Chemfiles Vol. 10, No. 4 | Enantioselective Synthesis | Distillation

Aldrich

Volume 10, Number 4 • 2010

Asymmetric Synthesis Catalysis Chemical Biology Organometallics
Fe(S,S-PDP) - an electrophilic iron catalyst for site-selective C-H oxidation

Building Blocks Synthetic Reagents Stockroom Reagents Labware Notes Chemistry Services

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Introduction
Volume 10, Number 4

Haydn Boehm, Ph. D. Global Marketing Manager: Chemical Synthesis haydn.boehm@sial.com

Introduction

Sigma-Aldrich Corporation 6000 N. Teutonia Ave. Milwaukee, WI 53209, USA
Editorial Team Haydn Boehm, Ph.D. Wesley Smith Dean Llanas Sharbil J. Firsan, Ph.D. Weimin Qian, Ph.D. Production Team Cynthia Skaggs Carrie Spear Chris Lein Tom Beckermann Christian Hagmann Denise de Voogd Chemistry Team Daniel Weibel, Ph.D. Josephine Nakhla, Ph.D. Matthias Junkers, Ph.D. Mark Redlich, Ph.D. Troy Ryba, Ph.D. Todd Halkoski Paula Freemantle Mike Willis Aldrich ChemFiles Subscriptions To request your FREE subscription to Aldrich ChemFiles, either visit our website at: aldrich.com/chemfiles or contact your local Sigma-Aldrich office (see back cover). Aldrich ChemFiles Online Aldrich ChemFiles is also available in PDF format on the Internet at aldrich.com/chemfiles. Aldrich Chemistry Products Aldrich brand products are sold through Sigma-Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its products conform to the information contained in this and other Sigma-Aldrich publications. Purchaser must determine the suitability of the product for its particular use. See reverse side of invoice or packing slip for additional terms and conditions of sale. All prices are subject to change without notice. To Place Orders or Contact Customer/ Technical Services Please contact your local Sigma-Aldrich office (see back cover). Aldrich ChemFiles (ISSN 1933–9658) is a publication of Aldrich Chemical Co., Inc. Aldrich is a member of the Sigma-Aldrich Group. © 2010 Sigma-Aldrich Co.

Dear Chemists Firstly I would like to offer congratulations from all of us here at Sigma-Aldrich to Prof. Richard Heck of the University of Delaware in Newark, US, Prof. Ei-ichi Negishi of Purdue University, US, and Prof. Akira Suzuki of Hokkaido University in Japan, who were awarded the 2010 Nobel Prize for chemistry. These three pioneers of synthetic organic chemistry were acknowledged for their eponymous palladium-catalyzed cross-coupling reactions, which form new carbon-carbon bonds under mild conditions, and are now indispensable to both research laboratories and industrial processes around the world. Indeed this news has proven very timely as Prof. Negishi was our second speaker in the new Aldrich Chemistry Webinars series, and his ZACA Reaction Webinar was broadcast live from the 5th Annual Negishi-Brown and CAOSS Lectures from Purdue University on Tuesday, October 12, in partnership with the American Chemical Society and C&EN Webinars. If you were unable to attend the webinar then you can access it via aldrich.com/cheminars. The cover molecule of our fourth edition of the new Aldrich ChemFiles is Fe(S,S-PDP), which was originally reported by Prof. Christina White, and is now available from Aldrich Chemistry as part of our chiral 2,2’-bipyrrolidines portfolio (Asymmetric Synthesis). In Aldrich ChemFiles 10.4 we also introduce the latest building blocks for chemical biology (Chemical Biology), PEMB for reductive aminations (Synthetic Reagents), new gold catalysts (Catalysis), new organotins and organozincs (Organometallic Reagents), and our new oxetane portfolio (Building Blocks). I hope that Aldrich ChemFiles 10.4 keeps you informed of the new Aldrich Chemistry products that facilitate the latest research methodologies and trends, and allows you to access key starting materials and reagents more efficiently.

Thanks for reading,

Haydn Boehm, Ph. D.

Table of Contents
Asymmetric Synthesis ...............................................................................................................................4 Catalysis ................................................................................................................................................................6 Chemical Biology ....................................................................................................................................... 10 Organometallic Reagents.................................................................................................................... 12 Building Blocks ............................................................................................................................................ 14 Synthetic Reagents ................................................................................................................................... 16 Stockroom Reagents ............................................................................................................................... 18 Labware Notes.............................................................................................................................................. 20 Chemistry Services ................................................................................................................................... 22

3

Asymmetric Synthesis
Daniel Weibel, Ph.D. European Market Segment Manager, Chemistry

Asymmetric Synthesis

daniel.weibel@sial.com

Chiral 2,2’-Bipyrrolidines
C2-symmetrical, chiral 2,2’-bipyrrolidines have recently emerged as interesting structural chiral motifs in a number of ligands for asymmetric transformations (Figure 1). When the two nitrogen atoms function either in a bidentate chelate ligand or are covalently bonded to another atom, the two pyrrolidines adopted a stair-like structure, which creates a highly asymmetric environment.
H H N H HO2C OH N H OH CO2H N H HO2C OH H H N H OH CO2H

On the basis of this set of selectivity rules the preferential oxidation of the electron-rich and sterically unencumbered tertiary C–H bond at C-10 of antimalarial tetracyclic compound (+)-artemisinin (361593) was predicted. In addition to the site selectivity issue posed in this substrate, a chemoselectivity challenge is present in the form of a sensitive endoperoxide moiety known to be prone to Fe(II)-mediated cleavage.3 (+)-10β-Hydroxyartemisinin was generated in diastereomerically pure form as the major product in 54% yield (after recycling of artemisinin). Interestingly, (+)-artemisinin (361593) has previously been transformed enzymatically with microbial cultures of Cunninghamella echinulata to 10β-hydroxyartemisinin in 47% yield with substantially longer reaction times and a 10-fold lower volume throughput.3 The ability of the simple, small molecule iron catalyst Fe(S,S-PDP) (730459) with broad substrate scope to achieve P-450-like tailoring enzyme selectivities is remarkable.
H CH3 H3C OH H2O2 H3C H CH3 O (+)-artemisinin N N N N
2

H H N H 1.5• HO2C N H CO2H H3C

H O O NCCH3 (SbF6 )2 NCCH3 O O O 54% H CH3

O O O O

Fe

688622

688746

712116

Figure 1. Commercially available chiral 2,2’-bipyrrolidines.

