Catalytic Asymmetric Synthesis E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1359

Veröffentlichungsjahr: 2013

Beschreibung

Praise for the previous editions "An excellent text . . . will no doubt provide the benchmark for comparative works for many years." --Journal of the American Chemical Society "An excellent state-of-the-art compilation of catalytic asymmetric chemistry . . . should be included in any chemistry reference collection." --Choice "This is a tremendous resource and an excellent read. I recommend immediate purchase." --Perkin Transactions Since this important work was first published in 1993, the field of catalytic asymmetric synthesis has grown explosively, spawning effective new methods for obtaining enantiomerically pure compounds on a large scale and stimulating new applications in diverse fields--from medicine to materials science. Catalytic Asymmetric Synthesis, Third Edition addresses these rapid changes through contributions from highly recognized world leaders in the field. This seminal text presents detailed accounts of the most important catalytic asymmetric reactions known today, and discusses recent advances and essential information on the initial development of certain processes. An excellent working resource for academic researchers and industrial chemists alike, the Third Edition features: * Six entirely new chapters focusing on novel approaches to catalytic asymmetric synthesis including non-conventional media/conditions, organocatalysis, chiral Lewis and Bronsted acids, CH activation, carbon-heteroatom bond-forming reactions, and enzyme-catalyzed asymmetric synthesis * A new section focusing on the important new reaction, asymmetric metathesis, in carbon-carbon bond-forming reactions * Updated chapters on hydrogenation, carbon-carbon bond-forming reactions, hydrosilylations, carbonylations, oxidations, amplifications and autocatalysis, and polymerization reactions Retaining the best of its predecessors but now thoroughly up to date, Catalytic Asymmetric Synthesis, Third Edition serves as an excellent desktop reference and text for researchers and students from the upper-level undergraduates through experienced professionals in industry or academia.

Leseprobe

Contents

Cover

Half Title page

Title page

Copyright page

Preface

Preface to the Second Edition

Preface to the First Edition

Contributors

Chapter 1: Catalytic Asymmetric Synthesis in Nonconventional Media/Conditions

1.1. Introduction

1.2. Catalytic Asymmetric Synthesis in Water

1.3. Catalytic Asymmetric Synthesis in Alternative Reaction Media

1.4. Microwave-Assisted Catalytic Asymmetric Synthesis

1.5. Conclusion/Perspective

References

Chapter 2: Asymmetric Organocatalysis

Chapter 2A: Enantioselecttve Organocatalysis Involving Iminium, Enamine, SOMO, and Photoredox Activation

2A.1. Introduction

2A.2. Iminium-Based Catalysis [1,2]

2A.3. Enamine Catalysis [1,9]

2A.4. New Developments in Organocatalysis

References

Chapter 2B: Asymmetric Acid–Base Bifuncttonal Catalysis with Organic Molecules

2B.1. Introduction

2B.2. Highly Enanttoselecttve Acid and Base Catalysis by Monofunctional Organic Catalysts

2B.3. Acid-Base Bifunctional Catalysis by Small Chiral Organic Molecules

2B.4. Control Of Enantioselectivity and Diastereoselectivity in Asymmetric Transformations with Acid-Base Bifunctional Organic Catalysts

2B.5. Emerging Acid-Base Bifunctional Chiral Organic Catalysts

2B.6. Conclusion and Outlook

Acknowledgments

References

Chapter 2C: Asymmetric Phase-Transfer and Ion Pair Catalysis

2C.1. Introduction

2C.2. Pioneering Work

2C.3. Alkylation

2C.4. Michael Addition

2C.5. Aldol and Mannich Reactions

2C.6. Epoxidation and Aziridination

2C.7. Strecker Reaction

2C.8. Amination

2C.9. Ion Pair Catalysts

2C.10. Conclusion

References

Chapter 3: Chiral Lewis Acids and Brønsted Acids in Asymmetric Synthesis

3.1. Introduction

3.2. BLA Catalysis

3.3. LLA Catalysis

3.4. LBA Catalysis

3.5. Chiral Phosphoric Acid Catalysis [49]

3.6. Conclusion

References

Chapter 4: Asymmetric Synthesis Through C–H Activation

4.1. Introduction

4.2. Asymmetric C–H Activation via Metal Carbenoid Insertion

4.3. Metal Nttrenoid-Mediated C–H Insertion

4.4. C–H Activation via Direct C–H Oxidation

4.5. Conclusions and Future Outlook

Acknowledgments

References

Chapter 5: Asymmetric Carbon-Heteroatom Bond-Forming Reactions

5.1. Introduction

5.2. Allylic Substitution

5.3. AZA-Claisen Rearrangement and Related Reactions

5.4. Addition to Alkenes and Allenes

5.5. Aziridination of Olefins

5.6. α-Amination and α-Oxygenation of Carbonyl Compounds

5.7. Recent Progress of Other Carbon–Heteroatom Bond Formation

References

Chapter 6: Enzyme-Catalyzed Asymmetric Synthesis

6.1. Introduction

6.2. Enantioselecitve Acylation of Alcohols and Amines with Carboxylates

6.3. Hydrolytic Reactions

6.4. Carbon-Carbon Bond-Forming Reactions

6.5. Enantioselective Reductions

6.6. Asymmetric Oxidations

6.7. Summary

References

Chapter 7: Transition Metal-Catalyzed Homogeneous Asymmetric Hydrogenation

7.1. Introduction

7.2. Chiral Ligands for Asymmetric Hydrogenation

7.3. Asymmetric Hydrogenation of Unsaturated Compounds

7.4. Conclusion

References

Chapter 8: Asymmetric Carbon–Carbon Bond-Forming Reactions

Chapter 8A: Catalytic Asymmetric Conjugate Addition

8A.1. Introduction

8A.2. Catalytic Asymmetric Conjugate Addition of Organometallics

8A.3. Catalytic Asymmetric Conjugate Addition of Other Carbon-Centered Nucleophiees

8A.4. Catalytic Asymmetric Tandem Conjugate Addition Reaction

8A.5. Catalytic Asymmetric Conjugate Addition of Heteroatom Nucleophiles

Acknowledgments

References

Chapter 8B: Enantioselecttve Allylic Substitutions with Carbon Nucleophiles

8B.1. Introduction and Scope

8B.2. Palladium-Catalyzed Enantioselective Allylic Alkylations

8B.3. Nickel- and Platinum-Catalyzed Allylic Alkylations

8B.4. Molybdenum- and Tungsten-Catalyzed Enantioselective Allylic Alkylations

8B.5. Iron- and Ruthenium-Catalyzed Allylic Alkylations

8B.6. Rhodium-Catalyzed Allylic Alkylations

8B.7. Iridium-Catalyzed Enantioselective Allylic Alkylations

8B.8. Copper-Catalyzed Enantioselective Allylic Alkylations

Notes and References

Chapter 8C: Asymmetric Carbometallation and Carbocyclizations

8C.1. Introduction

8C.2. Zr-Catalyzed Asymmetric Carboalumination (ZACA) Reactions

8C.3. Enantioselective Hydrogen-Mediated C–C Bond Formation

8C.4. Asymmetric Carbocyclizations

8C.5. Asymmetric Heck Reactions

References

Chapter 8D: Asymmetric Ene Reactions and Cycloadditions

8D.1. Introduction

8D.2. Mechanistic Considerations

8D.3. Intermolecular Carbonyl-Ene Reaction

8D.4. Intermolecular Imine-Ene Reaction

8D.5. Intramolecular Carbonyl-Ene Reaction

8D.6. Ene-Type Cyclization

8D.7. D-A-Type Reaction

References

Chapter 8E: Catalytic Enantioselective Olefin Metathesis Reactions

8E.1. Introduction

8E.2. Enantioselective Ring-Closing Metathesis (RCM) Reactions

8E.3. Catalytic Enantioselective Ring-Opening/Ring-Closing Metathesis (RORCM) and Ring-Opening/Cross-Metathesis (ROCM)

8E.4. Catalytic Enantioselecttve Cross-Metathesis (CM)

