Cinchona Alkaloids inSynthesis and Catalysis

Ligands, Immobilization and Organocatalysis

Edited byChoong Eui Song

57268File Attachmentcover.jpg

Cinchona Alkaloids in

Synthesis and Catalysis

Edited by

Choong Eui Song

Further Reading

Crabtree, R. H. (ed.)

Handbook of Green Chemistry- Green Catalysis2009

HardcoverISBN: 978-3-527-31577-2

Kollár, L (ed.)

Modern CarbonylationMethods2008

HardcoverISBN: 978-3-527-31896-4

Börner, A. (ed.)

Phosphorus Ligands inAsymmetric CatalysisSynthesis and Applications

2008

HardcoverISBN: 978-3-527-31746-2

Yamamoto, H., Ishihara, K. (eds.)

Acid Catalysis in ModernOrganic Synthesis2008

HardcoverISBN: 978-3-527-31724-0

Maruoka, K. (ed.)

Asymmetric Phase TransferCatalysis2008

HardcoverISBN: 978-3-527-31842-1

Stepnicka, P. (ed.)

FerrocenesLigands, Materials and Biomolecules

Hardcover

ISBN: 978-0-470-03585-6

Christmann, M., Bräse, S. (eds.)

Asymmetric Synthesis -The Essentials

2008

SoftcoverISBN: 978-3-527-32093-6

Hudlicky, T., Reed, J. W.

The Way of SynthesisEvolution of Design and Methods

for Natural Products

2007

HardcoverISBN: 978-3-527-32077-6

Hiersemann, M., Nubbemeyer, U. (eds.)

The Claisen RearrangementMethods and Applications

2007

HardcoverISBN: 978-3-527-30825-5

Cornils, B., Herrmann, W. A.,Muhler, M., Wong, C.-H. (eds.)

Catalysis from A to ZA Concise Encyclopedia

2007

HardcoverISBN: 978-3-527-31438-6

Cinchona Alkaloids inSynthesis and Catalysis

Ligands, Immobilization and Organocatalysis

Edited byChoong Eui Song

The Editor

Prof. Choong Eui SongSungkyunkwan UniversityDept. of ChemistryCheoncheon-dong 300, Jangan-guSuwon 440-746Republik Korea

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# 2009 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim

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Printed in the Federal Republic of GermanyPrinted on acid-free paper

ISBN: 978-3-527-32416-3

To my wife Teresa

Contents

Preface XVBiography XVIIList of Contributors XIX

1 An Overview of Cinchona Alkaloids in Chemistry 1Choong Eui Song

1.1 Brief History 11.2 Active Sites in Cinchona Alkaloids and Their Derivatives 31.3 Structural Information on Cinchona Alkaloids 41.4 How This Book Is Organized 8

References 9

Part One Cinchona Alkaloid Derivatives as Chirality Inducersin Metal-Catalyzed Reactions 11

2 Cinchona Alkaloids as Chirality Transmitters in Metal-CatalyzedAsymmetric Reductions 13Hans-Ulrich Blaser

2.1 Introduction 132.2 Homogeneous Systems for Ketone Reductions 142.3 Heterogeneous Pt and Pd Catalysts Modified with

Cinchona Alkaloids 152.3.1 Background 152.3.2 Catalysts 162.3.3 Modifiers and Solvents 162.3.4 Substrate Scope for Pt Catalysts 172.3.4.1 a-Keto Acid Derivatives 172.3.4.2 a,g-Diketo Esters 182.3.4.3 Fluorinated Ketones 182.3.4.4 a-Keto Acetals 202.3.4.5 a-Keto Ethers 202.3.4.6 Miscellaneous Ketones 21

VII

2.3.5 Substrate Scope for Pd Catalysts 212.4 Industrial Applications 222.5 Conclusions 25

References 26

3 Cinchona Alkaloids as Chiral Ligands in Asymmetric Oxidations 29David J. Ager

3.1 Introduction 293.2 Asymmetric Dihydroxylation of Alkenes 303.2.1 Early Reactions 303.2.2 Bisalkaloid Ligands 333.2.3 Mechanism 353.2.4 Variations 363.2.5 Substrates and Selectivity 383.2.5.1 Simple Alkenes 383.2.5.2 Functionalized Alkenes 383.2.5.3 Polyenes 433.2.5.3.1 Nonconjugate Olefins 433.2.5.3.2 Conjugated Polyenes 433.2.5.4 Double Asymmetric Induction 443.2.5.5 Resolutions 503.2.6 Some Reactions of 1,2-Diols 513.2.6.1 Cyclic Sulfates and Sulfites 543.3 Aminohydroxylation 563.4 Sulfur Oxidations 613.5 Summary 61

References 62

4 Cinchona Alkaloids and their Derivatives as Chirality Inducersin Metal-Promoted Enantioselective Carbon–Carbon andCarbon–Heteroatom Bond Forming Reactions 73Ravindra R. Deshmukh, Do Hyun Ryu, and Choong Eui Song

