Polymeric Chiral Catalyst Design and Chiral Polymer Synthesis E-Book

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

Seitenzahl: 698

Veröffentlichungsjahr: 2011

Beschreibung

This book reviews chiral polymer synthesis and its application to asymmetric catalysis. It features the design and use of polymer-immobilized catalysts and methods for their design and synthesis. Chapters cover peptide-catalyzed and enantioselective synthesis, optically-active polymers, and continuous flow processes. It collects recent advances in an important field of polymer and organic chemistry, with leading researchers explaining applications in academic and industry R & D.

Leseprobe

Contents

Cover

Title Page

Copyright

Preface

Foreword

Contributors

Chapter 1: An Overview of Polymer-Immobilized Chiral Catalysts and Synthetic Chiral Polymers

1.1 Introduction

1.2 Polymeric Chiral Catalyst

1.3 Synthesis of Optically Active Polymers

References

Chapter 2: Polymer-Immobilized Chiral Organocatalyst

2.1 Introduction

2.2 Synthesis of Polymer-Immobilized Chiral Organocatalyst

2.3 Polymer-Immobilized Cinchona Alkaloids

2.4 Other Polymer-Immobilized Chiral Basic Organocatalysts

2.5 Polymer-Immobilized Cinchona Alkaloid Quaternary Ammonium Salts

2.6 Polymer-Immobilized MacMillan Catalysts

2.7 Polymer-Immobilized Pyrrolidine Derivatives

2.8 Other Polymer-Immobilized Chiral Quaternary Ammonium Salts

2.9 Polymer-Immobilized Proline Derivatives

2.10 Polymer-Immobilized Peptides and Poly(amino acid)s

2.11 Polymer-Immobilized Chiral Acidic Organocatalysts

2.12 Helical Polymers as Chiral Organocatalysts

2.13 Cascade Reactions Using Polymer-immobilized Chiral Organocatalysts

2.14 Conclusions

List of Abbreviations

References

Chapter 3: Asymmetric Synthesis Using Polymer-Immobilized Proline Derivatives

3.1 Introduction

3.2 Polymer-Supported Proline

3.3 Polymer-Supported Prolinamides

3.4 Polymer Supported Proline-Peptides

3.5 Polymer-Supported Pyrrolidines

3.6 Polymer-Supported Prolinol and Diarylprolinol Derivatives

3.7 Conclusions and Outlooks

References

Chapter 4: Peptide-Catalyzed Asymmetric Synthesis

4.1 Introduction

4.2 Poly(amino acid) Catalysts

4.3 Tri- and tetrapeptide Catalysts

4.4 Longer peptides with a secondary structure

4.5 Others

4.6 Conclusions and Outlooks

References

Chapter 5: Continuous Flow System using Polymer-Supported Chiral Catalysts

5.1 Introduction

5.2 Asymmetric Polymer-Supported, Metal-Based Catalysts and Reagents

5.3 Polymer-Supported Asymmetric Organocatalysts

5.4 Polymer-Supported Biocatalysts

5.5 Conclusions

References

Chapter 6: Chiral Synthesis on Polymer Support: A Combinatorial Approach

6.1 Introduction

6.2 Chiral Synthesis of Complex Polyfunctional Molecules on Polymer Support

6.3 Conclusions

References

Chapter 7: Synthesis and Application of Helical Polymers with Macromolecular Helicity Memory

7.1 Introduction

7.2 Macromolecular Helicity Memory

7.3 Enantioselective Reaction Assisted by Helical Polymers with Helicity Memory

7.4 Conclusions

References

Chapter 8: Poly(isocyanide)s, Poly(quinoxaline-2,3-diyl)s, and Related Helical Polymers Used as Chiral Polymer Catalysts in Asymmetric Synthesis

8.1 Introduction

8.2 Asymmetric Synthesis of Poly(isocyanide)s

8.3 Asymmetric Synthesis of Poly(quinoxaline)s

8.4 Enantioselective Catalysis using Helical Polymers

8.5 Conclusions

References

Chapter 9: C2 Chiral Biaryl Unit-Based Helical Polymers and Their Application to Asymmetric Catalysis

9.1 Introduction

9.2 Synthesis of C2 Chiral Unit-Based Helical Polymers

9.3 Asymmetric Reactions Catalyzed by Helical Polymer Catalysts

9.4 Conclusions

References

Chapter 10: Immobilization of Multicomponent Asymmetric Catalysts (MACs)

10.1 Introduction

10.2 Dendrimer-Supported and Dendronized Polymer-Supported MACs

10.3 Nanoparticles as Supports for Chiral Catalysts [13]

10.4 The Catalyst Analog Approach [24]

10.5 Metal-Bridged Polymers as Heterogeneous Catalysts: An Immobilization Method for MACs Without Using Any Support [26]

10.6 Conclusion

References

Chapter 11: Optically Active Polymer and Dendrimer Synthesis and Their Use in Asymmetric Synthesis

11.1 Introduction

11.2 Synthesis and Application of BINOL/BINAP-Based Optically Active Polymers

11.3 Synthesis and Application of Optically Active Dendrimers

11.4 Conclusions

Acknowledgment

References

Chapter 12: Asymmetric Polymerizations of N-Substituted Maleimides

12.1 Introduction

12.2 Chirality of 1-Mono- or 1,1-Disubstituted and 1,2-Disubstituted Olefins

12.3 Asymmetric Polymerizations of Achiral N-Substituted Maleimides

12.4 Anionic Polymerization Mechanism of RMI

12.5 Asymmetric Polymerizations of Chiral N-Substituted Maleimides

12.6 Structure and Absolute Stereochemistry of Poly(RMI)

12.7 Asymmetric Radical Polymerizations of N-Substituted Maleimides

12.8 Chiral Discrimination using Poly(RMI)

12.9 Conclusions

References

Chapter 13: Synthesis of Hyperbranched Polymer Having Binaphthol Units via Oxidative Cross-Coupling Polymerization

13.1 Introduction

13.2 Oxidative Cross-Coupling Reaction between 2-Naphthol and 3-Hydroxy-2-Naphthoate

13.3 Oxidative Cross-Coupling Polymerization Affording Linear Poly(binaphthol)

13.4 Oxidative Cross-Coupling Polymerization Leading to a Hyperbranched Polymer

13.5 Photoluminescence Properties of Hyperbranched Polymers

13.6 Conclusions

References

Chapter 14: Optically Active Polyketones

14.1 Introduction

14.2 Asymmetric Synthesis of Isotactic Poly(propylene-ALT-CO)

14.3 Asymmetric Synthesis of Isotactic Syndiotactic Poly(styrene-ALT-CO)

14.4 Asymmetric Terpolymers Consisting of Two Kinds of Olefins and Carbon Monoxide

14.5 Asymmetric Polymerization of Other Olefins with CO

14.6 Chemical Transformations of Optically Active Polyketones

14.7 Conformational Studies on the Optically Active Polyketones

14.8 Conclusions

References

Chapter 15: Synthesis and Function of Chiral π-Conjugated Polymers from Phenylacetylenes

15.1 Introduction

15.2 Helix-Sense-Selective Polymerization (HSSP) of Substituted Phenylacetylenes and Function of the Resulting One-Handed Helical Poly(phenylacetylene)s

15.3 Chiral desubstitution of Side Groups In Membrane State

15.4 Synthesis of chiral polyradicals

References

Chapter 16: P-Stereogenic Oligomers, Polymers, and Related Cyclic Compounds

16.1 Introduction

16.2 P-Stereogenic Oligomers Containing Chiral “P” Atoms in the Main Chain

16.3 P-Stereogenic Polymers Containing Chiral “P” Atoms in the Main Chain

16.4 Cyclic Phosphines Using P-Stereogenic Oligomers as Building Blocks

16.5 Conclusions

References

colour plates

Index

Copyright © 2011 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Polymeric chiral catalyst design and chiral polymer synthesis / edited by Shinichi Itsuno.

p. cm.

Includes index.

ISBN 978-0-470-56820-0 (cloth)

1. Enantioselective catalysis. 2. Polymers–Synthesis. 3. Chirality. I. Itsuno, Shinichi.

QD505.P64 2011

668.9–dc22

2010053405

oBook ISBN: 978-1-118-06396-5

ePDF ISBN: 978-1-118-06394-1

ePub ISBN: 978-1-118-06395-8

Preface

Polymer-immobilized chiral catalysts and reagents have received considerable attention in regard to organic synthesis of optically active compounds. The use of polymer-immobilized catalysts has become one of the essential techniques in organic synthesis. They can be easily separated from the reaction mixture and reused many times. It is even possible to apply the polymeric catalysts to a continuous flow system. From the point of view of green chemistry, the polymer-immobilized chiral catalysis method should provide a clean and safe alternative to conventional methods of asymmetric processes. Not only their practical aspect but also the particular microenvironment they create in a polymer network will make them attractive for utilization in organic reactions, especially in stereoselective synthesis. In some cases, a polymer-immobilized catalyst accelerates the reaction rate. In other cases, polymer- immobilized chiral catalyst realizes higher stereoselectivity compared with its low-molecular-weight counterpart. These examples clearly show that the design of a polymeric catalyst is very important to understanding the efficient catalytic process. Chiral polymer synthesis that is directed toward a novel immobilization method of chiral catalysts must also be developed.