8E.5. Conclusions and Future Outlook

Acknowledgments

References

Chapter 9: Asymmetric Hydrosilylation of Carbon-Carbon Double Bonds and Related Reactions

9.1. Introduction

9.2. Asymmetric Hydrosilylation of Alkenes

9.3. Asymmetric Hydroboration of Alkenes

9.4. Asymmetric Hydroalumination and Hydrostannation of Alkenes

9.5. Conclusion

References

Chapter 10: Asymmetric Carbonylations

10.1. Introduction

10.2. Asymmetric Hydroformylation

10.3. Asymmetric Alkoxycarbonylation and Related Reactions

10.4. Asymmetric Alternating Co- and Terpolymerization of Olefins With Co

10.5. Conclusions

References

Chapter 11: Asymmetric Oxidations and Related Reactions

11.1. General Introduction

11.2. Asymmetric Oxidation of Alcohols

11.3. Asymmetric Epoxidation

11.4. Asymmetric Sulfide Oxidation

11.5. Asymmetric Baeyer-Villiger Oxidation

11.6. Asymmetric Dihydroxylation

11.7. Asymmetric Aziridination

References

Chapter 12: Asymmetric Amplification and Autocatalysis

12.1. Introduction

12.2. Asymmetric Amplification

12.3. Asymmetric Autocatalysis

12.4. Experimental Approaches to Understand the Origins of Biological Homochirality

12.5. Chiral Discrimination by Asymmetric Autocatalysis with Amplification of EE

12.6. Summary

Acknowledgment

References

Chapter 13: Asymmetric Polymerization

13.1. Introduction

13.2. Asymmetric Synthesis Polymerization

13.3. Helix-Sense-Selective Polymerization

13.4. Enantiomer-Selective Polymerization

13.5. Summary and Outlook

References

Index

CATALYTIC ASYMMETRIC SYNTHESIS

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Library of Congress Cataloging-in-Publication Data

Catalytic asymmetric synthesis / [edited by] Iwao Ojima. − 3rd ed. p. cm. Includes index. ISBN 978-0-470-17577-4 (cloth) 1. Asymmetric synthesis. 2. Catalysis. I. Ojima, Iwao, 1945– QD262.C357 2010 547′.2–dc22 2009052132

PREFACE

The first and second editions of Catalytic Asymmetric Synthesis published in the fall of 1993 and spring of 2000, respectively, were very warmly received by research communities in academia and industries, from graduate students, research associates, faculty, staff, senior researchers, and others. The first book was published at the very moment that the Food and Drug Administration (FDA) in the United States clarified the situation in “Chiral Drugs,” the word “chirotechnology” was created, and chirotechnology industries were spawning in the United States and Britain. In the Preface of the first edition, I correctly positioned the significance and advancement of catalytic asymmetric synthesis as follows: “Extensive research on new and effective catalytic asymmetric reactions will surely continue beyond the year 2000, and catalytic asymmetric processes promoted by man-made chiral catalysts will become mainstream chemical technology in the 21st century.” The second edition published in 2000 covered explosive development of catalytic asymmetric synthesis since 1993 by adding newly emerging reactions in that period, but keeping the historically important chapters in the first book. In 2001, the Nobel Prize in Chemistry was given to W. Knowles, K. B. Sharpless, and R. Noyori for their outstanding contributions to the advancement of catalytic asymmetric synthesis, pushing up this chemistry and chemical technology to a practical level for the benefit of mankind. Again, I wrote about their exceptional achievements in the Preface of the first edition as follows: “Among the significant achievements in basic research, (i) asymmetric hydrogenation of dehydroamino acids, a ground-breaking work by W. S. Knowles et al., (ii) the Sharpless epoxidation by K. B. Sharpless et al., and (iii) the second generation asymmetric hydrogenation processes developed by R. Noyori et al. deserve particular attention because of the tremendous impact that these processes have made in synthetic organic chemistry.” In many cases, Nobel Prize in Chemistry is given to scholar(s) in a certain field of research that is fully matured. However, this Nobel Prize recognized the chemical science that was still very actively growing and expanding, hence significantly fueled further advances in this field. Accordingly, 8 years after the second edition, it became very clear that an updated and/or newer version of this book was necessary for the synthetic chemistry community. Thus, a third edition was planned.

This third edition, however, is organized in a manner different from that of the second edition. Since the chapters in the second edition are still very informative and the ingenious methodologies as well as innovative approaches described there are highly inspiring and stimulating even today, those chapters are regarded as “classics in catalytic asymmetric synthesis.” Thus, I decided to edit essentially a new book, which would become the most useful desktop reference and text, in addition to the “classics” in the second edition, for researchers at all levels, highlighting the most significant advances in catalytic asymmetric synthesis since 2000. Although the third edition does not aim to be comprehensive in nature, it covers the reactions most needed by today’s practicing researchers and graduate students in synthetic organic, medicinal, and materials chemistry. New to the third edition, six new chapters focusing on novel approaches to catalytic asymmetric synthesis are introduced, including non-conventional media/conditions, organocatalysis, Lewis and Bronsted acids, CH activation, carbon-heteroatom bond forming reactions, and enzyme-catalyzed asymmetric synthesis (Chapters 1–6). I believe it is time for synthetic organic chemists to recognize and embrace the importance and power of “enzyme-catalyzed reactions” in asymmetric synthesis. Moreover, another very important reaction (metathesis, the subject of the 2005 Nobel Prize in Chemistry) for catalytic asymmetric synthesis is introduced as a new chapter (Chapter 8E) in the section of the carbon-carbon bond forming reactions. Updated chapters are on hydrogenation (Chapter 7), carbon-carbon bond forming reactions (conjugate additions, allylic alkylations, carbometallations and carbocyclizations, transition metal catalyzed ene reactions, and cycloadditions) (Chapter 8), hydrosilylation (Chapter 9), carbonylations (Chapter 10), oxidations (Chapter 11), amplifications and autocatalysis (Chapter 12), and polymerization (Chapter 13). It is obvious that these reactions and processes provide powerful methods for the highly efficient synthesis of enantio-enriched or enantiopure compounds of biological, medicinal, agrochemical, and materials/nano-science–related interests.

The authors of these chapters are all world leaders in this field, who provide systematic, in-depth state-of-the-art coverage of the basic principles, scope and limitations, strategies, and perspectives for future development of each reaction.

I sincerely hope that this book attracts the interests of broad range of synthetic organic, medicinal, and materials chemists, especially among the younger generation researchers in both academia and industry, who will introduce original and creative ideas into this fascinating field of research and advance catalytic asymmetric synthesis by highly innovative approaches in the years to come.

Iwao Ojima November 2009

PREFACE TO THE SECOND EDITION

The first edition of Catalytic Asymmetric Synthesis, published in the fall of 1993, was very warmly received by research communities in academia and industries from graduate students, research associates, faculty, staff, senior researchers, and others. The book was published at the very moment that the Food & Drug Administration (FDA) in the United States clarified the situation in “Chiral Drugs,” the word “chirotechnology” was created, and chirotechnology industries were spawning in the United States and Britain.

As accurately predicted in the preface of the first edition, extensive research on new and effective catalytic asymmetric reactions has been continuing, in an explosive pace, and it is now obvious that these catalytic asymmetric processes promoted by man-made chiral catalysts will be the mainstream chemical technology in the 21st century. About five years from the publication of the original book, there was a clear demand in the synthetic community for an updated version of this book because advances in the field were accelerated during this period. Accordingly, I have agreed with the publisher to edit a second edition of this book.