730459

Prof. Denmark has exploited this feature in the development of a highly selective catalyst for asymmetric allylations.1 The addition of allylic trichlorosilanes to unsaturated aldehydes can be catalyzed by chiral bisphosphoramide derived from 2,2’-bipyrrolidine (for the corresponding chiral bisphosphoramide catalyst derived from N,N′-dimethyl-1,1′-binaphthyldiamine, (715549) to give homoallylic alcohols with excellent diastereo- and enantioselectivities (Scheme 1).

Scheme 2: Selective aliphatic iron-catalyzed C–H oxidation

Recently, Prof. White reported the same bulky, electrophilic iron catalyst is capable of site-selective oxidation of isolated, unactivated secondary C–H bonds to afford mono-oxygenated products in preparatively useful yields without the use of directing or activating groups (Scheme 3).4
H H EWG n H H O CH3 H3CO O 50% 51% CH3 H3CO CH3 54% CH3 730459 (15 mol %) AcOH (1.5 eq) H2O2 (3.6 eq) CH3CN, rt, 30 min O O EWG n H H O CH3 H3CO 43% CH3 O CH3 CH3

H H

N P N

O

O N (CH2)5 P N N N CH3 CH3

H H H3CO OH R R1 R2 OH CH2

O

O

O

R1 R2

SiCl3

O + R H OH CH2 R CH3

1. (5-10 mol %) Hunig's base, -78°C 2. NaHCO3, KF OH CH2 R CH3 54-91% anti/syn: >95/5 88-95% ee (syn) CH2

Scheme 3: Selective iron-catalyzed methylene oxidation

OH R

R CH2 H3C CH3 70-89% 88-96% ee

84-92% 80-88% ee

57-83% anti/syn: 99/1 81-86% ee (anti)

Scheme 1: Highly selective asymmetric allylic allylations using a bisphosphoramide organocatalyst

In 2007, Prof. Christina White reported on an iron-based small molecule catalyst Fe(S,S-PDP) (730459) bearing the (S,S)-1,1’-bis(2pyridinylmethyl)-2,2’-bipyrrolidine (712361) moiety as chelating ligand that uses hydrogen peroxide to oxidize a broad range of substrates.1 Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C–H bonds, without the need for directing groups. This type of general and predictable reactivity stands to enable aliphatic C–H oxidation as a method for streamlining complex molecule synthesis (Scheme 2).

In 2008, Prof. Lawrence Que developed an iron catalyst bearing the optically active 6-Me2-BPBP ((R,R)-1,1’-bis(6-methyl-2pyridinylmethyl)-2,2’-bipyrrolidine) ligand (712337) for asymmetric olefin dihydroxylation.5 This complex is hitherto one of the most effective reported to date achieving up to 97% enantiomeric excess of the syn-diol product from cis-disubstituted olefins (Scheme 4). These ee values are comparable to those obtained with the osmium-based AD α or β mixes (392758 or 392766). These results demonstrate for the first time that a synthetic nonheme iron catalyst can approach the high enantioselectivity found in syn-dihydroxylating enzymatic systems.

4

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Chiral 2,2’-Bipyrrolidines
N H H N N N
2

CH3 OTf OTf CH3 HO2C N H

H H N H OH CO2H OH N H HO2C

H H N H OH CO2H OH N H

Fe

H H N H CO2H

1.5• HO2C

Asymmetric Synthesis

R'

2 mol % 35% H2O2 (10 eq) R CH3CN, rt, 20 min

OH R'
∗ ∗

R'

OH OH O

688622

688746
H H

712116
H H

OH H3C
∗ ∗

OH
∗ ∗

CH3 H3C

CH3

H3C 78% ee

OH H3C

O

CH3 H H

N N N N
2

OH 97% ee

OH 96% ee

OH

OH 76% ee

NCCH3 (SbF6 )2 NCCH3

N

N

N

N

Fe

N • 4HCl

N

N • 4HCl

N

Scheme 4: Iron-catalyzed asymmetric olefin cis-dihydroxylation
References (1) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488. (2) Chen, M. S.; White, M. C. Science 2007, 318, 783. (3) Zhan, J.; Guo, H.; Dai, J.; Zhang, Y.; Guo, D. Tetrahedron Lett. 2002, 43, 4519. (4) Chen, M. S.; White, M. C. Science 2010, 327, 566. (5) Suzuki, K.; Oldenburg, P. D.; Que, L, Jr. Angew. Chem. Int. Ed. 2008, 47, 1887.

730459
H H N N

712353
H H N N

712361

N

N

N

N

H3C CH3 • 4HCl

H3C CH3 • 4HCl

712337

712345

For a complete list of bipyrrolidines available from Aldrich Chemistry, please visit aldrich.com/bipyrrolidines

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5

Catalysis
Josephine Nakhla, Ph.D. Market Segment Manager Organometallics & Catalysis

+ P Au NCCH3

SbF6

Catalysis

josephine.nakhla@sial.com

H3CO2C H3CO2C R2 R1

R3

(2 mol %) CH2Cl2, rt

H3CO2C H3CO2C H R2 R1

R3

Alkyne Hydration
The hydration of alkynes has been extensively studied for more than 100 years. This reaction allows access to various carbonyl derivatives from alkyne precursors. Nolan and coworkers reported alkyne hydration using a gold catalyst. Nolan, a pioneer in the use of N-heterocyclic carbenes (NHCs) as ligands in various catalytic transformations with different metals, developed conditions employing a gold-NHC complex and silver hexafluoroantimonate for the hydration of alkynes (Scheme 1). It is important to note that an acid is not needed for this transformation and the reaction was feasible at low catalyst loadings (10 ppm).

H3CO2C H3CO2C H CH 3

R3

H3CO2C H3CO2C H

CN

H3CO2C H3CO2C H Ph H

NO2

74% 78%

58%

O (5 mol %) AgSbF6 (5 mol %) CH2Cl2, rt

P AuCl 3 R R

R R

PhO2S PhO2S

HO

O

94% N N

56%

Scheme 2: Intramolecular cycloaddition of 1,3-enynes with alkenes
Au Cl (0.01 mol %) AgSbF6 R1 R2 1,4-Dioxane/H2O (2:1) 120 °C, 18 h O F H3CO O R1

O R2

Reference (1) Nieto-Oberhuber, C.; Pèrez-Galán, P.; Herrero-Gómez, E.; Lauterbach, T.; Rodriguez, C.; López, S.; Bour, C.; Rosellón, A.; Cárdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2008, 130, 269.

