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POLYMERIC CHIRALCATALYST DESIGN ANDCHIRAL POLYMERSYNTHESIS
POLYMERIC CHIRALCATALYST DESIGN ANDCHIRAL POLYMERSYNTHESIS
Edited by
SHINICHI ITSUNOToyohashi University of TechnologyToyohashi, Japan
Copyright � 2011 by John Wiley & Sons, Inc. All rights reserved
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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
Printed in Singapore.
oBook ISBN: 978-1-118-06396-5
ePDF ISBN: 978-1-118-06394-1
ePub ISBN: 978-1-118-06395-8
10 9 8 7 6 5 4 3 2 1
CONTENTS
PREFACE xiii
FOREWORD xvii
CONTRIBUTORS xix
1 An Overview of Polymer-Immobilized Chiral Catalystsand Synthetic Chiral Polymers 1
Shinichi Itsuno
1.1 Introduction / 1
1.2 Polymeric Chiral Catalyst / 2
1.2.1 Polymers Having a Chiral Pendant Group / 4
1.2.2 Main-chain Chiral Polymers / 4
1.2.3 Dendrimer-supported Chiral Catalysts / 6
1.2.4 Helical Polymers / 6
1.2.5 Multicomponent Asymmetric Catalysts / 7
1.2.6 Continuous Flow System / 8
1.3 Synthesis of Optically Active Polymers / 8
1.3.1 Asymmetric Reaction on Polymer / 9
1.3.2 Helical Polymers and Hyperbranched Polymers / 9
1.3.3 Heteroatom Chiral Polymers / 10
1.3.4 Asymmetric Polymerization / 11
References / 11
v
2 Polymer-Immobilized Chiral Organocatalyst 17
Naoki Haraguchi and Shinichi Itsuno
2.1 Introduction / 17
2.2 Synthesis of Polymer-immobilized Chiral Organocatalyst / 18
2.3 Polymer-immobilized Cinchona Alkaloids / 22
2.4 Other Polymer-immobilized Chiral Basic Organocatalysts / 27
2.5 Polymer-immobilized Cinchona Alkaloid Quaternary
Ammonium Salts / 28
2.6 Polymer-immobilized MacMillan Catalysts / 35
2.7 Polymer-immobilized Pyrrolidine Derivatives / 42
2.8 Other Polymer-immobilized Chiral Quaternary
Ammonium Salts / 46
2.9 Polymer-immobilized Proline Derivatives / 46
2.10 Polymer-immobilized Peptides and Poly(amino acid)s / 50
2.11 Polymer-immobilized Chiral Acidic Organocatalysts / 50
2.12 Helical Polymers as Chiral Organocatalysts / 51
2.13 Cascade Reactions Using Polymer-immobilized
Chiral Organocatalysts / 52
2.14 Conclusions / 54
References / 56
3 Asymmetric Synthesis Using Polymer-ImmobilizedProline Derivatives 63
Michelangelo Gruttadauria, Francesco Giacalone, and Renato Noto
3.1 Introduction / 63
3.2 Polymer-supported Proline / 66
3.3 Polymer-supported Prolinamides / 73
3.4 Polymer-supported Proline-Peptides / 75
3.5 Polymer-supported Pyrrolidines / 78
3.6 Polymer-supported Prolinol and Diarylprolinol
Derivatives / 80
3.7 Conclusions and Outlooks / 84
References / 85
4 Peptide-Catalyzed Asymmetric Synthesis 91
Kazuaki Kudo and Kengo Akagawa
4.1 Introduction / 91
4.2 Poly(amino acid) Catalysts / 94
4.3 Tri- and Tetrapeptide Catalysts / 99
vi CONTENTS
4.4 Longer Peptides with a Secondary Structure / 110
4.5 Others / 118
4.6 Conclusions and Outlooks / 119
References / 120
5 Continuous Flow System using Polymer-SupportedChiral Catalysts 125
Santiago V. Luis and Eduardo Garcıa-Verdugo
5.1 Introduction / 125
5.2 Asymmetric Polymer-supported, Metal-based Catalysts
and Reagents / 132