In the second edition, I intended to incorporate all important reaction types that I am aware of, while keeping the monumental discovery and initial development of certain processes from the first edition, and highlighting recent advances in this field. The original book had 13 chapters (9 general-reaction types), which covered most of the important developments at that time. However, the second edition has 21 chapters (11 general-reaction types) (a total of 21 chapters for the 21st century is intriguing, isn’t it?). reflecting the tremendous expansion in the scope of catalytic asymmetric synthesis in the past several years. In addition to the nine general-reaction types covered in the original book, the second edition includes “Asymmetric Carbometallations” (Chapter 4), “Asymmetric Amplification and Autocatalysis” (Chapter 9), and “Asymmetric Polymerization” (Chapter 11). “Cyclopropanation” in the original book has been replaced with “Asymmetric Carbene Reactions” (Chapter 5), which now includes powerful asymmetric intramolecular carbene insertion to C–H bonds. As the Table of Contents shows, there has been significant expansion and development in the asymmetric carbon–carbon bond-forming reactions (Chapter 8). Thus, this section consists of eight chapters dealing with cycloaddition reactions, aldol reactions, ene reactions, Michael reactions, allylic substitution reactions, cross-coupling reactions, and intramolecular Heck reactions. These processes provide very useful methods for the highly efficient synthesis of enantio-enriched or enantiopure compounds of biological, medicinal, agrochemical, and material science related interests.

Once again, the authors of these chapters are all world-leaders in this field, who outline and discuss the essence of each catalytic asymmetric reaction. Because the separate list of the chiral ligands in the original book was very well received, a convenient list of the chiral ligands with citation of relevant references appears in this book as an Appendix.

This book will, once again, serve as an excellent reference book for graduate students as well as chemists at all levels in both academic and industrial laboratories.

Iwao Ojima

PREFACE TO THE FIRST EDITION

Biological systems, in most cases, recognize a pair of enantiomers as different substances, and the two enantiomers will elicit different responses. Thus, one enantiomer may act as a very effective therapeutic drug whereas the other enantiomer is highly toxic. The sad example of thalidomide is well-known. It is the responsibility of synthetic chemists to provide highly efficient and reliable methods for the synthesis of desired compounds in an enantiomerically pure state, that is, with 100% enantiomeric excess (% ee), so that we shall not repeat the thalidomide tragedy. It has been shown for many pharmaceuticals that only one enantiomer contains all of the desired activity, and the other is either totally inactive or toxic. Recent movements of the Food & Drug Administration (FDA) in the United States clearly reflect the current situation in “Chiral Drugs,” that is, pharmaceutical industries will have to provide rigorous justification to obtain the FDA’s approval of racemates. Several methods are used to obtain enantiomerically pure materials, which include classical optical resolution via diastereomers, chromatographic separation of enantiomers, enzymic resolution, chemical kinetic resolution, and asymmetric synthesis.

The importance and practicality of asymmetric synthesis as a tool to obtain enantiomerically pure or enriched compounds has been fully acknowledged to date by chemists in synthetic organic chemistry, medicinal chemistry, agricultural chemistry, natural products chemistry, pharmaceutical industries, and agricultural industries. This prominence is due to the explosive development of newer and more efficient methods during the last decade.

This book describes recent advances in catalytic asymmetric synthesis with brief summaries of the previous achievements as well as general discussions of the reactions. A previous book reviewing this topic. Asymmetric Synthesis, Vol. 5—Chiral Catalysis, edited by J. D. Morrison (Academic Press, Inc., 1985), compiles important contributions through 1982. Another book. Asymmetric Catalysis, edited by B. Bosnich (Martinus Nijhoff, 1986) also concisely covers contributions up to early 1984. In 1971, an excellent book, Asymmetric Organic Reactions, by J. D. Morrison and H. S. Mosher, reviewed all earlier important work on the subject and compiled nearly 850 relevant publications through 1968, including some papers published in 1969. In the early 1980s, a survey of publications dealing with asymmetric synthesis (in a broad sense) indicated that the total number of papers in this area of research published in the 10 years after the Morrison/Mosher book, that is, 1971–1980, was almost the same as that of all the papers published before 1971. This doubling of output clearly indicates the attention paid to this important topic in 1970s. Since the 1980s, research on asymmetric synthesis has become even more important and popular when enantiomerically pure compounds are required for the total synthesis of natural products, pharmaceuticals, and agricultural agents. It would not be an exaggeration to say that the number of publications on asymmetric synthesis has been increasing exponentially every year.

Among the types of asymmetric reactions, the most desirable and the most challenging is catalytic asymmetric synthesis because one chiral catalyst molecule can create millions of chiral product molecules, just as enzymes do in biological systems. Among the significant achievements in basic research: (i) asymmetric hydrogenation of dehydroamino acids, a ground-breaking work by W.S. Knowles et al.; (ii) the Sharpless epoxidation by K. B. Sharpless et al.; and (iii) the second-generation asymmetric hydrogenation processes developed by R. Noyori et al. deserve particular attention because of the tremendous impact that these processes have made in synthetic organic chemistry. Catalytic asymmetric synthesis often has significant economic advantages over stoichiometric asymmetric synthesis for industrial-scale production of enantiomerically pure compounds. In fact, a number of catalytic asymmetric reactions, including the “Takasago Process” (asymmetric isomerization), the “Sumitomo Process” (asymmetric cyclopropanation), and the “Arco Process” (asymmetric Sharpless epoxidation) have been commercialized in the 1980s. These processes supplement the epoch-making “Monsanto Process” (asymmetric hydrogenation), established in the early 1970s. This book uncovers other catalytic asymmetric reactions that have high potential as commercial processes. Extensive research on new and effective catalytic asymmetric reactions will surely continue beyond the year 2000, and catalytic asymmetric processes promoted by man-made chiral catalysts will become mainstream chemical technology in the 21st century.

This book covers the following catalytic asymmetric reactions: asymmetric hydrogenation (Chapter 1); isomerization (Chapter 2); cyclopropanation (Chapter 3); oxidations (epoxidation of allylic alcohols as well as unfunctionalized olefins, oxidation of sulfides, and dihydroxylation of olefins) (Chapter 4); hydrocarbonylations (Chapter 5); hydrosilylation (Chapter 6); carbon–carbon bond-forming reactions (allylic alkylation, Grignard cross-coupling, and aldol reaction) (Chapter 7); phase-transfer reactions (Chapter 8); and Lewis acid-catalyzed reactions (Chapter 9). The authors of the chapters are all world-leaders in this field, who outline and discuss the essence of each catalytic asymmetric reaction. (In addition, a convenient list of the chiral ligands appearing in this book, with citation of relevant references, is provided as an Appendix.)

This book serves as an excellent reference for graduate students as well as chemists at all levels in both academic and industrial laboratories.

Iwao Ojima March 1993

CONTRIBUTORS

Kohsuke Aikawa, Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan

Albert S. C. Chan, Department of Applied Biology and Chemical Technology, Room M1711, Li Ka Shing Tower, The Hong Kong Polytechnic University, Hunghom, Kowloon, Hong Kong; Email: [email protected]

Stephen J. Chaterpaul, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794

Cheol Hong Cheon, Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue (GHJ 409), Chicago, IL 60637

Carmen Claver, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain; Email: [email protected]

Huw M. L. Davies, Department of Chemistry, Emory University, 440 Atwood Hall, Emory University, 1515 Dickey Drive, Atlanta, GA 30322; Email: [email protected]

Li Deng, Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454-9110; Email: [email protected]

Montserrat Diéguez, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain

Sebastian Förster, Organisch-Chemisches Institut der Universität Heidelberg, D-69120 Heidelberg, Germany

Cyril Godard, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007,Tarragona, Spain

Harald Gröger, Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, Henkestr. 42, 91054 Erlangen, Germany; Email: [email protected]

Jin Wook Han, Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul 133–791, Korea

Jørn Hansen, Department of Chemistry, Emory University, 440 Atwood Hall, Emory University, 1515 Dickey Drive, Atlanta, GA 30322

Tamio Hayashi, Department of Chemistry, Faculty of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; Email: [email protected]

Günter Helmchen, Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany; Email: [email protected]

Amir H. Hoveyda, Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467; Email: [email protected]

Shingo Ito, Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8656, Japan

Jian-Xin Ji, Chendu Institute of Biology, Chinese Academy of Sciences, Chengdu, China

Joseph J. Kaloko, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794

Tsutomu Katsuki, Department of Chemistry, Faculty of Science, Graduate School, Kyushu University, 6-10-1 Hakozaki Higashi-ku, Fukuoka 812-8581, Japan; Email: [email protected]

Tsuneomi Kawasaki, Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

Uli Kazmaier, Institut für Organische Chemie, Universität des Saarlandes, D-66123 Saarbrücken, Germany

