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Matthew Todd

Separation of Enantiomers

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Edited by Matthew Todd

Separation of Enantiomers

Synthetic Methods

The Editor

Dr. Matthew ToddThe University of SydneyFaculty of ScienceSchool of ChemistrySydney, NSW 2006Australia

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V

Contents

List of Contributors IX

1 Introduction: A Survey of How and Why to Separate Enantiomers 1Matthew Todd

1.1 Classical Methods 21.2 Kinetic Resolution (‘KR’) 31.3 Dynamic Kinetic Resolution (‘DKR’) 51.4 Divergent Reactions of a Racemic Mixture (‘DRRM’) 71.5 Other Methods 8

Acknowledgments 9References 9

2 Stoichiometric Kinetic Resolution Reactions 13Mahagundappa R. Maddani, Jean-Claude Fiaud, and Henri B. Kagan

2.1 Introduction 132.2 Kinetic Treatment 142.2.1 Reactions First-Order in Substrate 142.2.1.1 Scope and Validity of Equation 2.6 182.2.1.2 Equivalent Formulations of the Basic Equation 2.6 192.2.2 Reactions Zero- or Second-Order in Substrate 192.2.3 Improvement of Kinetic Resolution Processes 202.2.4 Use of Enantio-Impure Auxiliaries 212.3 Chiral Reagents and Racemic Substrates 222.3.1 Esterification 222.3.2 Amide and Peptide Formation 302.3.3 Cycloaddition Reactions 352.3.4 Conjugate Additions 392.3.5 Borane-Involving Reactions 412.3.6 Kinetic Resolution of Allenes 432.3.7 Olefination Reactions 452.3.8 Deprotonation Reactions 482.3.9 Miscellaneous 492.4 Enantiodivergent Formation of Chiral Product 51

VI Contents

2.4.1 Introduction 512.4.2 Creation of a Stereogenic Unit 522.4.3 Formation of Regioisomers 542.5 Enantioconvergent Reactions 552.6 Diastereomer Kinetic Resolution 562.7 Some Applications of Kinetic Resolution 582.7.1 Organometallics and Analogues 582.7.2 Racemic Catalysts 612.7.3 Enantiomeric excess’s and Stereoselectivity Factor Measurements by

Mass Spectrometry 632.7.4 Mechanistic Studies. The Hoffmann Test 662.7.5 Miscellaneous 692.8 Conclusion 702.A Table of s Factors Higher than 10 for Some Reactions 70

References 71

3 Catalytic Kinetic Resolution 75Helene Pellissier

3.1 Introduction 753.2 Kinetic Resolution of Alcohols 763.2.1 KR of Alcohols Using Chiral Acylation Catalysts 763.2.2 Oxidative KR of Alcohols 813.2.3 Miscellaneous Kinetic Resolutions 873.3 Kinetic Resolution of Epoxides 883.3.1 Hydrolytic Kinetic Resolution 883.3.2 Ring Opening of Epoxides by Nucleophiles Other than Water 923.4 Kinetic Resolution of Amines 933.5 Kinetic Resolution of Alkenes 973.6 Kinetic Resolution of Carbonyl Derivatives 1013.7 Kinetic Resolution of Sulfur Compounds 1023.8 Kinetic Resolution of Ferrocenes 1033.9 Conclusions 105

Abbreviations 105References 107

4 Application of Enzymes in Kinetic Resolutions, Dynamic KineticResolutions and Deracemization Reactions 123Cara E. Humphrey, Marwa Ahmed, Ashraf Ghanem, andNicholas J. Turner

4.1 Introduction 1234.2 Kinetic Resolutions Using Hydrolytic Enzymes 1234.2.1 Lipases in Organic Synthesis 1234.2.2 Structural Features of Lipases 1244.2.3 Typical Substrates for Lipases and Esterases 1254.2.4 Monitoring the Progress of Lipase-Catalysed Resolutions 126

Contents VII

4.2.5 Kazlauskas’ Rule 1274.2.6 Activated Acyl Donors 1284.2.7 Examples of Lipase-, Lipolase- and Hydrolase-Catalysed Reactions in

Synthesis 1294.2.7.1 Resolution of Secondary Alcohols 1294.2.7.2 Resolution of Amines 1314.2.7.3 Hydrolysis of Lactams and Nitriles 1324.2.7.4 Epoxide Hydrolases 1334.2.8 Strategies for Controlling and Enhancing the Enantioselectivity of

Enzyme-Catalysed Reactions 1344.2.8.1 Substrate Engineering 1344.2.8.2 Solvent Engineering 1354.2.8.3 Immobilization and Chemical Modification 1364.2.8.4 Directed Evolution and Enzyme Libraries 1374.3 Dynamic Kinetic Resolution 1384.3.1 Non-Enzyme-Catalysed Racemization 1394.3.1.1 In Situ Racemization via Protonation/Deprotonation 1394.3.1.2 In Situ Racemization via Addition/Elimination 1404.3.1.3 In Situ Racemization via Oxidation/Reduction 1404.3.1.4 In Situ Racemization via Nucleophilic Substitution 1414.3.1.5 In Situ Racemization via Free Radical Mechanism 1414.3.2 Metal-Catalysed Racemization 1414.3.2.1 Ruthenium-Based Catalysts 1424.3.2.2 Non-Ruthenium Catalysts 1454.3.3 Enzyme-Catalysed Racemization 1474.4 Deracemization 1484.4.1 Deracemization of Secondary Alcohols 1484.4.2 Deracemization of Carboxylic Acids 1504.4.3 Deracemization of Amino Acids and Amines 1514.4.4 Deracemization of Enol Actates 1524.5 Enantioconvergent Reactions 1534.6 Conclusions 153