Most polymeric support materials used for the chiral catalyst have been cross-linked polystyrene derivatives, mainly because of their easy preparation and introduction of functional groups on the side chain of the polymer. However, there are so many different types of synthetic polymers, including both organic and inorganic polymers. Not only linear polymers but also cross-linked, branched, dendritic polymers are available as support for the chiral catalyst. Each polymer support would provide a specific microenvironment for the reaction if they can be precisely designed. Various kinds of polymers have recently been used as support for the chiral catalyst. Although the choice of solvent in an organic reaction is limited, the choice of polymer network structure may be almost infinite. The most suitable polymer network for each reaction may be easily found. In some cases, even water can be used as reaction media in asymmetric reactions with a polymeric catalyst, if amphiphilic polymers are used as the support.

Although a substantial amount of work has been carried out using side-chain functionalized polymers for the preparation of a polymeric catalyst, only a limited number of investigations have been performed to elucidate the use of main-chain functional polymers. For example, polycondensation of chiral monomers simply produces main-chain chiral polymers. Asymmetric polymerization is also applied to prepare new chiral polymers. Recently some main-chain chiral polymers including helical polymers have been successfully applied to a chiral catalyst in various kinds of asymmetric reactions. Because of the importance of main-chain chiral polymers in an asymmetric catalyst, this book also focuses on the synthesis of polymers having main-chain chirality. Other types of chiral polymers such as chiral dendrimers and hyperbranched polymers are also involved. Application of these chiral polymers to polymeric asymmetric catalysis are introduced in this book.

Several review articles on asymmetric reactions using a polymer-immobilized catalyst have been published. However they do not contain a detailed discussion on chiral polymer synthesis, which can be used as a polymeric chiral catalyst. This book comprises 16 review-type chapters, which involve an overview of the research area of asymmetric catalysis using a polymer-immobilized catalyst and synthesis of chiral polymers. Chapter 1 (S. Itsuno) provides an overview of polymer-immobilized chiral catalyst design and synthetic chiral polymers, which should offer guidance to a broad audience. Chapter 2 (N. Haraguchi and S. Itsuno) describes recent developments on the study of a polymer-immobilized chiral organocatalyst. Chapters 3 (M. Gruttadauria, F. Giacalone, and R. Noto) and 4 (K. Kudo and K. Akagawa) describe polymer-immobilized amino acids and peptides and their application to asymmetric catalysis. One of the most important practical applications of an immobilized catalyst is its use in a continuous flow system. S. V. Luis and E. Garcia-Verdugo present details of the system in asymmetric synthesis (Chapter 5). An important method for creating chiral molecules is chiral synthesis on the polymer. D. B. Salunke and C.-M. Sun describe the chiral synthesis on polymer support in Chapter 6. Chapters 7 (H. Iida and E. Yashima), 8 (M. Suginome and Y. Nagata), and 9 (T. Maeda and T. Takata) describe helical polymer synthesis and its application to asymmetric synthesis. Chapter 10 (H. Sasai and S. Takizawa) presents a unique approach to preparing chiral polymeric catalyst, so-called muticomponent asymmetric catalysts (MACs). BINOL-based chiral polymers, dendrimers, and hyperbranched polymers are reviewed in Chapters 11 (Q.-S. Hu and L. Pu) and 13 (S. Habaue). Asymmetric synthesis polymerization has only recently been developed. Asymmetric polymerization of N-substituted maleimiedes is described in Chapter 12 (K. Onimura and T. Oishi). Another successful example of asymmetric polymerization is the synthesis of chiral polyketones, which is presented in Chapter 14 (K. Nozaki). Helical polymers of phenylacetylenes have also been vigorously developed during the past decade. T. Aoki, T. Kaneko, and M. Teraguchi present the synthesis and function of these polymers in Chapter 15. There are limited numbers of examples for the synthesis of chiral polymers containing chiral heteroatoms. P-stereogenic polymers are one topic of great interest. Y. Morisaki and Y. Chujo describe such chiral polymers in Chapter 16.

The aim of this book is to provide a concise and comprehensive treatment of this continuously growing field of chiral polymers, focusing not only on the design of the polymer-immobilized asymmetric catalysts but also on the synthetic aspects of chiral polymers and dendrimers. I gratefully acknowledge the work of all authors in presenting up-to-date contributions. Without their efforts, this book would not have been possible.

Shinichi Itsuno

Toyohashi, Japan

October 2010

Foreword

Chiral polymers have found widespread applications as separation media for the separation of enantiomers. For example, the chiral media pioneered decades ago by Y. Okamoto are used extensively not only in analytical laboratories but also in the pharmaceutical industry on an industrial scale. In the related field of chiral catalysis, polymers are finding increasingly significant applications. The Editor of this book, Professor Shinichi Itsuno, who played a crucial role in the development of the field, has now assembled an excellent team of experts to cover the field of chiral polymers from their preparation to their application in various forms of catalysis.

The book is thorough in its coverage of the field, exploring both polymers with chirality in the side chain and polymers with chirality in the main chain. The former have been the most extensively explored, which is attributed in large part to their ease of preparation from readily obtained precursors. The latter, already widely used in chiral separations, are also generating increasing interest for their applications in catalysis.

Interest in the field of polymer-based chiral catalysts may be traced in part to the pioneering work of Bruce Merrifield and Robert Letsinger who demonstrated the advantages of using polymers in the solid-phase synthesis of oligopeptides and oligonucleotides, respectively. One key advantage of these approaches was the ease of isolation of materials attached to a solid polymer support. This advantage proved critical in the early stages of development of chiral polymers as catalysts by facilitating their removal from the reaction mixture and enabling their recycling. As the field grew, the importance of a microenvironment within the polymer catalyst was recognized and a great variety of different support materials, each providing a specific microenvironment, was explored.

Today, chiral polymer catalysts are being examined as viable alternatives to small molecules in a variety of organic reactions. In the particular case of stereoselective syntheses, their performance has matched and, in some cases, exceeded that of small-molecule analogs in terms of both stereoselectivity and reaction kinetics while providing clear processing and recycling advantages. The emergence of intrinsically chiral helical polymers and of globular hyperbranched, star, or dendritic macromolecules with an engineered microenvironment surrounding one or more chiral sites promises more exciting developments in the field, bringing it ever closer to the dream of robust and versatile polymer-based “artificial enzymes.”

This book, which presents the state of the art in the field, is highly recommended to all practitioners of catalysis and asymmetric synthesis as it will no doubt foster ambitious research projects and multiple creative developments in the field.

Jean Frechet

Berkeley and Thuwal

April 2011

Contributors

Kengo Akagawa,  The University of Tokyo, Tokyo, Japan

Toshiki Aoki,  Niigata University, Niigata, Japan

Yoshiki Chujo,  Kyoto University, Kyoto, Japan

Eduardo García-Verdugo,  UAMOA, University Jaume I/CSIC, Castellón, Spain

Francesco Giacalone,  Università di Palermo, Palermo, Italy

Michelangelo Gruttadauria,  Università di Palermo, Palermo, Italy

Shigeki Habaue,  Chubu University, Kasugai, Japan

Naoki Haraguchi,  Toyohashi University of Technology, Toyohashi, Japan

Qiao-Sheng Hu,  College of Staten Island and the Graduate Center of the City, University of New York, Staten Island, New York, USA