4.1 Introduction 734.2 Nucleophilic Addition to Carbonyl or Imine Compounds 744.2.1 Organozinc Addition 744.2.1.1 Dialkylzinc Addition to Aldehydes 744.2.1.2 Dialkylzinc Addition to Imines 754.2.1.3 Addition of Alkynylzincs to Carbonyls 774.2.2 Asymmetric Reformatsky Reaction 784.2.3 Indium-Mediated Addition 794.2.4 Asymmetric Cyanation 814.2.4.1 Cyanohydrin Synthesis 814.2.4.2 Strecker Synthesis 844.2.5 Reactions of Chiral Ammonium Ketene Enolates as Nucleophiles

with Different Electrophiles 86

VIII Contents

4.2.5.1 Lewis Acid Assisted Nucleophilic Addition of Ketenes (or Sulfenes)to Aldehydes: b-Lactone and b-Sultone Synthesis 86

4.2.5.2 Lewis Acid Assisted Nucleophilic Addition of Ketenesto Imines: b-Lactam Synthesis 90

4.2.5.3 Applications of Chiral Ketene Enolates to Formal [4 þ 2] typeCyclization 92

4.2.6 Aza-Henry Reaction 924.2.7 Enantioselective Hydrophosphonylation 934.3 Miscellaneous Reactions 944.3.1 Claisen Rearrangements 944.3.2 Pd-Catalyzed Asymmetric Allylic Substitutions 954.3.3 Pauson–Khand Reaction 974.3.4 Asymmetric Dimerization of Butadiene 984.3.5 Enantiotopic Differentiation Reaction of Mesocyclic Anhydrides 984.4 Cinchona-Based Chiral Ligands in C–F Bond

Forming Reactions 994.5 Conclusions 100

References 101

Part Two Cinchona Alkaloid Derivatives as Chiral Organocatalysts 105

5 Cinchona-Based Organocatalysts for Asymmetric Oxidationsand Reductions 107Ueon Sang Shin, Je Eun Lee, Jung Woon Yang, and Choong Eui Song

5.1 Introduction 1075.2 Cinchona-Based Organocatalysts in Asymmetric Oxidations 1085.2.1 Epoxidation of Enones and a,b-Unsaturated Sulfones

Using Cinchona-Based Chiral Phase-Transfer Catalysts 1085.2.1.1 Epoxidation of Acyclic Enones 1085.2.1.2 Epoxidation of Cyclic Enones 1135.2.1.3 Synthetic Applications of the Asymmetric Epoxidation of Enones

Using Chiral PTCs 1155.2.1.4 Epoxidation of a,b-Unsaturated Sulfones 1175.2.2 Organocatalytic Asymmetric Epoxidation of Enones via

Iminium Catalysis 1185.2.3 Aziridination of Enones Using Cinchona-Based Chiral

Phase-Transfer Catalyst 1205.3 Cinchona-Based Organocatalysts in Asymmetric Reductions 1255.4 Conclusions 127

References 128

6 Cinchona-Catalyzed Nucleophilic a-Substitution of CarbonylDerivatives 131Hyeung-geun Park and Byeong-Seon Jeong

6.1 Introduction 131

Contents IX

6.2 Organocatalytic Nucleophilic a-Substitution ofCarbonyl Derivatives 131

6.3 Cinchona Alkaloids in Asymmetric Organocatalysis 1336.4 The Pioneer Works for Phase-Transfer Catalytic a-Substitution 1346.5 a-Substitution of a-Amino Acid Derivatives via PTC 1356.5.1 Monoalkylation of Benzophenone Imines of Glycine Esters 1356.5.2 Alkylation of a-Monosubstituted a-Amino Acid Derivatives 1486.6 a-Substitution of Other Carbonyl Derivatives via PTC 1506.6.1 a-Substitution of Monocarbonyl Compounds 1506.6.2 a-Substitution of b-Keto Carbonyl Compounds 1536.7 a-Heteroatom Substitution via PTC 1566.7.1 a-Hydroxylation of Carbonyl Derivatives 1566.7.2 a-Fluorination of Carbonyl Derivatives 1576.8 Nucleophilic a-Substitution of Carbonyl Derivatives via

Non-PTC 1576.8.1 a-Arylation of Carbonyl Derivatives 1586.8.2 a-Hydroxylation of Carbonyl Derivatives 1596.8.3 a-Halogenation of Carbonyl Derivatives 1606.8.4 a-Amination of Carbonyl Derivatives 1626.8.5 a-Sulfenylation of Carbonyl Derivatives 1656.9 Conclusions 165

References 166

7 Cinchona-Mediated Enantioselective Protonations 171Jacques Rouden

7.1 Introduction 1717.2 Preformed Enolates and Equivalents 1727.3 Nucleophilic Addition on Ketenes 1757.4 Michael Additions 1787.5 Enantioselective Decarboxylative Protonation 1847.5.1 Copper-Catalyzed EDP 1847.5.2 Palladium-Catalyzed EDP 1857.5.3 Organocatalyzed EDP 1887.6 Proton Migration 1927.7 Summary of Cinchona-Mediated Enantioselective Protonations 194