References 154

5 Dynamic Kinetic Resolution (DKR) 161Keiji Nakano and Masato Kitamura

5.1 Introduction 1615.2 Definition and Classification 1625.3 Dynamic Kinetic Resolution (DKR) 1645.3.1 Tautomerization 1645.3.2 Pyramidal Inversion, Deformation and Rotation 1815.3.3 Elimination–Addition and Addition–Elimination 1845.3.4 Nucleophilic Substitution 1935.3.5 Others 1985.4 Mathematical Expression 201

VIII Contents

5.5 DKR-Related Methods 2045.5.1 DYKAT through a Single Enantiomeric Intermediate 2055.5.2 DTR of Two Diastereomeric Intermediates 2065.5.3 Stereoinversion 2065.5.4 Cyclic Deracemization 2075.5.5 Enantio-Convergent Transformation 2075.6 Concluding Remarks 208

References 209

6 Enantiodivergent Reactions: Divergent Reactions on a Racemic Mixtureand Parallel Kinetic Resolution 217Trisha A. Russell and Edwin Vedejs

6.1 Introduction: The Conceptual Basis for Kinetic Resolution andEnantiodivergent Reactions 217

6.2 Divergent RRM Using a Single Chiral Reagent: KetoneReduction 222

6.2.1 Racemic Ketones and Chiral Non-Enzymatic Hydride Donors 2276.3 Divergent RRM under Oxidative Conditions 2296.4 Organometallic Reagents and Regiodivergent RRM 2376.5 Regiodivergent RRM in Selective Reactions of Difunctional

Substrates 2486.6 Divergent RRM Using Two Chiral Reagents: Parallel Kinetic

Resolution (PKR) 2526.7 Conclusion 262

Acknowledgement 262References 262

7 Rare, Neglected and Potential Synthetic Methods for the Separation ofEnantiomers 267Matthew Todd

7.1 Resolution through the Selfish Growth of Polymers: StereoselectivePolymerization 267

7.2 Resolution through Photochemical Methods 2717.3 Combinations of Crystallization and Racemization 2747.3.1 Crystallization-Induced Dynamic Resolution (CIDR) 2757.3.2 Ripening 2777.4 Destruction Then Recreation of Stereocentres: Enantioselective

Protonations 2787.5 Dynamic Combinatorial Chemistry 2807.6 Asymmetric Autocatalysis 2827.7 Miscellaneous 2837.8 Concluding Remarks 283

Acknowledgements 284References 284

Index 291

IX

List of Contributors

Marwa AhmedUniversity of CanberraFaculty of Education, Science,Technology & Mathematics(ESTeM)Biomedical Science DisciplineKirinari Street, BruceCanberra, ACT 2601Australia

Jean-Claude FiaudUniversite Paris-SudLaboratoire de CatalyseMoleculaire (UMR 8182)Institut de Chimie Moleculaire etdes Materiaux d’Orsay15 rue Georges Clemenceau91405 OrsayFrance

Ashraf GhanemUniversity of CanberraFaculty of Education, Science,Technology & Mathematics(ESTeM)Biomedical Science DisciplineKirinari Street, BruceCanberra, ACT 2601Australia

Cara E. HumphreyInvestigator IIINIBR/GDC/PSB Prep LabsWKL-122.U1.28Klybeckstrasse 1414057 BaselSwitzerland

Henri B. KaganUniversite Paris-SudLaboratoire de CatalyseMoleculaire (UMR 8182)Institut de Chimie Moleculaire etdes Materiaux d’Orsay15 rue Georges Clemenceau91405 OrsayFrance

Masato KitamuraNagoya UniversityDepartment of BasicMedicinal ScienceGraduate School ofPharmaceutical ScienceFuro-cho, Chikusa-kuNagoya 464-8601Japan

X List of Contributors

Mahagundappa R. MaddaniMangalore UniversityDepartment of ChemistryMangalagangotri-574199KarnatakaIndia

Keiji NakanoKochi UniversityDepartment of Applied Science2-5-1 Akebono-choKochi 780-8520Japan

Helene PellissierAix Marseille UniversiteCentrale MarseilleCNRSiSm2 UMR 7313Marseille 13397France

Trisha A. RussellWhitworth UniversityDepartment of Chemistry300 W. Hawthorne Rd.Spokane, WA 99218USA

Matthew ToddThe University of SydneyFaculty of ScienceSchool of ChemistrySydney, NSW 2006Australia

Nicholas J. TurnerThe University of ManchesterManchester Institute ofBiotechnology-3.019School of Chemistry131 Princess StreetManchester M13 9PLUK

Edwin VedejsUniversity of MichiganDepartment of Chemistry930 N. University Ave.Ann Arbor, MI 48109USA

1

1Introduction: A Survey of How and Why to Separate EnantiomersMatthew Todd

This book is about the separation of enantiomers by synthetic methods, which isto say methods involving some chemical transformation as part of the separationprocess. We do not in this book cover chromatographic methods for the separationof enantiomers [1]. Nor do we focus on methods based on crystallizations asthese have been amply reviewed elsewhere (see below). We are concerned mainlytherefore with resolutions that involve a synthetic component, so mostly with thevarious flavours of kinetic resolutions through to more modern methods such asdivergent reactions of a racemic mixture (DRRM). This introduction briefly clarifiesthe scope of the book.