O

Propargyl Claisen Rearrangement
Toste and coworkers reported the use of the gold catalyst [(Ph3PAu)3O]BF4 for the rapid two-step, one-pot sequence of a Claisen rearrangement of a propargyl vinyl ether followed by a reduction of the resulting aldehyde functionality to provide a variety of homoallenic alcohols. The reactions are generally high yielding and the robust catalyst system is able to induce almost complete chirality transfer (in most cases, ee’s were >90%). Low catalyst loadings (1 mol %) and substitution at the alkyne is well tolerated generating the desired allenes in high yields (Scheme 3).
Reference (1) Sherry, B. S.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
BF4 O Au Ph3P R1 O R3 Au Au PPh3 OH • R1 OH • H PivO F3C 78% 81% 86% • R3 OH (1 mol %) CH2Cl2, rt; NaBH4, MeOH, rt OH •

88% O

97% O

72%

O

76%

95%

Scheme 1: Hydration of alkynes using gold-NHC complex
Reference (1) Marion, N.; Ramón, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448.

Intramolecular Cycloaddition of 1,3-Enynes with Alkenes
Echavarren and co-workers employed a crystalline gold complex containing either the o-biphenyl phosphine ligand JohnPhos, or a bulky aryl ether phosphine under mild conditions to effect the [4+2] cycloaddition of 1,3-enynes with olefins. A family of biand tricyclic scaffolds were prepared in good yields (Scheme 2). Both electron-withdrawing and electron-donating groups were tolerated on the aryl moiety.

PPh3

Scheme 3: Preparation of homoallenic alcohols via Claisen rearrangement/ reduction sequence

6

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TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.

Gold Catalysts from Sigma-Aldrich
Au N C CH3 t-Bu P t-Bu SbF6
-

AuCl P P AuCl

AuCl t-Bu P t-Bu

CH3 H3C P AuCl CH3

Catalysis

697575

254037

715050

679771

404217

AuCl H3C P H3C CH3 H3C H3C S AuCl

i-Pr N

i-Pr N i-Pr i-Pr i-Pr P AuCl P CH3 AuCl

i-Pr Au i-Pr Cl

288225

420727

696277

687510

702749

P
1/ CH C H O Au O 2 3 6 5 F3C S N S CF3 O O

O Au Ph3P Au

PPh3 Au

BF4− PPh3

NaAuCl4 • 2H2O

AuBr3

AuCl

677922

665142

298174

398470

481130

AuCl3
N

• AuCl3

334049

677876

Silver Salt Additives
O S Ag N S O O CF3 H3C CF3 O O S OAg O O F3C S OAg O

AgSbF6

AgBF4

AgPF6

668001

176427

227730

208361

227722

176435

For a complete list of Gold Catalysts available from Aldrich Chemistry, please visit aldrich.com/gold

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

7

Aldrich® Chemistry Webinars

Zirconium-catalyzed Asymmetric Carboalumination of Alkenes (ZACA Reaction)
Your speaker for this Aldrich sponsored webinar is:

To watch a recording of this webinar, please visit aldrich.com/ ZACAwebinar
Overview: Many, if not the majority, of the organic compounds that are of interest and importance to mankind are chiral or optically active. Until recently, the major route to such chiral compounds and biocatalysts was the biosynthesis performed by nature, which employed enzymes as synthetic tools. Slowly but surely, other methods have emerged and their significance was predicted to increase significantly during the 21st century, when W. Knowles, R. Noyori, and K. B. Sharpless were awarded the 2001 Nobel Prize for their pioneering research using non-biological asymmetric methods for C–H and C–O bond formation.

Ei-ichi Negishi, Ph.D. H. C. Brown Distinguished Professor of Chemistry Purdue University Co-Winner of 2010 Nobel Prize in Chemistry

What about the all-important C–C bond formation for asymmetric organic skeleton formation? This webinar introduces the discovery, development and application of the ZACA reaction, and showcases how its efficient, selective, potentially green and economical syntheses of biologically and medicinally important chiral organic compounds can benefit mankind.
i) R23Al, Cat. (-)-(NMI)2ZrCl2 R2 R1 OH

Areas covered in the webinar:

R1

ii) O2

• Discovery and development of the ZACA
reaction

(-)-(NMI)2ZrCl2=

2

ZrCl2

R2 = Me, 68–92% yield, 70–90% ee R2 = Et, 56–90% yield, 85–95% ee R2 = Higher primary alkyl groups, 74–85% yield, 90–95% ee

Its application to efficient and selective synthesis of chiral natural products

• Synthesis of vitamins (E, K, etc.) and other
compounds of dietary and medicinal interest

To view previous and future webinars, please visit aldrich.com/cheminars Hosted by:

Who should attend:

• Organic Chemists • Medicinal Chemists • Anyone involved in research in academic or
corporate labs

©2010 Sigma-Aldrich Co. All rights reserved. Sigma-Aldrich and Aldrich are trademarks belonging to Sigma-Aldrich Co. and its affiliate Sigma-Aldrich Biotechnology, L.P.

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Chemical Biology
Matthias Junkers, Ph.D. Product Manager matthias.junkers@sial.com

Proline Analogs
Proline is a non-polar, natural amino acid that forms a tertiary amide when incorporated into peptides. Thus, it is the only proteinogenic amino acid that does not act as a hydrogen bond donor in a peptide chain. Proline is known as a classical breaker of both the α-helical and β-sheet secondary structures in proteins and peptides, and it plays a crucial role in protein folding. Synthetic proline derivatives, mimetics and analogs offer further options to tune the biological, pharmaceutical, or physicochemical properties of peptides and proteins. In recent years proline derivatives and analogs have also found increasing popularity as organocatalysts in asymmetric synthesis.4
CH HC O N OH Boc O N OH Boc H2C O N OH Boc

Chemical Biology

New Building Blocks for Chemical Biology
Modern automated synthesis protocols allow the fast and efficient production of biopolymers like peptides and even proteins, or oligonucleotides. In recent years, even the automated synthesis of complex carbohydrates has been described.1 Automated synthesis procedures build the bridge to Chemical Biology. It does not require a fully trained chemist to perform automated synthesis. Even groups with a primary focus on biology research can utilize synthesizers to produce primers, test molecules, probes, etc., quickly and efficiently. On the other hand, chemistry benefits equally from automated procedures. Synthesis challenges that used to take weeks or months can today be completed in a matter of hours or a few days accelerating research tremendously. Fast and efficient synthesis is only possible if all necessary tools are readily available. Sigma-Aldrich is proud to offer a leading choice of tools and building blocks for advancing science in the "omics" era (genomics, proteomics, glycomics, metabolomics – to name just a few). This issue of Aldrich ChemFiles highlights some examples of recent additions to our portfolio.

