, irrespective of yield
97% avg
• Potent inhibitors of
R1 R1 LEF-1/β-catenin mediated gene
210 electrophiles O transcription
BOCN N R2 N N R2
3
R –CO2H R3
O R3–SO2Cl O 5´ 3´
R3–OCOCl LEF-1 c-fos Luciferase
R3–NCO 350 individual binding promoter
piperazinone sites
HCl−EtOAc
RCO2H, EDCI products
80% avg 67% avg overall yield, >95% pure
Boger, D. L. et al. Helv. Chim. Acta, 2000, 83, 1825.
Polymer-supported Scavenging Reagents
I. polymer-supported reagent • Addresses the purification problem in

solution phase synthesis
XB filter
A A–B + X A–B
(> 1eq) • Entrain impurities upon completion of
solution-phase reactions, either
II. polymer-supported catalyst covalently or ionically
X filter • Covalent scavengers:
A + B A–B + X A–B
(< 1eq) nucleophile–electrophile
III. polymer-supported scavenging reagent • Ionic scavengers: a series of anion and
(excess reagents, starting materials) cation exchange resins
(liquid–solid extraction)
Side X
A + B A–B +
Products
Boger, D. L. et al. J. Am. Chem. Soc. 1996,
A–B + Y
filter
A–B 118, 2567.
Flynn, D. L. et al. J. Am. Chem. Soc. 1997,
Reviews: 119, 4874.
Booth, R. J.; Hodges, J. C.
Acc. Chem. Res. 1999, 32, 18. Hodges, J. C. et al. J. Am. Chem. Soc. 1997,
Flynn, D. L.; Parlow, J. J. 119, 4882.
Curr. Opin. Drug Discovery Kaldor, S. W. et al. Tetrahedron Lett. 1996,
Dev. 1998, 1, 41. 37, 7193.
477
Solution Phase Combinatorial Synthesis of Biaryl Libraries

Employing Heterogeneous Conditions for Catalysis and Isolation
O O NHR RHN • convergent, mixture
O O synthesis
RHN NHR
10% Pd–C • purification by acid/base
Et3N liquid–liquid or liquid–solid
I O O (ion exchange) extractions
NHR RHN and filtration of catalyst
remove by acid extraction
remove by filtration purify by size exclusion • final purification possible
R1
H chromatography by size exclusion
N O
R1 chromatography
R 2 10% Pd–C
HN
Et3N
O R2 • scanning and deletion
R1 O synthesis deconvolution
I
meta, para NH libraries prepared
R2 6 R1 groups
6 R2 groups 64,980 compounds
10 linkers
Boger, D. L.; Jiang, W.; Goldberg, J. J. Org. Chem. 1999, 64, 7094.
Boger, D. L.; Goldberg, J.; Andersson, C.-M. J. Org. Chem. 1999, 64, 2422.
Resin Capture of Product ("Fishing Out" Principle)

• Libraries of β-amino alcohols are synthesized by parallel synthesis in solution
• Purification is achieved by "fishing out" the desired products with a PEG-bound dialkylborane
• Precipitation of the polymer-bound product allows the removal of unreacted starting materials
and any byproducts
• Treatment with HCl releases the product from the polymer support in high purity
O
Cl R2 NH2 R2
R1 R1 R1 N
O H
1° or 2° OH
phenol or amine
sulfonamide (Not purified) Impure mixture
H R1
B
O N R2 R2
B HCl R1 N
H
OH
(PEG Polymer)
Pure product
purify by PEG
precipitation/filtration
Janda, K. D. et al. J. Org. Chem. 1998, 63, 889.
Ugi reaction with polymer bound carboxylic acid: Armstrong, R. W. Tetrahedron Lett. 1996, 37, 1149.
478
Dale L. Boger
Resin Release Only of Product

OH
O
• A wide range of 3° amines can
Cl be synthesized on solid support
R1
O HN • The product is released via
O
R2 R1 β-elimination
O O N
R2 • Only the activated (quaternary)
product is released, ensuring
R3X
i
purities >95%
Pr2NEt
O • After cleavage of product, the
+ R1 resin is regenerated and can be
R1 O N 2
R3 N R reused
R3
R2
Morphy, J. R. et al. J. Am. Chem. Soc. 1997, 119, 3288.
Iterative Deconvolution SURF Deconvolution