The reasons such methods are of continued importance are threefold:

1) Society: the need for enantiopure compounds. New molecules as single enan-tiomers are important to our continued well-being because they are thefeedstocks of new medicines, agrochemicals, fragrances and other features ofmodern society in a chiral world. Of the 205 new molecular entities approvedas drugs between 2001 and 2010, 63% were single enantiomers [2]. Natureprovides an abundance of enantiopure compounds, but we seek, and need, toexceed this by obtaining useful unnatural molecules as single enantiomers,and we may reasonably want to access both enantiomers of some compounds.

2) Academia: the basic science involved in the behaviour of chiral compounds. Ifwe seek the state of the art in our discipline, we cannot help but think thatrapid and selective chemical distinction between enantiomers, which results intheir facile separation, is something beautiful in itself. There have been manysuccessful methods developed for the synthetic separation of enantiomers, aswe shall see, and these are both de facto interesting and instructive to considerfor the design of future examples of such processes. The relationship betweenkinetic resolution and asymmetric catalysis is strong, and one can inform thedesign of the other. It is hoped that the diverse examples described in this bookstimulate thoughts in the reader of what is possible next.

3) Industry: the need for new methods. There remain many classes of compoundsthat still cannot be resolved, or where efficiencies are too low for widespread

Separation of Enantiomers: Synthetic Methods, First Edition. Edited by Matthew Todd.c© 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.

2 1 Introduction: A Survey of How and Why to Separate Enantiomers

adoption. It is still the case that classical resolution techniques are overwhelm-ingly used over other more complex methods. Of the 128 drug candidatemolecules assessed in a recent industry survey, half were being developed assingle enantiomers, and the sources of the stereocentres were mainly the chiralpool (55%) with resolution (28%) and asymmetric synthesis (10%) responsiblefor fewer examples [3]. This is, predictably, a feature of economics as muchas science and one must not be too quick to judge new fields like asymmetriccatalysis versus older ones like classical resolution. Pasteur added somethingenantiopure to a racemate in 1853 [4], whereas the catalytic prowess of a metalcentre surrounded by chiral ligands was first demonstrated only in 1968 [5].In addition, many chiral acids and bases have proven to be useful in classicalresolutions, while Nature does not seem to be so generous in its supply ofmolecules that can effect catalytic, asymmetric transformations. The greatprogress made in synthetic chemistry has not (yet) brought us to the posi-tion that allows us to make any enantiopure substance in quantity given thatresources are always limited. That leaves us with the synthesis of a racematefrom which we pick one enantiomer out. Such a process can be remarkablyefficient and cost-effective, if such tools are available, but the great successesdescribed in this book should not hide the fact that we require better separationmethods with wide applicability if we are to avoid an overreliance on just usingwhatever Nature provides.

The various methods considered in this book may be classified as follows.

1.1Classical Methods

A racemate can be resolved with ease if it happens that the enantiomers formseparate crystals – a so-called conglomerate. It becomes possible to separate,physically, the enantiomorphic crystals – a process sometimes referred to as triage.This is what Pasteur famously achieved in 1848 with a sample of ammoniumsodium tartrate [6]. Such good fortune is quite rare and is in any case not a‘synthetic method’ in the strictest sense (nor is it practical on a large scale).Other physical processes (alone, without any attendant synthetic process) such asevaporation or sublimation can be used to increase the enantiomeric excess oforganic compounds, including amino acids [7].

Another important but non-synthetic method involves harvesting crops of enan-tioenriched crystals by seeding a supersaturated racemate and is known as resolutionby entrainment, or preferential crystallization. These approaches have been wellreviewed and will not be covered here [8]. Rare (but spectacular) examples wherecrystallizations of conglomerates are observed combined with racemization eventsin solution, leading to total spontaneous resolutions [9], are briefly mentioned inChapter 7 as there have been interesting recent developments on that front.Included therein are special cases where diastereomeric interactions in solutioncombined with racemization may yield more than a 50% yield of one enantiomer,

1.2 Kinetic Resolution (‘KR’) 3

often known as a deracemization. Racemization is treated as a synthetic process ofsorts, but we essentially stop short of processes where stereochemistry is createdfrom prochiral intermediates since such a subject is formally the province of asym-metric catalysis. We will not be covering separations based on physical partitioningof enantiomers using, for example, chiral solvents, macrocycles or membranes [10].

Clearly the best-known non-chromatographic method for the separation ofenantiomers, the so-called classical resolution, involves combination of a racemateand an enantiopure compound to form diastereomers that can be separatedbased on physical properties and the enantiomerically pure compound re-isolated(Scheme 1.1).