Shū Kobayashi, Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Email: [email protected]

Wei Li, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854

Chi-Feng Lin, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794

David W. C. MacMillan, Department of Chemistry, Frick Laboratory, Princeton University, Washington Road, Princeton, NJ 08544; Email: [email protected]

Steven J. Malcolmson, Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467

Keiji Maruoka, Department of Chemistry, Faculty of Science, Graduate School, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; Email: [email protected]

Kazuhiro Matsumoto, Department of Chemistry, Faculty of Science, Graduate School, Kyushu University, 6-10-1 Hakozaki Higashi-ku, Fukuoka 812-8581, Japan

Simon J. Meek, Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467

Koichi Mikami, Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan; Email: [email protected]

Hideto Miyabe, School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Kobe 650-8530, Japan

Kyoko Nozaki, Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8656, Japan; Email: [email protected]

Chikako Ogawa, Eisai Research Institute, Lead Identification, 4 Corporate Drive, Andover, MA 01810

Iwao Ojima, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794; Email: [email protected]

Oscar Pàmies, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain

Aurora Ruiz, Department of Physical Chemistry and Inorganic Chemistry, Universität Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain

Gao Shang, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854

Takanori Shibata, Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan

Seiji Shirakawa, Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan

Kenso Soai, Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan; Email: [email protected]

Yoshiji Takemoto, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan; Email: [email protected]

Yu-Han Gary Teng, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794

Yi Wang, Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454-9110

Allan J. B. Watson, Department of Chemistry, Frick Laboratory, Princeton University, Washington Road, Princeton, NJ 08544

Hisashi Yamamoto, Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue (GHJ 409), Chicago, IL 60637; Email: [email protected]

Xumu Zhang, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road Piscataway, NJ 08854; Email: [email protected]

Adil R. Zhugralin, Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467

CHAPTER 1

CATALYTIC ASYMMETRIC SYNTHESIS IN NONCONVENTIONAL MEDIA/CONDITIONS

CHIKAKO OGAWA* and SHŪ KOBAYASHI

Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

1.1. INTRODUCTION

Conventionally, catalytic asymmetric synthesis has been carried out in organic solvents, because most organic materials are not soluble in other solvents. However, asymmetric catalysis in other solvents (nonconventional solvents) is now of interest for many reasons. First and most significantly, the negative characteristics of organic solvents have come to the fore recently; many organic solvents are volatile, flammable, sometimes explosive, and have a damaging effect on human health (e.g., mutagenic or carcinogenic) or on the environment. On the other hand, recovery and reuse of catalysts is crucial in organic synthesis not only from an economical aspect but also from an environmental point of view. Use of nonconventional solvents often enables the recovery and reuse of catalysts.

In this chapter, water, fluorous solvents, supercritical fluids (SCFs), and ionic liquids (ILs) are discussed as nonconventional solvents, and characteristic features of asymmetric catalysis are surveyed. Microwave-assisted catalytic asymmetric synthesis is also described.

1.2. CATALYTIC ASYMMETRIC SYNTHESIS IN WATER

Water is remarkable in nature; indeed, nature chooses water as a “solvent.” Many elegant in vitro reactions, mainly catalyzed by enzymes, are carried out in an aqueous environment in our bodies. Given that nature so gracefully exploits water, why should mankind not perform synthesis in water too?

1.2.1. Chiral Lewis Acid Catalysis in Water

In general, the formation of chiral Lewis acid complex is much more difficult in water than in organic media, since a chiral ligand competes with water in coordination with Lewis acid. Although there are successful reports to realize chiral Lewis acid catalyzed asymmetric reactions in aqueous media, it is still very challenging to use water as sole solvent [1,2].

1.2.1.1. Mannich-Type Reaction in Water

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active β-amino ketones and esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [3]. Diastereo- and enantioselective Mannich-type reactions of α-hydrazono ester 1 with silicon enolates in aqueous media can be successfully achieved with a ZnF2–chiral diamine L-1 complex (Scheme 1.1) [4]. This complex enables reactions in water without any organic cosolvents or additives to proceed smoothly, affording the corresponding products in high yields and high stereoselectivities (Conditions A) [5]. In the reaction of α-monosubstituted ketone-derived silyl enol ether with 1, cetyltrimethyl ammonium bromide (CTAB) is necessary to accelerate the reaction. It is also noted that, in contrast to most asymmetric Mannich-type reactions, either syn- or anti-adducts are stereospecifically obtained from (E)- or (Z)-silicon enolates in the present reaction (Conditions B). Moreover, the amount of ZnF2 and L-1 can be successfully reduced to 10 and 5 mol %, respectively, maintaining the same level of result (Conditions C).

Scheme 1.1.

1.2.1.2. Michael Reaction in Water

AgOTf–PPh3 complex-catalyzed Michael additions of β-ketoesters to nitroalkenes proceed efficiently only in water but not in organic solvents (Scheme 1.2).

Scheme 1.2.

Based on these results, a plausible mechanism is shown in Scheme 1.3. In the formation of metal enolate B, TfOH is generated and the reaction mixture becomes heterogeneous, where metal enolate B stays in organic phase, while TfOH is excluded to water phase because of the difference of hydrophobicity between them. On the other hand, in the case of a normal organic solvent system, the reaction mixture becomes homogeneous, leading the reverse reaction from B to A fast. As a result, metal enolate B does not make contact with TfOH, and the reverse reaction from B to A is suppressed. Metal enolate B and nitrostyrene would thus combine in high concentration, and the Michael addition step (B to C in Scheme 1.3) may proceed smoothly. Moreover, this reaction system can be applied to catalytic asymmetric synthesis in water (Scheme 1.4) [6,7].

Scheme 1.3.

Scheme 1.4.

1.2.1.3. Epoxide Ring-Opening Reaction in Water

Scandium trisdodecylsulfate (Sc(DS)3) was designed as a Lewis acid as well as a surfactant as illustrated in Scheme 1.5. In the model reaction of benzaldehyde with the silyl enol ether derived from propiophenone in water, Sc(DS)3 catalyzes the reaction smoothly, while the reaction proceeds sluggishly when Sc(OTf)3 is used as a catalyst (Scheme 1.6).

Scheme 1.5.

Scheme 1.6.

A key to the success in this system is assumed to be the formation of stable emulsions. Physical property of the droplets was investigated, and transmission electron microscopy (TEM) analysis revealed that only about 0.08 mol % of Sc(DS)3 is sufficient to form monolayers (Scheme 1.7). Based on these results, it is expected that highly hydrophobic environment is formed inside of the emulsion.

Scheme 1.7.

To explore this catalyst further, chiral Sc(DS)3 catalyst has been investigated. The complex Sc(OTf)3•L-3 was found to be effective in asymmetric hydroxymethylation using aqueous formaldehyde solution in DME (1,2-dimethoxyethane)/H2O cosolvent condition [8,9]. Therefore, there was a possibility that Sc(DS)3 could form chiral complex with L-3 in water. First, the asymmetric ring opening of cis-stilbene oxide with aniline in water was investigated.

Chiral β-amino alcohol units can be found in many biologically active compounds and chiral auxiliaries/ligands used in asymmetric reactions [10]. Catalytic enantioselective synthesis of these chiral building blocks mainly relies on the asymmetric ring opening of meso-epoxides. Indeed, several examples using a chiral catalyst (typically a chiral Lewis acid) are reported in literature [11]; however, all these reactions proceeded in organic solvents. It is probable that epoxides are readily decomposed under acidic conditions in water.

Using 1 mol % of Sc(DS)3 and 1.2 mol % of L-3 in water, the reaction proceeded smoothly in high yield with high enantioselectivity (Scheme 1.8). It is noted that the ring-opening reaction proceeded smoothly in water, and that no diol formation was observed. This is to date the first example of an asymmetric epoxide ring opening in water as a sole solvent [12,13].

Scheme 1.8.

Moreover, catalytic asymmetric ring-opening reactions of meso-epoxides with indoles, alcohols, and thiols proceed smoothly in the presence of catalytic amounts of Sc(DS)3 and chiral bipyridine ligand L-3 in water to afford β-amino alcohols in high yields with high enantioselectivities (Schemes 1.9 and 1.10) [14,15]. These results suggest that an excellent asymmetric environment is created in water.

