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Handbook of
CHIRAL CHEMICALS
e d i t e d b y
D a v i d J . A g e r NSC Technologies
Mount Prospect, lllinois
M A R C E L
MARCEL DEKKER, INC. NEW YORK - BASEL D E K K E R
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ISBN: 0-8247-1058-4
This book is printed on acid-free paper.
Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540
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Copyright 0 1999 by Marcel Dekker, Inc. All Rights Reserved.
Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
Current printing (last digit): 10 9 8 7 6 5 4 3 2
PRINTED IN THE UNITED STATES OF AMERICA
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Preface
The purpose of this book is to highlight the problems associated with the produc-tion of chiral compounds on a commercial scale. With the movement by pharma-ceutical companies to develop single enantiomers as drug candidates, the focushas turned to problems associated with this subclass of organic synthesis. Themajor classes of natural products are also discussed since the stereogenic centercan be derived from nature through the use of ‘‘chiral pool’’ starting materials.
Despite the explosion of asymmetric methods over the past 20 years, veryfew can be performed at scale due to limitations in cost, thermodynamics, orequipment. The major reactions that have been used are covered in this volume.Resolution, whether chemical or enzymatic, still holds a key position. This ishighlighted by a short discussion of the best-selling compounds of 1996. Manyare obtained either by resolution or by fermentation methods.
The most mature chemical method is asymmetric reductions and hydroge-nations. This is highlighted by chapters on the uses of new ligands for hydrogena-tion and hydride-reducing agents. Although we have made considerable advancesin this area, the general catalyst is still elusive. The struggle goes on to identify theultimate hydrogenation catalyst; for example, the use of enzymes and biologicalsystems for the production of chiral compounds continues to increase at an almostexplosive rate. Now that we have learned to manipulate nature’s catalysts, thisarea will continue to grow and become more important.
The chapter on amino acid derivatives is the result of a considerable amountof research on the new methods for the preparation of unnatural amino acids andderivatives at scale. Their findings carry over into other classes of compounds,but the principles are highlighted exclusively within this field.
The chapters are grouped by topic. The first three are an introduction anddiscussion of the requirements of sourcing chiral intermediates. Another chapterpresents an overview of the current large-volume chiral compounds and how theyare synthesized.
The next three chapters discuss how the key subclasses of the chiral pool
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ii PREFACE
are obtained. The amino acid chapter is specific to the chiral pool materials asthere are more examples of amino acid syntheses contained within other chapters.
The next eight chapters cover methods that can be used to introduce orcontrol stereogenic centers. In some cases, such as asymmetric hydrogenations,the approach is well established and has been employed for the large-scale synthe-sis of a number of commercially important compounds. In other cases, such aspericyclic reactions, the potential exists, but has not yet been used. One chaptercovers enzymatic methods, an area that seems to be becoming more importantas we learn how to manipulate enzymes by allowing them to catalyze new reac-tions or take new substrates. The rush to market for pharmaceutical companiesis forcing the chemical development time to be minimized. This is leading tolarge-scale usage of chiral auxiliaries.
The chapter on resolutions has a number of examples as illustrations show-ing that this methodology is still important to obtain chiral compounds. Although,ultimately, it may not be the most cost-effective method, it can provide materialin a rapid manner, and can usually be scaled up. The introduction of large-scalechromatographic techniques, as well as the availability of a large number of en-zymes that can be used to perform reactions on only one enantiomer, will ensurethat this approach remains a useful tool in the future.
The remaining chapters discuss various examples and topics to augmentother chapters and provide a perspective of the different methods available.
I would like to thank all the authors who contributed to this book and whohave worked on it with me for the past few years. I would especially like tothank my colleagues at NSC Technologies for writing a number of the chaptersand for having supplied numerous suggestions and ideas. Not only have theydeveloped new methodology, but they have also proceeded to use it at scalewithin a very short timeframe. They continue to inspire me, as do many othersworking in the arena of asymmetric synthetic methodology.
David J. Ager
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Contents
Preface iContributors ix
1. Introduction 1David J. Ager
1.1. Chirality 11.2. Chiral Pool 21.3. Chiral Reagents 21.4. Chiral Catalysts 21.5. Stoichiometric Reagents 41.6. Resolution 51.7. Synthesis at Scale 51.8. Analysis 81.9. Summary 8
References 8
2. Sourcing Chiral Compounds for the PharmaceuticalIndustry 11Graham J. Tucker
2.1. Introduction 112.2. Consideration of Sources 122.3. Major, Medium, and Minor Players 282.4. Technology 282.5. Available Chiral Compounds 322.6. Conclusion 32
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iv CONTENTS
3. Synthesis of Large-Volume Products 33David J. Ager
3.1. Introduction 333.2. Pharmaceuticals 333.3. Food Ingredients 403.4. Agricultural Products 433.5. Summary 45
References 45
4. Synthesis of Phenylalanine by Fermentation andChemoenzymatic Methods 49Ian G. Fotheringham
4.1. Introduction 494.2. l-Phenylalanine Overproducing Microorganisms 504.3. Biotransformation Routes to l-Phenylalanine 574.4. Resolution-Based l-Phenylalanine Synthesis 604.5. Conclusions 63
References 64
5. Carbohydrates in Synthesis 69David J. Ager
5.1. Introduction 695.2. Disaccharides 705.3. Monosaccharides and Related Compounds 725.4. Glyceraldehyde Derivatives 755.5. Hydroxy Acids 765.6. Summary 79
References 79
6. Terpenes: Expansion of the Chiral Pool 83Weiguo Liu
6.1. Introduction 836.2. Isolation 846.3. Monoterpenes 846.4. Reactions of Monoterpenes 926.5. Summary 99
References 100
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CONTENTS v
7. Substitution Reactions 103David J. Ager
7.1. Introduction 1037.2. SN2 Reactions 1037.3. Epoxide Openings 1057.4. Cyclic Sulfate Reactions 1077.5. Iodolactonizations 1087.6. Allylic Substitutions 1087.7. Summary 110
References 110
8. Resolutions at Large Scale: Case Studies 115Weiguo Liu
8.1. Introduction 1158.2. Chemical Resolution 1168.3. Enzymatic Resolutions 1288.4. Summary 138
References 138
9. Transition Metal Catalyzed Hydrogenations,Isomerizations, and Other Reactions 143Scott A. Laneman
9.1. Introduction 1439.2. Homogeneous Catalysts 1479.3. Asymmetric Heterogeneous Catalysts Implemented
in Industry 1659.4. Asymmetric Hydrogen Transfer 1689.5. Hydroformylation 1699.6. Hydrosilylation 1709.7. Asymmetric Cyclopropanations 1719.8. Conclusions 171
References 173
10. Pericyclic Reactions 177Michael B. East
10.1. Introduction 17710.2. The Diels-Alder Reaction 17710.3. Claisen-Type Rearrangements 187
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vi CONTENTS
10.4 The Ene Reaction 19010.5. Dipolar Cycloadditions 19110.6. [2,3]-Sigmatropic Rearrangements 19210.7. Other Pericyclic Reactions 19410.8. Summary 195
References 196
11. Asymmetric Reduction of Prochiral Ketones Catalyzedby Oxazaborolidines 211Michel Bulliard
11.1. Introduction 21111.2. Stoichiometric Reactions 21111.3. The Catalytic Approach 21211.4. Industrial Application in the Synthesis of
Pharmaceuticals 22011.5. Conclusion 224
References 224
12. Asymmetric Oxidations 227David J. Ager and David R. Allen
12.1. Introduction 22712.2. Sharpless Epoxidation 22712.3. Asymmetric Dihydroxylation 23212.4. Jacobsen Epoxidation 23612.5. Halohydroxylations 23812.6. Enzymatic Methods 23912.7. Summary 239
References 239
13. Biotransformations: ‘‘Green’’ Processes for the Synthesisof Chiral Fine Chemicals 245David P. Pantaleone
13.1. Introduction 24513.2. Biocatalyst Classifications 24613.3. Metabolic Pathway Engineering 27213.4. Screening for Biocatalysts 27613.5. Summary 278
References 278
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CONTENTS vii
14. Industrial Applications of Chiral Auxiliaries 287David R. Schaad
14.1. Introduction 28714.2. Chiral Auxiliary Structures in Pharmaceuticals 28914.3. Application of Chiral Auxiliaries in Industry 29014.4. Potential Applications of Chiral Auxiliaries 29314.5. Conclusions 298
References 298
15. Synthesis of Unnatural Amino Acids: Expansion ofthe Chiral Pool 301David J. Ager, David R. Allen, Michael B. East, Ian G.Fotheringham, Scott A. Laneman, Weiguo Liu, David P.Pantaleone, David R. Schaad, and Paul P. Taylor
15.1. Introduction 30115.2. The Choice of Approach 30215.3. Small-Scale Approaches 30415.4. Intermediate-Scale Approaches 30815.5. Large-Scale Methods 31015.6. Summary 315
References 315
16. Synthesis of L-Aspartic Acid 317Paul P. Taylor
16.1. Introduction 31716.2. Commercial Production 31716.3. General Properties of Aspartase 31916.4. Biocatalyst Development 31916.5. Future Perspectives 323
References 326
17. Synthesis of Homochiral Compounds: A SmallCompany’s Role 329Basil J. Wakefield
17.1. Introduction 32917.2. Classical Resolution 32917.3. The Chiral Pool 33117.4. Enzyme-Catalyzed Kinetic Resolution 333
References 336
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viii CONTENTS
18. Asymmetric Catalysis: Development and Applicationsof the DuPHOS Ligands 339Mark J. Burk
18.1. Introduction 33918.2. Chiral Ligands 34018.3. Asymmetric Catalytic Hydrogenation Reactions 34318.4. Commercial Development and Application of
Asymmetric Catalysis 35618.5. Summary 358
References 358
Index 361
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Contributors
DAVID J. AGER, PH.D. Fellow, NSC Technologies, Mount Prospect, Illinois
DAVID R. ALLEN, B.S. Senior Process Chemist, NSC Technologies, MountProspect, Illinois
MICHEL BULLIARD, PH.D. Research and Development Manager, PPG-SIPSY,Avrille, France
MARK J. BURK, PH.D. Head, ChiroTech Technology Limited, ChirosciencePlC., Cambridge, United Kingdom
MICHAEL B. EAST, PH.D. Senior Research Scientist, NSC Technologies, MountProspect, Illinois
IAN G. FOTHERINGHAM, PH.D. NSC Technologies, Mount Prospect, Illinois
SCOTT A. LANEMAN, PH.D. Senior Research Scientist, NSC Technologies,Mount Prospect, Illinois
WEIGUO LIU, PH.D. Senior Research Scientist, NSC Technologies, MountProspect, Illinois
DAVID P. PANTALEONE, PH.D. Group Leader, Protein Biochemistry, NSCTechnologies, Mount Prospect, Illinois
DAVID R. SCHAAD, PH.D. Senior Research Scientist, Department of ChemicalProcess Development, NSC Technologies, Mount Prospect, Illinois
PAUL P. TAYLOR, PH.D. NSC Technologies, Mount Prospect, Illinois
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x CONTRIBUTORS
GRAHAM J. TUCKER, B.SC. The R-S Directory, Kenley Chemicals, Kenley, Sur-rey, United Kingdom
BASIL J. WAKEFIELD, PH.D., D.SC. Chemicals Director, Ultrafine Chemicals,UFC Pharma, Manchester, United Kingdom
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1Introduction
DAVID J. AGERNSC Technologies, Mount Prospect, Illinois
This book discusses various aspects of chiral fine chemicals, including their syn-thesis and uses at scale. There is an increasing awareness of the importance ofchirality in biological molecules, as the two enantiomers can sometimes havedifferent effects. [1–4].