711985
O N H OCH3 F

711977
O N OH Boc

717045

712884

717010

Unsaturated Amino Acids
Recent developments in Chemical Biology research have increased the demand of amino acid building blocks with unsaturated side chains. Alkyne moieties can be used in bioorthogonal synthesis strategies to form hybrid structures, introduce chemical probes into biomolecules, or link large fragments with each other. The most prominent technique relies on the Huisgen dipolar cycloaddition reaction between an azide and an alkyne. Olefin moieties open amino acids and peptides to metathesis reactions and a full range of other bioorthogonal synthesis routes. Olefin metathesis is a key to the production of hydrocarbon stapled peptides.5 Stapled peptides are currently in discussion as a new class of superpotent drugs or magical bullets promising to make peptide α-helices more potent and cell permeable by locking them in the most active conformation.6
References: (1) Timmer, M.S.M.; Adibekian, A.; Seeberger, P.H. Angew. Chem. Int. Ed. 2005, 44, 7605. (2) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206. (2) Seebach, D.; Beck, A.K.; Bierbaum, D.J. Chem. Biodiv. 2004, 1, 1111. (4) (a) Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 125, 450. (b) Dalko, P.I.; Moisan, L.; Angew. Chem. Int. Ed. 2004, 43, 5138. (5) Walensky, L.D. et al. Science 2004, 305, 1466. (6) Kritzer, A.K. Nature Chemical Biology 2010, 6, 566.

Beta Amino Acids
Although they are less abundant than their α-analogues, β-amino acids occur in nature both in free form and bound to peptides. Oligomers composed exclusively of β-amino acids (so-called β-peptides) might be the most thoroughly investigated peptidomimetics. Besides being remarkably stable to metabolism, exhibiting slow microbial degradation, and inherently stable to proteases and peptidases, they fold into well-ordered secondary structures consisting of helices, turns, and sheets. In this respect, the most intriguing effects have been observed when β2-amino acids are present in the β-peptide backbone.2 A whole new “world” has emerged from the design of fascinating new peptidic macromolecules from β- and γ-homologated proteinogenic amino acids and other components. Sigma-Aldrich has a history as a leading supplier of β3-amino acids. Now, the portfolio of β2-amino acids is significantly increased with members that had not yet been available commercially.

10

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New Amino Acid Building Blocks
CH3 O H3C OH NH2 • HCl H3C CH3 O OH • HCl NH2 H2N O OH OH

Monosaccharides
OH HO H2N • 2HBr OH H3C NH2 O O O O CH3 CH3 HO HO N3 O N3 O O O

Chemical Biology

714135

714143

714119
O

714216
OH

714224
N3 O O O O O CH3 O

725978

O H2N OH OH Boc

H N O

OH N H

O OH Boc O H3C H3C

O O O CH3 H3C H3C

O H OH OH OH

714127

713821
O OH O N Boc CH3

713856
O OH Boc OH O OBn OBn

H3C

H3C

712167
H N O

712736
OAc AcO O N3 OAc CN OAc

725862
N3 HO O OH OH

Boc

N H

OH

713848
O OH Boc

713724
O OH Boc

713813

OCH3 OBn

712140
Boc NH O O

712817

712752

N H

N H

For a complete list of building blocks available from Aldrich Chemistry, please visit aldrich.com/chemprod

713864
O Boc NH OH

713872
O H2N • HCl OCH3 H2N

713473
O O H3C CH3 • HCl

670243
O H2N HN OH Boc HC

726273
O OH HN Boc HC

726354
O OH HN Boc

726230
O HC HN OH HC Boc

712221

714240

NH2 O OH • HCl

714232

711926

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

11

Organometallics
Josephine Nakhla, Ph.D. Market Segment Manager Organometallics & Catalysis

New Boronic Acids and Boronate Esters— cont'd
H3C H3C O CH3 O CH3 H3C H3C H3 C O CH3 O B N N O N H3C H3C H3C CH3 O B N N N H

Organometallics

josephine.nakhla@sial.com
H3C H3C

B

O

Suzuki Coupling
The cross-coupling of organoborons with organic electrophiles in the presence of a palladium catalyst (Scheme 1), is one of the most widely utilized methods for C–C bond formation in transition metal chemistry. Organoboron reagents are readily prepared or are commercially available, relatively non-toxic, and do not react with common functional groups. Several new product additions to our boron portfolio are highlighted below.
R1 X + R2 BY2 PdLn R1 R2 + BY2X

N H

CH3 CH3

716251
H3C CH3 H3C CH3 O O B CN N Cl

716227

715557
CH3 O B N S N

H 3C H3C H3C

CH3 O B N N N

H3C H3C H3C

O

O

718920
H3C H 3C O

715476
H3C H3C N B N O H3C CH3 O H3C O H 3C

715565
H3C CH 3 O O B N H3C N CH3

O B N N O

R1 = aryl, heteroaryl, alkenyl R2 = aryl, heteroaryl, alkenyl, alkyl X = Cl, Br, I, OTf B BYn = Y=(OH)2, F3K, O or

H3C N B O O (MIDA) O O

724270

718823

716243

O B O

Scheme 1: The Suzuki reaction
Reference: Wolfe, J. P.; Nakhla, J. S. The Suzuki Reaction. Name Reactions for Homologations. John Wiley & Sons, Inc. (2009), (Pt. 1), 163–184.

718491

New Boronic Acids and Boronate Esters
HO OH B HO N H N N NH2 N OH B N Br OH B OH

For a complete list of boron reagents available from Aldrich Chemistry, please visit aldrich.com/boron

Stille Coupling
The cross-coupling of organotins with organic electrophiles in the presence of a transition-metal catalyst (Scheme 2), remains one of the most viable methods for the formation of C–C bonds in organic chemistry, particularly with heterocyclic nucleophiles. The Stille reaction, like other commonly used cross-couplings, has been employed in methodology development, countless elegant natural product syntheses, and in materials science.
R1 X + R2 Sn(alkyl)3 M(0) R 1 R2 + X Sn(alkyl)3

706256
OH B OH Br N H3C

706221
OH B OH O N

686816
HO B OH S O CH3

666556

718815
OH B N N H HO • HCl

701939
OH • HCl N N H

B

HO

N B OH N H

R1

HO

= aryl, heteroaryl, alkenyl, acyl, benzyl, alkyl R2 = aryl, heteroaryl, alkenyl, alkynyl, allyl, benzyl, alkyl X = Cl, Br, I, OTf

720828

715409
OH B OH Boc N H N

709379
OH B OH

Scheme 2: The Stille reaction
Reference: Mascitti, Vincent. Stille coupling. Name Reactions for Homologations. John Wiley & Sons, Inc. (2009), (Pt. 1), 133–162.