5.2.1 Enantioselective Additions to C¼O Groups / 132
5.2.2 Diels–Alder and Related Cycloaddition
Reactions / 136
5.2.3 Enantioslective Cyclopropanation Reactions / 139
5.2.4 Reduction Reactions / 142
5.2.5 Oxidation Reactions / 143
5.3 Polymer-supported Asymmetric Organocatalysts / 147
5.4 Polymer-supported Biocatalysts / 151
5.5 Conclusions / 152
References / 153
6 Chiral Synthesis on Polymer Support: A CombinatorialApproach 157
Deepak B. Salunke and Chung-Ming Sun
6.1 Introduction / 157
6.2 Chiral Synthesis of Complex Polyfunctional Molecules on Polymer
Support / 160
6.2.1 Spirocyclic Compound Libraries / 160
6.2.2 Macrocyclic Compound Libraries / 165
6.2.3 Heterocyclic Compound Libraries / 168
6.2.4 Natural-product–inspired Compound Libraries / 176
6.2.5 Libraries Through Combinatorial Decoration of Natural
Products / 184
6.2.6 Divergent Synthesis of Small Molecular Libraries / 188
6.2.7 Chiral Molecules Through Sequential Use of
Polymer-supported Reagents / 192
6.3 Conclusions / 194
References / 195
CONTENTS vii
7 Synthesis and Application of Helical Polymerswith Macromolecular Helicity Memory 201
Hiroki Iida and Eiji Yashima
7.1 Introduction / 201
7.2 Macromolecular Helicity Memory / 203
7.2.1 Macromolecular Helicity Memory in Solution / 203
7.2.2 Macromolecular Helicity Memory in a Gel
and a Solid / 213
7.3 Enantioselective Reaction Assisted by Helical Polymers with
Helicity Memory / 218
7.4 Conclusions / 219
References / 219
8 Poly(isocyanide)s, Poly(quinoxaline-2,3-diyl)s, and RelatedHelical Polymers Used as Chiral Polymer Catalystsin Asymmetric Synthesis 223
Yuuya Nagata and Michinori Suginome
8.1 Introduction / 223
8.2 Asymmetric Synthesis of Poly(isocyanide)s / 224
8.2.1 Synthesis of Poly(isocyanide)s Bearing Chiral Side
Chains / 224
8.2.2 Nonracemic Poly(isocyanide)s Without Chiral Pendant
Groups / 239
8.3 Asymmetric Synthesis of Poly(quinoxaline)s / 244
8.3.1 Polymerization of 1,2-diisocyanobenzenes / 244
8.3.2 Preparation of Nonracemic Poly(quinoxaline)s / 246
8.4 Enantioselective Catalysis using Helical Polymers / 255
8.4.1 Chiral Polymer Catalysts with Chiral Groups in the Close
Proximity of the Reaction Sites / 255
8.4.2 Chiral Polymer Catalysts with No Chiral Groups in the
Proximity of the Reaction Sites / 258
8.5 Conclusions / 262
References / 263
9 C2 Chiral Biaryl Unit-Based Helical Polymers and TheirApplication to Asymmetric Catalysis 267
Takeshi Maeda and Toshikazu Takata
9.1 Introduction / 267
9.2 Synthesis of C2 Chiral Unit-based Helical
Polymers / 269
viii CONTENTS
9.2.1 Use of C2 Chiral Biaryl Moieties as Chirally Twisted Units in
the Polymer Main Chain / 269
9.2.2 Synthesis of Stable Helical Polymers by the Fixation of
Main-chain Conformation / 277
9.3 Asymmetric Reactions Catalyzed by Helical Polymer
Catalysts / 282
9.4 Conclusions / 289
References / 290
10 Immobilization of Multicomponent AsymmetricCatalysts (MACs) 293
Hiroaki Sasai and Shinobu Takizawa
10.1 Introduction / 293
10.2 Dendrimer-Supported and Dendronized Polymer-supported
MACs / 294
10.2.1 Dendrimer-supported MACs [4] / 294