Hiroki Iida,  Nagoya University, Nagoya, Japan

Shinichi Itsuno,  Toyohashi University of Technology, Toyohashi, Japan

Takashi Kaneko,  Niigata University, Niigata, Japan

Kazuaki Kudo,  The University of Tokyo, Tokyo, Japan

Santiago V. Luis,  UAMOA, University Jaume I/CSIC, Castellón, Spain

Takeshi Maeda,  Osaka Prefecture University, Sakai, Japan

Yasuhiro Morisaki,  Kyoto University, Kyoto, Japan

Yuuya Nagata,  Kyoto University, Kyoto, Japan

Renato Noto,  Università di Palermo, Palermo, Italy

Kyoko Nozaki,  The University of Tokyo, Tokyo, Japan

Tsutomu Oishi,  Yamaguchi University, Yamaguchi, Japan

Kenjiro Onimura,  Yamaguchi University, Yamaguchi, Japan

Lin Pu,  University of Virginia, Charlottesville, Virginia, USA

Deepak B. Salunke,  National Chiao Tung University, Hsinchu, Taiwan

Hiroaki Sasai,  Osaka University, Osaka, Japan

Chung-Ming Sun,  National Chiao Tung University, Hsinchu, Taiwan

Michinori Suginome,  Kyoto University, Kyoto, Japan

Toshikazu Takata,  Tokyo Institute of Technology, Tokyo, Japan

Shinobu Takizawa,  Osaka University, Osaka, Japan

Masahiro Teraguchi,  Niigata University, Niigata, Japan

Eiji Yashima,  Nagoya University, Nagoya, Japan

Chapter 1

An Overview of Polymer-Immobilized Chiral Catalysts and Synthetic Chiral Polymers

Shinichi Itsuno

1.1 Introduction

Polymer-immobilized chiral catalysts and reagents have received considerable attention in regard to organic synthesis of optically active compounds [1]. Use of polymer-immobilized catalysts has become an essential technique in the green chemistry process of organic synthesis. They can be easily separated from the reaction mixture and reused many times. It is even possible to apply the polymeric catalysts to the continuous flow system. Not only the practical aspect but also particular microenvironment created in the polymer network has sparked a fascination with their attractive utilization in organic reactions, especially in stereoselective synthesis. In some cases, the polymer-immobilized catalyst accelerates the reaction rate. In other cases, the polymer-immobilized chiral catalyst realizes higher stereoselectivity compared with its low-molecular-weight counterpart. These examples clearly show that the design of the polymeric catalyst is very important for understanding the efficient catalytic process. Chiral polymer synthesis that is directed toward the novel immobilization method of chiral catalysts also should be developed.

Most support materials used for the chiral catalyst have been cross-linked polystyrene derivatives, mainly because of their easy preparation. Various kinds of reactions have been used for the introduction of functional groups into the side chain of the polymer. However, there are so many different types of synthetic polymers, including both organic and inorganic polymers, which may be used as support material. Each polymer would provide a specific microenvironment for the reaction if it was precisely designed. Although the choice of solvent in organic reaction is limited, the choice of polymer network structure may be almost infinite. The most suitable polymer network for each reaction may be easily found.

Although a substantial amount of work has been carried out using side-chain functionalized polymers for the preparation of a polymeric catalyst, only a limited number of investigations have been performed to elucidate the use of main-chain functional polymers. Recently, some main-chain chiral polymers including helical polymers have been successfully applied to a chiral catalyst in various kinds of asymmetric reactions. Because of the importance of main-chain chiral polymers in an asymmetric catalyst, this book also focuses on the synthesis of polymers that have main-chain chirality. Polymerization of enantiopure monomers simply produces optically active polymers. Although most enantiopure monomers involve a chiral carbon center, polymerization of some monomers consists of chiral heteroatoms such as silicon and phosphorous, which also have been studied. Asymmetric polymerization by means of a repeated asymmetric reaction between prochiral monomers has been applied to obtain optically active polymers. Several types of main-chain chiral polymers have been prepared by asymmetric polymerization.

Helicity is an important factor in characterizing a chirality of macromolecules. Helical synthetic polymers have gained increasing interest on the basis of recent progress in asymmetric polymer synthesis [2–4]. Efficient induction of the main-chain helical sense to macromolecules, such as poly(methacrylate)s [5], poly(isocyanate)s [6, 7], poly(isocianide)s [8], poly(acetylene)s [9], poly(quinoxaline-2,3-diyl)s [10, 11], and polyguanidines [12], has been achieved. Other types of chiral polymers such as chiral dendrimers and hyperbranched polymers are also involved. Major application of these chiral polymers should be focused on the polymeric asymmetric catalyst.

1.2 Polymeric Chiral Catalyst

Synthetic chiral polymers include (1) polymers possessing side-chain chirality (Scheme 1.1), (2) polymers possessing main-chain chirality (Scheme 1.2), (3) dendritic molecules containing chiral ligands (Scheme 1.3), and (4) helical polymers (Scheme 1.4). The use of polymeric chiral catalysts in asymmetric synthesis is an area of considerable research interest, and it has been the subject of several excellent reviews during the last decade. [13–21]

Scheme 1.1 Polymer having a side-chain chiral ligand.

Scheme 1.2 Polymer containing a main-chain chiral ligand.

Scheme 1.3 Periferally modified chiral dendrimer.

Scheme 1.4 Helical polymer catalyst.

Polymeric catalysts obviously have considerable advantages over the corresponding low-molecular-weight counterparts. They can be easily separated from the reaction mixture, which can be reused many times. The catalyst stability is usually improved in the case of a polymeric catalyst. Catalyst immobilization on a polymer sometimes results in the site isolation effect, which is also important when the catalyst molecule has a tendency to be aggregated to each other. Immobilization of the catalyst can prevent the aggregation of catalysts. The insolubility of the polymeric catalysts usually facilitates their separation from the reaction mixture. The application of the polymeric catalyst to the continuous flow system becomes possible when the insoluble polymer is used. Although many heterogeneous reactions using the polymeric catalyst suppress the reactivity, in some cases, even higher stereoselectivity with sufficient reactivity in the asymmetric reaction is obtained by using well-designed polymeric chiral catalysts. The conformational influence of the polymeric chiral catalysts sometimes becomes a very important factor in the asymmetric reaction.

1.2.1 Polymers Having a Chiral Pendant Group

Polymer-immobilized chiral catalysts and reagents have received considerable attention in the organic synthesis of optically active compounds. A typical example of a polymeric catalyst is the polymer-immobilized catalyst. The achiral polymer chain possesses the chiral ligand as a side-chain pendant group. In most cases, polystyrene or cross-linked polystyrene has been used as the polymer support. Because phenyl groups in polystyrene can be easily modified to introduce functional groups, various kinds of chiral ligands are attached to the polystyrene supports (Scheme 1.5). Polyethylene fibers [22], polymeric monoliths [23, 24], poly(2-oxazoline) [25], polyacetylene [26], poly(ethylene glycol) [27], and poly(methylmethacrylate) [28] have also been developed.

Scheme 1.5 Cross-linked, polystyrene-supported chiral ligand (polymer reaction method).

An alternative method to preparing the polymer-supported chiral ligand is the polymerization of the chiral monomer with an achiral comonomer and cross-linking agent (Scheme 1.6). Styrene derivatives have been most frequently used as the chiral monomer because of their easy polymerizability with other vinyl monomers [29]. Acrylates and methacrylates have been sometimes used as the chiral monomer [30, 28].

Scheme 1.6 Cross-linked, polystyrene-supported chiral ligand (polymerization method).

Various kinds of chiral catalysts have been immobilized on the polymer. Because enantioselective organocatalysis has become a field of central importance within asymmetric synthesis, Chapter 2 focuses on polymer-immobilized chiral organocatalysts. Proline and its derivatives are also important organocatalysts, which are discussed in Chapter 3. The use of polymer-imobilized peptides as enantioselective catalysts have been vigorously studied as well and are discussed in Chapter 4.

1.2.2 Main-Chain Chiral Polymers

Many naturally occurring polymers are optically active and have several functionalities. In 1956, Akabori et al. reported that silk-palladium was used as a chiral catalyst for asymmetric hydrogenation of 4-benzylidene-2-methyl-5-oxazolone [31]. The catalyst was prepared by adsorption of palladium chloride on silk fibroin fiber. This was one of the first examples of the polymer-immobilized chiral catalyst for an asymmetric reaction. Silk is a polymer that has main-chain chirality.

Instead of naturally occurring proteins, synthetic poly(amino acid)s have been applied to asymmetric catalysis. Investigations have been performed to elucidate the use of main-chain functional polymers. N-Carboxyanhydride (NCA) prepared from an optically active α-amino acid can be polymerized with amine as an initiator to produce poly(α-amino acid). Juliá et al. discovered that the use of poly(L-alanine) as a “polymeric chiral organocatalyst” produced high enantioselectivities in the epoxidation of chalcone [32]. Itsuno and coworkers also developed cross-linked polystyrene-immobilized poly(α-amino acid)s that allowed for easier workup and recovery [33]. Well-designed peptides have also been used as catalysts in many asymmetric reactions. Chapter 4 includes the important examples of peptide catalysts.