HO

B OH

N N CH3

Br

O

OH

720798
OH B OH

717681
O H HO O B OH O O2N

718785
OH B OH

O 2N

O

OH

721042

717622

720771

12

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TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.

Organotin Reagents from Aldrich
S Bu3Sn S SnBu3 Bu3Sn Bu3Sn H3C N

Organozincs
H3C ZnBr ZnBr N ZnBr CH3

680982 717703 683930 719366
F ZnBr Bu3Sn Bu3Sn N N Bu3Sn Cl N F N Cl

680966
ZnI

499382
ZnI

Organometallics

N O

678333

698598

718807

710261
ZnBr

710296
ZnBr O O

630411

ZnBr

Bu3Sn N

N

Bu3Sn N

N Cl

Bu3Sn N

N

OCH3

710318
Br S ZnBr

710326
H3C S ZnBr

710288

719730

706868
Bu3Sn

707031

714356
N N CH3 Bu3Sn N CH3 N

710237

O OCH2CH3 Bu3Sn O N

For a complete list of organozinc reagents available from Aldrich Chemistry, please visit aldrich.com/zinc

706981

707813

717630

Bu3Sn

O N

Bu3Sn N

S

Br

N SnBu3 S

Common Catalysts Employed for Cross-Coupling
Pd(OAc)2 Pd2(dba)3 Pd(PPh3)4

520764 638617 642541
Bu3Sn N Bu3Sn N CH3 N CH3 Bu3Sn

706965

328774

216666

N N CH3

New Palladium Catalysts from Aldrich Chemistry
Pd Cl Cl Pd CH3 H3C Si CH3 Pd H3C Si CH3 CH3 CH3 H2C Cl Pd Pd CH2 Cl CH3 Pd CH2

675679

719501

718793

For a complete list of organotin reagents available from Aldrich Chemistry, please visit aldrich.com/organotin

720526

719986

700045

721689

Negishi Coupling
The cross-coupling of organozincs with organic electrophiles in the presence of a transition-metal catalyst (Scheme 3), is widely utilized due to the mild, yet reactive nature of organozinc halides.
R 1 X1 + R2 Zn X2 NiLn or PdLn R1 R2 + ZnX1X2

Common Ligand or Catalyst Families
t-Bu P Ph Ph Fe t-Bu Ph Ph O O PCy2 P(t-bu)3

Ph

R1 = aryl, alkenyl, acyl R2 = aryl, heteroaryl, alkenyl, allyl, benzyl, homoallyl, homopropargyl X1 = Cl, Br, I, OTf X2 = Cl, Br, I

675784 Hartwig
H3C

675709 Guram
CH3 CH3 H3C N N

570958 Fu

Pt-Bu2

Scheme 3: The Negishi reaction
H3C

Reference: Yet, Larry. Negishi Cross-Coupling Reaction. Name Reactions for Homologations. John Wiley & Sons, Inc. (2009), (Pt. 1), 70–99.

CH3 H3C Pd Cl

CH3

638439 Buchwald

709042 Nolan

For a complete list of catalysts available from Aldrich Chemistry, please visit aldrich.com/catalysis

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

13

Building Blocks
Mark Redlich, Ph.D. Product Manager

R1O R2HN Ph OH OH O O

O OH

O H OBz OAc

mark.redlich@sial.com

Building Blocks

Paclitaxel: R1 = Ac, R2 = Bz Docetaxel: R1 = H, R2 = Boc

Figure 1: Paclitaxel (Taxol®) and Docetaxel

Oxetanes
Oxetanes are the closest homologs to epoxides, but historically have received far less attention than their three-memberedringed brethren. However, oxetanes have received increasing exposure as attractive modules for drug discovery, largely due to a recent series of reports from Rogers-Evans, Carreira, and coworkers. They have demonstrated the improved physico- and biochemical properties of a molecular scaffold when an oxetane unit replaces a gem-dimethyl unit1 and also reported an oxetane ring can function as a surrogate for a carbonyl group.1b,2 More recently, they have demonstrated the use of 1,6-substituted azaspiro[3.3]heptanes containing an oxetane ring as alternatives to unstable 1,3-heteroatom substituted cyclohexanes.3 In most cases, 3-oxetanone, 731536, was the principal building block employed by the authors to install the oxetane unit (Scheme 1).
CN O HO O O O O

Figure 2: Merrilactone A
Br Br H N O N N H NH2

N H

Figure 3: β-Amino Acid Oxetin

We are pleased to now offer a wide selection of new oxetane building blocks for a variety of applications in synthetic and medicinal chemistry.

New Oxetanes
O OH I

O OEt P OEt

O

NO2

O

O

O

731536
O CN O O OEt O O

733296
O H2N O OH

731560
H N

O SO2Ph

O

O

731536 O Cl O O H

O

731579
NH

733091

731544

NH O O CH3 O O O

731587

731609

Scheme 1: Oxetane Derivatives Synthesized from 3-Oxetanone The presence of the oxetane moiety in drug-like and biologically active molecules is nothing new to synthetic and medicinal chemists. Perhaps the best-known examples of oxetane-containing drugs are the natural product paclitaxel (Taxol®) and its synthetic analog docetaxel (Figure 1). Joëlle Dubois and coworkers studied the effect of the deletion of the oxetane ring in analogs of docetaxel and found the analogs to be less active than docetaxel in biological assays.4 Merrilactone A (Figure 2) shows promise as a nonpeptidal neurotropic agent, 5 and the β-amino acid oxetin (Figure 3) has demonstrated both herbicidal and antibiotic activity.6

For a complete list of oxetanes available from Aldrich Chemistry, please visit aldrich.com/oxetane

14

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Halogenated Pyridines
Pyridines continue to be extremely popular building blocks for synthetic chemists across a number of disciplines. The pyridine moiety is found in a wide range of synthetic targets with applications in catalysis, drug design, molecular recognition, and natural product synthesis. Halogenated pyridines in particular are attractive building blocks for various cross-coupling methodologies. Sigma-Aldrich is pleased to offer these useful halogenated pyridines for your research.
I Br Br