R

S

RX

SX

Precipitate

Solution

X

R

S

Scheme 1.1 The classical resolution: the separation of intermediate diastereomers differingin their physical properties.

The process is subtle and complex, belying its apparent simplicity on paper.My own experience with obtaining an important drug as a single enantiomer wasinstructive, and the process was publicly laid out over time as the project was carriedout in an open source manner, meaning anyone could contribute to the solutionand alter the direction of the research [11]. The project began with an assessmentof a number of catalytic, asymmetric synthetic methods but feedback from thecommunity was heavily in favour of moving to a search for a resolution, partlybecause the drug was needed for a low price. Sure enough a resolution was thesolution. Sensitivity to conditions was illustrated by the eventual switch from oneresolving agent to another – the structural difference was merely the substitutionof the resolving agent’s methoxy group for a hydrogen atom – resulting in theopposite enantiomer of the desired compound being isolated in the solid. Thisimportant and endlessly surprising area of organic chemistry, now including theso-called Dutch resolution approach of using mixtures of resolving agents, hasbeen widely reviewed [12].

1.2Kinetic Resolution (‘KR’)

A conceptually simple and well-known method for the separation of enantiomersis the kinetic resolution. A racemate is subjected to some reaction using a chiralagent and one of the enantiomers of the racemate reacts more quickly than theother (Scheme 1.2). The ‘selectivity factor’, s, is an expression of the difference inthe rates of the two reactions.

The enantiomer ratio is shown using a formalism borrowed from Ed Vedejsin Chapter 6. As can be seen, the composition varies dynamically as the reaction

4 1 Introduction: A Survey of How and Why to Separate Enantiomers

R

S

kR

kS

Product from R

Product from S

Start

Low

Medium

High

Convers

ion

Scheme 1.2 Generic kinetic resolution showing the ratio of enantiomers with conversion.

proceeds. At the outset, the system displays its best synthetic selectivity betweenthe enantiomers because an equal amount of each enantiomer is present. As thereaction proceeds, statistics begins to interfere as the fast-reacting enantiomer isdepleted. Success is a curse – as the fast-reacting enantiomer concentration reducesit becomes difficult to stop the slow-reacting enantiomer from participating – a‘mass action’ problem. This explains the two best-known features of kineticresolutions – that the maximum yield for the process is necessarily 50%, but thathigh enantiomeric excesses are found at the extremes of conversion – that is, thatthe enantioenrichment of the product (whatever that may be) is largest at the startof the reaction while the enantiomeric excess of the starting material left behindis largest just before the end of the reaction. In a kinetic resolution, one cannotusually have one’s cake (high enantiomeric excess) and eat it (high yield).

A simple approach to kinetic resolution is to use a stoichiometric reagent.In the example shown in Scheme 1.3, an enantioenriched alcohol is obtainedfrom a racemate through the addition of an enantiopure-acylating agent [13]. If1 equivalent of the reagent were used, a 1 : 1 mixture of diastereomers would resultwith no kinetic differentiation. Stoichiometric kinetic resolutions thus necessarilyemploy a sub-stoichiometric amount of the reagent – in the example shown only0.1 equivalents is used. This method for the separation of enantiomers is describedin detail by Maddani, Fiaud and Kagan in Chapter 2.

OH

Ph

1.1 equiv MeMgBr

CH2Cl2 CH2Cl2, 0 °C, 2 h

O

Ph

O

Ph SaponificationOH

Ph

95% ee

O

NPh

OO

0.1 equiv

rac

Scheme 1.3 Example of a stoichiometric kinetic resolution: preparation of an enantioen-riched alcohol through the addition of an enantiopure-acylating agent.

1.3 Dynamic Kinetic Resolution (‘DKR’) 5

The obvious alternative is to use a chiral catalyst to effect some reaction on theracemate. Frequently, the reaction does not introduce a new stereocentre, anda typical example is shown in Scheme 1.4. This process, developed by Birman,involves an acylation of an alcohol effected by a catalytic quantity of an enantiopurenucleophilic catalyst [14]. Catalytic methods are covered by Helene Pellissier inChapter 3.

OH

Ph

rac

CO2H

MeO

O

O

O

OMe

(0.9 equiv)

(0.75 equiv)

i-Pr2NEt (1.8 equiv), CH2Cl2, rt, 12 h

O

Ph

OH

Ph

O

Ph

41% Yield 90% ee

46% Yield 75% ee

N

NPh

S

5 mol%

Scheme 1.4 Example of a catalytic kinetic resolution of a racemic alcohol.

The catalyst can be an enzyme, and some of the most impressive examples havebeen of this type. In the example shown in Scheme 1.5, a lipase acts on a kilogramof the racemic starting material to generate enantioenriched products that may beseparated by distillation after filtration of the enzyme from the reaction mixture[15]. The use of enzymes in kinetic resolutions is covered by Humphrey, Ghanemand Turner in Chapter 4.

OH

rac

NMe2 NMe2

OH O

NMe2

O

Candida antarctica lipase

O

O36% 45%, >95% ee

(R)-methadone

Scheme 1.5 Example of catalytic kinetic resolution effected by an enzyme.