Other than peptides and poly(α-amino acid)s, various kinds of optically active compounds can be polymerized to produce optically active polymers that have main-chain chirality. For example, a reaction between disodium salt of tartaric acid and achiral diol in the presence of toluene-p-sulfonic acid produced chiral polyester [34]. The linear poly(tartrate ester) was used as a polymeric chiral ligand in the asymmetric Katsuki–Sharpless epoxidation.

Binaphthol and its derivatives are well-known efficient chiral ligands in asymmetric catalysis. Pu and colleagues studied the pioneering work of enantiopure binaphthol polymers. A class of rigid and sterically regular polymeric chiral catalysts has been developed [35]. Detailed discussion on binaphthol polymers is shown in Chapter 11. Hyperbranched polymers that have binaphthol units are also discussed in Chapter 13.

The polymeric chiral salen ligand was prepared with a polycondensation reaction and subsequently used as a polymeric chiral ligand of Zn [36, 37]. Most polymer-supported chiral zinc catalysts have been prepared by side-chain chiral ligand polymers. The polymeric chiral zinc catalyst derived from the main-chain polymeric salen ligand showed high catalytic activity in the enantioselective alkynylation of ketones. The same salen ligand–Mn complex was used for the enantioselective epoxidation [38]. The chiral organometallic catalysts consist of optically active ligands and transition metals. They often involve optically active tertiary phophine ligands. Linkage of such phosphines to organic polymer backbones allows for the preparation of immobilized chiral catalysts.

Recently, chiral organocatalysts have received considerable attention as asymmetric reactions with a chiral organocatalyst meet the green chemistry requirements. One important chiral organocatalyst is optically active quaternary ammonium salt [39, 40]. Quaternary ammonium salts can be easily prepared by a reaction between tertiary amine and halide (Scheme 1.7). Polymerization of tertiary diamine and dihalide produces a quaternary ammonium polymer named “ionene” [41–44]. Polymers containing a chiral quaternary ammonium structure in the main chain can be easily prepared by this method. If the chiral quaternary ammonium compound has extra functionality such as the diol group, then the chiral diol is copolymerized with dihalide to produce chiral polymers that have a quaternary ammonium structure in their main chain [45]. These chiral quaternary ammonium polymers are discussed in Chapter 2.

Scheme 1.7 Chiral ionene polymer.

1.2.3 Dendrimer-Supported Chiral Catalysts

Dendritic molecules are a new class of polymers having well-defined, highly branched structures [46]. Several types of chiral catalyst immobilization on dendrimers have been reported. Core-functionalized chiral dendrimers, periferally modified chiral dendrimers, and solid-supported dendritic chiral catalysts are available (Scheme 1.8) [47]. In some cases, the dendritic chiral catalyst showed better performance compared with the corresponding low-molecular-weight catalyst. When a core-functionalized chiral dendrimer that has polymerizable groups on the peripheral site was copolymerized with an achiral monomer, a cross-linked chiral dendrimer was produced, which can be recycled many times [48].

Scheme 1.8 Dendritic chiral catalyst.

Optically active hyperbranched polymers have some structural similarity with chiral dendrimers. Synthesis of such polymers is relatively simple compared with the stepwise synthesis of a chiral dendritic molecule. Several types of optically active hyperbranched polymers have also been prepared and used as a polymeric chiral catalyst [49].

1.2.4 Helical Polymers

The conventional approach to the polymer-immobilized catalyst involves the introduction of the chiral ligand onto a sterically irregular polymer backbone, which sometimes results in less effective catalysts. A helix is one of the simplest and best-organized chiral motifs. Efficient induction of the main-chain helical sense to polymers produces optically active helical polymers. Several helical polymers with an excess of a preferred helix sense have been synthesized to mimic the structures and functions of biological polymers such as proteins and nucleic acids [50–52]. Helical polymers with catalytic active sites have been developed and used as chiral catalysts. Some helical polymers have been used as catalysts for enantioselective reactions [53]. Chapters 7, 8, 9 involve some typical examples of helical polymer catalysts for asymmetric reactions.

1.2.5 Multicomponent Asymmetric Catalysts

The highly organized multicomponent asymmetric catalysts shown in Scheme 1.9 have been developed and used as catalysts for several asymmetric transformations [54]. Some of these catalysts were attached to a polymer support by using the catalyst analog method. After copolymerization of a catalyst analog with a monomer in the presence of a cross-linker, the connecting group was exchanged by the catalytically active metal. The polymer-supported multicomponent asymmetric catalysts have been successfully used in some asymmetric reactions such as the Michael reaction [55]. Typical examples are summarized in Chapter 10.

Scheme 1.9 Multicomponent asymmetric catalysts.

The combination of the chiral multidentate ligand with a metal atom forms metal-bridged polymers (Scheme 1.10) [56]. Multicomponent asymmetric catalysts have been developed as efficient immobilization of the chiral catalyst in the polymer. Compared with the conventional approach, multicomponent asymmetric catalysts involve the regularly introduced catalyst sites. Moreover, this approach provides a simple and efficient method for immobilization without the need for a polymer support. For example, Al-Li-bis(binaphthoxide) and μ-oxodititanium complexes have been used as catalysts for the asymmetric Michael addition and the asymmetric carbonyl–ene reactions, respectively.

Scheme 1.10 Metal-bridged chiral polymeric catalyst.

1.2.6 Continuous Flow System

One of the most common methods of simplifying isolation has been to attach one reactant to an insoluble polymer bead. Once the reaction is complete, the species supported on the polymer will be easily separated from the others by simple filtration [57]. The polymer-immobilized catalysts are used not only for the batch system but also for the flow system when the catalyst is packed in a column. The advantage of the continuous system in organic synthesis is that it allows the products of the reaction to be isolated more quickly and easily than traditional methods. The flow system can eliminate the stirring that sometimes causes damage on the polymer beads. Application of the flow system to an asymmetric reaction was initiated by Itsuno et al. in asymmetric borane reduction of ketones [58]. The continuous flow system has been applied to various asymmetric reactions, including asymmetric Michael reacions [59] and alkylation [60, 61]. Glyoxylate–ene reaction [62], α-chlorination [63], Michael reaction [59], and cyclopropanation [64] facilitate the reaction process. Important examples of flow system are summarized in Chapter 5.

1.3 Synthesis of Optically Active Polymers

Most naturally occurring macromolecules, such as proteins, DNA, and cellulose, are optically active, and a well-controlled polymer chain configuration and conformation makes it possible to realize highly sophisticated functions in a living system. Considerable attention has been paid to their unique properties and functions. Optically active, higher ordered structures of these macromolecules would be essential in their functions, including molecular recognition, catalytic activity, and substrate specificity. These considerations have motivated considerable interest in the synthesis and application of optically active polymers [65]. The synthetic chiral polymers have many applications, such as separation of chiral compounds and polymeric catalysis in asymmetric reactions. Considerable effort has been devoted toward the synthesis of optically active polymers. A simple method to prepare optically active polymers is polymerization of enantiopure monomers. This method produces optically active polymers that have main-chain chirality. When some chiral functionality is introduced as a pendant group of the nonchiral polymers, the optically active polymers with side-chain chirality are available. Most polymeric chiral catalysts are classified as a side-chain chiral polymer. Chirality can also be created on a polymer by an asymmetric reaction. A highly stereoselective asymmetric reaction on a polymer produces a chiral polymer. Several applications are discussed in Chapter 6. Another method for preparing optically active polymers is a repetitive asymmetric reaction between prochiral monomers. Various asymmetric reactions can be used to synthesize optically active polymers with the asymmetric polymerization of prochiral monomers (Chapters 12 and 15) [8, 50, 52, 66–68].

1.3.1 Asymmetric Reaction on Polymer

An asymmetric reaction by using a polymer-immobilized catalyst and reagent has recently received a great deal of attention, as mentioned, for establishing green chemistry processes in organic synthesis of optically active compounds. However, asymmetric transformations on polymer support is also an important strategy for obtaining various kinds of optically active compounds. This methodology is especially useful in diversity-oriented synthesis, which involves the preparation of compound libraries [69, 70]. These libraries display a wide range of physical and biological properties, which can be useful in assays to identify novel lead compounds. Enantioselective catalysis is also used in diversity-oriented synthesis of optically active compounds. Achiral or chiral substrate molecules attached on the polymer support were transformed into a chiral product [71]. Synthesis of a variety of natural products using combinatorial chemistry methods also has been demonstrated [72].

1.3.2 Helical Polymers and Hyperbranched Polymers

Helical structures in polymers are among the most fundamental and important features of macromolecules [3, 52, 73]. Optically active helical polymers can be obtained by (1) polymerization of an optically active monomer, (2) asymmetric polymerization of an achiral monomer, and (3) enantiomer-selective polymerization of racemic monomers. Various kinds of helical polymers containing poly(isocyanate)s [74, 75], poly(isocyanide)s [76], polychloral [77], poly(alkylmethacrylate), polysilanes [78], poly(acetylene)s [79, 80], poly(thiophene)s [81], and polyguanidines [82, 83] have been synthesized.