Other New Building Blocks
O C CH2 H2C C O HC NH2

715018
OH HC CH3 CH3

714992

715190
CH3 H3C Si CH3

Building Blocks

NH2

• HCl

NH2

723800
NH2 N N F N NH2 NH2

720356
NH2 CH3 OCH3

686360
NH2 H3C OCH3

722170
Br N SH

722421
OH

720224
F3C N Cl

721492
NH2 H3CO CH3

721484
NH2 N H N

724688
HN Boc NH2

N

Cl

720895
Cl N F F

714445
I Cl N Cl

714488
I I N Cl

724661
HN CH3 Br

718084

709662
N

Boc N H

720208

730564
I CH3 Br

724084 727547
Br N H O O HO S

H2N

O

N

S

708399
H3CO NH2 F3C N H

723649
CH3 N H O H

Br N

Br OCH3

H3C N

N

Cl

722731
O OH Br Cl

724092

707325

722375
Br N

723789
CH3 H3C Si CH3

716529
Br N N H N

NH2 N Cl

I N

NH2 Cl

O

N

N

Cl

N CH3

724076
O F N Cl OH Br

720909
O OH N CH3 Br

720372
O OH N OCH3

717215
H3CO

723770

721050

N H

697338

717576

725250

724378

For a complete list of halogenated pyridines available from Aldrich Chemistry, please visit aldrich.com/hal-pyr

For a complete list of building blocks available from Aldrich Chemistry, please visit aldrich.com/bb
References: (1) (a) Wuitschik, G. et al. Angew. Chem., Int. Ed. 2006, 45, 7736. (b) Wuitschik, G. et al. J. Med. Chem. 2010, 53, 3227. (2) Wuitschik, G. et al. Angew. Chem., Int. Ed. 2008, 47, 4512. (3) Burkhard, J. A. et al. Org. Lett. 2010, 12, 1944. (4) Deka, V. et al. Org. Lett. 2003, 5, 5031. (5) (a) Birman, V. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080. (b) Huang, J.-M. et al. Tetrahderon Lett. 2000, 41, 6111. (c) Huang, J.-M. et al. Tetrahderon 2001, 57, 4691. (6) Omura, S. et al. J. Antibiot. 1984, 37, 1324.

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

15

Synthetic Reagents
Troy Ryba, Ph.D. Product Manager
Carbonyl CHO Amine

Selected Examples

Product Ph

Yield (%) MeOH

Yield (%) neat

troy.ryba@sial.com

Synthetic Reagents

PhNH2

N H

72

80

5-Ethyl-2-methylpyridine borane (PEMB): A New Reagent for Reductive Aminations
PEMB
C4H9
CH3 H3C N

CHO BnNH2

N H

Bn 87a 92a

CHO Pr2NH

N Pr H N

Pr 0b 96

CHO O

PhNH 2

C4H9 H N

Ph

92

94

PhNH2

.
O BnNH2 H N

Ph

92

93

BH3 5-Ethyl-2-methylpyridine borane (PEMB) 725080

Bn

83a

70a

O

Figure 1: Structure of the new reductive amination reagent, PEMB (725080).

H3C

C3H7

PhNH2

HN H3C

Ph 74 C3H7 Bn 84 C3H7 83 94

The reaction of a primary amine with an aldehyde or ketone in the presence of an appropriate hydride source provides quick access to an array of secondary amines. Critical to the success of this transformation is the nature of the reducing agent. Highly reactive hydrides will be intolerant not only with the weak Brönsted acid catalysts commonly employed but also with water generated upon iminium ion formation.
Useful Applications of PEMB

O H3C C3H7 BnNH2 HN H3C O CH3 BnNH2

HN

Bn 62c CH3 70

a b c

Isolated as the dialkylammonium acetate No reductive ammination product, benzyl alcohol generated Percent conversion in 1 h

O R H

AcOH R NH2, rt R

N

R H

1. PEMB 2. workup

R HN R H

Scheme 2: Selected reductive amination examples run in methanol and neat.
References: Burkhardt, E. R.; Coleridge, B. M. Tetrahedron Lett. 2008, 49, 5152–5155.

O R R

AcOH R NH2, 50 o C R

N

R R

R 1. PEMB 2. workup HN R R

Scheme 1: Representative transformation conditions for reduction amination with PEMB. 5-Ethyl-2-methylpyridine (PEMB) exhibits enhanced shelf stability relative to other amine-boranes for reductive aminations (Scheme 1). Studies have shown solvolysis is slow (less than 7% daily) in water/THF or methanol solutions. Reductive aminations with PEMB can be run in methanol. However, solvent can be eliminated completely and the reactions can be run neat, often with better yield than when run in solution (Scheme 2). Unlike some other hydride reducing agents, two of the three borane hydrides are utilized and usually an excess of reagent is not required.

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Amine Boranes
PhNEt2 H3C N BH3 N BH3 BH3

O N CH3 BH3

O N H BH3 Me2NH BH3 i-Pr2NEt BH3

Synthetic Reagents

654213

179752

179043

262323

180203

180238

253111

t-BuNH2 BH3

Et3N BH3

Me3N BH3

H3N BH3

197939

178977

178985

287717

For a complete list of Amine Boranes available from Aldrich Chemistry, please visit aldrich.com/amineboranes

Materials Science

Aldrich MOF Constructor
An Easy Way to Design your Own MOF
Metal-Organic Frameworks (MOFs) are porous coordination networks with record-setting surface areas. MOFs are built from metal ion clusters connected by organic linker molecules or struts. They are designed for specific applications requiring high surface area materials. Aldrich Materials Science is uniquely positioned to assist you in constructing your own MOF. Please review our current offering of organic linkers, high-purity metal salts, and solvents, or request custom-designed materials to meet your research needs.

Organic Linker Molecules for Metal-Organic Frameworks
For a complete list of organic linker molecules for MOFs, please visit aldrich.com/moflinkers
O HO HO O O O OH OH HO HO O O O O OH HO OH O OH O O O OH H2N HO O OH NH2 HO O O OH HO HO O O OH OH HO O O OH

716499

716502

714747

717312

523763
O OH HO

382132
O OH

185361
O OH

O O OH

N
O OH O OH

N N H CH3
R

R O R=* R OH HO

O

HN N N H N N N H

O OH HO O O OH HO O O OH

N H

482749

I202

M50850

706884

719250

715298

686859

High-Purity Metal Salts for Synthesis of Metal-Organic Frameworks
For a complete list of metal salts and other related materials, please visit aldrich.com/ceramics
Zn(NO3)2 • xH 2O
230006

Mg(NO3)2 • 6H2O
203696

Cu(NO3)2 • 2.5 H2O
467855

Al(NO3)3 • 9H2O
229415

Ni(NO3)2 • 6H2O
203874

Cu(NO3)2 • xH2O
229636

Co(NO3)2 • 6H2O
203106

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17

Stockroom Reagents
Todd Halkoski Market Segment Manager Solvents

National Association of Scientific Materials Managers (NAOSMM)
Sigma-Aldrich is a proud partner of NAOSMM. As an added benefit, their members receive savings on a wide range of SigmaAldrich Chemistry products.