References 194

8 Cinchona-Catalyzed Nucleophilic 1,2-Addition to C¼Oand C¼N Bonds 197Hyeong Bin Jang, Ji Woong Lee, and Choong Eui Song

8.1 Introduction 1978.2 Aldol and Nitroaldol (Henry) Reactions 1988.2.1 Aldol Reactions 1988.2.1.1 Mukaiyama-Type Aldol Reactions 1988.2.1.2 Direct Aldol Reactions 200

X Contents

8.2.2 Henry Reactions 2068.3 Mannich and Nitro-Mannich Reactions 2098.3.1 Mannich Reactions 2098.3.2 Nitro-Mannich (Aza-Henry) Reactions 2158.4 Aldol- and Mannich-Related Reactions 2188.4.1 Darzens Reactions 2188.4.2 Morita–Baylis–Hillman Reactions and Aza-Morita–Baylis–Hillman

Reactions 2218.4.2.1 Morita–Baylis–Hillman Reactions 2218.4.2.2 Aza-Morita–Baylis–Hillman Reactions 2258.4.3 Nucleophilic Addition of Ammonium Ketene Enolate to C¼O or

C¼N Bonds 2288.5 Cyanation Reactions 2298.5.1 Cyanohydrin Synthesis 2298.5.2 Strecker Synthesis 2328.6 Trifluoromethylation 2348.7 Friedel–Crafts Type Alkylation 2378.8 Hydrophosphonylation 2408.9 Conclusions 244

References 244

9 Cinchona-Catalyzed Nucleophilic Conjugate Additionto Electron-Deficient C¼C Double Bonds 249Ji Woong Lee, Hyeong Bin Jang, and Choong Eui Song

9.1 Introduction 2499.2 Conjugate Reaction of a,b-Unsaturated Ketones, Amides,

and Nitriles 2499.2.1 Natural Cinchona Alkaloids as Catalysts 2499.2.2 PTC-Catalyzed Enantioselective Michael Addition Reactions 2529.2.3 Non-PTC-Catalyzed Enantioselective Michael Addition

Reactions 2619.3 Conjugate Addition of Nitroalkenes 2749.4 Conjugate Addition of Vinyl Sulfones and Vinyl Phosphates 2849.4.1 Vinyl Phosphate 2869.5 Cyclopropanation and Other Related Reactions 2889.5.1 Cyclopropanation 2889.5.2 Epoxidation and Aziridination 2929.6 Conclusions 293

References 293

10 Cinchona-Catalyzed Cycloaddition Reactions 297Yan-Kai Liu and Ying-Chun Chen

10.1 Introduction 29710.2 Asymmetric Cycloadditions Catalyzed by Quinuclidine

Tertiary Amine 297

Contents XI

10.3 Asymmetric Cycloadditions Catalyzed by BifunctionalCinchona Alkaloids 308

10.4 Asymmetric Cycloaddition Reactions Catalyzed by Cinchona-BasedPrimary Amines 312

10.5 Asymmetric Cycloaddition Catalyzed by Cinchona-BasedPhase-Transfer Catalysts 320

10.6 Conclusion 323References 323

11 Cinchona-Based Organocatalysts for Desymmetrizationof meso-Compounds and (Dynamic) Kinetic Resolutionof Racemic Compounds 325Ji Woong Lee, Hyeong Bin Jang, Je Eun Lee, and Choong Eui Song

11.1 Introduction 32511.2 Desymmetrization of meso-Compounds 32611.2.1 Desymmetrization of meso-Cyclic Anhydrides 32611.2.1.1 Applications 33611.2.2 Desymmetrization of meso-Diols 33611.2.3 Desymmetrization of meso-Endoperoxides 34111.2.4 Desymmetrization of meso-Phospholenes via Alkene

Isomerization 34411.2.5 Desymmetrization of meso-Epoxy Phospholenes to Allyl Alcohols

via Rearrangement 34511.2.6 Desymmetrization of Prochiral Ketones by Means

of Horner–Wadsworth–Emmons Reaction 34611.3 (Dynamic) Kinetic Resolution of Racemic Compounds 34611.3.1 (Dynamic) Kinetic Resolution of Racemic Cyclic Anhydrides 34611.3.2 (Dynamic) Kinetic Resolution of Racemic N-Cyclic Anhydrides 34811.3.3 Dynamic Kinetic Resolution of Racemic Azlactones 35011.3.4 Catalytic Sulfinyl Transfer Reaction via Dynamic Kinetic Resolution

of Sulfinyl Chlorides 35111.4 Conclusions 354

References 355

Part Three Organic Chemistry of Cinchona Alkaloids 359

12 Organic Chemistry of Cinchona Alkaloids 361Hans Martin Rudolf Hoffmann and Jens Frackenpohl

12.1 Introduction 36112.2 Preparation of Quincorine and Quincoridine: Discovery of a

Novel Cleavage Reaction of Cinchona Alkaloids 36412.3 Transformations of the Quinoline Moiety 36612.4 Basic Transformations of the Vinyl Side Chain 36812.4.1 Alkyne Cinchona Alkaloids, Their Derivatives, and Basic