One of the most impressive studies on optically active helical polymers has been Yashima et al.'s discovery of the memory of helicity. When the chiral inducer was replaced with achiral compounds, the helicity was completely reproduced by the memory of the macromolecular helicity [84–89]. These helical polymers are described in Chapter 7.

Other important examples of helical polyacetylenes include chiral poly(N-propargylamide) [90] and poly(phenylacetylene) derivatives [91]. The helical structure in the polymer is stabilized by means of intramolecular hydrogen bonds. Helix-sense-selective polymerization of achiral and bulky phenylacetylene monomers was performed in the presence of [Rh(cod)Cl]2 and enantiopure 1-phenylethylamine [92]. Chiral π-conjugated polymers from phenylacetylenes are sumamrized in Chapter 15.

Polymerization of maleimides having optically active N-substituent produces one-handed helical polymers. Asymmetric polymerization of achiral N-substituted maleimide also has been investigated [93]. Details on asymmetric polymerization of maleimide derivatives are described in Chapter 12.

Helix-sense-selective polymerization of isocyandie was initiated by Nolte et al. [76]. Optically active amine-nickel(II) complexes catalyzed the polymerization of achiral isocyanide to produce helical polyisocyanide [76]. Another helix-sense-selective polymerization of achiral isocyanide was performed by using a single-handed helical oligomer complex [94]. Structurally related poly(quinoxaline-2,3-diyl) was developed by Ito and Suginome and Coworkers [10, 11, 95]. Highly screw-sense-selective polymerization of quinoxaline has been achieved by using optically active binaphthylpalladium(II) [96]. Recently Suginome et al. showed that high-molecular-weight, polyquinoxaline-based helically chiral phosphine was successfully used as a chirality-switchable, reusable, and highly enantioselective monodentate ligand in catalytic asymmetric hydrosilylation of styrene [97]. Related topics are detailed in Chapter 8.

1.3.3 Heteroatom Chiral Polymers

Polymers containing inorganic elements in the main chain have been widely synthesized. However, only a few optically active polymers containing chiral heteroatoms in the main chain have been reported. One typical example is a silicon containing chiral polymers. Although a silicon atom is not a stereogenic center, polysilanes adopt screw-sense helical structures [74]. Polycabosilans [98, 99], polysiloxans [100], polyc(siloxane)s [101], and oligosilanes are other examples of optically active polymers containing silicon as chiral heteroatoms.

An interesting approach to heteroatom chiral polymers is the incorporation of P-stereogenic centers into the polymer main chain. Chujo et al. have synthesized optically active polymers containing chiral phosphorous atoms in the main chain [102–105]. Because various types of P-stereogenic phosphimes have been used as chiral ligands for transition-metal–catalyzed asymmetric reactions, development of the corresponding polymeric catalysts is highly expected. Several recent reviews on chiral polymers with heteroatoms as chiral centers are described in Chapter 16.

1.3.4 Asymmetric Polymerization

Optically active polymers are definitely important in a variety of applications, including the polymeric catalysts in asymmetric synthesis and separation of racemic mixtures. Many naturally occurring polymers are optically active. Synthetic chiral polymers can also be prepared by several methods. Polymerization of optically active monomers simply produces chiral polymers. The main-chain chiral polymers discussed in Section 1.2.2 obviously belong to this category. Another way to prepare optically active polymers is asymmetric polymerization. Prochiral monomers are polymerized with a chiral catalyst to produce the optically active polymers (Scheme). A typical example is helical polymer synthesis by means of asymmetric polymerization.

Scheme 1.11 Asymmetric polymerization of prochiral monomers.

Basically, many asymmetric reactions can be applied to synthesize optically active polymers [68]. An asymmetric reaction between monomers should produce corresponding polymers that have chiral centers in the main chain of the polymer. For example, an asymmetric aldol reaction has been vigorously developed in the field of organic synthesis. Optically active polymers were prepared by means of a repeated asymmetric aldol reaction [106, 107]. Asymmetric allylation polymerization [108, 109] and asymmetric Diels–Alder polymerization [110, 111] were also developed.

Asymmetric polymeization of propyrene and CO has been successfully performed in the presence of the chiral phosphinephosphite Pd complex [112]. Chiral 1,4-polyketones bearing asymmetric carbons in the main chain have been prepared in an asymmetric manner initiated by optically active transition metal complexes. Chapter 14 covers the synthesis of optically active polyketones.

References

1. (a) In Handbook of Asymmetric Heterogeneous Catalysis (Ding, K.; Uozumi, Y., Eds.), Wiley-VCH Verlag GmbH, Weinheim, Germany (2008). (b) In Recoverable and Recyclable Catalysts (Benaglia, M., Ed.) Wiley, New York (2009).

2. (a) Nakano, T.; Okamoto, Y. Chem. Rev.2001, 101, 4013–4038. (b) Cornelissen, J. J. L. M.; Rowan, A. E.; Nolte, R. J. M.; Sommerdijk, N. A. J. M. Chem. Rev.2001, 101, 4039–4070. (c) Fujiki, M. Macromol. Rapid Comm.2001, 22, 539–563. (d) Yashima, E.; Maeda, K. In Foldamers: Structure, Properties, and Applications (Hecht, S. Huc, I., Eds.), Wiley-VCH: Weinheim, Germany, ch. 11 (2007).

3. Cornelissen, J. J. L. M.; Rowan, A. E.; Nolte, R. J. M.; Sommerdijk, N. A. J. M. Chem. Rev.2001, 101, 4039–4070.

4. Yashima, E.; Maeda, T.; Nishimura, T. Chem. Eur. J.2004, 10, 42–51.

5. Okamoto, Y.; Suzuki, K.; Ohta, K.; Harada, K.; Yuki, H. J. Am. Chem. Soc.1979, 101, 4763–4765.

6. Lifson, S.; Felder, C. E.; Green, M. M. Macromolecules, 1992, 25, 4142–4148.

7. Okamoto, Y.; Matsuda, M.; Nakano, T.; Yashima, E. Polymer J. 1993, 25, 391–396.

8. Suginome, M.; Ito, Y. Adv. Polymer Sci.2004, 171, 77–136.

9. Maeda, K.; Mochizuki, H.; Watanabe, M.; Yashima, E. J. Am. Chem. Soc.2006, 128, 7639–7650.

10. Ito, Y.; Ihara, E.; Murakami, M.; Shiro, M. J. Am. Chem. Soc.1990, 112, 6446–6447.

11. Ito, Y.; Miyake, T.; Hatano, S.; Shima, R.; Ohara, T.; Suginome, M. J. Am. Chem. Soc.1998, 120, 11880–11893.

12. Schlitzer, D. S.; Novak, B. M. J. Am. Chem. Soc.1998, 120, 2196–2197.

13. Bergbreiter, D. E. In Chiral Catalyst Immobilization and Recycling (De Vos, D. E.; Vankelecom, I. F. J.; Jacobs, P. A.Eds.), Wiley-VCH Verlag GmbH, Weinheim, Germany, pp. 43–80 (2000).

14. Clapham, B.; Reger, T. S.; Janda, K. D., Tetrahedron2001, 57, 4637–4662.

15. Leadbeater, N. E.; Marco, M. Chem. Rev.2002, 102, 3217–3273.

16. McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. Rev.2002, 102, 3275–3299.

17. Brase, S.; Lauterwasser, F.; Ziegert, R. E. Adv. Synth. Catal.2003, 345, 869–929.

18. El-Shehawy, A. A.; Itsuno, S. Curr. Top. Polymer Res.2005, 1–69.

19. Dioos, B. M. L.; Vankelecom, I. F. J.; Jacobs, P. A. Adv. Synth. Catal.2006, 348, 1413–1446.

20. Itsuno, S.; Haraguchi, N. In Handbook of Asymmetric Heterogeneous Catalysis (Ding, K. Uozumi, Y. Eds.), Wiley-VCH Verlag GmbH, Weinheim, Germany, pp. 73–129 (2008).

21. Cozzi, F. Adv. Synth. Catal.2006, 348, 1367–1390.

22. Degni, S.; Wilen, C. E.; Leino, R. Tetrahedron: Asymmetry2004, 15, 231–237.

23. Bruguete, M. I.; Verdugo, E. G.; Vincent, M. J.; Luis, S. V.; Pennemann, H.; Keyserling, N. G.; Martens, J. Org. Lett.2002, 4, 3947–3950.