Stockroom Reagents

todd.halkoski@sial.com

Supply Rewards® Program

Sigma-Aldrich is a leading global supplier and manufacturer of high quality, stockroom and essential research products.
We specialize in providing the most comprehensive product range and widest selection of purity grades to fulfill your particular application needs.

Get rewarded for choosing Sigma-Aldrich. Earn rewards for your team, your community, or yourself, every time you purchase selected products from Sigma-Aldrich. With over 1,500 eligible common laboratory products to choose from, earning reward points couldn't be easier.

New Lab Start-Up Program
Get your new lab set up in an easy and economical way. Your lab is eligible for the program if:

• Solvents
As a leading supplier of high-purity, research grade solvents, we have the solvent to meet your exact needs

• Acids and Bases
From ACS grade to TraceSELECT® Ultra for the ultra trace analysis levels down to ppb and ppt.

• You are starting a new lab • You are moving to a new location • You have received your first research grant
To learn more, visit us at sigma-aldrich.com/stockroom

• Routine Organic and Inorganic Reagents • Adsorbents, Filter Aids and Drying Agents
You will also find several programs that offer unique solutions to help control your costs. One may be right for you!

By always listening, Sigma-Aldrich delivers.
Monthly Savings from Sigma-Aldrich Easy-to-find site offers monthly savings on Chemistry, Life Science, Analytical and Labware products.
United States—sigma-aldrich.com/offers Europe—sigma-aldrich.com/offerseu For specific country discounts, visit us at sigma-aldrich.com The Sigma-Aldrich Pressure-Temperature Nomograph allows you to quickly and easily estimate boiling points at various pressures. Interactive controls simplify calculations to improve the efficiency of your distillation or evaporation process. Pressure Conversion Tab: Use the built-in Pressure Conversion Calculator to convert among five units of pressure using either numeric values or scientific notation. Temperature Conversion Tab: Quickly calculate temperature conversions without leaving the Nomograph. Printable: Need a hard copy to take with you? Simply right-click and select 'print'.

sigma-aldrich.com/nomograph

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Greener Alternatives
Check out our new Web portal to find out about our Greener Products and Programs

Unlock a Smarter, Greener Laboratory
Visit our new Greener Alternatives Web portal to learn how you can minimize your lab's environmental impact without compromising the quality of your data or research. Come see how Sigma-Aldrich® is meeting the research community's needs for products and services that can significantly lessen environmental impact. Put our commitment to environmental sustainability to work in your lab.

Greener Products
Sigma-Aldrich is committed to doing our part to minimize our footprint on the environment. Find greener alternative reaction media, solvents and reagents through our new Greener Alternatives and Technologies product lists.

Programs and Services
Green actions speak louder than words. We believe a company’s dedication to the environment should go beyond offering greener products and should be reflected in its actions. That’s why we offer a series of simple, easy-to-implement programs and services designed to minimize your environmental impact, without compromising the quality of your work.

For more information on our Greener Alternatives, Programs and Services, please visit us at sigma-aldrich.com/green

Learning Center
Check out resources and links to information regarding environmental sustainability from prominent journal reviews, books, industry websites and the Principles of Green Chemistry.

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Labware Notes
Paula Freemantle Product Manager

Labware Notes

labware@sial.com

Distillation Adapter for On-The-Fly Sampling
Distillation is the most widely used bulk separation method used in the laboratory as well as industry. Beyond purification, it is widely used to characterize complex fluids (such as fuels) through measurement of the distillation curve, a plot of the boiling temperature against volume distilled. A common theme in both of these applications is the desire to understand the composition. In purification, the goal is to monitor the distillation progress, and in fluid characterization, one seeks to relate the composition to the temperature data. The distillate sampling adapter (Figure 1) installed following a condenser or distillation column, can provide this important capability without the need for cumbersome, expensive and often unreliable fraction collectors.1–3 The flow of the distillate is focused to drop into a 0.05 mL “hammock” that is positioned directly below the flow path. The sampling port, equipped with a vacuum tight valve, allows access to the hammock with a standard chromatographic syringe, through a septum. To sample the distillate, one simply positions the chromatographic syringe, preferably equipped with a blunt tipped needle, in the well of the hammock. It is a simple matter to withdraw samples as the distillation progresses. The sample can then be directly injected into the gas chromatograph or spectrometer, or injected into an autosampler vial for analysis later. Indeed, any analytical technique that is applicable for liquid samples ranging in volume from 1 to 50 microliters can be used to characterize the distillate. This adapter has been used for many complex fluid analyses, including gasolines, diesel fuels, rocket kerosenes, jet fuels, crude oils, transformer fluids, waste oils and arson accelerants. Some of the analytical techniques applied to distillate fraction analysis include gas chromatography (with mass selective, flame ionization and chemiluminescence detection), FTIR spectroscopy, Karl Fischer coulombic titrimetry and refractometry. The ability to couple quantitative analysis with the distillation opens the door to thermochemical determinations such as the enthalpy of combustion of fuels, as a function of distillate cut. The adapter has also been used to measure corrosivity of crude oil fractions, with a copper coupon test performed at various distillate cuts.
Figure 1: Distillate sampling adapter.

For a complete list of adapters available from Aldrich Chemistry, please visit aldrich.com/labware Aldrich GC sampling adapter, with vacuum connection and PTFE valve
Joint size 14/20 24/40 29/32 Replacement valve septa Septum inserter for valve Cat. No. Z569895 Z569909 Z569917 33310-U 33311

References: (1) Bruno, T. J., Ott, L.S., Lovestead, T.M., Huber, M.L., The composition explicit distillation curve technique: relating chemical analysis and physical properties of complex fluids. J. Chromatogr. 2010, A1217, 2703–2715. (2) Bruno, T. J., Ott, L.S., Lovestead, T.M., Huber, M.L., Relating complex fluid composition and thermophysical properties with the advanced distillation curve approach. Chemical Eng. Tech. 2010, 33, (3), 363–376. (3) Bruno, T. J., Ott, L.S., Smith, B.L., Lovestead, T.M., Complex fluid analysis with the advanced distillation curve approach. Anal. Chem. 2010, 82, 777–783.