Transformations 368

XII Contents

12.4.1.1 The Ethynyl Group is Anything but a Spectator Substituent 37112.4.2 Fluorination of the Vinyl Side Chain 37412.4.3 Oxidation and Oxidative Cleavage of the Vinyl Group 37512.4.3.1 Oxidative Functionalization of Quincorine and Quincoridine 38012.4.4 Degradation of the Vinyl Side Chain: Synthesis of Cinchona

Alkaloid Ketones 38112.5 Selected Novel Transformations of the Quinuclidine Moiety of

Cinchona Alkaloids 38212.5.1 Cage Helicity and Further Consequences: Nucleophilic Attack

on Quinuclidin-3-ones 38212.5.2 Transformations at Carbon C6 and Formation of

Bridgehead Bicyclic Lactams 38912.5.3 Functionalization of Other Quinuclidine Carbons, for Example,

C5 and C7 39312.6 Nucleophilic Substitution at Carbon C9 39412.6.1 Unusual Steric Course of Solvolysis of C9-Activated Alkaloids: Access

to C9-epi-Configured Stereoisomers 39412.6.2 Replacing the C9-Hydroxy Group by Alternative Substituents 39612.6.3 Transformations of QCI and QCD at Carbon C9: Access to a Novel

Class of Small Molecule Ligands 39912.7 Novel Rearrangements of the Azabicyclic Moiety 40312.7.1 First Cinchona Rearrangement 40312.7.2 Second Cinchona Rearrangement 40712.8 General Experimental Hints and Obstacles 40912.9 Conclusions 412

References 415

Part Four Cinchona Alkaloid and Their Derivatives in Analytics 419

13 Resolution of Racemates and Enantioselective Analyticsby Cinchona Alkaloids and Their Derivatives 421Karol Kacprzak and Jacek Gawronski

13.1 Introduction 42113.2 Resolution of Racemates by Crystallization and Extraction of

Diastereoisomers 42313.2.1 Resolution of Racemates by Crystallization 42313.2.2 Resolution of Racemates by Enantioselective Extraction 43013.3 Enantioselective Chromatography and Related Techniques 43313.3.1 Early Attempts and Current Status 43413.3.2 Cinchona 9-O-Carbamates as CSPs in HPLC 43613.3.2.1 Applications 43713.3.2.2 Mechanistic Studies on Chiral Discrimination 44313.3.3 Other Cinchona-Based Selectors: Toward ‘‘Receptor-Like’’ CSPs 44713.3.4 Cinchona-Based Chiral Modifiers and Phases in Capillary

Electrophoresis and Capillary Electrochromatography 450

Contents XIII

13.3.5 Other Chromatographic Techniques 45213.4 Cinchona Alkaloids as Chiral Solvating (Shift) Agents in

NMR Spectroscopy 45313.5 Cinchona-Based Sensors, Receptors, and Materials for

Separation and Analytics 455References 464

Appendix: Tabular Survey of Selected Cinchona-PromotedAsymmetric Reactions 471Ji Woong Lee and Choong Eui Song

Index 507

XIV Contents

Preface

Since the pioneering works of H. Wynberg in the late 1970s and early 1980s,cinchona alkaloids have been intensively applied as either standalone catalysts orchiral ligands in catalytic asymmetric reactions and are now regarded as one of themost privileged chirality inducers. Indeed, today, nearly all classes of organic reac-tions can be effectively carried out with the use of cinchona alkaloids in a highlystereoselective fashion. Some of them are even used in large-scale processes, forexample, the heterogeneous hydrogenation of a-ketoesters catalyzed by cinchonaalkaloid-modified platinum, the Sharpless asymmetric dihydroxylation of olefins,and the asymmetric alkylation of indanones using cinchona alkaloid-derived chiralphase-transfer catalysts, and so on. Of these reactions, the osmium-catalyzed asym-metric dihydroxylation of olefins using cinchona alkaloid derivatives as chiralligands has had the greatest impact on modern asymmetric catalysis. In 2001, theNobel Prize in Chemistry was awarded to Professor Sharpless ‘‘for his pioneeringwork on chirally catalyzed oxidation reactions’’.In spite of the huge amount of attention that has been given to this research area

and the immense success that has been obtained, surprisingly, no book on this topichas been published to date. So far, on this topic, only a few review articles on the useof cinchona alkaloids in asymmetric synthesis (Pracejus (up to 1967), Morrison andMosher (up to 1970), Wynberg (up to 1986), Song (up to 1999), Gawronski (up to2000), Deng (up to 2004), and Lectka (up to 2008), and so on) have appeared.However, these reviews are either dated or deal only with a specific reaction class.Thus, when I was invited to do so by Wiley-VCH Verlag GmbH, I felt that it wasindeed an honor to be asked to serve as editor of this new and first handbook oncinchona alkaloids. I accepted the invitation with full confidence that this new andtimely book would be warmly welcomed by many researchers.This multiauthor handbook will cover the whole spectrum of cinchona alkaloid

chemistry ranging from the fundamentals to industrial applications. This book isorganized in four units, namely, the use of cinchona alkaloids as chirality inducers inmetal-promoted reactions (Chapters 2–4), the use of cinchona alkaloids as chiralorganocatalysts (Chapters 5–11), the organic chemistry of cinchona alkaloids them-selves (Chapter 12), and the use of cinchona alkaloids as chiral discriminating agents

