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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

ISBN: 0-8247-1058-4

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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

i

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

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

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

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

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

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

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

ix

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

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).

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

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

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

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

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.

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.

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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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