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Hamilton® Syringe, 700 Series
This syringe is a good choice for use with the sampling adapter. volume 10 μL, needle size 22s ga (blunt tip) Cat. No. 58380-U

News and Innovation
New Aldrich Condenser Design Eliminates Puddling on Equipment
Condensate cup catches water that forms on the outer surface of the condenser during use and eliminates puddling on reactor and equipment. Tubing connects to cup's hose barb to drain away water automatically. Z568945 overall H 60 mm, Joint: ST/NS 14/20 Z568953 overall H 100 mm, Joint: ST/NS 14/20

Labware Notes

Aldrich Distillation Glassware

Z568961 overall H 200 mm, Joint: ST/NS 14/20 Z568988 overall H 200 mm, Joint: ST/NS 24/40 Z568996 overall H 200 mm, Joint: ST/NS 29/32 Z569003 overall H 300 mm, Joint: ST/NS 14/20 Z569038 overall H 300 mm, Joint: ST/NS 29/32 Z569011 overall H 300 mm, Joint: ST/NS 24/40 For a complete list of condensing products available from Aldrich Chemistry, please visit aldrich.com/labware

• • Condensers • Distilling columns and packings • Heads • Traps • Glassware kits
Apparatus

For a complete list of distillation products available from Aldrich Chemistry, please visit aldrich.com/labware

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21

Chemistry Services
Mike Willis Market Segment Manager

• Automatic conformational analysis: Each small molecule ligand
is flexed, in an energetically directed approach, and re-oriented thousands of times in the search for potential matches between the ligand and the protein surface.

Chemistry Services

mike.willis@sial.com

• Speed enables in silico screening of millions of small molecules:
3DPL employs a unique and patented derivative field grid to direct small molecules to favorable binding conformations. The use of these grids significantly reduces computational time. Running on a single 1.4 GHz server, 3DPL is able to evaluate over 8 million chemical structures for binding across the entire protein surface in less than 4 days—a 600-fold increase over the fastest technology available today. Much larger structure sets can be run, which eliminates the need to filter out large numbers of potentially valuable samples before the virtual screening experiment.

ChemNavigator® 3DPL™ (3-Dimensional ProteinLigand Search)
3DPL Provides fast identification of targeted molecules
3DPL offers a rapid approach for selecting a population of targeted molecules from starting sets of millions of small molecule structures. 3DPL technology uses a protein structure and large databases of small molecule structures to perform rapid, flexible virtual screening against all likely binding sites on the protein surface. 3DPL is used to identify highly targeted sets of small molecule structures likely to bind the protein surface. Discovery companies can assay sets of hundreds to low thousands of high value structures and avoid screening larger sets of tens of thousands of diverse compounds. 3DPL is designed to allow drug discovery companies to identify a target-focused set of chemistry and move to bioassay and lead identification as quickly and efficiently as possible. 3DPL has several major advantages that allow for rapid identification of potential active molecules: Advantages of 3DPL Searching

• 3D Version of on-line iResearch™ Library included: iResearch
Subscribers may now access a special on-line version of the iResearch Library that is configured to use with 3DPL. This provides access to over 20 million 3D ligands for use in virtual screening. Input to the system is a 3D protein model and a set of 3D small molecule structures; output is a selection of scored small molecule structures that have been calculated to show binding affinity for the protein surface. 3DPL can be used with ChemNavigator's iResearch Library of over million unique structures to provide access to the greatest diversity of commercially available small molecule compounds.

• Knowledge of active site not required: 3DPL includes technology
for automated identification of all sites on the protein surface of appropriate size for binding with a therapeutic molecule. This Convex Hull technology identifies all potential binding sites that can be used in flexible screening, and it eliminates the need for an identified binding site as input for the screening experiment. For a complete list of 3DPL or other cheminformatics available from Aldrich Chemistry, please visit chemnavigator.com/cnc/ products/3DPL.asp

• Entire protein surface may be considered: Each small molecule
is compared against all potential binding sites on the 3D protein surface to look for potential binding interactions. This approach offers the opportunity to identify ligands that would have been overlooked by virtual screening technologies that focus on only one or more pre-defined active sites on the protein surface.

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The Next Generation of Labeled Synthons
For Improved Site-Specific and Stereospecific Syntheses
Dr. Rodolfo Martinez and his group at Highlands Stable Isotopes have developed a novel set of patented stable isotope synthetic reagents. These exclusive reagents facilitate the production of site-specific and stereospecific labeled compounds. They also help improve the speed and quality of the synthesis of labeled materials. These versatile reagents include the following categories: Some of the most versatile compounds in the collection include the methyl addition reagents of which methyl-13C phenyl sulfide (716081) is a notable example. Methyl phenyl sulfide has a rich chemistry and, if prepared with carbon and deuterium labels in the methyl group, is a versatile labeling precursor easily converted into a nucleophilic or an electrophilic synthon.
S Ph
13

Cl C H2

SO2Cl2 or NCS
Ph

S
13

sec -BuLi
CH3 Ph

S
13

Li C H2

Labeled methyl phenyl sulfide can be oxidized, adjusting the pKa and allowing for subsequent modifications. A Raney® Ni mediated desulfurization can be used to remove the sulfur, leaving a labeled methylene group. Alternatively, a 13C-labeled aldehyde, carboxylic acid, or carboxylic ester can be prepared directly.
O
13

• Protected methyl addition
reagents
H13C H 3C O
13

O
13

O 1. TFAA OR 2. H2O H LDA
13 13

C OR

1. PhSO CH2Li Ph S O H
13

13

C

C OR

H13C
13

H13C
13

• α-Keto amide, acid, and ester
precursors

CH

CH R' x

CH

C H

C O

• • Phenyl vinyl compounds • Thioethers and dithioethers • Phthalimides and succinimides
Olefination reagents To view the Next Generation of Labeled Synthons offered by ISOTEC® Stable Isotopes, visit sigma-aldrich.com/sinext For additional information, please email the Stable Isotope Technical Service Group at isosales@sial.com
Reference: Martinez, R. A.; Alvarez, M. A.; Velarde, S. P.; Silks, L. A. P.; Stotter, P. L.; Schmidt, J. G.; Unkefer, C. J. Large-Scale Preparation of [13C]-Methyl Phenyl Sulfide from [13C]Methanol by a One-Step Process. Org. Process Res. Dev. 2002, 6, 851.
O
13

O
13

O Raney® Ni OR H13C
13 13

C

C OR

H13C Ph S O H
13 13

CH H213C

CH

C R’

R’

O H3 C OBn N
13

O
13

C

C OBn R X H13C
13

C OR

PhS

CH3

CH

X = O,S,NR2,SiR 3

O O n = 0-2 S H C
13 13

n = 0-2

S
13

CH3

S
13

CH

CH OH

13

CH2

H213C

[13C]Methyl phenyl sulfide 716081

X O S
13 C H2 n = 0-2 13

Y
13C

O C
13

O
13C 13C

CH2 Br H
13C

H13C
13

OR

W

13

CH

H13C

Z

W,X,Y,Z = H,O,S,NR2,SiR3
CH

O

Raney is a registered trademark of W.R. Grace and Co.

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