XV

in modern analysis (Chapter 13), reflecting the comprehensive current state of theart on cinchona alkaloid chemistry. All of the chapters are written by organicchemists at the forefront of research in this field and are able to provide an insidersview.In addition, a collection of carefully selected representative catalytic examples,

organized by reaction type, is given in the Appendix. These tables will offer a greatdeal of information and be invaluable to anyone who wants to get the information ofthe current state of the art on this topic within a short time.I hope this book will be of interest to all those involved in this field, from graduate

students to independent organic researchers, both academic and industrial. Espe-cially, this book should be a must to read for anyone working in the field ofasymmetric synthesis.Last but definitely not the least, I am very grateful to all of my colleagues for their

excellent contributions to this book, despite their busy time schedules. Gratefulacknowledgments are offered to the Wiley-VCH editorial staff, in particular to DrElke Maase, who gave me the good fortune of being the editor of this first handbookand who offered a great deal of help at the beginning of this project. I also thank DrStefanie Volk for her professional work during the production process.Finally, I can hardly wait to see the spectacular achievements that will doubtless be

made in this rapidly evolving research field in the near future and that will requirethis manual to be rapidly updated.

Suwon, February 2009 Choong Eui Song

XVI Preface

Biography

Choong Eui Song has been a full professor at the Sungkyunkwan University since2004. He received his B.S. in 1980 from Chungang University and obtained adiploma (1985) and a Ph.D. (1988) at RWTH Aachen in Germany. After completinghis Ph.D., he worked as Principal Research Scientist at the Korea Institute of Scienceand Technology (KIST). In 2001, he was appointed as head of the National ResearchLaboratory for Green Chirotechnology in Korea. In 2004, he moved to his currentposition and in 2006 he was appointed as a director at the Research Institute ofAdvanced Nanomaterials and Institute of Basic Sciences at the SungkyunkwanUniversity. His research interests focus on asymmetric catalysis, ionic liquid chem-istry, and nanochemistry. He received the Scientist of the Month Award from theMinistry of Science and Technology of Korea in 2001.

XVII

List of Contributors

XIX

David J. AgerDSM Pharmaceutical ChemicalsPMB 150, 9650 Strickland Road,Suite 103Raleigh, NC 27615USA

Hans-Ulrich BlaserSolvias AGP.O. BoxCH-4002 BaselSwitzerland

Ying-Chun ChenSichuan UniversityWest China School of PharmacyDepartment of Medicinal ChemistryChengdu 610041China

Ravindra R. DeshmukhSungkyunkwan UniversityDepartment of Chemistry300 Cheoncheon, Jangan, SuwonGyeonggi 440-746Korea

Jens FrackenpohlBayer CropScience AGGebäude G 836, Industriepark Höchst65926 Frankfurt am MainGermany

Jacek GawronskiAdam Mickiewicz UniversityDepartment of ChemistryGrunwaldzka 660-780 PoznanPoland

Hans Martin Rudolf HoffmannUniversity of HannoverDepartment of Organic ChemistrySchneiderberg 1B30167 HannoverGermany

Hyeong Bin JangSungkyunkwan UniversityDepartment of Chemistry300 Cheoncheon, Jangan, SuwonGyeonggi 440-746Korea

Byeong-Seon JeongYeungnam UniversityCollege of PharmacyGyeongsan 712-749South Korea

Karol KacprzakAdam Mickiewicz UniversityDepartment of ChemistryGrunwaldzka 660-780 PoznanPoland

Je Eun LeeSungkyunkwan UniversityDepartment of Chemistry300 Cheoncheon, Jangan, SuwonGyeonggi 440-746Korea

Ji Woong LeeSungkyunkwan UniversityDepartment of Chemistry300 Cheoncheon, Jangan, SuwonGyeonggi 440-746Korea

Yan-Kai LiuSichuan UniversityWest China School of PharmacyDepartment of Medicinal ChemistryChengdu 610041China

Hyeung-geun ParkSeoul National UniversityCollege of PharmacySeoul 151-742South Korea

Jacques RoudenUniversité de Caen-Basse NormandieLaboratoire de Chimie Moléculaire etThio-organique, ENSICAEN, CNRS6 Boulevard du Maréchal Juin14050 CaenFrance

Do Hyun RyuSungkyunkwan UniversityDepartment of Chemistry300 Cheoncheon, Jangan, SuwonGyeonggi 440-746Korea