Scheme 1.9.

Scheme 1.10.

1.2.1.4. Hydroxymethylation in Water

Several asymmetric organic reactions have been achieved in water without any organic cosolvents. These reactions proceeded smoothly by creating hydrophobic areas in water to stabilize and concentrate organic substrates or by suppressing the undesired pathway in the reaction mechanism by water. One of the key factors for these successes is hydrophobicity of substrates. Therefore, asymmetric reactions in water with hydrophilic substrates are far more challenging.

An aqueous formaldehyde solution, or formalin, is one of the most important C1 electrophiles as well as a representative of hydrophilic substrates. Asymmetric hydroxymethylation using an aqueous formaldehyde solution has been investigated in water-organic cosolvent systems [16,17], Since the hydrophobicity of a substrate is an important factor, it is assumed that hydrophilic substrates are very difficult to handle in water.

Hydroxymethylation of silicon enolate 2 with 36% aqueous formaldehyde solution (aq. HCHO) was studied in detail. The yield of 3 was improved when the amount of formaldehyde was increased from 1 to 5 equiv with a catalyst loading dependency (Scheme 1.11, Part 1a) and for an 8-h reaction (Part 1b). The concentration of aq. HCHO also affected the yield of 3 (Part 1c). With an Sc loading level (10 and 20 mol %) in the presence of 5 equiv of aq. HCHO, the yields were improved to >80% as the concentrations increased up to 2.0 M; however, no improvement was observed by further increasing the concentration. In the cases of the lower Sc loading level (2 and 5 mol %), the yields leveled off at much lower concentrations, 0.5 and 1.0 M, respectively. These results indicated that Sc(DS)3 might be saturated by aq. HCHO. Based on the experiments, it can be said that, in spite of the extreme solubility of HCHO in water, the population of HCHO in the hydrophobic environment increases in the presence of Sc(DS)3 due to Lewis acid–Lewis base interaction between Sc(DS)3 and HCHO, and therefore, the reaction of HCHO with silicon enolate 2 can proceed smoothly even in water.

Scheme 1.11. Part 1a. Hydroxymethylation of 2 (catalyst loading and HCHO equiv, reaction concentration was 1.0 M, reaction time was 1 h). Part 1b. Hydroxymethylation of 2 (reaction time and HCHO equiv, reaction concentration was 1.0 M). Part 1c Hydroxymethylation of 2 (catalyst loading and concentration, reaction time was 8 h).

Furthermore, the hydroxymethylation of various silyl enol ethers proceeded smoothly (Scheme 1.12). Consequently, these experiments suggest that Lewis acid-surfactant combined catalyst (LASC) reaction system can be applied to hydrophilic substrates as well as hydrophobic substrates.

Scheme 1.12.

Lewis acid-catalyzed asymmetric reactions in water using hydrophilic substrates are recognized as highly challenging [18], considering the importance of Lewis acid–Lewis base interactions, since Lewis acids lose their acidity upon coordination from chiral ligands. Additionally, chiral ligands compete with substrates and water molecules for coordination with Lewis acids. Therefore, the development of chiral Lewis acid-catalyzed hydroxymethylation using aq. HCHO with water as the sole solvent would make a great impact in the field.

The investigation of asymmetric variants of hydroxymethylations using aq. HCHO revealed that the addition of a chiral ligand and a small amount of a surfactant suppressed the competitive hydrolysis of silicon enolates. Eventually, catalytic asymmetric hydroxymethylation reactions are successfully carried out in the presence of a catalytic amount of Sc(DS)3, chiral ligand L-3 [19], or L-4 [20] in the presence of additives to afford the desired products in high yields with high selectivities. It is noteworthy that thioketene silyl acetals, which are known to be much less stable than silyl enol ethers (ketone-derived silicon enolates) in water, reacted smoothly under the conditions to afford the desired hydroxymethylated adducts in good yields with high enantioselectivities (Scheme 1.13).

Scheme 1.13.

This method could be applied to the synthesis of an artificial odorant (S)-(+)-3 (Scheme 1.14) [12]. Hydroxymethylation of 1 was performed using Sc(DS)3•L-3 as a catalyst. After the reaction, the reaction mixture was centrifuged (3000 rpm, 20 min) to separate the colloidal white dispersion into three phases. The upper, middle, and bottom phases are water, surfactant, and organic layers, respectively. After the separation of organic phase, followed by hydrogenation with polymer incarcerated palladium (PI-Pd) [13] in benzotrifluoride (BTF), the compound (S)-(+)-3 was obtained in 56% yield with 91% ee over two steps. It should be noted that the synthesis has been accomplished using a catalytic asymmetric reaction in water and a hydrogenation with an immobilized catalyst, which are suitable for green sustainable chemistry [3,14].

Scheme 1.14.

1.2.1.5. Silica Gel-Supported Scandium with Ionic Liquid (Silica-Sc-IL)

A novel heterogeneous scandium catalyst system, Silica-Sc-IL, has been developed (Scheme 1.15) [21].

Scheme 1.15.

The catalyst 4 coated with an IL, [DBIm]SbF6, works efficiently in Mukaiyama aldol reaction in water (Scheme 1.16). The reaction proceeds much faster in water than in organic solvents, without solvent or in the absence of IL.

Scheme 1.16.

These experiments clearly suggest that Silica-Sc-IL and IL forms hydrophobic reaction environments in water (Scheme 1.17). It should be noted that water-labile reagents such as 5 can work well in water under the conditions, and that this is the first demonstration of a combination of silica gel-supported metal catalysts and ILs to create efficient hydrophobic environments for organic reactions in water.

Scheme 1.17.

Although there is room to improve the results, an asymmetric catalysis can be realized using Silica-Sc-IL combined with a ligand L-3 (Scheme 1.18).

Scheme 1.18.

1.2.2. Chiral Organocatalysis in Water

In contrast to metal-based catalysts, organocatalyses are easy to handle, since they are, in general, stable in water. Amino acids are representative of organocatalysts and their derivatives have been widely investigated. Tert-butyldimethylsilyl (TBS)-protected hydroxyproline L-5 catalyzes a direct-type aldol reaction, leading to the aldol adduct in good yield with high diastereo- and enantioselectivities. And a Michael reaction of a ketone or an aldehyde with β-nitrostyrene in brine can be catalyzed by a proline derivative L-6 to afford the corresponding product in good yield with good diastereo- and enantioselectivities (Scheme 1.19). Moreover, a threonine derivative L-7 catalyzes Mannich reaction to produce the product in good yield with high diastereo- and enantioselectivities (Scheme 1.20) [22].

Scheme 1.19.

Scheme 1.20.

The Diels–Alder reaction is a powerful transformation method in organic chemistry. Chiral imidazolidinone can successfully catalyze the reaction of α,β-unsaturated ketones with dienes, where chiral Lewis acid catalysts showed lower enantioselectivities (Scheme 1.21) [23,24].

Scheme 1.21.

1.2.3. Others

1.2.3.1. Asymmetric Reactions Using Alkynes

[25] Optically active propargylamines are important synthetic intermediates for various nitrogen-containing compounds, a structural feature of many biologically active compounds and natural products. The most reliable and efficient methods for the preparation of optically active propargylic amines are still dependent on the addition of appropriate organometallic reagents to chiral imine derivatives. While methods for catalyzed preparation of optically active propargylic amines are still limited, highly enantioselective direct-type alkyne-imine addition was recently reported using a chiral Cu(I)•L-9 complex. The process is simple and provides a diverse range of propargylic amines in high enantioselectivity (Scheme 1.22) [26].

Scheme 1.22.

The conjugate addition reaction of terminal alkynes to C=C bond can be catalyzed by copper in water. The reaction only proceeds with derivatives of Meldrum’s acids in the presence of Cu(I) produced by Cu(OAc)2 and sodium ascorbate in water, and a large excess amount of phenylacetylyne. Combined with chiral ligand L-10, enantioselective versions of this addition reaction can be achieved to 82–97% ee of products with useful yields [27] (Scheme 1.23).

