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POLYMERIC CHIRALCATALYST DESIGN ANDCHIRAL POLYMERSYNTHESIS

POLYMERIC CHIRALCATALYST DESIGN ANDCHIRAL POLYMERSYNTHESIS

Edited by

SHINICHI ITSUNOToyohashi University of TechnologyToyohashi, Japan

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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

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2010053405

Printed in Singapore.

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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


2.2 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


3.2 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


4.2 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


5.2 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


References / 153

6 Chiral Synthesis on Polymer Support: A CombinatorialApproach 157

Deepak B. Salunke and Chung-Ming Sun


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


References / 195

CONTENTS vii

7 Synthesis and Application of Helical Polymerswith Macromolecular Helicity Memory 201

Hiroki Iida and Eiji Yashima


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


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


8.2 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


References / 263

9 C2 Chiral Biaryl Unit-Based Helical Polymers and TheirApplication to Asymmetric Catalysis 267

Takeshi Maeda and Toshikazu Takata


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


References / 290

10 Immobilization of Multicomponent AsymmetricCatalysts (MACs) 293

Hiroaki Sasai and Shinobu Takizawa


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


11.2 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


Acknowledgment / 361

References / 361

12 Asymmetric Polymerizations of N-SubstitutedMaleimides 365

Kenjiro Onimura and Tsutomu Oishi


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


References / 385

13 Synthesis of Hyperbranched Polymer Having BinaphtholUnits via Oxidative Cross-Coupling Polymerization 389

Shigeki Habaue


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


References / 404

14 Optically Active Polyketones 407

Kyoko Nozaki


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


References / 420

15 Synthesis and Function of Chiral p-ConjugatedPolymers from Phenylacetylenes 423

Toshiki Aoki, Takashi Kaneko, and Masahiro Teraguchi


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


16.2 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


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


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


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).


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).


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.


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.


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.


polymeric chiral - download.e-bookshelf.de · 1.1 introduction / 1 1.2 polymeric chiral catalyst /...

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