1.3Dynamic Kinetic Resolution (‘DKR’)

Kinetic and classical resolutions both suffer from the weakness that the maximumyield of a product is 50%. This limit is removed if the enantiomers of the startingmaterial can be interconverted (Scheme 1.6). The challenge is significant – to run akinetic resolution in the forward direction and a simultaneous racemization of the

6 1 Introduction: A Survey of How and Why to Separate Enantiomers

starting materials that leaves any compound derived from the starting materialsunaffected. The racemization needs to be rapid with respect to the asymmetrictransformation, to prevent build-up of the slow-reacting enantiomer.

R

S

kR

kS

Product from R

Product from S

start

Low

Medium

High

Convers

ion

Scheme 1.6 Generic dynamic kinetic resolution showing the ratio of enantiomers withconversion.

This seemingly insurmountable task has been solved, with several impressivesystems having been demonstrated to date, although the number of cases isfar lower than those for regular kinetic resolutions. In the example shown inScheme 1.7, the kinetic resolution of secondary alcohols is achieved with a lipasewhile the racemization is effected by a ruthenium complex [16]. This exampleillustrates well the striking effectiveness of two orthogonal chemical processes thatmight a priori be expected to interfere with each other. Dynamic kinetic resolutions(DKRs) are reviewed by Nakano and Masato Kitamura in Chapter 5. The chapteralso includes a description of rarer processes that are frequently confused with DKRbut which are mechanistically distinct [17], such as the dynamic kinetic asymmetrictransformation (DYKAT); the similarity is that DYKAT and DKR achieve completeconversion of a racemate to one enantioenriched product but the DYKAT productis typically not convertible back to starting material (needed for a separation of

OH

OAc

Cl

Ru

CO

H

OC

Ru

OCCO

Ph Ph

PhPh

O

Ph

PhPh

O H

Ph

2 mol%

3 equiv

Toluene, 70 °C, 46 h

Candida antarctica lipase

O

O

80% yield, 99% eerac

Scheme 1.7 Example of dynamic kinetic resolution.

1.4 Divergent Reactions of a Racemic Mixture (‘DRRM’) 7

enantiomers) and involves an intermediate that is chiral, unlike a true DKR thatproceeds via an achiral intermediate. Some of these distinctions are covered alsoin Chapter 7. The role of enzymes in DKR processes is covered also in Chapter 4.

1.4Divergent Reactions of a Racemic Mixture (‘DRRM’)

The essential weakness of a simple kinetic resolution is the build-up of the slow-reacting enantiomer of the starting material, a process that may be solved by DKR.There is another solution – to have the slow-reacting enantiomer be consumed byanother reaction, to give a second product that may be separated from the first.In other words, to have the enantiomers give distinct (enantioenriched but notenantiomeric) products at similar rates (Scheme 1.8) – known as a divergent reactionof a racemic mixture. As for the DKR process, the starting material ideally remainsas a racemate throughout, in which case the maximum yield of any given product is50%. Strictly speaking for the process to be called a resolution, there must be a meansof separating the products and converting them back to the enantiopure startingmaterials. The term DRRM encompasses processes that involve the addition of oneor two chiral reagents to a racemate. The concept is well illustrated by the latter,involving addition of two chiral reagents to a racemate as shown; this subclass ofDRRM is frequently referred to as parallel kinetic resolution (PKR).

R

S

kR

kS

Product from R

Product from S

Start

Low

Medium

HighConvers

ion

k′R

k′SProduct′ from S

Product′ from R

Reagent 2

Reagent 1

Scheme 1.8 Generic divergent reaction of a racemic mixture (note that the product from Ris not the enantiomer of the product from S).

The specific example shown (Scheme 1.9) involves two pseudo-enantiomericreagents [18]. One of the reagents reacts rapidly with the (R)-enantiomer of thestarting alcohol while the other reacts preferentially with the (S)-enantiomer.Although a kinetic resolution of the racemate would be possible with either reagentalone, the mass action problem would mean that the reagent’s selectivity wouldneed to be very high to match the yield and enantiomeric excess values obtainedfrom the DRRM. This process was discovered by Ed Vedejs, who reviews the fieldin Chapter 6.

8 1 Introduction: A Survey of How and Why to Separate Enantiomers

OH

N

OBn

NMe2

OO

A

FenchylACCl3

ClN

t-Bu t-Bu

OMe

NMe2

OO

B

Cl

B

Nph

1-NaphthylNph

O

Nph

O

O

A

O

Nph

O

O

A

Major (48%)

Major (43%)

Minor (1%)

O

Nph

O

O

B

O

Nph

O

O

B

Minor (3%)

− −

Scheme 1.9 Example of a divergent reaction of a racemic mixture.

1.5Other Methods

At the end of this book, I summarize a small number of ‘neglected’ cases not coveredelsewhere, such as the use of circularly polarized light, polymerizations, ‘ripening’processes, dynamic combinatorial chemistry and even several thermodynamicprocesses. In some of these cases, the potential for future significance in thesynthetic separation of enantiomers is clear but the fields are not yet maturebecause the methods are young, exhibit recurrent issues, or have been developedfor other reasons – in the case of polymerizations the eye of the polymer chemist istypically on the polymer, not on any enantiomeric excess that might be containedin the residual solution. This chapter is a little unusual – it appears that thesedisparate methods have never previously been collected together; the separate fieldstypically do not cite each other despite their ultimately sharing a common theme.