24. Svec, F.; Frechet, J. M. J. Science1996, 273, 205–211.

25. Zarka, M. T.; Nuyken, O.; Weberskirch, R. Chem. Eur. J.2003, 9, 3228–3234.

26. Sanda, F.; Araki, H.; Masuda, T. Chem. Lett.2005, 34, 1642–1643.

27. Wang, X.; Yin, L.; Yang, T.; Wang, Y. Tetrahedron: Asymmetry2007, 18, 108–114.

28. Sekiguti, T.; Iizuka, Y.; Takizawa, S.; Jayaprakash, D.; Arai, T.; Sasai, H. Org. Lett.2003, 5, 2647–2650.

29. Arakawa, Y.; Chiba, A.; Haraguchi, N.; Itsuno, S. Adv. Synth. Catal.2008, 350, 2295–2304.

30. Arai, T.; Sekiguchi, T.; Otsuki, K.; Takizawa, S.; Sasai, H. Angew. Chem. Int. Ed.2003, 115, 2194–2197.

31. Akabori, S.; Sakurai, S.; Izumi, Y.; Fujii, Y. Nature1956, 178, 323–324.

32. Juliá, S.; Masana, J.; Vega, J. C. Angew. Chem. Int. Ed. Engl.1980, 19, 929–931.

33. Itsuno, S.; Sakakura, M.; Ito, K. J. Org. Chem.1990, 55, 6047–6049.

34. Canali, L.; Karjalainen, J. K.; Sherrington, D. C.; Hormi, O. Chem. Comm.1997, 123–124.

35. Johannsen, M.; Jorgensen, K. A.; Zheng, X. -F.; Hu, Q. -S.; Pu, L. J. Org. Chem.1999, 64, 299–301.

36. Cozzi, P. G. Angew. Chem. Int. Ed.2003, 42, 2895–2898.

37. Pathak, K.; Bhatt, A. P.; Abdi, S. H. R.; Kureshy, R. I.; Khan, N. -U. H.; Ahmad, I.; Jasra, R.V. Chirality2007, 19, 82–88.

38. Kureshy, R. I.; Khan, N. H.; Abdi, S. H. R.; Singh, S.; Ahmed, I.; Jasra, R. V. J. Mol. Catal. Chem.2004, 218, 141–146.

39. Ooi, T.; Maruoka, K. Angew. Chem. Int. Ed.2007, 46, 4222–4266.

40. Hashimoto, T.; Maruoka, K. Chem. Rev.2007, 107, 5656–5682.

41. Casson, D.; Rembaum, A. Macromolecules1972, 5, 75.

42. Noguchi, H.; Rembaum, A. Macromolecules1972, 5, 253.

43. Rembaum, A.; Noguchi, H. Macromolecules1972, 5, 261.

44. Yu, Q.; Frömmel, J.; Wolff, T.; Stepanek, M.; Procházka, K. Langmuir2005, 21, 6797.

45. Itsuno, S.; Paul, D. K.; Ishimoto, M.; Haraguchi, N. Chem. Lett.2010, 39, 86–87.

46. Fréchet, J. M. J.; Tomalia, D. A. Dendrimers and Other Dendritic Polymers, Wiley, Chichester, U.K. (2002).

47. Fan, Q.; Deng, G.; Feng, Y.; He, Y. In Handbook of Asymmetric Heterogeneous Catalysis, (Ding, K. Uozumi, Y., Eds.), Wiley-VCH, Weinheim, Germany, p. 131 (2008).

48. Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem. Int. Ed., 2001, 40, 92–138.

49. Slagt, M. Q.; Stiriba, S. E.; Holger Kautz, H.; Gebbink, R. J. M. K.; Holger Frey, H.; Koten, G. Organometallics2004, 23, 1525–1532.

50. Okamoto, Y.; Nakano, T. Chem. Rev.1994, 94, 349–372.

51. Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.; Lifson, S. Science1995, 268, 1860–1866.

52. Nakano, T.; Okamoto, Y. Chem. Rev.2001, 101, 4013–4038.

53. Hasegawa, T.; Goto, H.; Furusho, Y.; Katagiri, H.; Yashima, E. Angew. Chem. Int. Ed.2007, 46, 5885–5888.

54. Shibasaki, M.; Yoshikawa, N. Chem. Rev.2002, 102, 2187–2209.

55. Arai, T.; Sekiguti, T.; Otsuki, K.; Takizawa, S.; Sasai, H. Angew. Chem. Int. Ed.2003, 42, 2144–2147.

56. Jayaprakash, D.; Takizawa, S.; Arai T.; Sasai, H. J. Exp. Nanosci.2006, 1, 477–510.

57. Mak, X. Y.; Laurino, P.; Seeberger, P. H. Beilstein J. Org. Chem. 2009. 5, 1–11.

58. Itsuno, S.; Ito, K.; Maruyama, T.; Kanda, N.; Hirao, A.; Nakahama, S. Bull. Chem. Soc. Jpn.1986, 59, 3329–3331.

59. Bonfils, F.; Cazaux, I.; Hodge, P.; Caze, C. Org. Biomol. Chem.2006, 4, 439–497.

60. Hodge, P.; Sung, D. W. L.; Stratford, P. W. J. Chem. Soc., Perkin. Trans.1999, 1, 2335–2342.

61. Pericas, M. A.; Herrerias, C. I.; Sola, L. Adv. Synth. Catal.2008, 350, 927–932.

62. Mandoli, A.; Orlandi, S.; Pini, D.; Salvadori, P. Tetrahedron: Asymmetry2004, 15, 3233–3244.

63. France, S.; Bernstein, D.; Weatherwax, A.; Lectka, T. Org. Lett.2005, 7, 3009–3012.

64. Burguete, M. I.; Cornejo, A.; García-Verdugo, E.; García, J.; Gil, M. J.; Luis, S. V.; Martínez-Merino, V.; Mayoral, J. A.; Sokolova, M. Green Chem. 2007, 9, 1091–1096.

65. Coates, G. W. In Comprehensive Asymmetric Catalysis, vol. III (Jacobsen, E. N.; Pfalts, A.; Yamamoto, H. Eds.). Springer, Berlin, Germany, pp. 1329–1349. (1999).

66. Pu, L. Acta Polym. 1997, 48, 116–141.

67. Nozaki, K.; Hiyama. T. J. Organomet. Chem.1999, 576, 248–253.

68. Itsuno, S. Prog. Polymer. Sci.2005, 30, 540–558.

69. Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem. Int. Ed.2009, 48, 104–109.

70. Spandl, R. J.; Bender, A. Org. Biomol. Chem.2008, 6, 1149–1158.

71. Stavenger, R. A.; Schreiber, S. L. Angew. Chem. Int. Ed.2001, 40, 3417–3421.

72. Doi, T.; Takahashi, T. In Combinatorial Synthesis of Natural Product-Based Libraries, (Boldi, A. M., Ed.), CRC Press, Boca Raton, Fl, pp. 227–245 (2006).

73. Green, M.; Andrea, C.; Reidy, N. J. Am. Chem. Soc.1988, 110, 4063–4065.

74. Fujiki, M. Macromol. Rapid Comm.2001, 22, 539–563.

75. Okamoto, Y.; Matsuda, M.; Yashima, E. J. Polymer Sci.: Part A1994, 32, 309–315.

76. (a) Kamer, P.; Nolte, R.; Drenth, W. J. Am. Chem. Soc.1988, 110, 6818–6825. (b) Kamer, P. C. J.; Nolte, R. J. M.; Drenth, W. J. Am. Chem. Soc.1988, 110, 6818–6825.