Ueon Sang ShinSungkyunkwan UniversityDepartment of Chemistry300 Cheoncheon, Jangan, SuwonGyeonggi 440-746Korea

Choong Eui SongSungkyunkwan UniversityDepartment of Chemistry300 Cheoncheon, Jangan, SuwonGyeonggi 440-746Korea

Jung Woon YangSungkyunkwan UniversityDepartment of Chemistry300 Cheoncheon, Jangan, SuwonGyeonggi 440-746Korea

XX List of Contributors

1An Overview of Cinchona Alkaloids in ChemistryChoong Eui Song

1.1Brief History

Cinchona alkaloids (Figure 1.1), isolated from the bark of several species of cinchonatrees, are the organic molecules with the most colorful biography [1]. Their historydates back to the early seventeenth century when they were first introduced into theEuropean market after the discovery of the antimalarial property of cinchona barkand the subsequent isolation of its active compound, quinine, by Pierre-JosephPelletier and Joseph Bienaim�e Caventou in 1820. Since then, cinchona alkaloids(especially, quinine) have played a pivotal medicinal role in human society for over300 years. Approximately 700metric tons of cinchona alkaloids is now extracted fromthe bark of Cinchona ledgeriana annually. Nearly half of this is used in the food andbeverages industry as a bitter additive, and much of the remaining quinine andquinidine is used as an important antimalarial drug and muscle relaxant compoundand as a cardiac depressant (antiarrhythmic), respectively.The role of cinchona alkaloids in organic chemistry was firmly establishedwith the

discovery of their potential as resolving agents by Pasteur in 1853, which ushered inan era of racemate resolutions by the crystallization of diastereomeric salts [3]. Today,there are countless examples in which cinchona alkaloids are used as chiral resolvingagents [4]. Besides the classical resolution process, significant progress has also beenmade in the past two decades in thefield of cinchona-based enantioseparation, aswellas in their use as enantioselective analytical tools (Chapter 13). The considerableeffort made to accomplish the stereoselective synthesis of quinine over the past 150years, whichwas initially triggered by the supply problem caused by political vagariesof the producing countries, has also undoubtedly laid the foundation for much ofmodern organic chemistry [5]. However, possibly the most interesting application ofcinchona alkaloids in chemistry resides in their ability to promote enantioselectivetransformations in both homogeneous andheterogeneous catalyses (Chapters 2–11).The first asymmetric reaction carried out using a cinchona base was publishedby Bredig and Fiske [6] as early as in 1912. These two German chemists reported

j1

that the addition ofHCN to benzaldehyde is accelerated by the pseudoenantiomericalkaloids, quinine and quinidine, and that the resulting cyanohydrins are opticallyactive and are of opposite chirality. However, the optical yields achieved were in therange of

1.2Active Sites in Cinchona Alkaloids and Their Derivatives

As mentioned in the previous section, nowadays, readily available and inexpensivecinchona alkaloids with pseudoenantiomeric forms, such as quinine and quinidineor cinchonine and cinchonidine, are among themost privileged chirality inducers inthe area of asymmetric catalysis. The key feature responsible for their successfulutility in catalysis is that they possess diverse chiral skeletons and are easily tunablefor diverse types of reactions (Figure 1.2). The presence of the 1,2-aminoalcoholsubunit containing the highly basic and bulky quinuclidine, which complements theproximal Lewis acidic hydroxyl function, is primarily responsible for their catalyticactivity.The presence of the quinuclidine base functionality makes them effective ligands

for a variety of metal-catalyzed processes (Chapters 2–4). The most representativeexample is the osmium-catalyzed asymmetric dihydroxylation of olefins [9]. Themetal binding properties of the quinuclidine nitrogen also allow to use cinchonaalkaloids as metal surface modifiers, for example, in the highly enantioselectiveheterogeneous asymmetric hydrogenation of a-keto esters (Chapter 2). Both

R = HR' = CH=CH2; CinchonidineR' = CH2CH3; DihydrocinchonidineR = OMeR' = CH=CH2; QuinineR' = CH2CH3; Dihydroquinine

R = HR' = CH=CH2; CinchonineR' = CH2CH3; DihydrocinchonineR = OMeR' = CH=CH2; QuinidineR' = CH2CH3; Dihydroquinidine

B. X = OH1) H-Bond donor or acid2) Metal coordination

C. X = NH2 or further derivatizations(with inversion of C(9)-configuration

1) Aminocatalysis (iminium and enamine catalysis)2) H-Bond donors (e.g.ureas, squaramides, amides)

A. Nitrogen of quinuclidine1) Metal binding ability: chiral ligands or chiral modifiers2) General base: deprotonation3) Nucleophilic catalyst4) N-Alkylation: chiral PTC (chiral ion pair mechanism)

N

R'

XN

HR N

XN

H R

R'

D. R = OH or thioureas1) H-Bond donor or acid

D. R = OH or thioureas1) H-Bond donor or acid

Common Names (X = OH)

Figure 1.2 Active sites in cinchona alkaloids and their derivatives.

1.2 Active Sites in Cinchona Alkaloids and Their Derivatives j3

reactions are classified as ligand-accelerated catalyses (LAC) [11]. In addition to itsutility for metal binding, the quinuclidine nitrogen can be used as a chiral base or achiral nucleophilic catalyst promoting the vast majority of organocatalytic reactions(Chapters 5–11). Finally, the related quaternized ammonium salts of cinchonaalkaloids have proved to catalyze numerous reactions under phase-transfer condi-tions, where asymmetric inductions occur through a chiral ion pairing mechanismbetween the cationic ammonium species and an anionic nucleophile [12].The secondary 9-hydroxy group can serve as an acid site or hydrogen bond

donor [13]. The derivatization of the OH group into ureas, amides, and so on, witheither the retention or inversion of the configuration, provides amore powerful acidicsite or hydrogenbonddonor. The 60-methoxy groupof quinine andquinidine can alsobe readily derivatized to the free OH group or thiourea moiety, which can serve asan effective H-bond donor. Moreover, the substitution of 9-OH into the free aminogroup with the inversion of the configuration enables enantioselective aminocata-lysis, which includes reactions of the so-called generalized enamine cycle [14] andcharge accelerated reactions via the formation of iminium intermediates [15].Representative examples of modified cinchona alkaloids are depicted in Figure 1.3.However, in general, these active sites in cinchona alkaloids and their derivatives

act in catalysis not independently but cooperatively; that is, they activate the reactingmolecules simultaneously. Furthermore, in many cases, the catalysis is also sup-ported by ap–p interactionwith the aromatic quinoline ring or by its steric hindrance.

1.3Structural Information on Cinchona Alkaloids

Cinchona alkaloids have characteristic structural features for their diverse con-formations and self-association phenomena. Therefore, knowledge of their realstructure in solution can provide original information on the chiral inducing anddiscriminating ability of these alkaloids.Conformational investigations of this class of alkaloids, based on computational

and spectroscopic methods, have been undertaken with the aim of providinginformation that would help understand these chiral induction and discriminationprocesses. Dijkstra et al. were the first to investigate in 1989 the conformationalbehavior by means of NMR spectroscopic and molecular mechanics (MM) calcula-tions and identify that the C8�C9 and C40�C9 bonds are the most importantin determining the overall conformation, resulting in four low-energy conformers(syn-closed, syn-open, anti-closed, and anti-open conformers) (Figure 1.4) [16]. MMcalculations showed that the parent alkaloids preferentially adopt an anti-openconformation in nonpolar solvents [16]. More sophisticated ab initio calculationsconducted later also revealed that anti-open is the most stable conformer in apolarsolvents [17, 18]. In polar solvents, two other conformers, syn-closed and anti-closed,are strongly stabilized compared to the anti-open conformer, due to the greatersupport provided by their large dipole moments [18]. For example, in polar solvents,the fraction of cinchonidine adopting a closed conformation is more than 50% at

4j 1 An Overview of Cinchona Alkaloids in Chemistry

OO

N

OM

e

N

Me

O

H

OO

NN

Et

Et

NN

OO

N

OM

e

N

Me

O

H

NN

Et

Et

NOM

e

N OT

MS

N NH

N

H

OM

e

NH

S

CF

3F

3C

N NH

2

NOM

e

N

N

H

OM

e

NS

OO

CF

3

CF

3

H

N

HN

NH O

Me

NH

O

O

F3C

CF

3

N O

N

H

OH

N OB

n

N

H

NH

NH

S

CF

3

F3C

6'

N ON

H

Br

6'

Figu

re1.3Rep

resentativeexam

ples

ofcincho

naalkaloid

derivatives.

1.3 Structural Information on Cinchona Alkaloids j5

room temperature. However, upon protonation, the anti-open conformation isobserved exclusively [18]. The protonation of cinchona alkaloids appears to hindertheir rotation around the C40�C9 andC9�C8 bonds and favor only a narrow range ofthe conformational space of the molecule [19].The pivotal role of the conformational behavior of a cinchona alkaloid (e.g.,

cinchonidine) in its enantioselectivity was nicely illustrated in the platinum-catalyzedenantioselective hydrogenation of ketopantolactone in different solvents [18]. Theachieved enantiomeric excess shows the same solvent dependence as the fraction ofanti-open conformer in solution, suggesting that this conformer plays a crucial role inthe enantiodifferentiation. As a more dramatic example, the solvent affects theabsolute chirality of the product in the 1,3-hydron transfer reaction catalyzed bydihydroquinidine [20]. An NMR study revealed that the changes in the ratio betweenthe two conformers of dihydroquinidine can explain the observed reversal of thesense of the enantioselectivity for this reaction when the solvent is changed fromo-dichlorobenzene (open/closed �60 : 40) to DMSO (open/closed �20 : 80).Undoubtedly, the modification of the structure of the cinchona alkaloid also has

a significant effect on its conformational behavior in solution; esters [17] and 9-O-carbamoyl derivatives [21] exist as a mixture of two major anti-closed and anti-openconformers, while C9 methyl ethers prefer an anti-closed arrangement in noncoor-dinating solvents [17]. Here again, protonation provides the anti-open conformationas the sole stable form [16b]. In addition to the solvent polarity, many other factorssuch as intermolecular interactions are also responsible for the complex conforma-tional behavior of cinchona alkaloids in solution.