One striking example mentioned in this final chapter requires us to bend the termracemate to include ‘very near racemates’ that contain a very small enantiomericexcess. Enrichment of such samples by direct crystallization-based methods wouldtypically only be attempted by committed optimists. In such a situation, we couldsynthesize more of the excess enantiomer preferentially if we had an appropriatelyasymmetric autocatalytic reaction – our initial excess enantiomer could replicateat the expense of the other. Preparatively, this is the effective separation of theenantiomers we used at the outset. Such a system has its physical realization in theSoai autocatalysis in which a very small enantiomeric excess of a pyrimidyl alcoholis amplified over several cycles to give an almost enantiopure sample of the alcohol(Scheme 1.10) [19].

References 9

N

N

H

O

N

N

OH

Nearly racemic

Zn(i-Pr)2

N

N

OH

High enantiomeric excess(after several cycles)

Scheme 1.10 The Soai reaction that achieves a form of synthetic separation of enan-tiomers through selective autocatalysis.

These and other processes are not by any means widespread or generalizable,and they have not yet had an impact on the industrial preparation of enantiopurecompounds, but are included as suggestions of where the vibrant and importantfield of the synthetic separation of enantiomers might go next. Some of thesemethods also remind us of the ‘prototypical’ synthetic separation of enantiomersthat may have played a role in the origin of life.

Acknowledgments

I thank Paul A Bartlett (UC Berkeley) and Craig Williams (University of Queens-land) for helpful comments.

References

1. (a) Toda, F. (2010) Enantiomer Sepa-ration – Fundamentals and PracticalMethods, Kluwer Academic Publish-ers, Dordrecht; (b) Chang, C., Wang,X., Bai, Y., and Liu, H. (2012) TRAC-Trend. Anal. Chem., 39, 195–206.doi: 10.1016/j.trac.2012.07.002; (c)Ward, T.J. and Ward, K.D. (2012)Anal. Chem., 84, 626–635, doi:10.1021/ac202892w

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13

2Stoichiometric Kinetic Resolution ReactionsMahagundappa R. Maddani, Jean-Claude Fiaud, and Henri B. Kagan

2.1Introduction

The resolution of a racemic mixture is a basic process, which was discovered byPasteur in 1848 by the manual separation of the 1 : 1 mixture of enantiomericcrystals of racemic ammonium sodium tartrate [1]. Later Pasteur discovered theresolution of a racemic mixture by the temporary combination with a chiral auxiliaryfollowed by the separation of diastereomers [2]. It was again Pasteur who found thatracemic ammonium tartrate in aqueous solution was half-destroyed by penicilliumglaucum mould, allowing the preparation of ‘unnatural’ (−)-tartaric acid for thefirst time [3]. Enzymatic kinetic resolutions (KRs) rapidly became the preferredmethod to isolate enantioenriched compounds from a racemic mixture, andremained so for many years (see Chapter 4). The first non-enzymatic KR occurredin 1899, when Marckwald and McKenzie [4] realized the partial esterificationof racemic mandelic acid by (−)-menthol, releasing a slightly enantioenriched(−)-mandelic acid. (−)-Borneol was also used in a similar reaction [5]. Severalexamples of KR (in homogeneous conditions) of alcohols or amines by chiralacylating agents were subsequently described. In those days, the isolation andpurification of end products were tedious, sometimes with contamination bychiral impurities. Moreover, measurement of the enantiomeric composition wasalways based on polarimetric measurements (hence the obsolete expression ‘opticalpurity’). Consequently, some reports on KRs until the end of 1960s needed to beconsidered with caution. Bredig and Fajans [6, 7] were the first to do a detailed kineticstudy on the example of partial asymmetric decarboxylation of camphorcarboxylicacid mediated by some alkaloids. Another early kinetic treatment was describedby Kuhn [8] during his investigations of photodecomposition of racemic N,N’-dimethyl-α-azidopropionamide with circularly polarized light.

We published in 1988 an extended review article on the basis of KR and themain results [9]. A chapter is devoted to KR in the stereochemistry textbook byEliel et al. [10]. Some recent reviews are available on various aspects of non-enzymatic KR [11], for example, practical considerations [12], metal-catalyzedKR processes (Chapter 3) [13], dynamic KR (Chapter 5) [14, 15], parallel KR

Separation of Enantiomers: Synthetic Methods, First Edition. Edited by Matthew Todd.c© 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.

14 2 Stoichiometric Kinetic Resolution Reactions

reactions (Chapter 6) [16, 17] or on various aspects of enantiodivergent reactions(Chapter 6) [18].

This chapter focuses on stoichiometric KR reactions. In Section 2.2, the mainkinetic treatments are discussed. In Section 2.3, some examples of the use of chiralreagents in KR are presented. In Sections 2.4 and 2.5, the cases of enantiodivergentand enantioconvergent reactions are discussed. The KR of diastereomers is kineti-cally similar to KR of enantiomers and is briefly presented in Section 2.6. Finally,some examples of applications of KR are collected in Section 2.7.