77. Ute, K.; Hirose, K.; Hatada, K. J. Am. Chem. Soc.1991, 113, 6305–6306.

78. Fujiki, M.; Koe, J. R.; Terao, K.; Sato, T.; Teramoto, A.; Watanabe, J. Polymer J. 2003, 35, 297–344.

79. Nakano, H.; Nomura, R.; Masuda, T. Macromolecules1999, 32, 2861–2864.

80. Yashima, E.; Huang, S.; Okamoto, Y. Macromolecules1995, 28, 4184–4193.

81. Langeveld-Voss, B.; Meijer, E. J. Am. Chem. Soc.1996, 118, 4908–4909.

82. Tian, G.; Lu, Y.; Novak, B. M. J. Am. Chem. Soc.2004, 126, 4082–4083.

83. Tang, H. Z.; Lu, Y.; Tian, G.; Capracotta, M. D.; Novak, B. M. J. Am. Chem. Soc.2004, 126, 3722–3723.

84. Yashima, E.; Maeda, K.; Okamoto, Y. Nature1999, 399, 449–451.

85. Hase, Y.; Ishikawa, M.; Muraki, R.; Maeda, K.; Yashima, E. Macromolecules2006, 39, 6003–6008.

86. Hase, Y.; Mitsutsuji, Y.; Ishikawa, M.; Maeda, K.; Okoshi, K.; Yashima, E. Chem. Asian J.2007, 2, 755–763.

87. Hasegawa, T.; Morino, K.; Tanaka, Y.; Katagiri, H.; Furusho, Y.; Yashima, E. Macromolecules2006, 39, 482–488.

88. Miyagawa, T.; Furuko, A.; Maeda, K.; Katagiri, K.; Furusho, Y.; Yashima, E. J. Am. Chem. Soc.2005, 127, 5018–5019.

89. Maeda, K.; Morino, K.; Okamoto, Y.; Sato, T.; Yashima, E. J. Am. Chem. Soc.2004, 126, 4329–4342.

90. Nomura, R.; Tabei, J.; Masuda, T. J. Am. Chem. Soc.2001, 123, 8430–8431.

91. Aoki, T.; Kaneko, T.; Maruyama, N.; Sumi, A.; Takahashi, M.; Sato, T.; Teraguchi, M. J. Am. Chem. Soc.2003, 125, 6346–6347.

92. Kaneko, T.; Umeda, Y.; Jia, H.; Hadano, S.; Teraguchi, M.; Aoki, T. Macromolecules2007, 40, 7098–7102.

93. Oishi, T.; Isobe, Y.; Onimura, K.; Tsutsumi, H. Polymer J. 2003, 35, 245–254.

94. Takei, F.; Yanai, K.; Onitsuka, K.; Takahashi, S. Angew. Chem. Int. Ed. Engl.1996, 35, 1554–1556.

95. Suginome, M.; Collet, S.; Ito, Y. Org. Lett.2002, 4, 351.

96. Ito, Y.; Ohara, T.; Shima R.; Suginome, M. J. Am. Chem. Soc.1996, 118, 9188–9189.

97. Yamamoto, T.; Yamada, T.; Nagata, Y.; Suginome, M. J. Am. Chem. Soc.2010, 132, 7899–7901.

98. Kawakami, Y.; Takeyama, T.; Komuro, K.; Ooi, O. Macromolecules1998, 31, 551–553.

99. Kakihana, Y.; Uenishi, K.; Imae, I.; Kawakami, Y. Macromolecules2005, 38, 6321–6326.

100. Oishi, M.; Kawakami, Y. Org. Lett., 1999, 1, 549–552.

101. Zhou, D.; Kawakami, Y. Macromolecules2005, 38, 6902–6908.

102. Morisaki, Y.; Saito, K.; Imoto, H.; Suzuki, K.; Ouchi, Y.; Chujo, Y. Polymer Sci. Ser. A2009, 51, 1218–1228.

103. Ouchi, Y.; Morisaki, Y.; Ogoshi, T.; Chujo, Y. Chem. Asian J.2007, 2, 397–402.

104. Morisaki, Y.; Ouchi, Y.; Tsurui, K.; Chujo, Y. J. Polymer Sci. Part A: Polymer Chem.2007, 45, 866–872.

105. Morisaki, Y.; Ouchi Y.; Tsurui, K.; Chujo Y. Polymer Bull. 2007, 58, 665–671.

106. Komura, K.; Itsuno, S.; Ito, K. Chem. Comm.1999, 35–36.

107. Itsuno, S.; Komura, K. Tetrahedron2002, 58, 8237–8246.

108. Itsuno, S.; Kumagai, T. Helv. Chim. Acta2002, 85, 3185–3196.

109. Kumagai, T.; Itsuno, S. Macromolecules2002, 35, 5323–5325.

110. Itsuno, S.; Tada, S.; Ito, K. Chem. Comm.1997, 933–934.

111. Kamahori, K.; Tada, S.; Ito, K.; Itsuno, S. Macromolecules1999, 32, 541–547.

112. Nozaki, K. J. Polymer Sci., Part A: Polymer Chem.2004, 42, 215–221.

Chapter 2

Polymer-Immobilized Chiral Organocatalyst

Naoki Haraguchi and Shinichi Itsuno

2.1 Introduction

Enantiomerically pure compounds are definitely important molecules or building blocks for biologically active molecules on medical, pharmaceutical, and agricultural science [1–3]. Because the use of enantiomerically pure compounds has emerged in the recent years, there is an ongoing interest in the asymmetric synthesis of this kind of compound [4]. Because the synthesis of biologically active molecules containing chirality requires asymmetric transformation methodology, the design of efficient chiral auxiliaries, ligands, and catalysts is strongly desired for success with asymmetric reactions.

Organocatalysts or organic catalysts, which are metal-free organic compounds of a relatively low molecular weight and a simple structure capable of promoting a reaction in a substoichiometric quantity, have received paramount interest recently [5–13]. Although the concept of organocatalysis was first introduced by Langenbeck in 1928 [14], and the expression “organische Katalyse” first appeared in the literature in 1931 [15], a generally accepted definition of organocatalyst still does not exist. Since 2000, when List et al. reported on the direct asymmetric aldol reaction catalyzed by proline [16], which followed the seminal Hajos–Parrish–Eder–Sauer–Wiechert reaction [17, 18], this topic has attracted many researchers worldwide. Organocatalysis was rediscovered as a powerful synthetic methodology. Most recent research activity in the field of organocatalysis has been devoted to chiral catalysts, and exceptional results have been obtained for a variety of different fundamental organic transformations.

The use of polymer supports in organic synthesis has become common practice, especially with the rapid development of combinatorial chemistry [19–28].

Starting with the introduction of Merrifield's solid-phase peptide synthesis [29, 30], cross-linked, insoluble, and soluble polymer supports have been implemented in a wide range of synthetic methodologies [31–33]. With the development of design and practical use of a chiral organocatalyst, some efforts were devoted to the immobilization of organocatalysts. Polymer-immobilized chiral organocatalysts, which enable the asymmetric synthesis of chiral compounds, have also received increasing interest within the last decades. The use of polymer-supported chiral organocatalysts offers the advantages mentioned in the following discussion.

The desired product can be isolated and purified by simple filtration in the case of polymer-immobilized chiral organocatalysts or by precipitation in the case of using soluble polymeric or dendritic chiral organocatalysts. After separation from the reaction mixture, the chiral organocatalysts can easily be recovered and be directly reused for additional syntheses. Furthermore, polymer-immobilized chiral organocatalysts can be integrated into continuous flow systems. Many of these advantages support the ideas of green chemistry to protect the environment and save valuable feedstocks.

The use of a polymer-immobilized catalyst in a heterogeneous system sometimes resulted in the lowering of the chemical yield of reaction mainly as a result of the insufficient interactions among substrate, catalyst, solvent, and addtives. However, well-designed, polymer-immobilized catalysts have been developed for various reactions, and excellent enantioselectivities in numbers of asymmetric reactions have been obtained by using polymer-supported chiral catalysts. In some cases, even a higher reaction rate and enantioselectivity were obtained by using a polymer-immobilized catalyst than those obtained by the corresponding low-molecular-weight catalyst. These results indicate that the polymer-support moiety itself is participated in the overall catalytic system to enhance catalyst performance by providing a favorable microenvironment around the organocatalyst, resulting in the improvement of both catalyst activity and enantioselectivity.

We herein focused on the concept of the polymer immobilization of chiral organocatalysts and their application as a polymeric chiral catalyst to a variety of asymmetric reaction.

2.2 Synthesis of Polymer-Immobilized Chiral Organocatalyst

Chiral organocatalysts traditionally operate via simplified enzyme-mimetic mechanisms, implicating mild reaction conditions and an improved leverage for the chemical inertness of the polymer matrix. Polymer-supported chiral organocatalysts have mainly been prepared by two methods: a coupling reaction of a functional polymer with a chiral organocatalyst (functionalization of Merrifield-like resin) and copolymerization of a monomer with a chiral organocatalyst (Scheme 2.1).

Scheme 2.1 Preparation of a polymer-immobilized chiral organocatalyst.

Most immobilization of chiral organocatalysts was focused on the attachment of a chiral organocatalyst onto cross-linked polystyrene (PS) beads because the methodology is well established for solid-phase peptide synthesis developed by Merrifield in 1963 [29, 30]. PS is still one of the most common polymeric materials because it is inexpensive, easily preparable or commercially available, mechanistically robust, chemically inert, and easily functionalized. Representative, functionalized polymers have been prepared by radical copolymerization of chloromethylstyrene, styrene, and divinylbenzene with 2,2′-azabis(2-methylpropionitrile) (AIBN) or benzoylperoxide (BPO) as an initiator.