N

OH

N

MeO

H

H

anti-closed

N

OH

N OMe

H

H

syn-closed

N

HO

H

H

syn-open

N

OMeN

HO

H

H

anti-open

N

MeO

4'

89

rotation along C9-C4'

rotation along C8-C9rotation along C8-C9

rotation along C9-C4'

Figure 1.4 The four conformers of quinidine showing the lowest energy.

6j 1 An Overview of Cinchona Alkaloids in Chemistry

Another characteristic structural feature of cinchona alkaloids is their multifunc-tional character and, thus, autoassociation phenomena are possible that could resultin the strong dependency of their efficiency on the concentration and tempera-ture [22, 23].In 1969, Uskokovic and coworkers observed a concentration-dependent intermo-

lecular interaction between dihydroquinine molecules [24]. The 1H NMR spectra of(�)-dihydroquinine and racemic dihydroquinine are clearly different under concen-trated conditions; that is, this molecule can generate its own nonequivalence.However, at high dilution (0.01M), this interaction disappeared. This indicates theexistence of a self-association process mediated by intermolecular hydrogen bond-ing [24]. Moreover, the measurement of the molecular weight of quinine usingosmometry conducted by Hiemstra and Wynberg revealed the presence of particleslarger than monomeric quinine at 37 �C for a 16mM solution in toluene. Forconcentrations less than 4mM, on the other hand, quinine was almost completelymonomeric [22].In 1992, the coexistence of the monomer and dimers of quinine in chloroform

solutionwas established by Salvadori and coworkers by investigating the temperatureand concentration dependence of theNMR spectral parameters (chemical shift, NOEeffect, relaxation time, etc.). The mole fraction of dimers was about 40% in 0.6Msolution [25]. The structure of the dimer determined fromNOESYand the relaxationrate data is given in Figure 1.5. As shown in Figure 1.5, the dimer of quinine wasshown to be ap–p complexwith nearly parallel quinoline rings. A study carried out onthe self-aggregation of chloroquine [26] gave similar results. Recently, the changesin the 13C chemical shifts at various concentrations were also used to study theself-association of quinine. T-shaped dimers formed by the quinoline rings wereproposed [27].Quite recently, we also observed that quinine-based thiourea derivatives showed

dramatic concentration and temperature effects on the enantioselectivity in thealcoholytic desymmetrization ofmeso-cyclic anhydrides, which can also be attributedto the self-association of the catalyst [23]. Of course, the possibility that the variation in

N OH

H

OHN

N OMeN

OMe

Figure 1.5 Conformation of quinine dimer from NMR results.

1.3 Structural Information on Cinchona Alkaloids j7

the enantioselectivity is caused by a concentration-dependent change in the con-formational composition cannot be ruled out. However, according to the resultsobtained by Salvadori [25], at least in the case of the parent alkaloids, the confor-mation is similar in the dimer and monomer. Quite recently, Soós and coworkersproved by means of NMR NOESY experiments and computational studies that thequinine thiourea catalyst exists in a dimeric formunder concentrated conditions dueto H-bond and T-type p–p interactions (Figure 1.6) [28].As discussed, the solvent dipole moments, concentration, and temperature play a

significant role in determining the structure of cinchona alkaloids and their deri-vatives in solution. In order to delineate the intimate details of the mechanism ofaction of cinchona alkaloids and their derivatives, a thorough understanding of theirreal structure in solution is needed. Furthermore, such detailed information on thereal structure in solution would make it possible to develop new and more powerfulchiral catalysts and discriminators.

1.4How This Book Is Organized

The goal of this handbook is to provide up-to-date information on thewhole spectrumof cinchona alkaloid chemistry. The authors have attempted to provide those whowant to learn about the current state of the art on this topic and are willing tocontribute actively to the extraordinary developments taking place in thisfieldwith aninsiders view of this subject. This book is organized in four units, namely, the use ofcinchona alkaloids as chirality inducers inmetal-promoted reactions (Chapters 2–4),as chiral organocatalysts (Chapters 5–11), the organic chemistry of cinchona alkaloidsthemselves (Chapter 12), and their use as chiral discriminating agents in modernanalysis (Chapter 13). In addition, a collection of carefully selected representativecatalytic examples organized according to the reaction type is given in the form of anappendix.

N

HMeO

N

N

S

CF3

CF3

H

HN

N

OMe

NN

S

F3C

F3C

HH

H

HN

intramolecularH-bond

intermolecularH-bond

T-Shapecharge transfer

Figure 1.6 Dimeric structure of 9-epiquinine thiourea.

8j 1 An Overview of Cinchona Alkaloids in Chemistry