2.2Kinetic Treatment

The expression ‘KR’ emphasizes that the racemic mixture undergoes a separationunder a chiral influence in a kinetically controlled process. In principle, the word‘resolution’ refers to the isolation of one of the enantiomers of racemic mixtureafter a partial transformation of the initial mixture. If the reaction product is chiral,as in the esterification of a racemic alcohol, then the KR will afford a productwith some enantiomeric excess. The full transformation of a racemic mixture bycoupling with a chiral auxiliary will give a 1 : 1 mixture of diastereomers and is notconsidered as a KR process, unless the reaction is stopped at an intermediate stage,leaving some enantioenriched starting material.

In an enantioselective reaction, such as an asymmetric hydrogenation of a ketone,the enantiomeric excess of the chiral product (eeprod) is generally constant withconversion. This is not true in a KR, where enantiomeric excess of the recoveredstarting material (eesm) and enantiomeric excess of the product (eeprod) change withconversion extent. These points are discussed on a quantitative basis in the nextsections.

2.2.1Reactions First-Order in Substrate

Scheme 2.1 indicates a general presentation of the KR of a racemic compound (R, S)when the product is chiral (case I) or achiral (case II). In both cases, the KR processis characterized by two competitive reactions going with different rates on the twoenantiomers of the racemic mixture. Each rate depends on the concentrations ofthe reactants, the rate constants and the kinetic law. A common situation is akinetic law first-order in substrate, here the (R) and (S) enantiomers (Scheme 2.1).

For an irreversible reaction, the basic set of equations is

d[R]dt

= −kR[R][Z∗] d[S]dt

= −kS[S][Z∗]

The concentration of the chiral auxiliary Z* will not influence the relative rate,which is expressed as follows.

d[R]∕dt

d[S]∕dt=(

kR

kS

)([R][S]

)(2.1)

2.2 Kinetic Treatment 15

S +

I

PR

PS

II

A

R + Z*

Z* S +

R + Z*

Z*

kR kR

kSkS

kR > kS

Scheme 2.1 Stoichiometric kinetic resolution process under the influence of a chiralreagent Z* with formation of a chiral product P (case I) or an achiral product A (case II).

Equation 2.1 simplifies into Equation 2.2 by elimination of time t and takingkR/kS = krel = s (stereoselectivity factor).

d[R][R]

= sd[S][S]

(2.2)

Integration of Equation 2.2 gives Equation 2.3 where [R0] and [S0] are defined asthe initial concentrations of the two enantiomers. This general equation character-izes homocompetitive reactions carried out on two different substrates.

s =ln([R]∕[R0])ln([S]∕[S0])

(2.3)

If one starts from a racemic mixture, then [R0]= [S0].The reaction time t was classically used as the parameter to discuss the course

of a KR [6–8, 19]. Conversion extent C gives equations that are easier to handle,especially if taken with values lying between 0 (initial state) and 1 (full transfor-mation) [20, 21]. Conversion C is denoted by C = 1−([R]+[S])/x0, where x0 is theinitial concentration of the racemic mixture. Enantiomeric excess of the remainingstarting material (eesm) is defined as follows.

eesm = ([S] − [R])([S] + [R])

(2.4)

In the above equation [S]> [R] because it was assumed that kR > kS, as inScheme 2.1.

From Equation 2.4, the values of [S], [R], [S0] and [R0] are derived (seeEquation 2.5).

[S] = 0.5 (1 + eesm) (1 − C)x0

[R] = 0.5 (1 − eesm) (1 − C)x0

[S0] = [R0] = 0.5x0 (2.5)

By using the values from Equation 2.5, Equation 2.3 gives the stereoselectivityfactor s that may be transformed into Equation 2.6.

s =ln[(1 − eesm) (1 − C)]n[(1 + eesm) (1 − C)]

(2.6)

Equation 2.6 allows one to compute the curves eesm = f(C) for various valuesof s. One example is indicated in Figure 2.1 with s= 10 and is discussed below. Asoftware is available for the drawing of such curves [22].

16 2 Stoichiometric Kinetic Resolution Reactions

0

0.1

0.2

0.3

0.4

0.5

0.6

eesm

0.7

0.8

0.9

1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

s = kR/kS = 10

eeprod

[S]

Conversion

eesm

C

A

E

Bx

x

x

x

x

[R]

[S–R]

D

Figure 2.1 Kinetic resolution first-order in substrate (s= krel = 10).

The curve eesm = f(C) in Figure 2.1 shows that the recovered material has acontinuous increase in eesm with conversion. At 50% conversion, eesm = 67%. Theevolution of [R] and [S] during the KR is given by Equation 2.5 and is plottedin Figure 2.1 (for x0 = 1). The excess in (S) enantiomer expressed by ([S]− [R])instead of eesm is also conversion dependent, with an intermediate optimum valueas [S]− [R] is equal to zero for C = 0 and 1. This maximum occurs because thedepletion in the fast-reacting (R)-enantiomer is such that accumulation of the(S)-enantiomer will invert the reaction rates. At the inversion point, the rate ofdestruction of the both enantiomers are equal, kS [S]= kR [R] or [S]/[R]= s. Here,eesm = (s− 1)/(s+ 1).