Scheme 1.23.

1.2.3.2. DNA-Based Asymmetric Catalysis in Water

The DNA-based asymmetric Diels–Alder reaction proceeds in water. There are three key structural features: a DNA-intercalating moiety, a spacer component, and a metal-binding group, which intimately anchored the metal complexes to DNA to use its chiral information. The substituent and the spacer length of the ligand are crucial for both of enantioselectivity and the enantiopreference [28].

1.2.3.3. Pauson–Khand-Type Reaction in Water

The chiral ligand BINAP [2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl] together with [RhCl(COD)]2/TPPTS (trisodium salt of 3,3′,3″-phosphanetriyl benzene sulfonic acid) is effective for the asymmetric Pauson-Khand-type reaction in water. Formaldehyde can be used as a source of carbon monoxide directly in water (Scheme 1.24) [29].

Scheme 1.24.

Rhodium-catalyzed asymmetric Pauson–Khand-type reactions in water work well in the presence of a chiral atropisomeric dipyridyldiphosphane ligand (S-P-Phos), transforming various enynes into the corresponding bicyclic cyclopentenones in good yields and ees (up to 95% ee) (Scheme 1.25) [30].

Scheme 1.25.

1.2.4. Conclusion and Perspective

Organic reactions in other, nonconventional solvents instead of organic solvents are now of interest in many aspects related to green sustainable chemistry. The first choice of a nonconventional solvent is water. Water is a clean, nontoxic, inexpensive, and the most environmentally friendly solvent. In addition, acid catalysis has occupied major parts of organic transformations. Therefore, the chiral acid catalysis in water we have discussed here will play a key role in this field.

As we described, organic reactions in water are difficult because most organic materials are not soluble and many reactive intermediates and catalysts are not stable in water. In addressing these issues, many focused research efforts have led to rapid progress, exemplified by elegant asymmetric catalysis in water, which was believed to be impossible 10 years ago. Moreover, systems have been developed for the recovery and reuse of catalysts utilizing biphasic reaction conditions that incorporate water.

As for the future of asymmetric catalysis in water, several important developments are predicted. Stereoselective carbon–carbon bond-forming reactions are still an important challenge in organic synthesis, and in particular, control of the stereogenic centers of products is crucial. From this aspect, the development of catalytic asymmetric reactions in water is still a major task, which represents significant challenges since most asymmetric catalysts, except for some late transition metal-based systems, are not stable in water. As such the design of water-compatible catalysts will be the key to the future of this work. Asymmetric aerobic oxidation in water is an important research target for the future. It will not be necessary to mention the importance of environmentally benign oxidation processes to this readership, but due to the high heat capacity and stability of water, the process is promising. The use of water-soluble small molecules such as formaldehyde and ammonia will be another critical area. These molecules are inexpensive and potentially useful carbon and nitrogen building blocks; however, they are not well utilized in conventional organic synthesis in organic solvents. Asymmetric catalysis using formaldehyde and ammonia will be a key project not only in academia but also in industry.

1.3. CATALYTIC ASYMMETRIC SYNTHESIS IN ALTERNATIVE REACTION MEDIA

Since many chiral catalysts are valuable and indeed expensive, recovery and reuse of the catalysts is especially important in industry. For this purpose, nonconventional solvents have been investigated. In this section, fluorous solvents, SCFs, and ILs are described.

1.3.1. Fluorous Solvents

Fluorous compounds with appropriate melting and boiling points can be used as solvents. Interestingly, these fluorous compounds are remarkably different from the corresponding hydrocarbons and form bilayers with conventional organic solvents. In terms of recovery and reuse of catalysts, fluorous media is of great interest. Since fluorous solvents tend to mix poorly with common organic solvents, some catalysts can be immobilized in fluorous solvents in biphasic systems. In addition, one of the characteristic points in fluorous-organic biphasic systems is that some combination of fluorous and organic solvents demonstrates increased miscibility at elevated temperature, and that heating can result in a completely homogeneous mixture in such cases. This is remarkably different from water-organic biphasic systems. Accordingly, in fluorous-organic biphasic systems, it is possible to carry out reactions under homogeneous conditions at elevated temperature, and after the reactions occur, the mixture is cooled to become two phases. While products are separated from organic solvent phases, catalysts can be recovered from fluorous solvent phases.

Since the first report of fluorous biphasic systems (FBSs) [31], reactions using fluorous solvents have been recognized as green reactions due to simple procedures and use of chemically inert and low toxicity fluorous solvents. In the past decade, FBSs have been widely applied to asymmetric reactions.

A typical and very successful application of FBS is chiral phase transfer catalyst for α-amino acid synthesis. Synthetically convenient 4,4′,6,6′-tetrasubstituted symmetrical chiral phase-transfer catalysts promote asymmetric alkylation of t-butylglycinate–benzophenone schiff base [32]. The substituent of the 4,4′,6,6′-positions of binaphthyl effects on chiral efficiency and the SiMe2(CH2CH2C8F17)-substituted catalyst designed as a recyclable fluorous chiral phase-transfer catalyst can promote the reaction’s good chiral efficiency and reusability (Scheme 1.26).

Scheme 1.26.

The chiral fluorous complex tetrakis-dirhodium(II)-(S)-N-(n-perfluorooctylsulfonyl) prolinate (L-13) displays good chemo- and enantioselectivity in intermoleculer cyclopropanation and C–H bond activation reactions (Scheme 1.27). The catalyst can be simply and thoroughly separated from the reaction mixture and is recyclable [33].

Scheme 1.27.

Rh-[Rf(CH2)3]2-BINAPHOS complex catalyzes hydroformylation of alkynes in fluorous solvents. “The desired branch product from styrene is obtained in comparable or even higher regio- and enantioselectivities than those of the conventional Rh-BINAPHOS (L-14) system [34].

More applications of FBSs to asymmetric reactions such as the hydrogenation of ketones [35], epoxidations [36], and C–C bond formations [37–41] have been reported.

1.3.2. Catalytic Asymmetric Synthesis in SCFs

SCFs are also focused as nonconventional solvents. SCFs are probably best known through their use for the decaffeination of coffee, which employs supercritical carbon dioxide (scCO2). SCFs represent a different type of nonconventional solvent from water, fluorous solvents, ILs, and even organic solvents, because they are not in the liquid state. An SCF is defined as a substance above its critical temperature (Tc) and pressure (Pc), but below the pressure required for condensation to a solid. The critical point represents the highest temperature and pressure at which the substance can exist as a vapor and liquid under equilibrium. Hence, in a closed system, as both temperature and pressure are increasing, the liquid becomes less dense due to thermal expansion, and the gas becomes dense as the pressure rises. The densities of both phases thus converge until they become identical at the critical point. At this point, the two phases become indistinguishable and an SCF is obtained. In such SCFs, remarkable reactivities and selectivities are sometimes observed. From a process perspective, scCO2 offers the advantage that simple depressurization removes residual scCO2, and, therefore, no hazardous solvent effluent is produced. This leads to a facile separation of products. This organic solvent-free process is of great interest in the pharmaceutical, cosmetic, food, and electronic industries where highly pure materials are very important.

Catalytic asymmetric synthesis in SCFs has been investigated. Iridium-catalyzed asymmetric hydrogenation of imines is successfully carried out in scCO2 [42]. Cationic Ir(I)•L-15 complex with a perfluoroalkyl group in the counter anion is very effective for efficient asymmetric catalysis. In the presence of 0.078 mol % of the catalyst, an imine derived from acetophenone is reduced within 1 h in scCO2 at 40°C under H2 (30 bar) to afford the corresponding amine in high yield with high enantioselectivity (Scheme 1.28). It is noted that the catalyst loading is decreased dramatically by using scCO2 instead of conventional solvents such as dichloromethane (DCM). The product is readily separated from the catalyst, which can be reused several times without significant loss of activity.

Scheme 1.28.