In many respects, chiral compounds have been regarded as special entitieswithin the fine chemical community. As we will see, the possession of chiralitydoes not, in many respects, make the compound significantly more expensive toobtain. Methods for the preparation of optically active compounds have beenknown for well over 100 years (many based on biological processes). The basicchemistry to a substrate on which an asymmetric transformation is then per-formed can offer more challenges in terms of chemistry and cost optimizationthan the ‘‘exalted’’ asymmetric step.
1.1. CHIRALITY
The presence of a stereogenic center within a molecule can give rise to chirality.Unless a chemist performs an asymmetric synthesis, equal amounts of the twoantipodes will be produced. To separate these, or to perform an asymmetric syn-thesis, a chiral agent has to be employed. This can increase the degree of complex-ity in obtaining a chiral compound in a pure form. However, nature has beenkind and does provide some chiral compounds in relatively large amounts. Chiral-ity does provide an additional problem that is sometimes not appreciated by thosewho work outside of the field: analysis of the final compound is often not a trivialundertaking.
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1.2. CHIRAL POOL
Nature has provided a wide variety of chiral materials, some in great abundance.The functionality ranges from amino acids to carbohydrates to terpenes (Chapters4–6). All of these classes of compounds are discussed in this book. Despite thebreadth of functionality available from natural sources, very few compounds areavailable in optically pure form at large scale. Thus, incorporation of a ‘‘chiralpool’’ material into a synthesis can result in a multistep sequence. However, withthe advent of synthetic methods that can be used at scale, new compounds arebeing added to the chiral pool, although they are only available in bulk by synthe-sis. When a chiral pool material is available at large scale, it is usually inexpen-sive. An example is provided by l-aspartic acid (Chapter 16), where the chiralmaterial can be cheaper than the racemate (see also Chapter 15).
How some of these chiral pool materials have been incorporated into syn-thesis of biologically active compounds is illustrated in this book. In addition,chiral pool materials are often incorporated, albeit in derivatized form, into chiralreagents and ligands that allow for the transfer of chirality from a natural sourceinto the desired target molecule.
1.3. CHIRAL REAGENTS
Chiral reagents allow for the transfer of chirality from the reagent to the prochiralsubstrate. Almost all of these reactions involve the conversion of an sp2 carbonto an sp3 center. For example, reductions of carbonyl compounds (Chapter 11),asymmetric hydrogenations (Chapter 9), and asymmetric oxidations of alkenes(Chapter 12) are all of this type. The reagents can be catalytic for the transforma-tion they bring about, or stoichiometric. The former is usually preferred becauseit allows for chiral multiplication during the reaction—the original stereogeniccenter gives rise to many product stereocenters. This allows for the cost of anexpensive catalyst to be spread over a large number of product molecules.
1.4. CHIRAL CATALYSTS
Considerable resources are being expended in the quest for new asymmetric cata-lysts for a wide variety of reactions (Chapter 9). In many cases, these catalystsare based on transition metals, where the ligands provide the chiral environment.However, as our understanding of biotransformations increases, coupled with ourability to produce mutant enzymes at scale, biocatalysts are beginning to becomekey components of our asymmetric synthetic tool box (Chapters 13 and 15).
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INTRODUCTION 3
1.4.1. Chemical Catalysts
The development of transition metal catalysts for the asymmetric reduction offunctionalized alkenes allowed synthetic chemists to perform reactions with astereochemical fidelity approaching that of nature (Chapter 9). We now have anumber of reactions at our disposal that can be performed with chemical catalysts,and the number continues to grow. However, there are still problems associatedwith this approach because many catalysts have specific substrates requirements,often involving just one alkene isomer of the substrate. The chiral multiplicationassociated with use of a chiral catalyst often makes for attractive economicaladvantages. However, the discovery and development of a chemical catalyst toperform a specific transformation is often tedious, time consuming, and expen-sive. There are many reports of chiral ligands in the literature, for example, toperform asymmetric hydrogenation, yet very few have been used at scale (Chap-ter 9). This highlights the problem that there are few catalysts that can be consid-ered general. As previously mentioned, the preparation of the substrate is oftenthe expensive part of a sequence, especially with catalysts that have high turnovernumbers and can be recycled.
1.4.2. Biological Catalysts
Biological catalysts have been used for asymmetric transformations in specificcases for a considerable period of time, excluding the chiral pool materials. How-ever, until recently, the emphasis has been on resolutions with enzymes ratherthan asymmetric transformations (Chapter 13). With our increasing ability to pro-duce mutant enzymes that have different or broad-spectrum activities comparedwith the wild types, the development of biological catalysts is poised for majordevelopment. In addition to high stereospecificities, an organism can be per-suaded to perform more than one step in the overall reaction sequence, and mayeven make the substrate (Chapter 15).
Unlike the design of a chemical catalyst, which has to be semi-empiricalin nature and is therefore very difficult to apply to a completely different transfor-mation, screening for an enzyme that performs a similar reaction is relativelystraightforward and often gives the necessary lead for the development of a potentbiological catalyst. The use of molecular biology, site-specific mutagenesis, andenzymology all contribute to the development of such a catalyst. This approachis often ignored because these methods are outside of traditional chemical meth-odologies.
There are a large number of reports of abzymes, or catalytic antibodies, inthe literature [5–10]. Although catalysis has been observed in a large number ofexamples, the problems associated with the production of large amounts of ab-zymes, compounded by the low turnover numbers often observed, makes this
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4 AGER
technology only a laboratory curiosity. The increasing use of mutant enzymeswithout isolation from the host organisms makes this latter approach economi-cally more attractive.
1.5. STOICHIOMETRIC REAGENTS
To understand a specific transformation, chemists have often developed asym-metric synthetic methods in a logical, stepwise manner. Invariably, the mecha-nism of the reaction and the factors that control the stereochemical outcome ofa transformation are paramount in the design of an efficient catalyst for use atscale with a wide variety of substrates. There are some noticeable exceptionsto this approach, such as the empirical approach used to develop asymmetrichydrogenation catalysts (Chapter 9). In other instances, an empirical approachprovided sufficient insight to allow for the development of useful chiral catalysts,such as the empirical rule for the oxidation of alkenes [11,12] that led to theasymmetric hydroxylation catalysts [13,14]. The first generation of asymmetricreagents are often chiral templates or stoichiometric reagents. These are thensuperseded by chiral auxiliaries, if the substrate has to be modified, or chiralcatalysts in the case of external reagents.
1.5.1. Chiral Auxiliaries
This class of compounds modifies the substrate molecule to introduce a ste-reogenic center that will influence the outcome of a reaction to provide an asym-metric synthesis. The auxiliary has to be put onto the substrate and removed.Although this involves two steps, concurrent protection of sensitive functionalitycan also take place, so that one inefficient sequence (protection and deprotection)is traded for another (auxiliary introduction and removal). A large number ofasymmetric transformations have been performed with chiral auxiliaries, provid-ing a wealth of literature. Thus, a precedence for most reactions is available,providing for a large degree of certainty that a specific reaction, even with a newsubstrate, will work (see Chapters 14 and 15). Due to the curtailed timelines forthe development of new pharmaceutical products, coupled with the decrease inthe costs of many auxiliaries, this approach is now being used at larger scale.
Although an auxiliary is recovered intact after the asymmetric transforma-tion and has the potential to be recycled, there are often problems associated withthe practical implementation of this concept.
1.5.2. Chiral Templates
Chiral templates can be considered a subclass of chiral auxiliaries. Unlike auxilia-ries that have the potential to be recycled, the stereogenic center of a template
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INTRODUCTION 5
is destroyed during its removal. Although this usually results in the formationof simple by-products that are easy to remove, the cost of the template’s ste-reogenic center is transferred to the product molecule. The development of atemplate is usually the first step in understanding a specific transformation, andthe knowledge gained is used to develop an auxiliary or catalyst system.