10.2.2 Dendronized Polymer-supported MACs [11] / 296
10.3 Nanoparticles as Supports for Chiral Catalysts [13] / 302
10.3.1 Micelle-derived Polymer Supports [14] / 302
10.3.2 Monolayer-protected Au Cluster (Au-MPC)-supported
Enantioselective Catalysts [21] / 307
10.4 The Catalyst Analog Approach [24] / 311
10.5 Metal-bridged Polymers as Heterogeneous Catalysts: An
Immobilization Method for MACs Without Using Any
Support [26] / 314
10.6 Conclusion / 318
References / 319
11 Optically Active Polymer and Dendrimer Synthesisand Their Use in Asymmetric Synthesis 323
Qiao-Sheng Hu and Lin Pu
11.1 Introduction / 323
11.2 Synthesis and Application of BINOL/BINAP-based Optically Active
Polymers / 324
11.2.1 Synthesis of BINOL-based Optically Active
Polymers / 324
11.2.2 Application of BINOL-based Optically Active
Polymers / 327
11.2.3 Synthesis and Application of a BINAP-containing
Polymer / 347
CONTENTS ix
11.2.4 Synthesis of an Optically Active BINOL–BINAP-based
Bifunctional Polymer and Application in Asymmetric
Alkylation and Hydrogenation / 351
11.3 Synthesis and Application of Optically Active Dendrimers / 355
11.3.1 Synthesis of BINOL-based Dendrimers and Application
in Asymmetric Alkylation / 355
11.3.2 Synthesis of Optically Active, Ephedrine-based Dendronized
Polymers / 358
11.4 Conclusions / 360
Acknowledgment / 361
References / 361
12 Asymmetric Polymerizations of N-SubstitutedMaleimides 365
Kenjiro Onimura and Tsutomu Oishi
12.1 Introduction / 365
12.2 Chirality of 1-Mono- or 1,1-Disubstituted and 1,2-Disubstituted
Olefins / 365
12.3 Asymmetric Polymerizations of Achiral N-Substituted
Maleimides / 368
12.4 Anionic Polymerization Mechanism of RMI / 371
12.5 Asymmetric Polymerizations of Chiral N-Substituted
Maleimides / 372
12.6 Structure and Absolute Stereochemistry of Poly(RMI) / 373
12.7 AsymmetricRadicalPolymerizationsofN-SubstitutedMaleimides / 378
12.8 Chiral Discrimination Using Poly(RMI) / 378
12.8.1 1H NMR Titration / 380
12.8.2 Optical Resolution Using Poly(RMI) / 381
12.9 Conclusions / 384
References / 385
13 Synthesis of Hyperbranched Polymer Having BinaphtholUnits via Oxidative Cross-Coupling Polymerization 389
Shigeki Habaue
13.1 Introduction / 389
13.2 Oxidative Cross-coupling Reaction between 2-Naphthol
and 3-Hydroxy-2-naphthoate / 391
13.3 Oxidative Cross-coupling Polymerization Affording Linear
Poly(binaphthol) / 392
13.4 Oxidative Cross-coupling Polymerization Leading
to a Hyperbranched Polymer / 396
x CONTENTS
13.5 Photoluminescence Properties of Hyperbranched Polymers / 400
13.6 Conclusions / 403
References / 404
14 Optically Active Polyketones 407
Kyoko Nozaki
14.1 Introduction / 407
14.2 Asymmetric Synthesis of Isotactic Poly(propylene-alt-co) / 409
14.3 Asymmetric Synthesis of Isotactic Syndiotactic
Poly(styrene-alt-co) / 411
14.4 Asymmetric Terpolymers Consisting of Two Kinds of Olefins
and Carbon Monoxide / 413
14.5 Asymmetric Polymerization of Other Olefins with CO / 414
14.6 Chemical Transformations of Optically Active Polyketones / 415