Asymmetric hydrogenation also proceeds smoothly in scCO2 by using the perfluoroalkyl-substituted ligand (R,S)-3-H2F6-BINAPHOS (L-16) and Rh complex (Scheme 1.29) [43]. Another Rh•L-17 complex for asymmetric hydrogenation in scCO2 has also been reported (Scheme 1.30) [44]. In these cases, the catalysts are soluble in scCO2 to form homogeneous systems during the reactions.

Scheme 1.29.

Scheme 1.30.

On the other hand, the continuous flow scCO2 system [45] has been applied to asymmetric hydrogenation using [Rh(COD)2]+[BF4]−/H3O40PW12/alumina (CATAXA®) and Josiphos 001 ligand (L-18) as an immobilized chiral catalyst [46]. A mixture of H2, CO2, and a substrate (dimethyl itaconate) in 2-propanol is poured into a hydrogenation reactor with the chiral Rh catalyst, and the product is obtained with 83% ee (Scheme 1.31). In this system, neither perfluoroalkyl-substituted ligands nor counter anions with perfluoroalkyl groups are used. scCO2 is utilized to dissolve H2 and for ease of product separation.

Scheme 1.31.

A similar flow system with an immobilized chiral Ru•L-19 complex for asymmetric cyclopropanation reaction in scCO2 has been reported. It is demonstrated that productivity in scCO2 has been increased 7.7-fold compared with that in DCM. Environmental friendliness and ease of product separation are further merits (Scheme 1.32) [47].

Scheme 1.32.

An inverted scCO2/aqueous biphasic system has been used as reaction media for Rh-catalyzed asymmetric hydrogenation. Chiral CO2-philic catalysts are efficiently immobilized in scCO2 as the stationary phase, while polar substrates and products are contained in water as a mobile phase. The catalyst phase is reused several times with high conversion and product recovery of more than 85%. The chiral ligand (R,S)-3-H2F6-BINAPHOS (L-16) allows highly enentioselective hydrogenation of itaconic acid and methyl-2-acetamidoacrylate under these conditions [48].

1.3.3. IL

ILs are defined as materials that are composed of ions and have melting points below 100°C (the temperature may be flexible). ILs have many properties that lend themselves to clean chemical synthesis, perhaps most notably that they are nonvolatile and are therefore not lost to the atmosphere. The main advantages are that catalyst lifetimes can be extended, often considerably, and rates of reactions are accelerated in many cases. In addition, recovery and reuse of catalysts is possible using biphasic or multiphasic catalyst systems. Efficient reactions with organic compounds under homogeneous conditions in an IL, followed by extraction of the products with scCO2, provide an ideal process without any volatile organic solvents. Typical ILs are shown in Scheme 1.33.

Scheme 1.33. Major classes of ionic liquids.

1.3.3.1. Asymmetric Hydrogenation in ILs

The catalytic enantioselective hydrogenation of unsaturated bonds such as C=C, C=O, and C=N in the presence of molecular hydrogen or hydrogen donor is one of the most useful chemical transformations. Since molecular hydrogen is used as the reactant in many cases, it is clear that the solubility of hydrogen gas in ILs is an important factor in catalyzed reactions. It has been suggested that increased reaction rates in biphasic hydrogenation reactions in ILs could be due to high solubility of hydrogen in the IL, and the correlation of ILs and the solubility of molecular hydrogen has been studied [49].

Since the first report of enantioselective metal-catalyzed reaction in ILs [50], asymmetric hydrogenation of carbon–carbon double bonds and carbon–heteroatom double bonds has been the most investigated transformation. Several combinations of transition metals, chiral ligands, and ILs have been studied for these reactions [51].

Rh and Ru-chiral phosphine or Ru-chiral diamine complexes are often combined with N,N’-dialkylimizazolium salts [52,53]. The Rh-catalyzed hydrogention of C=C bond such as α-acetoamide cinnamic acid and related enamides works well to give the corresponding products with high enantioselectivities (Scheme 1.34). The catalyst can be reused, and IL can suppress the catalyst aging in some cases; however, in other cases, the catalyst loses its activity in the process of recycling, probably because of leaching or deactivation [54].

Scheme 1.34.

Imidazolium moieties were introduced to chiral diphosphine ligand (L-21) in order to attach the catalyst to the IL phase. The modified catalyst can work efficiently in the hydrogenation and can be recovered and reused without significant loss of activity (Scheme 1.35) [55].

Scheme 1.35.

With a similar concept, Josephos ligands with an imidazolium tag can be applied to the asymmetric hydrogenation of methyl acetamidiacrylate and dimethyl itaconate in biphasic cosolvent/IL combinations (Scheme 1.36) [56,57]. The introduction of an imidazolium group in the Josephos ligand improves the affinity of the Rh complex for the IL to lead the suppression of catalyst leaching in the combination of t-butyl methyl ether (TBME)/[bmim]BF4. The catalyst can be recycled and reused with efficient product isolation.

Scheme 1.36.

Ru-BINAP and its derivative complexes are very common reagents for asymmetric hydrogenation [58]. [Ru(O2CMe)2•((R)-tolBINAP)] in [bmim][PF6]/H2O system promotes the hydrogenation of tiglic acid to give the corresponding product in excellent conversion with good ee (Scheme 1.37). The enantioselectivity depends on hydrogen pressure, and water enhances enantioselectivity at high pressure, while there is no effect of adding water at low pressure. To avoid the use of organic solvents, supercritical carbon dioxide (scCO2) can be applied to this reaction to recover the organic product from the reaction mixture. Since Ru catalyst is not soluble in scCO2, the product can be extracted from IL by scCO2 and is contaminated only by water. The catalyst can be immobilized to the IL layer, therefore efficiently reused multiple times without loss of activity and even with enhanced enantioselectivity [59].

Scheme 1.37.

1.3.3.2. Asymmetric Diels–Alder Reaction in ILs

Copper catalysts based on imidazolium-tagged bis(oxazolines) enhance the reaction rate and enantioselectivity of the corresponding product in the reaction of N-acyloyl and N-crotonyloxazohdinones with cyclopentadiene and 1,3-cyclohexadiene (Scheme 1.38) [60].

Scheme 1.38.

The induction of an imidazolium tag into bis(oxazolines) significantly improves the recovery and reuse of the catalyst for reactions performed in IL. The catalyst can be recycled at least 10 times without loss of activity and enantioselectivity. Furthermore, the imidazolium-functioned ligand does not leach into the organic phase [61,62].

1.3.3.3. Asymmetric Epoxidation in ILs

Mn-salen complex 11 catalyzes asymmetric epoxidation of alkenes efficiently in IL [63,64]. Since IL is solidified at the reaction temperature, the reaction requires the use of DCM to form homogenous solution. IL enhances the catalyst’s reactivity, and, moreover, IL and chiral complex can be recycled up to five times with only slight loss of ee and catalyst activity (Scheme 1.39).

Scheme 1.39.

1.3.3.4. Asymmetric Ring Opening of Epoxides in ILs

Cr(salen) complex (Cr•L-26) catalyzes ring opening of epoxides with TMSN3 in [C4C1im][PF6] and [C4C1im][OTf] at room temperature. The catalyst can be recycled up to five times without loss of ee and can even enhance its activity [65] (Scheme 1.40).

Scheme 1.40.

Chiral Co(III)(salen) complex catalyzes hydrolytic kinetic resolution of racemic epoxides in ILs. Co(II)(salen) complex is oxidized without acetic acid to catalytically active Co(III)(salen) complex during the reaction, and this oxidation state is stabilized against reduction to Co(II) complex. The catalyst can be reused 10 times without loss of ee and reactivity [66] (Scheme 1.41).

Scheme 1.41.

1.3.3.5. Asymmetric Dihydroxylation in ILs

Osmium-catalyzed asymmetric dihydroxylation constitutes a versatile method for the synthesis of chiral vicinal diols from alkenes. Its industrial utility suffers from several disadvantages, mainly the high cost of osmium and chiral ligands and the toxicity of the metal, which may contaminate the optically active product. To address these issues, many efforts to modify these catalysts have been made. The main way to utilize chiral OsO4 catalysts efficiently is to immobilize the catalyst to polymers [67], porous resins [68], and the other various solid supports [69]. IL can also provide functions to support the catalysts [70]. In the asymmetric dihydroxylation of trans-stilbene catalyzed by OsO4 (1.5 mol %) and ligand L-27 (2.0 mol %) in the presence of N-methylmorpholine N-oxide (NMO) (2.6 mol %) and [C4C1im][PF6] (2 mL for 2-mmol scale) in acetone–water (v/v, 10/1) at 0°C, the catalyst can be recovered in IL phase and reused up to three times without significant loss of activity and ee with only a small amount of OsO4 (<2% of the total amount) leaching from IL phase to organic phase [71].