(Synthetic Unrandomization of
Randomized Fragments)
XXX • Iterative deconvolution was first applied to peptide libraries

• The SURF procedure was described for nucleotide libraries
• Libraries are synthesized on solid phase by split synthesis
AXX BXX CXX
_ _ • Repetitive synthesis and screening of increasingly

+
simplified sets
• At each step of the deconvolution an additional position
is known
AAX ABX ACX
• Activity increases at each step, enhancing the accuracy
_ _ + of identification
• Most potent library member guaranteed to be found and
multiple hits lead to multiple parallel deconvolutions
ACA ACB ACC • Time between synthesis of libraries and hit identity long
and cumbersome
_ _
+
Houghten, R. A. et al. Nature 1991, 354, 84.
Ecker, D. J. et al. Nucleic Acids Res. 1993, 21, 1853.
479
Recursive Deconvolution
• The library (XXX) is synthesized by split synthesis

• At each stage 1/3 of the material is stored and labeled as a partial library
• These stored partial libraries are used to deconvolute the full library
XXA XXB XXC

Test 3 pools for activity
_ _
+
Couple A to saved and catalogued XA, XB, and XC
XAA XBA XCA Test 3 pools for activity

_ + _
Couple BA to saved and catalogued A, B and C
ABA BBA CBA Test 3 pools for activity
+ _ _
Janda, K. D. et al. Proc. Natl. Acad. Sci. USA
1994, 91, 11422.
Positional Scanning of Synthetic Peptide Combinatorial Libraries
• Deconvolution libraries produced

upfront for testing
O1 X X X X X-NH2
• Identifies most active residue at each
position in one round of testing X O2 X X X X-NH2
• Screen looking for increases in activity X X O3 X X X-NH2
• This combination is not always the

X X X O4 X X-NH2
most potent (ca. 20–40% of time) X X X X O5 X-NH2
• Best for identifying multiple hits in a X X X X X O6-NH2
library including weak activities
• Requires mixture synthesis, not

O = individual component
suited for solid phase X = mixture
Houghten, R. A. et al. Nature 1991, 354, 84.
480
Dale L. Boger
Scanning Deconvolution Applications
Proliferative response of TL 5G7 to

MBP and scanning peptide libraries
A: the response to a sizing scan

with completely randomized libraries
ranging in length from 6 to 15 amino acids
B: the response to peptide sublibraries
with fixed amino acid in position 1 to 11
phenylalanine (F), lysine (K), asparagine (N), or glycine (G)
• Mixture analysis so the number of compounds

assayed can be very large
• Identified single peptides 104−105x more active
than well known natural autoantigen
Hemmer, B. et al. J. Exp. Med. 1997, 185, 1651. (Multiple sclerosis)

Hemmer, B. et al. Nature Med. 1999, 5, 1375. (Lyme disease)
Deletion Synthesis Deconvolution

• Deconvolution libraries
produced upfront for testing X
dA1 X X X X dC1 X
• Identifies most active dA2 X X X X X dC2 X
residues at each position in
one round of testing X X dC3 X
dA3 X X X
• Screen library for loss of dA4 X X X X X dC4 X
activity versus full mixture
• Best at identifying potent

hits in a library, poor at X dB1 X X X X X dD1
identifying weak or multiple
hits X dB2 X X X X X dD2
X dB3 X X X X X dD3
• Requires mixture synthesis,
not suited for solid phase X dB4 X X X X X dD4
• Also suited for symmetrical
libraries not capable of dA1 = mixture minus A1 (delete A1)
being addressed by X = mixture
scanning deconvolution
481
Test Case Comparisons of Scanning
and Deletion Synthesis Deconvolution
6 R1 groups O 20 R2 groups O
O NHR2 O NHR2
N N
R1 CO2H R1 CONHMe
Library 1 (120 compounds) Library 2 (120 compounds)
Each individual compound and the scanning and deletion deconvolution sublibraries were
prepared and tested side by side to establish which would identify the newly discovered leads
Cytotoxic Activity (L-1210 IC50) of Mixture, Scanning, and Deletion Deconvolution Sublibraries
scanning deconvolution deletion deconvolution scanning deconvolution deletion deconvolution
B7 B6
B7
A5 B13 A4 A5 B17 A5 B14
B13
B17 B17
6 and 20 compd mix 100 and 114 compd mix
gain in activity loss in activity
Cytotoxic Activity (IC50, µM) for Individual Compounds
B7 B13 B17 B6 B14 B17
A4 5 26 25 A5 44 71 5
A5 >100 19 28
Deletion synthesis more effective at identifying most potent compound in library
Scanning deconvolution more sensitive and capable of identifying weak activities
Combination more powerful than either technique alone
Boger, D. L.; Lee, J. K.; Goldberg, J.; Jin, Q. J. Org. Chem. 2000, 65, 1467.
Assay and Deconvolution by Mass Spectrometry
Target-assisted isolation of mixture components
Separation of target–ligand complex by: size exclusion chromatography

ultrafiltration
capillary electrophoresis
affinity chromatography
Identification of the bound ligand after dissociation of the complex by:
ESI-MS: exceptional ability to detect ions present in solution with little fragmentation
MALDI-MS: advantages over ESI-MS are its tolerance against impurities, buffer salts
and formation of primarily singly charged ions
Analysis of mixtures, so numbers of compounds evaluated can be large
Direct detection and identification of target–ligand complexes
Study of intact non-covalent complexes is possible by FTICR-MS (FTICR: Fourier Transform Ion
Cyclotron Resonance). Advantages of FTICR-MS are its high sensitivity due to the accumulation
of certain ions in the trap that allows the study of minor mixture components
Review: Eliseev, A. V. Curr. Opin. Drug Discovery Dev. 1998, 1, 106.
482
Dale L. Boger
Active Protein-Binding Compounds Through SAR by NMR

15
• use of N-labeled target proteins makes it
possible to study the ligand–protein complex by
15N-HSQC, even at high ligand concentrations
screen and optimize

• less time consuming compared to the
first ligand combinatorial approach where a large number
of linked compounds have to be synthesized.
• linked ligands with nano molar binding constants

derived from individual ligands with micro molar
screen and optimize binding constants
second ligand
link ligands
Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Science 1996, 274, 1531.
Assay and Deconvolution by NMR
Direct detection and identification of target– ligand complexes (detect bound ligand)
Diffusion encoded spectroscopy (DECODES): combination of pulse field gradient (PFG) NMR
and total correlation spectroscopy (TOCSY).
Under PFG conditions, all resonances of low molecular weight ligands disappear from spectrum
while signals of target-bound ligand remain. Approach is only applicable for low molecular weight
molecules (200–400 Da) as targets and ligands.
Lin, M.; Shapiro, M. J.; Wareing, J. R. J. Am. Chem. Soc. 1997, 119, 5249.
Indirect detection and identification of target– ligand complexes (detect unbound ligands)
1D relaxation edited NMR and 1D difusion edited NMR:

Difference spectrum of the 1D edited library-, protein- and mixture of protein with library-spectrum
contains only signals from the bound ligand.
There is no need for deconvolution of the library to identify active compounds.
By removing the signals of the biomolecule there is no broadening or obscuring of the ligand's
signals by the macromolecule.
Hajduk, P. J.; Olejniczak, E. T.; Fesik, S. W. J. Am. Chem. Soc. 1997, 119, 12257.
483
Combinatorial Target-Guided Ligand Assembly
1. prepare a set of potential binding elements • no structural or mechanistic information

with a common chemical linkage group X required for this combinatorial method
X X X X X X • accomplished in 4 straightforward steps
• prelude to target assembled tight binding

ligand from combinatorial mixture?
2. screen potential binding elements to identify
elements that bind to target
X
X X
Ellman, J. A. et al. Proc. Natl. Acad.