Several functionalized polymers and resins are now commercially available (Figure 2.1).

Figure 2.1 Representative support resins.

In addition to the above resin, polyethyleneglycol (PEG) and poly(ethylene oxide) (PEO) are used as a support polymer. Oligo(ethylene glycol)- or PEG-supported catalysts were sometimes used in an asymmetric reaction in aqueous media and showed relatively higher reactivity. As with the other functionalized polymers, poly(acrylate)s, poly(acrylamide), poly(vinyl alcohol), poly(ethylene imine), poly(acrylic acid), poly(N-acryloxy succinimide), and cellulose were used.

With the progress that has been made in organic chemistry, several coupling reaction techniques are now available for coupling of a chiral ligand precursor with functionalized polymers. Because Merrifield-like resin and PEG was commonly used as a functionalized polymer, the Williamson reaction is mostly employed. The other important bond formation reactions such as the Diels–Alder reaction, Suzuki–Miyaura coupling reaction, aldol reaction, Grignard reaction, Mitsunobu reaction, and click reaction are available in the coupling reaction.

A chiral organocatalyst with a suitable functional group should be synthesized for the coupling reaction. The coupling reaction and functionalization of the chiral organocatalyst employed should be carefully selected under consideration of the reactivity of the chiral organocatalyst. The protection of the chiral organocatalyst moiety during the coupling reaction and the following quantitative deprotection of the protected group are also available.

In the coupling method, the quantitative coupling reaction, e.g., coupling efficiency is quantitative, is preferable because the coupling efficiency directly affects the substrate/catalyst (S/C) ratio of the following asymmetric reaction. The excess equivalent of a chiral ligand or catalyst is usually used to enhance the quantitative coupling reaction. Quantitative characterization of the coupling efficiency is necessary when the coupling reaction is not complete.

The degree of cross-linkage of a cross-linked functional polymer and the choice of solvent mainly determine the swelling rate of the cross-linked functional polymer. The rate is of significance in the coupling efficiency of the reaction and accessibility of a substrate to the polymer-supported chiral catalyst in the following asymmetric reaction.

The ion exchange method is one of the efficient immobilization methods. Cation- and anion-exchange resins using a polymer support are commonly employed in the industrial process. We expected that the method could be applied for immobilization of a chiral ligand or catalyst onto a polymer. The advantage using the ion exchange method is that further functionalization of a chiral ligand or catalyst is not required for the immobilization.

A polymer-supported chiral organocatalyst can also be synthesized by polymerization of a functional polymer possessing a chiral ligand. A variety of monomers can be used according to the style of polymerization. Styrenes, acrylates, acrylamides, ethylene oxide, and ethylene imine are representative monomers. Divinylbenzene (DVB) is the most commonly used difunctional monomer as a cross-linker. In addition to DVB, ethylene glycol dimethacrylate, N,N′-bis(acrylamide), and a difunctional styrene derivative with oligo(ethylene glycol) spacer have been used in vinyl polymerization (Figure 2.2). A functional monomer bearing a chiral organocatalyst, in other words, an organoacatalyst with a polymerizable group, should be required for polymerization.

Figure 2.2 Representative vinyl cross-linkers.

A variety of polymerization techniques can be used for the preparation of a polymer-supported catalyst. Several categories are shown as follows:

Polymerization styles: solution, liquid phase, bulk, gas phase, solid phase, emulsion, and suspension.

Polymerization types: addition polymerization, ring-opening polymerization, polycondensation, and polyaddition.

Polymerization mechanism: radical, anionic, cationic, and transition metal catalyzed.

These conditions should be carefully selected under consideration of the reactivity of a chiral ligand or catalyst. The protection of a chiral organocatalyst moiety during the polymerization and the following quantitative deprotection of a protected group can be an alternative method. The chiral organocatalyst content and degree of cross-linkage of the resulting polymer support can be easily controlled by the stoichiometry of each monomer present in the monomer feed, if the polymerizability of each monomer is similar.

2.3 Polymer-Immobilized Cinchona Alkaloids

Cinchona alkaloids, isolated from the bark of several species of cinchona trees, are natural, originated chiral amino alcohol. Readily available and inexpensive cinchona alkaloids with pseudoenantiomeric forms, such as quinine and quinidine or cinchonine and cinchonidine, are among the most privileged chirality inducers or chiral organocatalyst in the area of asymmetric catalysis (Figure 2.3).

Figure 2.3 Cinchona alkaloid derivatives.

Cinchona alkaloids as a chiral basic organocatalyst have been widely applied in some asymmetric reactions such as the Michael addition [34], decarboxylation [35], protonation [36], α-halogenation [37], α-hydroxylation [38], α-amination [39], α-sulfonylation [40], nitroaldol reaction [41], Mannich reaction [42], Morita–Baylis–Hillman reaction [43], cyanation reaction [44], Strecker reaction [45] Friedel–Crafts alkylation [46], hydrophosphonylation [47], conjugate addition of nitroalkene [48], cyclopropanation [49], cycloaddition [50], desymmetrization of meso-compound [51], and kinetic resolution [52].

Cinchona alkaloids possess some active sites that are suitable for the immobilization onto a polymer. The vinyl group at C-3, hydroxyl group at C-9, and hydroxyl group at C′-6 of the quinoline moiety after demethylation are readily available. Immobilization through the nitrogen of the amino functionalities is also possible, but the resulting quaternary ammonium salt has been used for the phase-transfer catalyst (PTC), as mentioned in Section 2.5.

The first immobilization of cinchona alkaloids through the vinyl group at the C-3 position (Figure 2.4) was carried out by Kobayashi as early as 1978 [53]. Radical copolymerization of cinchona alkaloids with acrylonitrile produced linear polymer-immobilized cinchona alkaloids 5, and the catalytic activity was evaluated in some Michael additions. Even though the high conversions were obtained, the enantioselectivities were below 60%ee [53–55]. Introduction of spacers between the polymer backbone and the cinchona alkaloid moiety by Oda and coworkers improved the enantioselectivity up to 65%ee [56]. An ene-thiol click reaction using DVB cross-linked PS resins afforded the DVB crosslinked PS-immobilized cinchona alkaloid 6. The catalytic activity in the addition of thiols to unsaturated ketones and nitrostyrene was evaluated, but the enantiomeric excess was up to 45%. However, the polymer-immobilized catalyst 6 could be recovered and reused three times without loss of the catalytic activity [57]. Significant improvement of the catalytic activity was achieved when the double bond of cinchona alkaloids was hydroxylated and the resulting alcohols were reacted with a carbonyl group of support resins. The cinchona alkaloids immobilized onto the DVB cross-linked PS 7 is separated from the polymer main chain by a longer spacer [58].

Figure 2.4 Polymer-immobilized cinchona alkaloid at the C-3 position.

The immobilization of cinchona alkaloids through the hydroxyl group at C-9 was also investigated. Polymerization of the acrylate functionalized with a cinchona alkaloid resulted in homo- or copolymers having a cinchona alkaloid moiety [59–62]. The methanol addition to phenylmethylketene was carried out, and the adduct was obtained with 35%ee. Not only polymerization but also coupling reactions such as esterification [63] and the Williamson reaction could be used for this type of immobilization. However, these enantioselectivities in different reactions were still low (<40%ee). PS-immobilized quinine was used effectively for the practical synthesis of β-lactams 11 (Scheme 2.2). A [2+2] Staudinger reaction of a ketene 9 and an imine 10 catalyzed by 8 produced 10:1 cis:trans, with a 93%ee for the major diastereomer 11. The polymeric catalyst maintained its efficiency for up to 60 cycles [64].

Scheme 2.2 [2+2] Staudinger reaction using polymer-immobilized cinchona alkaloid 8.

The other immobilization (Figure 2.5) was followed by Cozzi et al. for the preparation of soluble PEG-immobilized cinchona alkaloids 12. The conjugate addition of thiophenol to cyclohexanone catalyzed by 5 mol% of 12 affords the adduct in 75% yield with 22%ee [65].

Figure 2.5 PEG-immobilized cinchona alkaloid at the C′-6 position.

Stereoselective α-fluorination of α-nitro esters was performed using Selectfluor (Air Products and Chemicals, Inc., Allentown, PA) as a fluorinating reagent and O-acetylated cinchona alkaloid by Togni and coworkers [66]. Under the basic condition, an α-fluorinated product was obtained in 91% yield with relatively low enantioselectivity (up to 31%). Shibata and coworkers developed catalytic enantioselective α-fluorination using a cinchona-alkaloid–Selectfluor combination. Acyl enol ethers [67], allylsilane, silyl enol ester, and oxindoles [68] were scoped as the substrate for the reaction. They employed N