1.6. RESOLUTION
The separation of enantiomers through the formation of derivative diastereoiso-mers and the subsequent separation of these by physical means has been practicedat large scale for many years (Chapter 8). In addition, the racemic mixture canbe reacted with a chiral reagent, where the rates of reaction are very differentfor the two enantiomers, allowing for a resolution. This approach is applicableto chemical agents, such as the Sharpless epoxidation procedure [15–17], andbiological agents, such as enzymes (see Chapters 8, 12, and 13). Unless a meso-substrate is used, or the wrong isomer can be converted back to the racemate insitu, to provide a dynamic resolution, the ‘‘off-isomer’’ can present an economicproblem. It either has to be disposed of—this results in a maximum overall yieldof 50% from the racemic substrate—or epimerized to allow for recycle throughthe resolution sequence. The latter approach often involves additional steps in asequence that can prove to be costly. In either case, recovery of the resolvingagent also has to be considered. As the development of robust, general, asymmet-ric methods to a class of compounds becomes available, it is becoming apparentthat the more traditional resolution approaches are not economically viable. How-ever, there is still a place for resolutions (see Chapters 8 and 15).
1.7. SYNTHESIS AT SCALE
There are many problems associated with conducting asymmetric synthesis atscale. Many asymmetric transformations reported in the literature use the tech-nique of low temperature to allow differentiation of the two possible diastereo-meric reaction pathways. In some cases, the temperature requirements to see goodasymmetric induction can be as low as �100°C. To obtain this temperature ina reactor is not only costly in terms of cooling, but also presents problems associ-ated with materials of construction and the removal of heat associated with theexotherm of the reaction itself. It is comforting to see that many asymmetriccatalytic reactions do not require the use of low temperature. However, the smallnumber of ‘‘robust’’ reactions often leads development chemists to resort to afew tried and tested approaches, namely, chiral pool synthesis, use of a chiralauxiliary, or resolution. In addition, the scope and limitations associated with the
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6 AGER
use of a chiral catalyst often result in a less-than-optimal sequence either becausethe catalyst does not work well on the necessary substrate, or the preparation ofthat substrate is long and costly. Thus, the availability of a number of differentapproaches helps to minimize these problems (Chapter 15).
A short overview of the synthesis of some of the large-scale and monetaryvalue chiral products is given in Chapter 3. This illustrates the relative importanceof some of the approaches discussed within this book, especially the power ofbiological approaches.
1.7.1. Reactions That Are Amenable to Scale
When reactions that are ‘‘robust’’ are considered, only a relatively small numberare available. Each of these reaction types are discussed within this book, al-though some do appear under the chiral pool materials that allowed for the devel-opment of this class of asymmetric reagent. Such an example is the use of ter-penes, which have allowed for the development of chiral boranes (Chapter 6).
1.7.1.1. Biological Methods
This class of reagents holds the most promise for rapid development in the nearfuture as most reactions are asymmetric. The problems being overcome are thetight substrate specificity of many enzymes and the need for cofactor regenera-tion. Systems are now being developed for asymmetric synthesis rather than reso-lution approaches. Some of these reactions are discussed in Chapter 13.
1.7.1.2. Transition Metal Catalyzed Oxidations
The development of simple systems that allow for the asymmetric oxidation ofallyl alcohols and simple alkenes to epoxides or 1,2-diols has had a great impacton synthetic methodology as it allows for the introduction of functionality withconcurrent formation of one or two stereogenic centers. This functionality canthen be used for subsequent reactions that usually fall into the substitution reac-tion class. Because these transition metal catalysts do not require the use of lowtemperatures to ensure high degrees of induction, they can be considered robust.However, the sometimes low catalyst turnover numbers and the synthesis of thesubstrate can still be crucial economic factors. Aspects of asymmetric oxidationsare discussed in Chapter 12.
1.7.1.3. Transition Metal Catalyzed Reductions
As mentioned elsewhere (Chapter 9), the development of transition metal cata-lysts that allowed for high enantioselectivity in reduction reactions showed thatchemists could achieve comparable yields and enantiomeric excesses (ee’s) to
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INTRODUCTION 7
enzymes. A large number of transition metal catalysts and ligands are now avail-able. A number of reactions that use an asymmetric hydrogenation for the keychiral step have been scaled up for commercial production (Chapters 9 and 18).
1.7.1.4. Transition Metal Catalyzed Isomerizations
These reactions are closely related to asymmetric hydrogenations, especially assimilar catalysts are used. A number of these reactions are used at scale (Chap-ter 9).
1.7.1.5. Reductions
The reduction of a carbonyl group to an alcohol has been achieved at a laboratoryscale with a large number of reagents, many stoichiometric with a ligand derivedfrom the chiral pool. The development has culminated in boron-based reagentsthat perform this transformation with high efficiency (Chapter 11).
1.7.1.5.1. Hydroborations.
In addition to being useful reagents for the reductions of carbonyl compounds,boron-based reagents can also be used for the conversion of an alkene to a widevariety of functionalized alkanes. Because the majority of these reagents carrya terpene substituent, they are discussed under these chiral pool materials (Chap-ter 6).
1.7.1.6. Pericyclic Reactions
Many of these reactions are stereospecific and, because they have to be run attemperatures higher than ambient, are very robust. It is somewhat surprising thatthere are very few examples of pericyclic reactions being run at scale, especiallyin light of our understanding of the factors that control the stereochemical courseof the reaction, either through the use of a chiral auxiliary or catalyst (Chapter10).
1.7.1.7. Substitution Reactions (SN2)
This heading has been used to describe the conversion of one stereogenic centerto another. Of course, this means that the substrate stereogenic center has hadto be obtained by one of the reaction types outlined above, from the chiral pool,or by resolution. Reactions that fall into this category include epoxide and cyclicsulfate openings, and iodolactonizations (Chapter 7).
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1.8. ANALYSIS
The analysis of chiral compounds to determine their optical purity is still not atrivial task. The analysis method has to differentiate between the two antipodes,and, thus, has to involve a chiral agent. However, the development of chiralchromatography, especially high-performance liquid chromatography, has donea significant amount to relieve this problem. The purpose of this book is to discusslarge-scale synthetic reactions, but the development of chiral analytical methodsmay not have been a trivial undertaking in many examples.
1.9. SUMMARY
The development of optically active biological agents such as pharmaceuticalshas led to the increase in large-scale chiral synthesis. The chirality may be derivedfrom the chiral pool or a chiral agent such as an auxiliary, template, reagent, orcatalyst. There are, however, relatively few general asymmetric methods that canbe used at scale.
REFERENCES
1. Blashke, G., Kraft, H. P., Fickenscher, K., Kohler, F. Arzniem-Forsch/Drug Res.1979, 29, 10.
2. Blashke, G., Kraft, H. P., Fickenscher, K., Kohler, F. Arzniem-Forsch/Drug Res.1979, 29, 1140.
3. Powell, J. R., Ambre, J. J., Ruo, T. I. in Drug Stereochemistry; Wainer, I. W., Drayer,D. E., Eds. Marcel Dekker: New York, 1988, p. 245.
4. Ariëns, E. J., Soudijn, W., Timmermas, P. B. M. W. M. Stereochemistry and Biologi-cal Activity of Drugs; Blackwell Scientific: Palo Alto, 1983.
5. Lerner, R. A., Benkovic, S. J., Schultz, P. G. Science 1991, 252, 659.6. Blackburn, G. M., Kang, A. S., Kingsbury, G. A., Burton, D. R. Biochem. J. 1989,
262, 381.7. Schultz, P. G., Lerner, R. A. Acc. Chem. Res. 1993, 26, 391.8. Hilvert, D. Acc. Chem. Res. 1993, 26, 552.9. Stewart, J. D., Liotta, L. J., Benkovic, S. J. Acc. Chem. Res. 1993, 26, 396.
10. Stewart, J. D., Benkovic, S. J. Chem. Soc. Rev. 1993, 22, 213.11. Cha, J. K., Christ, W. J., Kishi, Y. Tetrahedron Lett. 1983, 24, 3943.12. Cha, J. K., Christ W. J., Kishi, Y. Tetrahedron 1984, 40, 2247.13. Sharpless, K. B., Behrens, C. H., Katsuki, T., Lee, A. W. M., Martin, V. S., Takatani,
M., Viti, S. M., Walker, F. J., Woodard, S. S. Pure Appl. Chem. 1983, 55, 589.14. Sharpless, K. B., Verhoeven, T. R. Aldrichimica Acta 1979, 12, 63.
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INTRODUCTION 9
15. Brown, J. M. Chem. Ind. (London) 1988, 612.16. Gao, Y., Hanson, R. M., Klunder, J. M., Ko, S. Y., Masamune, H., Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765.17. Ager, D. J., East, M. B. Asymmetric Synthetic Methodology; CRC Press: Boca Raton,
1995.
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2Sourcing Chiral Compounds forthe Pharmaceutical Industry
GRAHAM J. TUCKERThe R-S Directory, Kenley Chemicals, Kenley, Surrey, England
2.1. INTRODUCTION
In this chapter, some generalizations have been attempted, an exercise that isalways open to disagreement. It will no doubt be possible to cite exceptions,particularly in the field of chiral compounds. The focus is on sourcing for drugcandidates in development.
Sourcing a chiral raw material or intermediate is different from sourc-ing other fine chemicals. There is a perception in some quarters that chiralityoffers participation in a ‘‘sunrise’’ industry, somehow to be regarded similarlyto biotechnology. As such, there are more ‘‘start-up’’ companies to consi-der, some backed by venture capital, compared with the situation with other finechemicals.