Target Target Target Sci. USA 2000, 97, 2419.
3. prepare library of all possible combinations

of linked binding elements with variations in the link X X
4. screen library of linked
X X X X X X X X binding elements to identify
the tightest binding ligands
Target
Solid Phase or Solution Phase Combinatorial Synthesis?

Solid Phase Solution Phase
+ Simple removal of excess reagents + Chemistry not limited by support or
and reactants linker
+ Automation straightforward + Monitor by traditional techniques
+ Split and mix synthesis + Purification possible after each step
+ Pseudo-dilution effects + Unlimited amounts (scales) available

– Adapt chemistry to solid phase and + Avoids extra steps for linking, etc
develop linking/cleaving strategies
+ Automation by liquid–liquid techniques
– Reaction monitoring difficult
+ Mixture or parallel synthesis
– No purification possible
+ Convergent or linear synthesis
– Linear, cannot conduct convergent
synthesis – Removal of excess reagents and
reactants limits scope
– Limited scale
– Cannot conduct mixture synthesis
484
Dale L. Boger
Combinatorial Synthesis Using Soluble Polymers
• Reactions were performed in the homogeneous liquid-phase solution using a soluble polymer
(MeO-PEG: polyethylene glycol monomethyl ether)
• Homogeneous reaction conditions overcome the difficulties of solid-phase combinatorial synthesis
• Isolation can be accomplished by precipitation of PEG polymer at each stage
• Intermediates can also be purified by conventional means (e.g. chromatography)
• Analysis of intermediates is possible by conventional means (e.g. NMR)
MeO-PEG-OH
O
+
O MeO-PEG-O O
cat. Dibutyltinlaurate
O C N S Cl HN S Cl
CH2Cl2
O O
R−NH2, pyridine
CH2Cl2
O
O MeO-PEG-O O
0.5 N NaOH
H2N S NHR HN S NHR
O O
Janda, K. D. et al. Proc. Natl. Acad. Sci. USA 1995, 92, 6419.
Review: Janda, K. D. et al. Chem. Rev. 1997, 97, 489.
Fluorous-phase Combinatorial Synthesis

• Fluorous liquids: Immiscible in both water and organic solvents
• Simple purification of products by three-phase liquid−liquid extraction
• Accomplishment of a series of radical additions by homogeneous fluorous-phase
combinatorial synthesis
Early applications of fluorous bound substrate included
• Ugi reaction • Biginelli reaction • Stille coupling
• Solid-phase extraction with fluorous reverse-phase silica gel
Curran, D. P.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069.
Reagents on fluorous phase or

Substrates on fluorous phase
(C6F13CH2)3SnH, AIBN
R
R I + E E
CF3 72–92%
Fluorinert Fluid F-77

PhCO2C3H7 + PhCH2OH PhCO2CH2Ph + C3H7OH
tol/c-C6H11CF3
C8H17CH=CH2 + CO C8H17CH(CHO)CH3 + C10H21CHO
C6H13CH2CH2CF3)3P
Rh(CO)2(acac)
Curran, D. P. et al. J. Am. Chem. Soc. 1996, 118, 2531; Chemtracts, Org. Chem. 1996, 9, 75.
Science 1997, 275, 823; Angew. Chem. Int. Ed. 1998, 37, 1174.
485
A Combinatorial Approach to Materials Discovery
Application of the combinatorial approach to the discovery of new solid-state

materials with novel physical or chemical properties such as magnetoresistance or
high-temperature superconductance.
Substrates: polished MgO or LaAlO3 single crystals
Sputtering Targets: CuO, Bi2O3, CaO3, PbO, SrCO3, Y2O3, and BaCO3
Generation of a 128-member binary library using 7 deposition-masking steps
Superconducting materials: BiSrCaCuOx and YBa2Cu3Ox
(Binary masks used for library synthesis)
Schultz, P. G. et al. Science 1995, 268, 1738.
Comparison of Combinatorial Chemistry Techniques
Technique Single compound Speed of SAR Utility

/mixture synthesis retrieval
parallel synthesis single slow fast lead optimization
mixture synthesis mixture fast slow lead identification

(scanning/deletion (fast)
deconvolution)
parallel arrayed mixture moderate moderate lead identification

mixture
split and mix mixture moderate slow lead identification

(one compound lead optimization
per bead)
chemically encoded mixture moderate moderate lead identification
mix and split (one compound lead optimization
per bead)
mix and sort single moderate fast lead optimization
(microreactors) lead identification
Guiles, J. W. et al. Angew. Chem. Int. Ed. 1998, 37, 926.
486

Modern Organic Synthesis

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Modern Organic Synthesis

Uploaded by

Copyright:

Available Formats

Lecture Notes

Coordinated by Robert M. Garbaccio

Conformational Analysis Steven L. Castle

Kinetics and Thermodynamics Richard J. Lee

Oxidation Reactions and Bryan M. Lewis

Reduction Reactions and Clark A. Sehon

Enolate Chemistry and Jason Hongliu Wu

Key Ring Transformations Wenge Zhong

Olefin Synthesis Gordon D. Wilkie

Conjugate Additions Robert P. Schaum

Synthetic Analysis and Design Robert M. Garbaccio

Combinatorial Chemistry Joel A. Goldberg

Print First Edition 1999

Heinrich Friedrich von Delius (1720–1791)

II. Kinetics and Thermodynamics of Organic Reactions 17

III. Reaction Mechanisms and Conformational Effects on Reactivity 23

IV. Oxidation Reactions 41

VI. Reductions Reactions 95

VII. Hydroboration–Oxidation 139

VIII. Enolate Chemistry 147

IX. Metalation Reactions 207

XI. Olefin Synthesis 359

XII. Conjugate Additions: Organocuprate 1,4-Additions 395

XIII. Synthetic Analysis and Design 427

XIV. Combinatorial Chemistry 461

A. Acyclic sp3–sp3 Systems: Ethane, Propane, Butane

fully eclipsed gauche eclipsed staggered

H3C CH3 H3C H H3C H H3C H

FE FE - Note: the gauche butane

0 60 120 180 240 300 360

Egauche < Estaggered if X = OH, OAc and Y = Cl, F

B. Cyclohexane and Substituted Cyclohexanes, A Values (∆G°)

Hax Hax Hax

- Rapid interconversion at 25 °C (Ea = 10 kcal/mol, 20 kcal/mol available at 25 °C).

- Rel E = 6.9 kcal, not local minimum on energy surface.

- Half chair conformation

- The gauche butane interaction is most often identifiable as 1,3-diaxial interactions.

2 gauche butane interactions 0 gauche butane interactions

- A Value (–∆G°) = Free energy difference between equatorial and axial

R A Value (kcal/mol) R A Value (kcal/mol)

- Note on difference between iPr and tBu A values.

- Note on interconversion between axial and equatorial positions.

CH3 H2/Pt CH3

∆G = 1.87 kcal/mol (exp)

H H CH3 H H H CH3 H CH3 H H H

2 × (gauche interaction) 2 × (gauche interaction) 2 × (gauche interaction) + 0 × (gauche interaction)

CH3 H2/Pt CH3

- Determination of energy value of Me–Me 1,3-diaxial interaction.

CH3 CH3 H CH3

∆G = 3.7 kcal/mol (exp)

1,3-diaxial interactions ∆G° of common interactions

R/R ∆G° ax OH ax CH3 eq OH

One 1,3-diaxial interaction removed - half-chair

∆E between cis- and trans-decalin = 2.7 kcal/mol

4 gauche interactions 5 gauche interactions

∆E between cis- and trans-9-methyldecalin = 0.9 kcal/mol

E. Acyclic sp3–sp2 Systems

- Origin of destabilization for eclipsed conformations:

Lowe Prog. Phys. Org. Chem. 1968, 6, 1.

- Molecular orbital calculations: Repulsion of overlapping filled orbitals:

- Propionaldehyde: Butcher, Wilson J. Chem. Phys. 1964, 40, 1671.

- Propene: Allinger J. Am. Chem. Soc. 1968, 90, 5773.

- 1-Butene: Geise J. Am. Chem. Soc. 1980, 102, 2189.

Exp 0.0 1.0 - Two extreme conformations.