If the product is chiral (Scheme 2.1, case II), it is easy to calculate its enantiomericexcess (eeprod) defined by eeprod = ([ProdR]− [ProdS])/([ProdR]+ [ProdS]). There is anexcess of ProdR as kR/kS > 1. The material balance imposes a relationship betweenC, eesm and eeprod. By taking into account that 0.5 mol of (R)-enantiomer of theinitial racemic mixture is distributed between the chiral product and the recoveredstarting material, Equation 2.7 may be derived, which is independent of s.

eesm

eeprod= C

(1 − C)(2.7)

2.2 Kinetic Treatment 17

This allows to modify the fundamental equation (Equation 2.6), by introducingeeprod thanks to Equation 2.7. This leads to the following equation.

s =ln[1 − C(1 + eeprod)]ln[1 − C(1 − eeprod)]

(2.8)

On Figure 2.1 is also plotted the evolution of eeprod with conversion by usingEquation 2.9. There is a progressive decrease of eeprod from the initial value of(s− 1)/(s+ 1) to zero at full conversion of the racemic mixture.

Some following remarkable points are indicated in Figure 2.1.

Point A: initial eeprod, equal to (s+ 1)/(s− 1), because [ProdR]]/[ProdS]= s.Point B: crossing point with eeprod = eesm and C = 0.5 (as calculated usingEquation 2.7). Frequently KRs are run to 50% conversion.Point C: inversion rates, where eesm = (s− 1)/(s+ 1). The conversion value maybe calculated from Equation 2.3 by fixing, for example, x0 = 1.Point D: initial enantiomeric excess of the starting material (eesm = 0).Point E: end-point concerning the recovered material. It is close to 100% ee.

The fundamental equation (Equation 2.6) has been obtained by Sharpless et al.in 1981 [21] and was inspired by a previous treatment of one of us in 1974 [20] forphotoresolution (see Section 2.3). By varying the s value, families of curves wereplotted as shown in Figure 2.2.

It is interesting to recall that Equation 2.6 applies only for first-order kinetics insubstrate but is independent of the order in reagent Z*. Indeed, Z* is a common

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Conversion

ee

sm

s = 100

s = 10

s = 5

s = 2

Figure 2.2 Kinetic resolution first-order in substrate for various s values.

18 2 Stoichiometric Kinetic Resolution Reactions

Table 2.1 Values of eesm (%) for kinetic resolutions run to 50% conversion.

s 1.1 2.0 3.0 4.0 5.0 10.0 15.0 20.0 50.0 100 150 500 700eesm 3.3 23.6 36.4 44.8 50.9 67.0 74.3 78.7 88.7 93.3 95.1 98.1 98.5

Table 2.2 Conversion (%) necessary to recover starting material with eesm = 99%.

s 2.0 4.0 5.0 10.0 15.0 20.0 50.0 100 150 300 500 700C (%) 99.7 91.3 86.6 72.1 65.5 61.9 54.9 52.3 51.5 50.6 50.3 50.1

partner in the two parallel reactions of Scheme 2.1 and is eliminated during theestablishment of Equation 2.1. A similar situation occurs with a chiral catalyst,the two rate constants representing rate constants of pseudo first-order reactions.The s values are very useful to compare various KR reactions. For example, whichis the most efficient process: a KR that gives an eesm of 50% at 40% conversion,or the one where eesm is 40% at 30% conversion? The use of Equation 2.6 easilygives an answer to this question, as one calculates s= 11.4 and 42.9, respectively;the second process is the best.

From the fundamental equation (Equation 2.6), one can build tables relating s,eesm and C values. For example, in Table 2.1 are listed couples of s and eesm valuesfor 50% conversion (C = 0.5) of a racemic substrate. In Table 2.2 are similarlyindicated some pairs of C and s values necessary to recover the starting material in99% ee.

Similar calculations apply to the KR of a non-racemic mixture of initial enan-tiomeric excess ee0 = ([S]− [R])/([S]+ [R]), which gives the following.

s =ln[(1 − eesm)(1 − C)∕(1 − ee0)]ln[(1 + eesm)(1 − C)∕(1 − ee0)]

(2.9)

Horeau calculated which conversion (as a function of s) is needed to enhancean initial enantiomeric excess ee0 to a given final enantiomeric excess eesm (forexample, of 99%) [23].

2.2.1.1 Scope and Validity of Equation 2.6Equation 2.6 has been established for well-defined conditions: pseudo first-orderin substrate (but any order in chiral auxiliary, stoichiometric or catalytic) and nochange of mechanism during the course of the reaction, for example, no auto-induction by the products. Reactions with chiral catalysts are especially susceptibleto auto-induction. It is then useful to give the calculated s values with an indication ofthe correspondence between conversion and eesm or eeprod [11]. We advise runningexperiments for at least two values of conversion and subsequent verification thatthe s values obtained are identical or similar. If not, this can indicate a changein the structure of the reagent during the reaction or a non-first-order reaction insubstrate. The extrapolation of s at initial conversion is a characteristic value for a