1.3.3.6. Asymmetric Fluorination in ILs

Chiral Pd-BINAP complex-catalyzed enantioselecttive fluorination of β-ketoesters and β-ketophosphonates can be achieved in ILs (Scheme 1.42). The reactions proceed smoothly to afford the corresponding products in good yields with ees in most cases [72]. The catalyst can be reused up to 10 times with slight loss of activity.

Scheme 1.42.

1.3.3.7. Others

There are some more reactions such as asymmetric allylic substitution [73], asymmetric cyclopropanation [74], asymmetric synthesis of cyanhydrines [75], asymmetric allylation [76], asymmetric addition of alkynes to imines [77], and asymmetric hydroamination [78], These reactions have been investigated in ILs; however, considering the property, character, and aim of using ILs, reuse of the catalysts should be further investigated.

1.4. MICROWAVE-ASSISTED CATALYTIC ASYMMETRIC SYNTHESIS

Microwave irradiation has been widely accepted in academic chemical laboratories as well as pharmaceutical companies. The use of this nonconventional method in chemical transformations can be traced back several decades, and since the first reports were published [79], the number of publications regarding microwave-assisted organic synthesis has been increasing. Chemists generally use a microwave to heat chemical reactions on a laboratory scale [80]. Direct microwave heating can reduce chemical reaction times from days or hours to minutes or even seconds, and therefore suppress undesired side reactions, increase chemical yields, and improve reproducibility. Thus, microwave-assisted organic chemistry is an aspect of green chemistry. Two microwave effects are known.

(1) Microwave-enhanced thermal effects

Each material such as a solvent, a reagent, a reaction intermediate, and a catalyst has its own ability to absorb microwave energy and convert it into heat. Microwave-enhanced chemistry is based on this ability, induced by the electric dipole of the material. Compared with conventional heating, some specific features of microwave heating include (i) selective heating of specific reaction components, (ii) rapid heating rates and temperature gradients, (iii) elimination of reaction vessel wall effects, and (iv) superheating of solvents.

(2) Nonthermal microwave effects

These effects have been proposed in order to explain unusual observations in microwave chemistry, and do not involve the transfer of microwave energy into thermal energy, as the name suggests. The details are still under discussion.

In general, high reaction temperatures will invariably lead to the loss of selectivities. This phenomenon may be one of the reasons why comparatively few enantioselective processes under microwave heating have been reported, in contrast to non-enantioselective procedures. In this chapter, several representative examples of enantioselective reactions are described.

1.4.1. Asymmetric Allylic Alkylations

Molybdenum • ligand L-29 complex catalyzes asymmetric allylic alkylation of the carbonate 6 with dimethyl malonate under microwave heating with a shortened reaction time, affording the product 7 with excellent regio- and enantioselectivities, whereas 8 is obtained predominantly in the presence of a palladium catalyst (Scheme 1.43) [81,82]. The reaction proceeds at 220°C by flush heating in tetrahydrofuran (THF), far above its boiling point under normal pressure. Under microwave conditions, the reaction systems are exposed to considerable pressure in closed vessels. Any rate acceleration in such cases might be caused by high temperature and the change of the physical properties of the solvents. Therefore, it is difficult to compare microwave conditions and conventional heating conditions directly.

Scheme 1.43.

1.4.2. Enantioselective Arylation and Alkylation of Aromatic Aldehydes

Microwave irradiation also has an impact on arylation of aromatic aldehydes via arylzinc addition using aziridine-based ligand [83,84]. A reactive arylzinc is generated from an aryl boronic acid and Et2Zn by microwave irradiation for 10 min. Followed by the addition of an aldehyde and a ligand, further microwave heating for 5 min accelerates the reaction. The reaction time can be reduced from 1 h to 15 min by changing conventional heating to microwave radiation (Scheme 1.44).

Scheme 1.44.

1.4.3. Asymmetric Heck Reactions (1)

Asymmetric Pd-catalyzed Heck reaction, that is, coupling of an aryl or alkyl halide or triflate and an alkene, is one of the most powerful and versatile procedures in carbon–carbon bond-forming reactions, since it tolerates several functional groups. In an intermolecular Heck reaction such as 2,3-dihydrofuran with phenyl triflate, regioselectivity is problematic because the undesired product 10 is obtained in addition to 9 due to an isomerization in the reaction process (Scheme 1.45).

Scheme 1.45.

Several ligands such as phosphanyloxazoline (PHOX) ligands have been successfully discovered for intermolecular Heck reactions [85,86]. In spite of their accomplishments, one of the drawbacks with N, P ligands is long reaction times for full conversion. To address this issue, microwave irradiation has been applied to asymmetric Heck reactions [87–89]. The reaction of 2,3-dihydrofurane, cyclopentene, and 4,7-dihydro-1,3-dioxepin with phenyl- or cyclohexenyl triflate employing either ligand L-31 or L-32 combined with Pd catalyst produces the corresponding products in excellent conversion yields with high regio- and enantioselectivities (Scheme 1.46). Compared with the optimized conditions that require conventional heating at 50°C, microwave heating at 70°C dramatically shortens the reaction time from up to 2.5 days to 10–45 min.

Scheme 1.46.

1.4.4. Asymmetric Heck Reactions (2); Total Synthesis of (+)-Minfiensine [90]

Microwave irradiation has been applied to a key step, intramolecular asymmetric Heck reaction of substrate 11, in the total synthesis of (+)-minfiensine. The reaction is conducted at 170°C for 45 min to afford 12 in high yield with excellent ee. Furthermore, the shorter reaction time allowed the catalyst loading to be reduced to 10 mol % of Pd. In the second generation of the total synthesis of (+)-minfiensine, hydroboration of 13 proceeds under microwave heating with 9-BBN at 100°C in THF, whereas no reaction takes place under reflux conditions. Followed by the oxidation with trans-chelating chiral bisphosphine ligands (TPAP)/NMO, the desired ketone 14 is obtained as a major product in 63% yield. Consequently, (+)-minfiensine is successfully synthesized in 6.5% overall yield (15 steps) (Scheme 1.47).

Scheme 1.47.

1.4.5. Organocatalyzed Asymmetric Reactions

Proline-catalyzed Mannich reactions have been intensively investigated [91,92]. Although high enantioselectivities and high yields have been achieved for several substrates, two drawbacks have been pointed out: relatively high catalyst loading and relatively longer reaction times.

Direct asymmetric Mannich reactions among cyclohexanone, formaldehyde, and various anilines are performed under microwave heating, and the reactions are thermally accelerated in the presence of only 0.5 mol % of catalyst. Mannich products with up to 98% ee are obtained after a short reaction time. In situ reduction of the resulting ketones affords N-aryl amino alcohols in up to 86% yield (Scheme 1.48) [93].

Scheme 1.48.

Chiral organocatalyzed aldol reaction, Michael-type reaction, and Diels–Alder reaction have been applied to microwave-assisted reactions [94]. In all cases, the reaction times are dramatically shortened. The most successful example in terms of enantioselectivity was bipyrrolidine-catalyzed Michael-type reaction. Compared with conventional heating (Conditions B), it is clear that microwave heating accelerates the reaction without loss of diastereo- and enantioselectivities (Scheme 1.49).

Scheme 1.49.

1.5. CONCLUSION/PERSPECTIVE

Catalytic asymmetric synthesis in nonconventional media/conditions has been surveyed. While chiral catalysts have been developed in conventional organic solvents, nonconventional media/conditions are important not only from a scientific aspect but also from an economical point of view. Since many elegant in vitro reactions are carried out in an aqueous environment in our bodies, catalytic symmetric reactions in water under in vitro