14.7 Conformational Studies on the Optically Active Polyketones / 416
14.8 Conclusions / 419
References / 420
15 Synthesis and Function of Chiral p-ConjugatedPolymers from Phenylacetylenes 423
Toshiki Aoki, Takashi Kaneko, and Masahiro Teraguchi
15.1 Introduction / 423
15.2 Helix-sense-selective Polymerization (HSSP) of Substituted
Phenylacetylenes and Function of the Resulting One-handed Helical
Poly(phenylacetylene)s / 425
15.2.1 Synthesis of Chiral p-Conjugated Polymers from
Phenylacetylenes by Asymmetric-induced Polymerization
(AIP) and Helix-sense-selective Polymerization (HSSP) of
Chiral and Achiral Phenylacetylenes / 425
15.2.2 (HSSP) of Three Types of Monomers RDHPA, RDAPA,
and RDIPA, Scheme 15.4a / 427
15.2.3 Modified HSSP / 432
15.2.4 Functions of One-handed Helical Polyphenylacetylenes
Prepared by HSSP / 434
15.3 Chiral Desubstitution of Side Groups in Membrane State / 439
15.3.1 Polymer Reaction in Membrane State(RIM) / 439
15.3.2 Reaction in One-handed Helical Polymer Membranes:
Synthesis of One-handed Helical Polymers with no Chiral Side
Groups and no Chiral Carbons / 439
15.3.3 Reaction in Polystyrene Monolith: Synthesis
of Chiral Porous Materials / 444
CONTENTS xi
15.4 Synthesis of Chiral Polyradicals / 446
15.4.1 Molecular Design of Optically Active Helical Polyradicals / 446
15.4.2 Copolymerization of the Monomers Possessing Radical
and Chiral Moieties / 447
15.4.3 Synthesis of Chiral Polyradicals via HSSP of Achiral
Monomers / 450
References / 454
16 P-Stereogenic Oligomers, Polymers, and Related CyclicCompounds 457
Yasuhiro Morisaki and Yoshiki Chujo
16.1 Introduction / 457
16.2 P-Stereogenic Oligomers Containing Chiral “P” Atoms
in the Main Chain / 458
16.2.1 P-Stereogenic Tetraphosphines Containing Two Chiral
“P” Atoms / 458
16.2.2 P-Stereogenic Hexaphosphines Containing Four Chiral
“P” Atoms / 461
16.2.3 P-Stereogenic Oligomers Containing 6, 8, and 12 Chiral
“P” Atoms / 464
16.3 P-Stereogenic Polymers Containing Chiral “P” Atoms in the Main
Chain / 470
16.3.1 P-Stereogenic Polymers Containing Chiral “P” Atoms
in the Repeating Unit of the Main Chain / 470
16.3.2 Optically Active Dendrimers Containing the P-Chiral
Bisphosphine Unit as the Core / 473
16.3.3 Helical Polymers Containing Chiral “P” Atoms
in the Terminal Unit / 473
16.4 Cyclic Phosphines Using P-Stereogenic Oligomers
as Building Blocks / 475
16.4.1 Stereospecific Synthesis of trans-1,4-
Diphosphacyclohexane / 475
16.4.2 Synthesis of 1,4,7,10-Tetraphosphacyclodocecane,
12-Phosphacrown-4 / 478
16.4.3 Synthesis of 18-Diphosphacrown-6 / 480
16.5 Conclusions / 485
References / 485
INDEX 489
xii CONTENTS
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, poly-
mer- 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 intro-
duction 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
xiii
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 polymer-
ization 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
xiv PREFACE
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
PREFACE xv
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.