Another different factor in sourcing chiral materials is that, in many cases,the ways to potentially obtain them can be diverse and often more novel thanfor racemates. The overwhelming majority of racemic intermediates is still madethrough the use of organic, often classical, chemical processes with conventionalphysical methodology used to isolate and purify the product. However, there aresome exceptions in which a biological process is used to make an achiral materialsuch as acrylamide. Nonetheless, nature is decidedly not evenhanded, and biolog-ical-based processes with prochiral substrates often yield chiral materials. Suchprocesses join asymmetric chemical synthesis as candidate technologies to accessa specific enantiomer. A further possibility to obtain a single antipode is separa-tion of a racemic compound through the less conventional physical technique ofchiral chromatography. All of these methods are in a state of rapid evolution,
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12 TUCKER
fueled by the increase in number of chiral compounds required for pharmaceuticaldevelopment.
How important is chirality? Based on the percentage of chiral compoundsentering phase I development in the last year, the importance of chirality variesgreatly between companies. In one case, all phase I candidates were chiral, inanother, just 5%. In the recent past, some discovery groups were deliberatelyavoiding chiral molecules to circumvent perceived complications.
2.2. CONSIDERATION OF SOURCES
Suppliers can be classified as chiral center creators (CCCs), of which there arerelatively few, or chiral center elaborators (CCEs), of which there are many.
CCCs may obtain chiral compounds by classical resolution, kinetic resolu-tion using chemical or enzymatic methods, biocatalysis (enzyme systems, wholecells, or cell isolates), fermentation (from growing whole microorganisms), andstereoselective chemistry (e.g., asymmetric reduction, low-temperature reactions,use of chiral auxiliaries). CCCs may also be CCEs by capitalizing on a key rawmaterial position and ‘‘going downstream.’’ Along with companies manufactur-ing chiral molecules primarily for other purposes, such as amino acid producers,these will be the key sources for the asymmetric center.
CCCs may be companies that specialize in chiral compounds, such asCelgene, Chiroscience, and Oxford Asymmetry, or may have developed into achiral raw material supplier to an industry other than its original main customerbase [e.g., Takasago, a flavor manufacturer, who developed a catalytic route to(�)-menthol, and used related technology to make beta-lactam intermediates].
CCEs elaborate an available chiral raw material to a further chiral molecule,for example, an amino acid to an amino alcohol and then to an oxazolidinoneauxiliary. Thus, there are at least nine suppliers of (S)-phenylalaninol and sixof (S)-4-benzyl-2-oxazolidinone, although not all of these might be consideredcommercial in terms of potential for competitive production at scale. Often, onlya few compounds are made by CCEs, just in response to market demand. Manyfine chemical intermediate manufacturers can be CCEs, although, to be viablesources in the longer term, they must possess expertise or patented/proprietarytechnology covering the utilization of the chiral raw material. There will also becases of advantageous access to the required chiral raw material or, perhaps, theprocess will involve a hazardous reactant that a particular plant is equipped tohandle. Although offering a chiral product, these companies’ role as competitivesuppliers arises from factors other than particular expertise in chirality itself (Ta-ble 1). One might suspect that some fine chemical producers mention chiral com-pounds not because they have anything special to offer, but merely because theywant to participate in a field with perceived growth potential.
-
SOURCING CHIRAL COMPOUNDS 13
TA
BLE
1C
hira
lC
ompo
unds
Ava
ilabl
eat
Scal
ea
Com
poun
dFo
rmul
aSu
pplie
r
(3R
,4R
)-4-
Ace
toxy
-3-[
(R)-
t-bu
tyld
imet
hyls
ilylo
xy)e
thyl
]-2-
azet
idin
one
C13
H25
NO
4Si
Kan
eka,
Nip
pon
Soda
,T
akas
ago
N-A
cety
l-(4
S)-b
enzy
l-2-
oxaz
olid
inon
eC
12H
13N
O3
NSC
Tec
hnol
ogie
s(R
)-O
-Ace
tylm
ande
licac
idC
10H
10O
4Y
amak
awa
(S)-
O-A
cety
lman
delic
acid
C10
H10
O4
Yam
akaw
a(S
)-(�
)-A
cety
l-3-
mer
capt
o-2-
met
hylp
ropi
onic
acid
C6H
10O
3SD
SMA
nden
o,K
anek
a,Su
mito
mo
Seik
aN
-Ace
tyl-
d-3-
(2-n
apht
hyl)
alan
ine
C15
H15
NO
3R
exim
/Deg
ussa
,Sy
nthe
tech
(R)-
Ace
tylth
io-2
-met
hylp
ropi
onyl
chlo
ride
C6H
9O2C
ISK
anek
ad-
Ala
nina
mid
eH
Cl
C3H
9ClN
2O
Tan
abe,
Synt
hete
chd-
Ala
nine
C3H
7N
O2
Ajin
omot
o,K
anek
a,N
ippo
n,K
ayak
u,R
ecor
dati,
Rex
im/D
egus
sa,
Tan
abe,
Tor
ay(R
)-(�
)-2-
Am
inob
utan
olC
4H
11N
OT
hem
is(S
)-(�
)-2-
Am
inob
utan
olC
4H
11N
OT
hem
is(1
R,2
S)-(
�)-
eryt
hro-
2-A
min
o-1,
2-di
phen
ylet
hano
lC
14H
15N
O2
Yam
akaw
a(1
S,2R
)-(�
)-er
ythr
o-2-
Am
ino-
1,2-
diph
enyl
etha
nol
C14
H15
NO
2Y
amak
awa
(�)-
cis-
(1S,
2R)-
Am
inoi
ndan
-2-o
lC
9H
11N
OC
hire
x(R
)-(�
)-2-
Am
ino-
3-m
ethy
l-1-
buta
nol
(d-V
alin
ol)
C5H
9N
OB
oehr
inge
r,N
ewpo
rt,
Rex
im/D
egus
sa(S
)-(�
)-2-
Am
ino-
3-m
ethy
l-1-
buta
nol
(l-V
alin
ol)
C5H
13N
OB
oehr
inge
r,N
ewpo
rt,
Rex
im/D
egus
saL
-(�
)-2-
Am
ino-
2-m
ethy
l-3-
(3,4
-dim
etho
xyph
enyl
)pro
pion
itrile
C12
H16
N2O
2A
lfa
Che
mic
als
Ital
iana
(S)-
(�)-
2-A
min
o-3-
met
hyl-
1-pe
ntan
ol(l
-(�
)-Is
oleu
cino
l)C
6H
15N
OB
oehr
inge
r,R
exim
/Deg
ussa
(R)-
(�)-
2-A
min
o-4-
met
hyl-
1-pe
ntan
ol(d
-(�
)-L
euci
nol)
C6H
15N
OR
exim
/Deg
ussa
(S)-
(�)-
2-A
min
o-4-
met
hyl-
1-pe
ntan
ol(l
-(�
)-L
euci
nol)
C6H
15N
OB
oehr
inge
r,R
exim
/Deg
ussa
[R-(
R,R
)]-2
-Am
ino-
1-[4
-(m
ethy
lthio
)phe
nyl]
-1,3
-pro
pane
diol
C10
H15
NO
2S
Zam
bon
[S-(
R,R
)]-2
-Am
ino-
1-[4
-(m
ethy
lthio
)phe
nyl]
-1,3
-pro
pane
diol
C10
H15
NO
2S
Zam
bon
(R)-
(�)-
2-A
min
o-2-
phen
ylbu
tyri
cac
idC
10H
13N
O2
Sips
y(S
)-(�
)-2-
Am
ino-
2-ph
enyl
buty
ric
acid
C10
H13
NO
2Si
psy
(Tab
leco
ntin
ues)
-
14 TUCKER
TA
BLE
1C
ontin
ued
Com
poun
dFo
rmul
aSu
pplie
r
(R)-
(�)-
2-A
min
o-1-
prop
anol
(d-A
lani
nol)
C3H
9N
OB
oehr
inge
r,N
ewpo
rt(S
)-(�
)-2-
Am
ino-
1-pr
opan
ol(l
-Ala
nino
l)C
3H
9N
OB
oehr
inge
r,N
ewpo
rt,
Synt
hete
chd-
Arg
inin
eC
6H
14N
4O
2A
jinom
oto,
Rex
im/D
egus
sa,
Tan
abe
d-A
spar
ticac
idC
4H
7N
O4
Ajin
omot
o,R
exim
/Deg
ussa
,T
anab
ed-
(�)-
α-A
zido
phen
ylac
etic
acid
C8H
7N
3O
2D
ynam
itN
obel
d-(�
)-α-
Azi
doph
enyl
acet
ylch
lori
deC
8H
6C
lN3O
Dyn
amit
Nob
el(1
S,2R
)-(�
)-ci
s-2-
Ben
zam
idoc
yclo
hexa
neca
rbox
ylic
acid
C14
H17
NO
3Y
amak
awa
(1R
,2S)
-(�
)-ci
s-2-
Ben
zam
idoc
yclo
hexa
neca
rbox
ylic
acid
C14
H17
NO
3Y
amak
awa
(R)-
(�)-
1-B
enzo
yl-2
-t-b
utyl
-3-m
ethy
l-4-
imid
azol
idin
one
C15
H20
N2O
2R
exim
/Deg
ussa
(S)-
(�)-
1-B
enzo
yl-2
-t-b
utyl
-3-m
ethy
l-4-
imid
azol
idin
one
C15
H20
N2O
2R
exim
/Deg
ussa
(R)-
(�)-
Ben
zylg
lyci
dyl
ethe
rC
10H
12O
2D
aiso
(S)-
(�)-
Ben
zylg
lyci
dyl
ethe
rC
10H
12O
2D
aiso
(1S,
2R)-
(�)-
cis-
N-B
enzy
l-2-
(hyd
roxy
met
hyl)
cycl
ohex
ylam
ine
C14
H21
NO
Yam
akaw
a(1
R,2
S)-(
�)-
cis-
N-B
enzy
l-2-
(hyd
roxy
met
hyl)
cycl
ohex
ylam
ine
C14
H21
NO
Yam
akaw
a(R
)-N
-Ben
zyl-
3-hy
drox
ypyr
rolid
ine
C11
H15
NO
Kan
eka,
Tor
ay(S
)-N
-Ben
zyl-
3-hy
drox
ypyr
rolid
ine
C11
H15
NO
Kan
eka,
Tor
ayB
enzy
l(R
)-(�
)-m
ande
late
C15
H14
O3
Yam
akaw
aB
enzy
l(S
)-(�
)-m
ande
late
C15
H14
O3
Yam
akaw
a(R
)-(�
)-N
-Ben
zyl-
α-m
ethy
lben
zyla
min
eC
15H
17N
Yam
akaw
a(S
)-(�
)-N
-Ben
zyl-
α-m
ethy
lben
zyla
min
eC
15H
17N
Yam
akaw
a(R
)-(�
)-4-
Ben
zyl-
2-ox
azol
idin
one
C10
H11
NO
2B
oehr
inge
r,N
agas
e,N
ewpo
rt,
Rex
im/
Deg
ussa
,U
rqui
ma
(S)-
(�)-
4-B
enzy
l-2-
oxaz
olid
inon
eC
10H
11N
O2
Boe
hrin
ger,
Nag
ase,
New
port
,NSC
Tec
h-no
logi
es,
Rex
im/D
egus
saB
enzy
l(S
)-1,
2,3,
4-te
trah
ydro
isoq
uino
line-
3-ca
rbox
ylat
eC
24H
25N
O5S
Fine
Org
anic
s,N
SCT
echn
olog
ies,
p-to
luen
esul
phon
ate
Tan
abe
-
SOURCING CHIRAL COMPOUNDS 15
Ben
zyl
(R)-
2-to
sylo
xypr
opio
nate
C17
H18
O5S
Dai
cel,
Tan
abe
(R)-
(�)-
1,1-
Bi-
2-na
phth
olC
20H
14O
2Fi
nete
ch,
Mits
ubis
hi,
Oxf
ord,
Stre
m(S
)-(�
)-1,
1-B
i-2-
naph
thol
C20
H14
O2
Fine
tech
,M
itsub
ishi
,O
xfor
d,St
rem
(R)-
(�)-
1,1′
-Bin
apht
hyl-
2,2-
diyl
hydr
ogen
phos
phat
eC
20H
13O
4P
Fine
tech
(S)-
(�)-
1,1′
-Bin
apht
hyl-
2,2-
diyl
hydr
ogen
phos
phat
eC
20H
13O
4P
Fine
tech
(4R
,5R
)-B
is[b
is(3
′,5′-d
imet
hyl-
4′-m
etho
xyph
enyl
)pho
sphi
nom
ethy
l]-
C42
H56
O6P
2T
oyot
ama
2,2-
dim
ethy
l-1,
3-di
oxol
ane
(4S,
5S)-
Bis
[bis
(3′,5
′-dim
ethy
l-4′
-met
hoxy
phen
yl)p
hosp
hino
met
hyl]
-2,2
-C
42H
56O
6P
2T
oyot
ama
dim
ethy
l-1,
3-di
oxol
ane
(R)-
(�)-
2,2′
-Bis
(dip
heny
lpho
sphi
no)-
1,1′
-bin
apht
hyl
C44
H32
P2
Fine
tech
(S)-
(�)-
2,2′
-Bis
(dip
heny
lpho
sphi
no)-
1,1′
-bin
apht
hyl
C44
H32
P2
Fine
tech
(2R
,3R
)-(�
)-2,
3-B
is(d
iphe
nylp
hosp
hino
)but
ane
C28
H28
P2
Fine
tech
N-α
-BO
C-d
-3-(
3-B
enzo
thie
nyl)
alan
ine
C16
H19
NO
4S
Synt
hete
chN
-α-B
OC
-l-3
-(3-
Ben
zoth
ieny
l)al
anin
eC
16H
19N
O4S
Synt
hete
chN
-α-B
OC
-d-3
-(4-
Bip
heny
l)al
anin
eC
20H
23N
O4
Synt
hete
chN
-α-B
OC
-l-3
-(4-
Bip
heny
l)al
anin
eC
20H
23N
O4
Synt
hete
ch(R
)-(�
)-1-
BO
C-2
-t-B
utyl
-3-m
ethy
l-4-
imid
azol
idin
one
C13
H24
N2O
3R
exim
/Deg
ussa
(S)-
(�)-
1-B
OC
-2-t
-But
yl-3
-met
hyl-
4-im
idaz
olid
inon
eC
13H
24N
2O
3R
exim
/Deg
ussa
N-α
-BO
C-d
-3-(
4-C
hlor
ophe
nyl)
alan
ine
C14
H18
ClN
O4
Rex
im/D
egus
sa,
Synt
hete
chN
-α-B
OC
-l-3
-(4-
Chl
orop
heny
l)al
anin
eC
14H
18C
lNO
4Sy
nthe
tech
N-α
-BO
C-d
-3,3
-Dip
heny
lala
nine
C20
H23
NO
4Sy
nthe
tech
N-α
-BO
C-l
-3,3
-Dip
heny
lala
nine
C20
H23
NO
4Sy
nthe
tech
N-α
-BO
C-l
-Oct
ahyd
roin
dole
-2-c
arbo
xylic
acid
C14
H23
NO
4Sy
nthe
tech
N-B
OC
-d-O
rnith
ine
C10
H20
N2O
4T
anab
eN
-α-B
OC
-d-3
-(4-
Pent
afluo
roph
enyl
)ala
nine
C14
H14
F5N
O4
Synt
hete
chN
-α-B
OC
-l-3
-(4-
Pent
afluo
roph
enyl
)ala
nine
C14
H14
F5N
O4
Synt
hete
chN
-α-B
OC
-d-3
-(2-
Pyri
dyl)
alan
ine
C13
H18
N2O
4Sy
nthe
tech
N-α
-BO
C-l
-3-(
2-Py
ridy
l)al
anin
eC
13H
18N
2O
4Sy
nthe
tech
N-α
-BO
C-(
3S,4
S)-S
tatin
eC
13H
25N
O5
Synt
hete
ch(2
R)-
Bor
nane
-10,
2-su
ltam
C10
H17
NO
2S
New
port
(Tab
leco
ntin
ues)
-
16 TUCKER
TA
BLE
1C
ontin
ued
Com
poun
dFo
rmul
aSu
pplie
r
(2S)
-Bor
nane
-10,
2-su
ltam
C10
H17
NO
2S
New
port
(R)-
(�)-
2-B
rom
obut
yric
acid
C4H
7B
rO2
Lin
z(S
)-(�
)-2-
Bro
mob
utyr
icac
idC
4H
7B
rO2
Lin
z(�
)-3-
Bro
moc
amph
orC
10H
15B
rOC
alai
re(�
)-3-
Bro
mo-
8-ca
mph
orsu
lpho
nic
acid
amm
oniu
msa
ltC
10H
18B
rNO
4S
Cal
aire
(�)-
3-B
rom
o-8-
cam
phor
sulp
honi
cac
idam
mon
ium
salt
C10
H18
BrN
O4S
Cal
aire
(R)-
(�)-
2-B
rom
opro
pion
icac
idC
3H
5B
rO2
Lin
z(S
)-(�
)-2-
Bro
mop
ropi
onic
acid
C3H
5B
rO2
Lin
z,Z
enec
a(R
)-(�
)-1,
3-B
utan
edio
lC
4H
10O
2B
oehr
inge
r,D
aice
l,T
anab
e(2
R,3
R)-
(�)-
2,3-
But
aned
iol
C4H
10O
2U
rqui
ma
(R)-
(�)-
3-B
uten
e-2-
olC
4H
8O
Boe
hrin
ger,
Chi
rosc
ienc
e(S
)-(�
)-3-
But
ene-
2-ol
C4H
8O
Boe
hrin
ger,
Chi
rosc
ienc
e(S
)-(�
)-3-
t-B
utyl
amin
o-1,
2-pr
opan
edio
lC
7H
17N
O2
DSM
And
eno
But
yl(S
)-(�
)-2-
chlo
ropr
opio
nate
C7H
13C
lO2
Dai
cel,
Tan
abe
(3S,
4S)-
3-(R
)-(t
-But
yldi
met
hyls
ilylo
xy)e
thyl
)-4-
[(R
)-ca
rbox
yeth
yl]-
2-C
14H
27N
O4Si
Kan
eka,
Tak
asag
oaz
etid
inon
e(2
R,3
R)-
3-B
utyl
glyc
idol
C7H
13O
2Si
psy
(2S,
3S)-
3-B
utyl
glyc
idol
C7H
13O
2Si
psy
(S)-
(�)-
But
ylla
ctat
eC
7H
14O
3B
oehr
inge
r(S
)-4-
t-B
utyl
-2-o
xazo
lidin
one
C7H
13N
O2
Rex
im/D
egus
sa(S
)-3-
t-B
utyl
-2,5
-pip
eraz
indi
one
C8H
14N
2O
2R
exim
/Deg
ussa
(S)-
3-B
utyn
-2-o
lC
4H
6O
DSM
And
eno
(�)-
Cam
phor
icac
idC
10H
16O
4C
hina
Cam
phor
(�)-
Cam
phor
-10-
sulp
honi
cac
idC
10H
16O
4S
Cal
aire
,C
hina
Cam
phor
(�)-
Cam
phor
-10-
sulp
honi
cac
idC
10H
16O
4S
Cal
aire
(�)-
Cam
phor
-10-
sulp
hony
lch
lori
deC
10H
15C
lO3S
Cal
aire
(�)-
(Cam
phor
sulp
hony
l)ox
azir
idin
eC
10H
15N
O3S
New
port
-
SOURCING CHIRAL COMPOUNDS 17
(�)-
(Cam
phor
sulp
hony
l)ox
azir
idin
eC
10H
15N
O3S
New
port
N-α
-CB
Z-d
-3-(
1-N
apht
hyl)
alan
inol
C21
H21
NO
3Sy
nthe
tech
N-α
-CB
Z-d
-3-(
2-N
apht
hyl)
alan
inol
C21
H21
NO
3Sy
nthe
tech
(R)-
2-C
hlor
obut
yric
acid
C4H
7C
lO2
Kan
eka
(R)-
(�)-
4-C
hlor
o-3-
hydr
oxyb
utyr
onitr
ileC
4H
6C
lNO
Dai
so(S
)-(�
)-4-
Chl
oro-
3-hy
drox
ybut
yron
itrile
C4H
6C
lNO
Dai
so(R
)-3-
Chl
orol
actic
acid
C3H
5C
lO3
Kan
eka
1-[(
S)-3
-Chl
oro-
2-m
ethy
lpro
pion
yl]-
l-pr
olin
eC
9H
14C
lNO
3K
anek
ad-
3-(4
-Chl
orop
heny
l)al
anin
eC
9H
10C
lNO
2D
egus
sa,
Synt
hete
chl-
3-(4
-Chl
orop
heny
l)al
anin
eC
9H
10C
lNO
2Sy
nthe
tech
(R)-
(3-C
hlor
ophe
nyl)
-1,2
-eth
aned
iol
C8H
9C
lO2
Chi
rex
(S)-
(3-C
hlor
ophe
nyl)
-1,2
-eth
aned
iol
C8H
9C
lO2
Chi
rex
(R)-
2-(4
-Chl
orop
heny
l)-3
-phe
nylp
ropi
onic
acid
C15
H13
ClO
2Su
mito
mo
(S)-
2-(4
-Chl
orop
heny
l)-3
-phe
nylp
ropi
onic
acid
C15
H13
ClO
2Su
mito
mo
(R)-
(�)-
3-C
hlor
o-1,
2-pr
opan
edio
lC
3H
7C
lO2
Kan
eka
(R)-
(�)-
2-C
hlor
opro
pion
icac
idC
3H
5C
lO2
Lin
z,M
arks
(S)-
(�)-
2-C
hlor
opro
pion
icac
idC
3H
5C
lO2
BA
SF,
Lin
z,M
arks
,Z
enec
a(R
)-3-
Chl
oros
tyre
neox
ide
C8H
7C
lOK
anek
a,C
hire
x,Si
psy
(S)-
3-C
hlor
osty
rene
oxid
eC
8H
7C
lOK
anek
a,C
hire
x,Si
psy
(R)-
(�)-
Citr
amal
icac
idC
5H
8O
5L
onza
(S)-
(�)-
Citr
amal
icac
idC
5H
8O
5L
onza
d-C
itrul
line
C6H
13N
3O
3R
exim
/Deg
ussa
d-C
yclo
hexy
lala
nine
C9H
16N
O2
Rex
im/D
egus
sa,
NSC
Tec
hnol
ogie
sl-
Cyc
lohe
xyla
lani
neC
9H
16N
O2
Rex
im/D
egus
sa,
NSC
Tec
hnol
ogie
s(S
)-C
yclo
hexy
lala
nino
lC
9H
18N
ON
SCT
echn
olog
ies
d-C
yclo
hexy
lgly
cine
C8H
14N
O2
Rex
im/D
egus
sal-
Cyc
lohe
xylg
lyci
neC
8H
14N
O2
Rex
im/D
egus
sad-
Cys
tein
eC
3H
7N
O2S
Ajin
omot
o,N
ippo
nR
ikag
akuy
akuh
in,
Tan
abe
d-C
ystin
eC
6H
12N
2O
4S
2N
ippo
nR
ikag
akuy
akuh
in (T
able
cont
inue
s)
-
18 TUCKER
TA
BLE
1C
ontin
ued
Com
poun
dFo
rmul
aSu
pplie
r
(1R
,2R
)-(�
)-1,
2-D
iam
inoc
yclo
hexa
neC
6H
14N
2C
hire
x,T
oray
(1S,
2S)-
(�)-
1,2-
Dia
min
ocyc
lohe
xane
C6H
14N
2C
hire
x,T
oray
(S)-
(�)-
2,6-
Dia
min
o-1-
hexa
nol
(l-(
�)-
Lys
inol
)C
8H
16N
2O
Boe
hrin
ger
(R)-
1,2-
Dia
min
opro
pane
(as
salt)
C3H
10N
2T
oray
(S)-
1,2-
Dia
min
opro
pane
(as
salt)
C3H
10N
2T
oray
Dib
enzo
yl-d
-(�
)-ta
rtar
icac
idC
18H
14O
8E
lso
Veg
yi,
Tor
ay,
Uet
ikon
Dib
enzo
yl-l
-(�
)-ta
rtar
icac
idC
18H
14O
8E
lso
Veg
yi,
Kno
ll,T
oray
,U
etik
on(R
)-2,
2-D
iben
zyl-
2-hy
drox
y-1-
met
hyle
thyl
amin
eC
17H
21N
OSu
mito
mo
(S)-
2,2-
Dib
enzy
l-2-
hydr
oxy-
1-m
ethy
leth
ylam
ine
C17
H21
NO
Sum
itom
o(R
)-N
,N-D
iben
zylp
heny
lala
nino
lC
23H
25N
ON
SCT
echn
olog
ies
(S)-
N,N
-Dib
enzy
lphe
nyla
lani
nol
C23
H25
NO
NSC
Tec
hnol
ogie
s(�
)-[(
8,8-
Dic
hlor
ocam
phor
yl)s
ulph
onyl
]oxa
ziri
dine
C10
H13
Cl 2
NO
3S
New
port
(�)-
[(8,
8-D
ichl
oroc
amph
oryl
)sul
phon
yl]o
xazi
ridi
neC
10H
13C
l 2N
O3S
New
port
l-3-
(3,4
-Dic
hlor
ophe
nyl)
alan
ine
C9H
9C
l 2N
O2
Synt
hete
chci
s-(1
S,2R
)-1,
2-D
ihyd
ro-3
-bro
moc
atec
hol
C6H
7B
rO2
Zen
eca
cis-
1,2-
Dih
ydro
cate
chol
C6H
8O
2Z
enec
aci
s-(1
S,2R
)-1,
2-D
ihyd
ro-3
-chl
oroc
atec
hol
C6H
7C
lO2
Zen
eca
cis-
(1S,
2R)-
1,2-
Dih
ydro
-3-fl
uoro
cate
chol
C6H
7FO
2Z
enec
a(2
S,3S
)-(�
)-2,
3-D
ihyd
ro-3
-hyd
roxy
-2-(
4-m
etho
xyph
enyl
)-1,
5-C
16H
15N
O3S
Del
mar
,Z
ambo
nbe
nzot
hiaz
epin
-4(5
H)-
one
cis-
(1S,
2R)-
1,2-
Dih
ydro
-3-m
ethy
lcat
echo
lC
7H
7F
3O
2Z
enec
aci
s-(1
S,2R
)-1,
2-D
ihyd
ro-3
-met
hylc
atec
hol
C7H
10O
2Z
enec
ad-
(�)-
α-D
ihyd
roph
enyl
glyc
ine
C8H
11N
O2
Der
etil,
DSM
And
eno
d-(�
)-α-
Dih
ydro
phen
ylgl
ycin
ech
lori
dehy
droc
hlor
ide
C8H
11C
l 2N
OD
SMA
nden
od-
(�)-
α-D
ihyd
roph
enyl
glyc
ine
Dan
esa
ltm
ethy
lso
dium
C13
H16
NO
4D
eret
il,D
SMA
nden
od-
(3,4
-Dih
ydro
xy)-
α-ph
enyl
glyc
ine
C8H
9N
O4
Kan
eka
-
SOURCING CHIRAL COMPOUNDS 19
(�)-
Diis
opin
ocam
phey
lchl
orob
oran
eC
20H
34B
Cl
Cal
lery
(�)-
Diis
opin
ocam
phey
lchl
orob
oran
eC
20H
34B
Cl
Cal
lery
Diis
opro
pyl-
d-(�
)-ta
rtra
teC
10H
18O
6T
oray
,U
etik
onD
iisop
ropy
l-l-
(�)-
tart
rate
C10
H18
O6
Uet
ikon
(R)-
3,3-
Dim
ethy
l-2-
amin
obut
ane
C6H
15N
Cel
gene
(S)-
3,3-
Dim
ethy
l-2-
amin
obut
ane
C6H
15N
Cel
gene
(3R
-cis
)-3,
6-D
imet
hyl-
1,4-
diox
ane-
2,5-
dion
e(R
-Lac
tide)
C6H
8O
4B
oehr
inge
r(3
S-ci
s)-3
,6-D
imet
hyl-
1,4-
diox
ane-
2,5-
dion
e(S
-Lac
tide)
C6H
8O
4B
oehr
inge
r(R
)-(�
)-2,
2-D
imet
hyl-
1,3-
diox
olan
e-4-
met
hano
lC
6H
12O
3C
hem
iS.
p.A
.(S
)-(�
)-2,
2-D
imet
hyl-
1,3-
diox
olan
e-4-
met
hano
lC
6H
12O
3C
hem
iS.
p.A
.,In
alco
(R)-
(�)-
2,2-
Dim
ethy
l-1,
3-di
oxol
an-4
-ylm
ethy
lto
syla
teC
13H
18O
5S
Che
mi
S.p.
A.
(S)-
(�)-
2,2-
Dim
ethy
l-1,
3-di
oxol
an-4
-ylm
ethy
lto
syla
teC
13H
18O
5S
Che
mi
S.p.
A.
Dim
ethy
l-d-
(�)-
tart
rate
C6H
10O
6U
etik
onD
imet
hyl-
l-(�
)-ta
rtra
teC
6H
10O
6U
etik
on(�
)-2,
2-D
imet
hyl-
α,α,
α′,α
′-tet
raph
enyl
-1,3
-dio
xola
ne-3
,4-d
imet
hano
lC
31H
30O
4U
rqui
ma
(R)-
2,2-
Dip
heny
l-2-
hydr
oxy-
1-m
ethy
leth
ylam
ine
C15
H17
NO
Sum
itom
o(S
)-2,
2-D
iphe
nyl-
2-hy
drox
y-1-
met
hyle
thyl
amin
eC
15H
17N
OSu
mito
mo
(R)-
(�)-
Dip
heny
lpro
linol
C17
H19
NO
Boe
hrin
ger,
Sips
y(S
)-(�
)-D
iphe
nylp
rolin
olC
17H
19N
OB
oehr
inge
r,R
exim
/Deg
ussa
,Si
psy,
Urq
uim
a(R
)-2,
3-D
iphe
nylp
ropi
onic
acid
C15
H14
O2
Sum
itom
o(S
)-2,
3-D
iphe
nylp
ropi
onic
acid
C15
H14
O2
Sum
itom
o(R
)-D
iphe
nylv
alin
olC
17H
21N
ON
ewpo
rt(S
)-D
iphe
nylv
alin
olC
17H
21N
ON
ewpo
rtD
i-p-
tolu
oyl-
d-ta
rtar
icac
idC
20H
18O
8E
lso
Veg
yi,
Tor
ay,
Uet
ikon
Di-
p-to
luoy
l-l-
tart
aric
acid
C20
H18
O8
Els
oV
egyi
,L
inz,
Tor
ay,
Uet
ikon
(R)-
(�)-
Epi
chlo
rhyd
rin
C3H
5C
lOD
aiso
,K
anek
a,N
agas
e(S
)-(�
)-E
pich
lorh
ydri
nC
3H
5C
lOD
aiso
,N
agas
eN
-(1-
(S)-
Eth
oxyc
arbo
nyl-
3-ph
enyl
prop
yl)-
l-al
anin
eC
15H
21N
O4
Dai
cel,
DSM
And
eno,
Kan
eka,
Tan
abe
N-(
1-(S
)-E
thox
ycar
bony
l-3-
phen
ylpr
opyl
)-l-
alan
yl-N
-car
boxy
anhy
drid
eC
16H
19N
O5
DM
SA
nden
o,K
anek
aE
thyl
(S)-
(�)-
2-ch
loro
prop
iona
teC
5H
9C
lO2
Dai
cel,
Tan
abe
(Tab
leco
ntin
ues)
-
20 TUCKER
TA
BLE
1C
ontin
ued
Com
poun
dFo
rmul
aSu
pplie
r
Eth
yl(R
)-2-
hydr
oxy-
4-ph
enyl
buty
rate
C12
H16
O3
Dai
cel,
DSM
And
eno,
Kan
eka,
Rec
orda
ti,T
anab
eE
thyl
(R)-
(�)-
man
dela
teC
10H
12O
3Y
amak
awa
Eth
yl(S
)-(�
)-m
ande
late
C10
H12
O3
Yam
akaw
aE
thyl
(R)-
(�)-
2-to
sylo
xypr
opio
nate
C12
H16
O5S
Boe
hrin
ger
Eth
yl(S
)-(�
)-2-
tosy
loxy
prop
iona
teC
12H
16O
5S
Boe
hrin
ger
d-3-
(4-F
luor
ophe
nyl)
alan
ine
C9H
10FN
O2
Synt
hete
chl-
3-(4
-Flu
orop
heny
l)al
anin
eC
9H
10FN
O2
Synt
hete
chN
-α-F
MO
C-d
-3-(
4-B
iphe
nyl)
alan
ine
C30
H25
NO
4Sy
nthe
tech
N-α
-FM
OC
-l-3
-(4-
Bip
heny
l)al
anin
eC
30H
25N
O4
Synt
hete
chN
-α-F
MO
C-l
-Oct
ahyd
roin
dole
-2-c
arbo
xylic
acid
C24
H25
NO
4Sy
nthe
tech
(R)-
(�)-
Form
ylm
ande
loyl
chlo
ride
C9H
7C
lO3
DSM
And
eno,
Tor
ay(S
)-(�
)-Fo
rmyl
man
delo
ylch
lori
deC
9H
7C
lO3
Tor
ayd-
Glu
tam
icac
idC
5H
9N
O4
Ajin
omot
o,K
anek
a,R
exim
/Deg
ussa
,T
anab
ed-
Glu
tam
ine
C5H
10N
2O
3A
jinom
oto
(R)-
(�)-
Gly
cero
l-1-
tosy
late
C10
H14
O5
Che
mi
S.p.
A.
(S)-
(�)-
Gly
cero
l-1-
tosy
late
C10
H14
O5S
Che
mi
S.p.
A.
(R)-
(�)-
Gly
cido
lC
3H
6O
2Si
psy
(S)-
(�)-
Gly
cido
lC
3H
6O
2Si
psy
(R)-
(�)-
Gly
cidy
l-3-
nosy
late
C9H
9N
O6S
Dai
so,
Sips
y(S
)-(�
)-G
lyci
dyl-
3-no
syla
teC
9H
9N
O6S
Dai
so,
Sips
y(R
)-(�
)-G
lyci
dyl
tosy
late
C10
H12
O4S
Dai
so,
Lon
za,
Sips
y(S
)-(�
)-G
lyci
dyl
tosy
late
C10
H12
O4S
Dai
so,
Sips
yd-
His
tidin
eC
6H
9N
3O
2A
jinom
oto,
Rex
im/D
egus
sa,
Tan
abe
l-H
omoc
yste
ine
C4H
9N
O2S
Tan
abe
d-H
omoc
yste
inet
hiol
acto
neH
Cl
C4H
8C
lNO
SR
exim
/Deg
ussa
-
SOURCING CHIRAL COMPOUNDS 21
l-H
omoc
yste
inet
hiol
acto
neH
Cl
C4H
8C
lNO
SR
exim
/Deg
ussa
d-H
omop
heny
lala
nine
C10
H13
NO
2R
ecor
dati,
Synt
hete
chl-
Hom
ophe
nyla
lani
neC
10H
13N
O2
Dai
cel,
Rex
im/D
egus
sa,
Synt
hete
ch,
Tan
abe
l-H
omos
erin
eC
4H
9N
O3
Tan
abe
(S)-
(�)-
3-H
ydro
xybu
tyro
lact
one
C4H
6O
3K
anek
al-
5-H
ydro
xyly
sine
C6H
14N
2O
3R
exim
/Deg
ussa
(R)-
2-H
ydro
xy-4
-phe
nylb
utyr
icac
idC
10H
12O
3K
anek
ad-
(�)-
α-p-
Hyd
roxy
phen
ylgl
ycin
eC
8H
9N
O3
Alf
aC
hem
ical
sIt
alia
na,
Der
etil,
DSM
And
eno,
Kan
eka,
Nip
pon
Kay
aku,
Rec
-or
dati
d-(�
)-α-
p-H
ydro
xyph
enyl
glyc
ine
chlo
ride
HC
lC
8H
9C
l 2N
O2
Nip
pon
Kay
aku
d-(�
)-α-
p-H
ydro
xyph
enyl
glyc
ine
Dan
esa
ltet
hyl
pota
ssiu
mC
14H
16N
O5K
Nip
pon
Kay
aku
d-(�
)-α-
p-H
ydro
xyph
enyl
glyc
ine
Dan
esa
ltm
ethy
lso
dium
C13
H14
NO
5N
aN
ippo
nK
ayak
ud-
(�)-
α-p-
Hyd
roxy
phen
ylgl
ycin
eD
ane
salt
(pot
assi
umm
ethy
l)C
13H
14K
NO
5A
lfa
Che
mic
als
Ital
iana
,D
eret
il,D
SMA
nden
o,K
anek
a,R
ecor
dati
d-c
is-4
-Hyd
roxy
prol
ine
C5H
9N
O3
Rex
im/D
egus
sal-
(�)-
Hyd
roxy
prol
inol
C5H
11N
O2
Boe
hrin
ger,
Rex
im/D
egus
sa(R
)-3-
Hyd
roxy
pyrr
olid
ine
C4H
9N
OR
exim
/Deg
ussa
,T
oray
(S)-
3-H
ydro
xypy
rrol
idin
eC
4H
9N
OR
exim
/Deg
ussa
,T
oray
(R)-
3-H
ydro
xypy
rrol
idin
ehy
droc
hlor
ide
C4H
10C
lNO
Kan
eka,
Rex
im/D
egus
sa(S
)-3-
Hyd
roxy
pyrr
olid
ine
hydr
ochl
orid
eC
4H
10C
lNO
Kan
eka,
Rex
im/D
egus
sa(S
)-(�
)-In
dolin
e-2-
carb
oxyl
icac
idC
9H
9N
O2
DSM
And
eno
d-3-
(4-I
odop
heny
l)al
anin
eC
9H
10IN
O2
Synt
hete
chl-
3-(4
-Iod
ophe
nyl)
alan
ine
C9H
10IN
O2
Synt
hete
chIs
obut
yl(S
)-(�
)-2-
chlo
ropr
opio
nate
C7H
13C
lO2
BA
SF,
Dai
cel,
Tan
abe
d-al
lo-I
sole
ucin
eC
6H
13N
O2
Rex
im/D
egus
saIs
oleu
cino
lse
e2-
Am
ino-
3-m
ethy
l-1-
pent
anol
2,3-
O-I
sopr
opyl
iden
e-(R
)-gl
ycer
alde
hyde
C6H
10O
3C
hem
iS.
p.A
.(R
)-(�
)-N
-Iso
prop
yl-α
-met
hylb
enzy
lam
ine
C11
H17
NY
amak
awa
(Tab
leco
ntin
ues)
-
22 TUCKER
TA
BLE
1C
ontin
ued
Com
poun
dFo
rmul
aSu
pplie
r
(S)-
(�)-
N-I
sopr
opyl
-α-m
ethy
lben
zyla
min
eC
11H
17N
Yam
akaw
a(R
)-(�
)-4-
Isop
ropy
l-2-
oxaz
olid
inon
eC
6H
11N
O2
Boe
hrin
ger,
New
port
,R
exim
,D
egus
sa(S
)-(�
)-4-
Isop
ropy
l-2-
oxaz
olid
inon
eC
6H
11N
O2
Boe
hrin
ger,
New
port
,R
exim
/Deg
ussa
,U
rqui
ma
(R)-
(�)-
3-Is
opro
pyl-
2,5-
pipe
razi
ndio
neC
7H
12N
2O
2R
exim
/Deg
ussa
(S)-
(�)-
3-Is
opro
pyl-
2,5-
pipe
razi
ndio
neC
7H
12N
2O
2R
exim
/Deg
ussa
(S)-
(�)-
Isos
erin
eC
3H
7N
O3
Rex
im/D
egus
sa(R
)-(�
)-L
acta
mid
eC
3H
7N
O2
Boe
hrin
ger
(S)-
(�)-
Lac
tam
ide
C3H
7N
O2
Boe
hrin
ger
Lac
tide
see
cis-
Dim
ethy
l-1,
4-di
oxan
e-2,
5-di
one
d-L
euci
neC
6H
13N
O2
Ajin
omot
o,N
ippo
nR
ikag
akuy
akuh
in,
Rex
im/D
egus
sa,
Tan
abe
l-te
rt-L
euci
ne[L
-ter
t-B
utyl
glyc
ine;
2-A
min
o-3,
3-di
met
hylb
utyr
icac
id]
C6H
13N
O2
Chi
rosc
ienc
e,N
SCT
echn
olog
ies,
Rex
im/D
egus
saL
euci
nol
see
2-A
min
o-4-
met
hyl-
1-pe
ntan
olL
-ter
t-L
euci
nol
C6H
15N
OR
exim
/Deg
ussa
d-L
ysin
eH
Cl
C6H
15C
lN2O
2A
jinom
oto,
Kan
eka,
Rex
im/D
egus
sa,
Tan
abe
l-(�
)-L
ysin
ol,
see
2,6-
Dia
min
o-1-
hexa
nol
(R)-
(�)-
Man
delic
acid
C8H
8O
3N
ippo
nC
hem
ical
,N
ippo
nK
ayak
u,N
itto,
Uet
ikon
,Yam
akaw
a,Z
eela
nd(S
)-(�
)-M
ande
licac
idC
8H
8O
3N
ippo
nK
ayak
u,N
orse
,U
etik
on,
Yam
a-ka
wa,
Zee
land
(S)-
1-M
erca
ptog
lyce
rol
C3H
8O
2S
Kan
eka
d-M
ethi
onin
eC
5H
11N
O2S
Ajin
omot
o,K
anek
a,R
exim
/Deg
ussa
,T
a-na
bel-
Met
hion
inol
C5H
13N
OS
Rex
im/D
egus
sa2-
Am
inot
etra
linde
riva
tives
.C
10H
15N
OC
elge
ne
-
SOURCING CHIRAL COMPOUNDS 23
(R)-
α-M
ethy
lben
zyla
min
eC
8H
11N
Cel
gene
,D
ynam
itN
obel
,Y
amak
awa,
Zee
land
(S)-
α-M
ethy
lben
zyla
min
eC
8H
11N
Cel
gene
,D
ynam
itN
obel
,Y
amak
awa
(4S)
-2-M
ethy
l-4-
benz
ylox
azol
eC
11H
13N
ON
SCT
echn
olog
ies
(R)-
α-M
ethy
l-4-
chlo
robe
nzyl
amin
eC
8H
10C
lNC
elge
ne,
Yam
akaw
a(S
)-α-
Met
hyl-
4-ch
loro
benz
ylam
ine
C8H
10C
lNC
elge
ne,
Yam
akaw
aM
ethy
l(S
)-(�
)-2-
chlo
ropr
opio
nate
C4H
7C
lO2
Dai
cel,
Tan
abe
(R)-
(�)-
Met
hyl
glyc
idyl
ethe
rC
4H
8O
2D
aiso
,Si
psy
(S)-
(�)-
Met
hyl
glyc
idyl
ethe
rC
4H
8O
2D
aiso
,Si
psy
(R)-
(�)-
Met
hyl
3-hy
drox
ybut
yrat
eC
5H
10O
3K
anek
a,N
SCT
echn
olog
ies
(S)-
(�)
Met
hyl
3-hy
drox
ybut
yrat
eC
5H
10O
3K
anek
a(R
)-(�
)-M
ethy
l-β-
hydr
oxyi
sobu
tyra
teC
5H
10O
3K
anek
a(S
)-(�
)M
ethy
l-β-
hydr
oxyi
sobu
tyra
teC
5H
10O
3K
anek
aM
ethy
l(R
)-(�
)-3-
hydr
oxyp
enta
noat
eC
6H
12O
3K
anek
aM
ethy
l(S
)-(�
)-3-
hydr
oxyp
enta
noat
eC
6H
12O
3K
anek
a(R
)-(�
)-M
ethy
lα,
β-is
opro
pylid
eneg
lyce
rate
C7H
12O
4C
hem
iS.
p.A
.(R
)-(�
)-M
ethy
lla
ctat
eC
4H
8O
3B
oehr
inge
r,D
aice
l,T
anab
e(S
)-(�
)-M
ethy
lla
ctat
eC
4H
8O
3B
oehr
inge
rM
ethy
l(R
)-(�
)-m
ande
late
C9H
10O
3Y
amak
awa
Met
hyl
(S)-
(�)-
man
dela
teC
9H
10O
3Y
amak
awa
(R)-
α-M
ethy
l-2-
met
hoxy
benz
ylam
ine
C9H
13N
OC
elge
ne,
Sum
itom
o(S
)-α-
Met
hyl-
2-m
etho
xybe
nzyl
amin
eC
9H
13N
OC
elge
ne,
Sum
itom
o(R
)-α-
Met
hyl-
3-m
etho
xybe
nzyl
amin
eC
9H
13N
OC
elge
ne,
Sum
itom
o,Y
amak
awa
(S)-
α-M
ethy
l-3-
met
hoxy
benz
ylam
ine
C9H
13N
OC
elge
ne,
Sum
itom
o,Y
amak
awa
(R)-
α-M
ethy
l-4-
met
hoxy
benz
ylam
ine
C9H
13N
OC
elge
ne,
Sum
itom
o(S
)-α-
Met
hyl-
4-m
etho
xybe
nzyl
amin
eC
9H
13N
OC
elge
ne,
Sum
itom
o(R
)-α-
Met
hyl-
4-m
ethy
lben
zyla
min
eC
9H
13N
Cel
gene
,Y
amak
awa
(S)-
α-M
ethy
l-4-
met
hylb
enzy
lam
ine
C9H
13N
Cel
gene
,Y
amak
awa
(R)-
α-M
ethy
l-4-
nitr
oben
zyla
min
eH
Cl
C8H
11C
lN2O
2E
MS-
Dot
tikon
,Y
amak
awa
(S)-
α-M
ethy
l-4-
nitr
oben
zyla
min
eH
Cl
C8H
11C
lN2O
2E
MS-
Dot
tikon
,Y
amak
awa
(Tab
leco
ntin
ues)
-
24 TUCKER
TA
BLE
1C
ontin
ued
Com
poun
dFo
rmul
aSu
pplie
r
(R)-
Met
hylo
xaza
boro
lidin
eC
18H
20B
NO
Cal
lery
(S)-
Met
hylo
xaza
boro
lidin
eC
18H
20B
NO
Cal
lery
(4R
,5S)
-4-M
ethy
l-5-
phen
yl-2
-oxa
zolid
inon
eC
10H
11N
O2
Urq
uim
a(R
)-(�
)-1-
Met
hyl-
3-ph
enyl
prop
ylam
ine
C10
H15
NT
oray
(S)-
(�)-
1-M
ethy
l-3-
phen
ylpr
opyl
amin
eC
10H
15N
Tor
ay(R
)-(�
)-2-
Met
hylp
iper
azin
eC
5H
12N
2T
oray
,Y
amak
awa
(S)-
(�)-
2-M
ethy
lpip
eraz
ine
C5H
12N
2T
oray
,Y
amak
awa
Met
hyl
(R)-
2-to
sylo
xypr
opio
nate
C11
H11
O5S
Dai
cel
(R)-
(�)-
4-M
ethy
l-4-
(tri
chlo
rom
ethy
l)-2
-oxe
tano
neC
5H
5C
l 3O
2L
onza
(S)-
(�)-
4-M
ethy
l-4-
(tri
chlo
rom
ethy
l)-2
-oxe
tano
neC
5H
5C
l 3O
2L
onza
d-3-
(1-N
apht
hyl)
alan
ine
C13
H13
NO
2R
exim
/Deg
ussa
,Sy
nthe
tech
l-3-
(1-N
apht
hyl)
alan
ine
C13
H13
NO
2Sy
nthe
tech
d-3-
(2-N
apht
hyl)
alan
ine
C13
H13
NO
2R
exim
/Deg
ussa
,Sy
nthe
tech
l-3-
(2-N
apht
hyl)
alan
ine
C13
H13
NO
2Sy
nthe
tech
(R)-
(�)-
1-(1
-Nap
hthy
l)et
hyla
min
eC
12H
13N
Yam
akaw
a(S
)-(�
)-1-
(1-N
apht
hyl)
ethy
lam
ine
C12
H13
NY
amak
awa
l-N
eope
ntyl
glyc
ine
C7H
15N
O2
Rex
im/D
egus
sad-
3-(4
-Nitr
ophe
nyl)
alan
ine
C9H
10N
2O
4Sy
nthe
tech
l-3-
(4-N
itrop
heny
l)al
anin
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