xvii
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 macro-
molecules 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
xviii FOREWORD
CONTRIBUTORS
KENGO AKAGAWA, The University of Tokyo, Tokyo, Japan
TOSHIKI AOKI, Niigata University, Niigata, Japan
YOSHIKI CHUJO, Kyoto University, Kyoto, Japan
EDUARDO GARCIA-VERDUGO, UAMOA, University Jaume I/CSIC, Castellon, Spain
FRANCESCO GIACALONE, Universit�a di Palermo, Palermo, Italy
MICHELANGELO GRUTTADAURIA, Universit�a 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, Castellon, Spain
TAKESHI MAEDA, Osaka Prefecture University, Sakai, Japan
YASUHIRO MORISAKI, Kyoto University, Kyoto, Japan
xix
YUUYA NAGATA, Kyoto University, Kyoto, Japan
RENATO NOTO, Universit�a 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
xx CONTRIBUTORS
CHAPTER 1
AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTSAND 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 fascina-
tion 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 stereo-
selectivity 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
Polymeric Chiral Catalyst Design and Chiral Polymer Synthesis, First Edition. Edited by Shinichi Itsuno.� 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.
1
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 somemonomers consists of chiral heteroatoms such
as silicon and phosphorous, which also have been studied. Asymmetric polymeriza-
tion 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) den-
dritic 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]
Polymeric catalysts obviously have considerable advantages over the correspond-
ing low-molecular-weight counterparts. They can be easily separated from the
reaction mixture, which can be reused many times. The catalyst stability is usually
chiral ligand
SCHEME 1.1. Polymer having a side-chain chiral ligand.
2 AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS
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 reac-
tions using the polymeric catalyst suppress the reactivity, in some cases, even higher
chiral ligand
SCHEME 1.2. Polymer containing a main-chain chiral ligand.
chiral ligand
SCHEME 1.3. Periferally modified chiral dendrimer.
chiral ligand
SCHEME 1.4. Helical polymer catalyst.
POLYMERIC CHIRAL CATALYST 3
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(methyl-
methacrylate) [28] have also been developed.
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 mono-
mers [29]. Acrylates and methacrylates have been sometimes used as the chiral
monomer [28, 30].
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 organo-
catalysts. 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 functional-
ities. In 1956, Akabori et al. reported that silk-palladium was used as a chiral catalyst
X
chiral ligand
SCHEME 1.5. Cross-linked, polystyrene-supported chiral ligand (polymer reaction method).
4 AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS
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 a-amino acid can be polymerized with amine as an initiator to
produce poly(a-amino acid). Juli�a 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(a-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(a-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 asym-
metric 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
chiral ligand
++
SCHEME 1.6. Cross-linked, polystyrene-supported chiral ligand (polymerization method).
POLYMERIC CHIRAL CATALYST 5
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 asym-
metric 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.
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 den-
drimers 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].
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
X R1 X N R2 N N R2 NR1
n
X X
+* *
SCHEME 1.7. Chiral ionene polymer.
6 AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS
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 transforma-
tions [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
Core-functionalized chiral dendrimer
Periferally modified chiral dendrimer
Solid supported dendrimer
SCHEME 1.8. Dendritic chiral catalyst.
N
N
P
P O
O
OO
O
O
O
O
O
O
X
XChiral ligand Metal
SCHEME 1.9. Multicomponent asymmetric catalysts.
POLYMERIC CHIRAL CATALYST 7
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.
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 m-oxodititanium complexes
have been used as catalysts for the asymmetric Michael addition and the asymmetric
carbonyl–ene reactions, respectively.
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],
a-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.
X
X
X
X
X
X
X
X
M
n
M : Metal atom
Chiral multidentate ligandMetal bridged polymer
Multicomponent asymmetric catalyst
SCHEME 1.10. Metal-bridged chiral polymeric catalyst.
8 AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS