Polymeric Chiral Catalyst Design and Chiral Polymer Synthesis

POLYMERIC CHIRAL CATALYST DESIGN AND CHIRAL POLYMER SYNTHESIS

POLYMERIC CHIRAL CATALYST DESIGN AND CHIRAL POLYMER SYNTHESIS

Edited by SHINICHI ITSUNO Toyohashi University of Technology Toyohashi, Japan

Copyright Ó 2011 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. 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 Catalysts and Synthetic Chiral Polymers

1

Shinichi Itsuno

1.1 1.2

Introduction / 1 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

vi

2

CONTENTS

Polymer-Immobilized Chiral Organocatalyst

17

Naoki Haraguchi and Shinichi Itsuno

2.1 2.2 2.3 2.4 2.5

Introduction / 17 Synthesis of Polymer-immobilized Chiral Organocatalyst / 18 Polymer-immobilized Cinchona Alkaloids / 22 Other Polymer-immobilized Chiral Basic Organocatalysts / 27 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-Immobilized Proline Derivatives

63

Michelangelo Gruttadauria, Francesco Giacalone, and Renato Noto

3.1 3.2 3.3 3.4 3.5 3.6

Introduction / 63 Polymer-supported Proline / 66 Polymer-supported Prolinamides / 73 Polymer-supported Proline-Peptides / 75 Polymer-supported Pyrrolidines / 78 Polymer-supported Prolinol and Diarylprolinol Derivatives / 80 3.7 Conclusions and Outlooks / 84 References / 85 4

Peptide-Catalyzed Asymmetric Synthesis Kazuaki Kudo and Kengo Akagawa

4.1 4.2 4.3

Introduction / 91 Poly(amino acid) Catalysts / 94 Tri- and Tetrapeptide Catalysts / 99

91

CONTENTS

vii

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-Supported Chiral Catalysts

125

Santiago V. Luis and Eduardo Garcı´a-Verdugo

5.1 5.2

Introduction / 125 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 Combinatorial Approach

157

Deepak B. Salunke and Chung-Ming Sun

6.1 6.2

Introduction / 157 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

viii

7

CONTENTS

Synthesis and Application of Helical Polymers with Macromolecular Helicity Memory

201

Hiroki Iida and Eiji Yashima

7.1 7.2

Introduction / 201 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 Related Helical Polymers Used as Chiral Polymer Catalysts in Asymmetric Synthesis

223

Yuuya Nagata and Michinori Suginome

8.1 8.2

Introduction / 223 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 Their Application to Asymmetric Catalysis Takeshi Maeda and Toshikazu Takata

9.1 9.2

Introduction / 267 Synthesis of C2 Chiral Unit-based Helical Polymers / 269

267

CONTENTS

ix

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 9.2.1

10

Immobilization of Multicomponent Asymmetric Catalysts (MACs)

293

Hiroaki Sasai and Shinobu Takizawa

10.1 10.2

Introduction / 293 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 Synthesis and Their Use in Asymmetric Synthesis

323

Qiao-Sheng Hu and Lin Pu

11.1 11.2

Introduction / 323 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

x

CONTENTS

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-Substituted Maleimides

365

Kenjiro Onimura and Tsutomu Oishi

12.1 12.2

Introduction / 365 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 Asymmetric Radical Polymerizations of N-Substituted Maleimides / 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 Binaphthol Units via Oxidative Cross-Coupling Polymerization Shigeki Habaue

13.1 13.2 13.3 13.4

Introduction / 389 Oxidative Cross-coupling Reaction between 2-Naphthol and 3-Hydroxy-2-naphthoate / 391 Oxidative Cross-coupling Polymerization Affording Linear Poly(binaphthol) / 392 Oxidative Cross-coupling Polymerization Leading to a Hyperbranched Polymer / 396

389

CONTENTS

xi

13.5 Photoluminescence Properties of Hyperbranched Polymers / 400 13.6 Conclusions / 403 References / 404 14

Optically Active Polyketones

407

Kyoko Nozaki

14.1 14.2 14.3

Introduction / 407 Asymmetric Synthesis of Isotactic Poly(propylene-alt-co) / 409 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-Conjugated Polymers from Phenylacetylenes

423

Toshiki Aoki, Takashi Kaneko, and Masahiro Teraguchi

15.1 15.2

Introduction / 423 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

xii

CONTENTS

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 Cyclic Compounds

457

Yasuhiro Morisaki and Yoshiki Chujo

16.1 16.2

Introduction / 457 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-1,4Diphosphacyclohexane / 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

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 crosslinked 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 xiii

xiv

PREFACE

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

PREFACE

xv

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.

xvii

xviii

FOREWORD

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 smallmolecule 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 GARCI´A-VERDUGO, UAMOA, University Jaume I/CSIC, Castello´n, Spain FRANCESCO GIACALONE, Universita di Palermo, Palermo, Italy MICHELANGELO GRUTTADAURIA, Universita 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, Castello´n, Spain TAKESHI MAEDA, Osaka Prefecture University, Sakai, Japan YASUHIRO MORISAKI, Kyoto University, Kyoto, Japan xix

xx

CONTRIBUTORS

YUUYA NAGATA, Kyoto University, Kyoto, Japan RENATO NOTO, Universita 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

FIGURE 4.1 (a) Crystal structure of a-chymotrypsin [4]. Only the main chain of the polypeptide is shown. Data were obtained from the Protein Data Bank [5]. (b) a-Helix and (c) b-turn found in a-chymotrypsin. OH

O +

Cl PS

N

CA L-B Bu

O

92% Yield, scCO2 99.9 % e e 10.6 mo l/min, 50 ºC, 10MPa

N

Zeolite CP811E/ [BMIM][P F6]

O O

OH +

FIGURE 5.25 Multistep continuous enzymatic kinetic resolution of alcohols catalyzed by CALB supported on SILLPs and using scCO2 as the mobile phase. Zeolite CP811E covered with [BMIM][PF6] was used as the acid catalyst.

(a) Helix-sense-selective polymerization achiral or prochiral monomer

H3C

H

CH3 H2C C n C O O

C n CH3 N CH3

C O n CCl3

2 CH3

PdIL2

N

PrO PrO

N

N n C18H37

p-Tol N

R* =

N N

n R*

CH3

5

3

C

1

N C

N OHC

4

p-Tol Ph

Ph

(b) Polymerization of optically active monomers optically active monomer O

C10H21

C N n

Si

n

n

H

N

D

C

6

7

8

9

N n C6H13

(c) Memory of helical chirality

or

optically active compound

achiral compound

FIGURE 7.1 Three methods for helical polymer syntheses and representative structures (a and b).

(a) Loss of macromolecular helicity

n H

Memory Efficiency (%)

(b)

Memory of macromolecular helicity

Helicity induction

X

(c)

87

CH2N2 for 12

82 54

50 CH2N2 for 12

0 15

16

17

18

19 20

X= O

R'O

HO

P

O O

OH

11: R'= H 12: R'= Et

10

=

Storage of macromolecular helicity

0

NH2 n

HO

n = 2 15 n = 5 16

=

17

H2N

OH 13

NH2

HO

O

S

(R)-14

C4H9 NH2 18 (H3C)3C NH2 19

NH2

= P

Ph

Ph 20

EtO

O OMe

21

FIGURE 7.2 (a) Schematic illustration of a helicity induction in 10–13 with (R)-14, and loss and memory of the induced helicity after removing of (R)-14 and replacement by achiral amines (15–20), respectively (See text for full caption.) Retention of the axial chirality in biphenyl units

n

H

Diastereomers Helicity induction

22

O HO = H2N

(R)-14

Inversion of the axial chirality in biphenyl units

== C4H9 NH2 18

HO

NH2 15

FIGURE 7.3 Schematic illustration of a helicity induction in 22 upon complexation with (R)-14, memory of macromolecular helicity and axial chirality of the biphenyl units of 22 induced by (R)-14 assisted by interactions with achiral 18 and 15.

(a) n

PhO

Heating

(R)-14

H

in DMSO

Cooling

Helix induction

Helix inversion

O

P

OH

Left-handed helix

23

Right-handed helix

H2N (R )-14

(R)-14

Memory of macromolecular helicity

(b)

H2N

NH2 24

(R)-14

Enantiomers

Left-handed helix

Right-handed helix

FIGURE 7.4 (a) Schematic illustration of an induced one-handed helicity in optically inactive 23, helix inversion with temperature, and subsequent memory of the diastereomeric macromolecular helicity at different temperatures. (See text for full caption.) (a) OH OH

n

H

(S)-43 NH+Cl–

H 4TPPS 2–

(R)-43

Helicity Induction

41·HCl Helicity Induction

(b)

ChiralJ-Aggregates Induction

Memoryof Supramolecular ChiralJ-Aggregates

n

H O O

N

O

L-Trp·

D -Trp

44

HClO4

O O

O

42 R

= R

N + H + NH HN H N

R

R= SO3–

R

2–

H4TPPS

O

=

N I

O 2

N

44

FIGURE 7.7 Schematic illustration of the induction of a preferred-handed helicity in 41-HCl (a) and 42 (b) upon complexation with (S)-43 and D-Trp, respectively, subsequent formation of supramolecular helical aggregates of achiral H4TPPS2- and 44, and memory of the supramolecular chirality after inversion of the helicity of the polymer backbone by addition of excess (R)-43 and L-Trp, respectively.

Opticallyactive st-PMMA/C60 complex C60

(a)

Optically active stereocomplex * X

it-PMMA

(R)-or (S)-51 toluene

X = OH (R)-or(S)-51 X = NH2 (R)- or(S)-52

(R)-or (S)-51

OCH3 C O C CH3 n

C70

C60

extraction

CH3 CH2 C CH2 C O OCH3 st-PMMA

(b)

C70

st-PMMA/C70 complex andfree C60 higher C60 fullerenes

(c) extraction (R)-or (S)-52

(R)-or (S)-52

opticallyactive st-PMMA gel

fullerene mixture

st-PMMA/higher fullerenes complex gel

optically active higher fullerenes

FIGURE 7.9 (a) Schematic illustration of a helicity induction in st-PMMA in the presence of C60 with (S)- or (R)-51, memory of the induced helicity after removal of 51, and subsequent “optically active” stereocomplex formation after the addition of it-PMMA, resulting from replacement of the encapsulated C60 molecules by it-PMMA strands. (b) Schematic illustration of the preferential encapsulation of C70 over C60 by st-PMMA and (c) selective extraction and resolution of higher fullerenes by helical st-PMMA with the induced helicity.

2000 1 mer 2 mer 3 mer 4 mer 4 mer

1500

O

R

O

8 mer

O

R R

OR'

n

1000

R

(R)-25; R' =H or SiMe2Bu n = 0, 1, 2, 3, 4

t

Δε / dm3mol–1

OR'

4 mer 2 mer

500

1 mer 0 3 mer

–500

–1000

–1500 solvent : THF –2000 200

250 Wavelength / nm

FIGURE 9.7 CD spectra of model oligomers (R)-25.

300

FIGURE 9.8 X-ray crystal structure of a 1 : 1 mixture of (R) and (S) model tetramers of (R)-25.

O

(a) OHHO

O

O

Bis(4-nitrophenyl) carbonate DMAP (2eq) (R)toluene, reflux n

(R)-28 [α] D20 = +27.6

poly-(R)-28 [α]D 20 = +116 (c = 0.1, THF)

(b)

FIGURE 9.9 Synthesis of poly-(R)-28 (a) and MM2-optimized structure of poly-(R)-28 (b).

Fix by Coordination to Metal Ions Polymerized

Conformation Change

Unit Structure

FIGURE 9.14 Schematic representation of synthetic strategy of helical polymers constructed a priori.

(c)

(a) Top view

210 0 eq

(L mol-1 cm-1)

140

ca. 6 Å

1.33 eq

70

0

0 eq 0.13 0.27 0.67 1.00 1.33

-70

ca. 13 Å

-140

-210 200

(b) Side view

1.33 1.00 0.67 0.27 0.13 0 eq

300

400 500 600 Wavelength (nm)

700

ca. 6 Å

FIGURE 9.16 MM2-optimized structures of poly-(R)-34e(Cu) (a, b, 10-mer model) and CD spectral change of poly-(R)-34e to poly-(R)-34e(Cu) upon mixing with Cu(II) in THF (c).

SCHEME 15.7 Unique properties of one-handed helical polyphenylacetylenes prepared by HSSP of RDHPA.

SCHEME 15.8 HSSP by using one-handed helical polyphenylacetylenes prepared by HSSP as a chiral cocatalyst.

CHAPTER 1

AN OVERVIEW OF POLYMERIMMOBILIZED 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

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

2

AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS

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(quinoxaline2,3-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] 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

chiral ligand

SCHEME 1.1. Polymer having a side-chain chiral ligand.

POLYMERIC CHIRAL CATALYST

3

chiral ligand

SCHEME 1.2. Polymer containing a main-chain chiral ligand.

chiral ligand

SCHEME 1.3. Periferally modified chiral dendrimer.

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

chiral ligand

SCHEME 1.4. Helical polymer catalyst.

4

AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS

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(2oxazoline) [25], polyacetylene [26], poly(ethylene glycol) [27], and poly(methylmethacrylate) [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 monomers [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 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

X

chiral ligand

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

POLYMERIC CHIRAL CATALYST

+

5

+

chiral ligand

SCHEME 1.6. Cross-linked, polystyrene-supported chiral ligand (polymerization 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 mainchain 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

6

AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS

X R1 X

+

N R2* N

X X R1 N R2* N

n

SCHEME 1.7. Chiral ionene polymer.

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. 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]. 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 bestorganized 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

POLYMERIC CHIRAL CATALYST

Core-functionalized chiral dendrimer

7

Solid supported dendrimer

Periferally modified chiral dendrimer

SCHEME 1.8. Dendritic chiral catalyst.

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 O N

P

O

O

N

P

O

O

O O

O O

X X

Chiral ligand

Metal

SCHEME 1.9. Multicomponent asymmetric catalysts.

O

8

AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS

X

X

X

X

M : Metal atom

X

X M

X

X

Chiral multidentate ligand

n

Metal bridged polymer Multicomponent asymmetric catalyst

SCHEME 1.10. Metal-bridged chiral polymeric catalyst.

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 metalbridged 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.

SYNTHESIS OF OPTICALLY ACTIVE POLYMERS

9

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 14) [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.

10

AN OVERVIEW OF POLYMER-IMMOBILIZED CHIRAL CATALYSTS

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(Npropargylamide) [90] and poly(phenylacetylene) derivatives [91]. The helical structure in the polymer is stabilized by means of intramolecular hydrogen bonds. Helixsense-selective polymerization of achiral and bulky phenylacetylene monomers was performed in the presence of [Rh(cod)Cl]2 and enantiopure 1-phenylethylamine [92]. Chiral p-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-senseselective polymerization of achiral isocyanide was performed by using a singlehanded helical oligomer complex [94]. Structurally related poly(quinoxaline-2,3diyl) 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.

REFERENCES

11

chiral catalyst A

A

+

B

B

Prochiral monomer

* *

* *

* *

* *

Chiral polymer

SCHEME 1.11. Asymmetric polymerization of prochiral monomers.

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 1.11). A typical example is helical polymer synthesis by means of asymmetric polymerization. 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.

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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 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.

17

18

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

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). 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

19

+

Cl

+

Cl

Polymerization

+

Coupling Reaction

Monomer with Chiral Organocatalyst

Functionalization

Chiral Organocatalyst

Functional Polymer (Reactive resin)

Cl

SCHEME 2.1. Preparation of a polymer-immobilized chiral organocatalyst.

Polymerization

Chiral Organocatalyst

Polymer-immobilized Chiral Organocatalyst

20

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

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 2,20 -azabis(2-methylpropionitrile) (AIBN) or benzoylperoxide (BPO) as an initiator. Several functionalized polymers and resins are now commercially available (Figure 2.1). 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.

X Cl

PS

PS

Merrifield

O Me O

n nO

X

ArgoGelTM PS

O OH Wang Cl

PS

O n

TentaGelTM

O

O

X JandaJelTM

FIGURE 2.1. Representative support resins.

O 9.5

SYNTHESIS OF POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

21

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. Cationand 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,N0 -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. 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.

O

O

O

O

O

N H

N H

O

O

O

n

n=1, 2, 3

FIGURE 2.2. Representative vinyl cross-linkers.

22

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

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 crosslinkage 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). 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], a-halogenation [37], a-hydroxylation [38], a-amination [39], a-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 C0 -6 of the quinoline moiety after demethylation are readily available.

OMe N

N OH

OH

N

N

Cinchonidine 1

Quinine 2 MeO

HO

HO N

N N

N Cinchonine 3

Quinidine 4

FIGURE 2.3. Cinchona alkaloid derivatives.

23

POLYMER-IMMOBILIZED CINCHONA ALKALOIDS

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 polymerimmobilized 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 crosslinked 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 polymerimmobilized 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]. 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 b-lactams 11 (Scheme 2.2). A [2þ2] 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].

PS m

PS S

O

O

n CN

O

N

N

OH N

OH N

5

N OH N

6

7

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

24

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

OMe N O N

PS

O

O 8

O

R CO2Et

8

R

CO2Et

+ O 9

Ts

N

N

Solvent, -43 oC, 2 h

O

10

Ts 11

62% Yield 93:7 dr 90% ee

SCHEME 2.2. [2þ2] 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]. Stereoselective a-fluorination of a-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 a-fluorinated product was obtained in 91% yield with relatively low enantioselectivity (up to 31%). Shibata and coworkers developed catalytic enantioselective a-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-fluorobenzenesulfonimide (NFSI) as a fluorinating reagent with a cinchona alkaloid dimer. Cahard and coworkers synthesized linear polystyrene-immobilized cinchona alkaloids 13 and applied them to enantioselective a-fluorination (Scheme 2.3) [69]. Soluble 13 along with the fluorinating reagent resulted in nearly quantitative O N

MeO-PEG5000

OH N 12

FIGURE 2.5. PEG-immobilized cinchona alkaloid at the C0 -6 position.

POLYMER-IMMOBILIZED CINCHONA ALKALOIDS

25

OMe N O O N 13

OSiMe3

O

13 (0.1 mol%), Selectfluor

F Bn 14

THF-MeCN, -40 oC, 18 h

Bn 15 98% Yield Up to 82% ee

SCHEME 2.3. Enantioselective a-fluorination using polymer-immobilized cinchona alkaloid 13.

chemical yields and high optical yields. Recovery of 13 by solid/liquid separation was easy, and 13 was reused without loss of enantioselectivity in fourth runs. In addition to a-fluorination, a-chlorination and a-bromination catalyzed by a cinchona alkaloid were also investigated. Lectka and coworkers reported a-chlorination of acid halide by using Wang resign-immobilized quinine 16 via a columnbased flush and flow system in 2005 (Scheme 2.4) [70]. To a column of 16 were added acid chloride 18, then tetrahydrofuran (THF) as eluent was flowed by flushing to afford the corresponding a-chloroesters 19 up to 94%ee. The catalytic asymmetric Sharpless dihydroxylation of olefins is a very efficient method for the catalytic preparation of chiral vicinal diols [71–75]. Sharpless and coworkers investigated the asymmetric dihydroxylation of olefins catalyzed by an asymmetric catalyst derived from cinchona alkaloids in 1988 [75]. As this is the seminal report, the asymmetric dihydroxylation was so thoughtfully investigated that nearly all classes of diols can be synthesized in good yield and enantioselectivity. Janda and coworkers have examined asymmetric dihydroxylation of some olefins by using a soluble MeO-PEG supported cinchona alkaloid 20 prepared by Becker and Sharpless from a dihydroquinidine derivative and mono-hydroxyl-terminated PEG in 1996 [76, 77]. Janda et al. mentioned that the reaction was complete within the same time frame as that of its solution counterpart with no decrease of yields and enantioselectivities (Scheme 2.5). Although insoluble polymeric ligand was tested in the reaction, the reactivity was lower probably because of the heterogeneous reaction. Cinchona-based bifunctional thiourea [78] and sulfonamide [79] organocatalysts are also highly effective in facilitating a variety of useful asymmetric reactions. Song and coworkers developed a polymer-immobilized, cinchona-based sulfonamide

26

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

OMe N O O Wang

N 16

O O Cl

Cl

Cl

O

Cl O R

Cl Cl 17

16,

Cl

Cl R

THF

18

O OC6Cl5

19 50-61% Yield Up to 94% ee

SCHEME 2.4. a-Chlorination using polymer-immobilized cinchona alkaloid 16.

MeO-PEG O O

O N

O N

OMe 20 20 N-methylmorpholine-N-oxide Ph

Ph

acetone/H2O (1/1), 5 h 21

Ph Ph

HO

OH 22 89% Yield 88% ee

SCHEME 2.5. Asymmetric dihydroxylation catalyzed by PEG-supported cinchona alkaloid 20.

OTHER POLYMER-IMMOBILIZED CHIRAL BASIC ORGANOCATALYSTS

27

N NH O S O

N

23

PS

O 23 (10 mol%)

CO2H

CO2Me

CO2Me

CO2H

O MeOH, MTBE, rt, 3-9 h O

CO2H

CO2H

CO2H

CO2H

CO2Me

CO2Me

CO2Me

CO2Me

>99% Yield, 96% ee

>99% Yield, 96% ee

CO2H

CO2Me

CO2Me

CO2H

>99% Yield, 96% ee

>99% Yield, 95% ee

>99% Yield, 97% ee

>99% Yield, 97% ee

SCHEME 2.6. Asymmetric desymmetrization catalyzed by polymer-immobilized cinchonabased sulfonamide 23.

23 [80]. The polymeric organocatalyst showed high activity and enantioselectivity in the methanolytic desymmetrization of meso-cyclic anhydrides (Scheme 2.6). 2.4 OTHER POLYMER-IMMOBILIZED CHIRAL BASIC ORGANOCATALYSTS Polystyrene- or Wang resin-immobilized 4-(dimethylamino)pyridine (DMAP) and prolinamide analog 24 [81] was used for the kinetic resolution of cis-1,2-cyclohexanol mono-4-dimethylaminobenzoate 25 [82]. The reaction was carried out in CH2Cl2 at room temperature, and the best results were obtained at 67% conversion, achieving 93%ee for the unreacted alcohol 26 (Scheme 2.7). Polymer-immobilized chiral phosphoramides 27 and 28 (Figure 2.6) have been prepared by homopolymerization of the corresponding styrene derivatives or by

28

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

PS

HN

N O

24

N

OH

OH 24 (5 mol%)

O O

O O

CH2Cl2, rt N

N

25

26 67% Conv. 93% ee

SCHEME 2.7. Kinetic resolution of chiral secondary alcohol using polymer-immobilized DMAP analog 24. PS PS

N N N

27

O P

N

N N

O P

N

28

FIGURE 2.6. Polymer-immobilized chiral phosphoramides.

copolymerzization with styrene. The allylation of benzaldehyde with allyl trichlorosilane using 27 and 28 was performed in the presence of an excess of diisopropylethylamine. The reactivity and enantioselectivity of 28 were found to be higher than those of 27. The reusability was not mentioned. 2.5 POLYMER-IMMOBILIZED CINCHONA ALKALOID QUATERNARY AMMONIUM SALTS One of the promising applications of cinchona alkaloids in an asymmetric reaction must be the application of the quaternary ammonium salt to PTC. Figure 2.7 shows

POLYMER-IMMOBILIZED CINCHONA ALKALOID QUATERNARY AMMONIUM SALTS

OR4

29

R3 X

N R1 OR2

N

FIGURE 2.7. Functionalization of cinchona alkaloids.

the functional group of cinchona alkaloids. The cinchona alkaloid can be immobilized onto a polymer mainly through the nitrogen (R1), the hydroxyl group of C-9 position (R2), the vinyl group of C-3, and 60 -position (4-position of quinoline moiety). The resulting polymer-supported cinchona alkaloid quaternary ammonium salts can be applied to a variety of organic reactions, including alkylation of amino acids imine [83, 84], hydrocyanation of imines [85], the Diels–Alder reaction [86], the aldol reaction [87], epoxidation [88], and the Darzens condensation [89]. To test the catalytic activity of cinchona alkaloid quaternary ammonium salts, the asymmetric alkylation of glycine derivatives was commonly used to produce optically active a-amino acids, which are the most important amino acids assembling into polypeptides with a wide range of vital biological functions (Scheme 2.8). O’Donnell and coworkers reported a highly enantioselective alkylation of a glycine Schiff base [90] under PTC conditions catalyzed by cinchona alkaloid quaternary ammonium salt in 1989 [83, 84]. A variety of modified cinchona alkaloid quaternary ammonium salts and the polymeric catalyst have been reported since the report (Figure 2.8). Cat. (10 mol%) Ph

N

CO2

Ph

R2Br

R1

Ph

Toluene, Base

N Ph

CO2R1

∗

R2

30: R1 = Et, R2 = Bn 32: R1 = iPr, R2 = Bn 34: R1 = tBu, R2 = Bn

29: R1 = Et 31: R1 = iPr 33: R1 = tBu

SCHEME 2.8. Asymmetric alkylation of N-diphenylmethylene glycine ester.

I

HO

PS Cl

N

N 8

OH N 35

PS

N 36

FIGURE 2.8. Polymer-immobilized cinchona alkaloid at the nitrogen position.

30

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

DVB cross-linked PS (or Merrifield-like resin)–immobilized cinchona alkaloid quaternary ammonium salts 35 were first prepared and used the alkylation of benzophenone imine of glycine tert-butyl ester, but both the chemical yield and the ee value were low [91]. N
ajera and coworkers reported on the synthesis of Merrifield resin-immobilized cinchona alkaloid quaternary ammonium salts 36 and the benzylation of benzophenone imine of glycine isopropyl ester 31. The corresponding (S)-phenylalanine derivative 32 was successfully obtained in 90% yield with 90%ee [92]. They optimized the reaction condition such as solvent, base, temperature, and reaction time, and the effect of the immobilization position and the kind of alkyl bromide were also examined [93]. Cahard and coworkers examined the effect of a spacer between the quinuclidium nitrogen and the backbone of a polymer support, and reaction conditions were optimized. A total of 60% yield and 81%ee (34, R-isomer) was obtained when the benzylation of benzophenone imine of glycine tert-butyl ester 33 was carried out with 50% aq. KOH in toluene at 0 C for 15 h using 10 mol% of polymer-immobilized cinchonium salt (spacer ¼ -(CH2)4-) [94]. Enantioselectivity was much improved when 9-halomethylanthracene was used for the N-quaternarization of cinchonidine. Overall, 94%ee of the (S)-phenylalanine derivative 34 was obtained for the asymmetric benzylation of 33 with use of the polymer-immobilized cinchonidium salt 37 [95] (Scheme 2.9). The immobilization through the C-3 vinyl group was reported in 2005 (Figure 2.9). The vinyl group was transformed into a terminal alkyne, which was further deprotonated to react with a Merrifield resin affording the polymerimmobilized cinchonium salt 38. Unfortunately, the catalytic activity was moderate (benzylation of 33, 72% yield, 73%ee, (R)-isomer) [96].

Cl

N O

N

PS 37 37 (10% mol) Ph

N

t

CO2 Bu

BnBr, CsOH H2O Toluene, -50 oC, 30 h

Ph 33

Ph

N

CO2tBu

Ph

Ph 34 67%, 94% ee

SCHEME 2.9. Asymmetric benzylation of N-diphenylmethylene glycine tert-butyl ester catalyzed by polymer-immobilized cinchonidium salt 37.

POLYMER-IMMOBILIZED CINCHONA ALKALOID QUATERNARY AMMONIUM SALTS

31

PS

O N Br N

38

FIGURE 2.9. PS-immobilized cinchonium salt at the C-3 position.

Recently, electrically modified Merrifield resin-immobilized hydrocinchonidium salts have been newly synthesized, and the catalytic activity for the asymmetric benzylation of 33 has been reported. The hydrogen bonding induced by functional group of a polymeric catalyst enhanced enantioselectivities [97] (Scheme 2.10). Water-soluble, polymer-supported cinchona ammonium salts based on PEG support allowed for performing the reaction in aqueous media. A variety of PEGsupported cinchona alkaloid quaternary ammonium salts have been reported from

Br

N

PS O

O N

NC 39

Ph

CO2tBu

N Ph 33

39 (20 mol%) BnBr (5 eqiv.) 50 wt% KOH Toluene:CHCl 3 (7:3) 0 oC, 20 h

Ph

CO2tBu

N Ph

Bn 34

88% Yield 91% ee

SCHEME 2.10. Asymmetric benzylation of 33 catalyzed by electrically modified Merrifield resin-immobilized hydrocinchonidium salt 39.

32

MeO-PEG5000

N

O

MeO-PEG5000

N

Cl

43

OH

N

O

N

45

O

N

O

N

N

O

41

O O

MeO-PEG5000

Cl OH

N

PEG5000-OMe

44

O

X

O

N

O

N

46

O

N

Cl

N

42

Cl

OH

N

OMe

Cl

OH

N

O

O

HN

47

N H

PEG2000 O

PEG5000-OMe

FIGURE 2.10. PEG-supported cinchona alkaloid quaternary ammonium salts.

OH

N

O

MeO-PEG5000

X

O

OH

Cl

O

N

40

PEG5000-OMe

N

HO Cl OMe

N

POLYMER-IMMOBILIZED CINCHONA ALKALOID QUATERNARY AMMONIUM SALTS

33

some groups (Figure 2.10) [65, 98, 99]. Higher yields up to 98% and enantioselectivities up to 83%ee were obtained by using polymeric catalyst 47 [100]. Not only the anchoring position but also the presence of a spacer was an important factor in enhancing these catalytic activities. We recently developed a novel immobilization method involving placement of quaternary ammonium salts onto polymer supports (Scheme 2.11) [101]. The synthesis is a new type of immobilization comprising an ionic bond between a chiral catalyst and a polymer support. Two synthetic methods for ionically polymersupported cinchonidium salts were demonstrated: one was via radical copolymerization of corresponding vinyl monomer 49, styrene, and divinylbenzene, and the other was via ion exchange reaction between sodium sulfonate introduced in DVB cross-linked PS and cinchonidium salts 48. Using the polymerization method, the polymer-immobilized chiral quaternary ammonium salts 50 can be obtained easily because any type of chiral quaternary ammonium salt can be transformed into its corresponding monomer without further functionalization. The latter ion exchange method is also useful if there is difficulty in the chiral monomer synthesis or in the polymerization. For the reason of practicality, these noncovalent immobilizations of

SO3 Cl

SO3 Na

N R OH

N

N R OH N 49

48 PS

Polymerization

Ion Exchange PS

+

SO3 Na

SO3 N R OH N 50

SCHEME 2.11. Facile immobilization of organocatalyst with chiral quaternary ammonium salt onto polymer.

34

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

chiral organocatalysts are highly desirable because modifications of the parent catalysts are generally minimized and the strategy is also facile and modular, thus allowing fine-tuning of the support structure and the organocatalyst and their combination. The alkylation of the glycine derivative with benzyl bromide catalyzed by 51 (via ion-exchange reaction) was performed in 50 wt% aqueous KOH and toluene at 0 C (Scheme 2.12). The desired product 34 was successfully obtained in 70% yield with excellent enantioselectivity (96%ee). This type of catalyst is considered to work as a PTC system, but in the case of a polymeric catalyst, phase transfer seems to be difficult. Although the reaction mechanism is not clear at this moment, we believe that aggregated ion pairs seem to be involved (Scheme 2.13). The results obtained from the polymer-immobilized catalysts lead to the assumption that the polymeric sulfonate must be closely involved in the transition state. Because of the strong affinity between the sulfonate anion and the ammonium cation, the polymeric quaternary ammonium sulfonate catalyst is always recovered. Other novel polymeric catalysts were reported in 2010. The Williamson reaction of a cinchonidium salt dimer with dibromide afforded novel optically active polymers containing a chiral quaternary ammonium salt structure in their main chain (Scheme 2.14) [102]. The same polymers can be readily synthesized by quaternarization reaction of a cinchonidine dimer with dibromide. PS

SO3 N OH N 51

Ph

CO2tBu

N Ph

51 (20 mol%) BnBr (5 eqiv.), 50 wt% KOH Toluene, -20 oC, 24 h

33

Ph

CO2tBu

N Ph

Bn 34

70% Yield 96% ee

SCHEME 2.12. Asymmetric benzylation of 33 catalyzed by polymer-supported cinchona alkaloid 51.

POLYMER-IMMOBILIZED MACMILLAN CATALYSTS

O S O O

Toluene NR*4

OtBu

O KOH

K

Br

N

H2O

Ph Ph

35

O S O NR*4 O OtBu O Ph KBr N

KOH

Ph Ph

Ph H2O

Toluene

SCHEME 2.13. A proposed reaction mechanism catalyzed by polymer-immobilized quaternary ammonium salt.

These polymers were used as a catalyst for asymmetric benzylation of N-diphenylmethylidene glycine tert-butyl ester 33. The reaction proceeded quantitatively within 24 h, and the desired product 34 was obtained in more than 70% yield and with up to 86%ee. The other novel type of main-chain chiral polymers that comprises a quaternary ammonium sulfonate repeating unit have been developed [103] (Scheme 2.15). Although a simple ion exchange reaction of cinchonidium salt dimer with disulfonate was used, a variety of main-chain chiral polymers have been synthesized. These chiral polymers were successfully used as a catalyst for asymmetric benzylation of 33. Interestingly, the enantioselectivity obtained from polymeric catalyst 56 was obviously higher than that obtained from the original dimer catalyst 55. Cinchona alkaloids have been commonly used in asymmetric epoxidation. In the middle of the 1970s, Wynberg et al. [104] found the cinchona-alkaloid–catalyzed asymmetric PTC epoxidation. The catalytic performance has been improved by Lygo and Wainwright [105] and by Corey and Zhang [106]. The asymmetric epoxidation with use of a PEG-supported cinchonidium salt dimer 47 in CH2Cl2 was reported by Wang et al. (Scheme 2.16) [99]. The asymmetric epoxidation of chalcone 57 was carried out, and the corresponding epoxide 58 was obtained in 90% yield with 86%ee. 2.6 POLYMER-IMMOBILIZED MACMILLAN CATALYSTS Chiral immidazolidin-4-one derivatives 59–61, originally proposed and developed as chiral organocatalysts by D. W. C. MacMillan and coworkers, is one of the most efficient designed organocatalysts [107–111]. The iminium salt can be widely applied to catalytic asymmetric reactions such as the Diels–Alder reaction [112], 1,3-dipolar cycloaddition [113, 114], Friedel–Crafts alkylation [115], indole alkylation [116], a-chlorination of aldehydes [117], direct aldol condensation [118], and epoxidation [119]. Like conventional effective chiral catalysts that have been reported, the immobilization of MacMillan’s iminium catalyst onto polymeric or inorganic materials has

36

N

N

O

N

Br

O

n

N

Ph

N

52

33

Br N

CO2tBu

N

Toluene:CHCl 3 (7:3) 0 oC, 15 h

53 or 54 (10 mol%) BnBr (5 eqiv.), 50 wt% KOH

Ether Formation & Polymerization

OH

Quaternarization

Ph

N

Br

Br

N

53

N

Br

OH

Br

Br

N

Ph

O

CO2tBu Bn 34

N

Br

N

53

N

53: 92%, 86% ee 54: 83%, 86% ee

Ph

O

Br

SCHEME 2.14. Optically active polymers containing a chiral quaternary ammonium salt structure in their main chain.

1

OH

N

Br

n

N

37

POLYMER-IMMOBILIZED MACMILLAN CATALYSTS

NaO3S Br

N N

O

O

N

N

SO3Na Br

55

Br

N N

O

O

N

O 3S

N

SO3

Na n

56 55 or 56 (10 mol%) CO2tBu

N

Ph Ph

33

BnBr, 50 wt% KOH

Toluene : CHCl 3 (7:3) -20 oC

N

Ph Ph

CO2tBu Ph

34

56: 93%, 94% ee 55: 92%, 86% ee

SCHEME 2.15. Novel type of main-chain chiral polymers that comprises a quaternary ammonium sulfonate repeating unit.

been developed by several groups. The MacMillan catalyst 62 is mainly immobilized onto a polymer at the benzyl group (R1) and N-CH3 group (R2) (Figure 2.11). The first example was reported by Benaglia and Cozzi and coworkers in 2002. Tyrosine was used for the synthesis of a MacMillan catalyst analog comprising a hydroxyl group. This was reacted with mesyl-terminated PEG to afford PEGimmobilized chiral imidazolidin-4-one, and the salt 63 was used for an asymmetric O

47 (5 mol%) KOH

tBuOOH,

57

CH2Cl2, 0 oC, 48 h

O

O

58 90% Yield 86% ee

SCHEME 2.16. Asymmetric epoxidation catalyzed by polymer-supported cinchona alkaloid 47.

38

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

O

O

O

N

N

N

N H2

N H2

N H2

X

59

X

60

X

61

R2

O N N H2

R1

X

62

FIGURE 2.11. Chiral immidazolidin-4-ones designed by MacMillan.

Diels–Alder reaction of acrolein and 1,3-cyclohexadiene (Scheme 2.17). The adduct 66 was obtained in moderate yield (67%) with high enantioselectivity (92%ee) after the optimization of reaction conditions [120]. The polymeric catalyst 63 was also used as a chiral catalyst for 1,3-dipolar cycloaddition [121] (Scheme 2.18). The isoxazolidine derivative 70 was obtained in 71% yield with 87%ee (trans). Efficient reuse was not achieved in both reactions because of the instability of the polymeric catalyst under these reaction conditions. PEG5000

O N O N H2 TFA O 63

63 (10 mol%)

H O 64

+

CHO

CH3CN/H2O, rt, 40 h 65

+

66

CHO 67

67% Yield 6:94 exo/endo 92% ee

SCHEME 2.17. Asymmetric Diels–Alder reaction catalyzed by polymer-immobilized MacMillan catalyst 63.

39

POLYMER-IMMOBILIZED MACMILLAN CATALYSTS

H N

O

+

O

63 (20 mol%) H2O, -20

oC,

N O

+

N O

120 h CHO

68

trans 70

69

CHO cis 71

71% Yield 85:15 trans/cis 87% ee (trans)

SCHEME 2.18. Enantioselective 1,3-dipolar cycloaddition catalyzed by polymer-immobilized MacMillan catalyst 63.

Pihko and coworkers used JandaJel for the polymer support, and 59 was immobilized from the N-position of the amide moiety [86]. Quantitative reaction conditions are required for the synthesis of the JandaJel-immobilized MacMillan catalyst because some reactions were carried out at the chain end of JandaJel support. The enantioselectivity in the Diels–Alder reaction of cyclopentadiene and cinnamaldehyde catalyzed by 72 was significantly higher than that of the other polymeric catalyst, and these adducts with 99%ee (endo) and 99%ee (exo) were obtained in 70% yield (Scheme 2.19).

JandaJel O N N H2 Cl 72 72 (20 mol%) O

CHO

+

CHO

CH3CN, rt, 24 h 73

74

75

76 70% Yield 1.2:1 exo/endo 99% ee (exo)

SCHEME 2.19. Asymmetric Diels–Alder reaction catalyzed by polymer-immobilized MacMillan catalyst 72.

40

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

Silica Gel

MCF MCF

O

O

O Si

N

N

N H2

N H2 TFA

O O Si O

N

X

N H2 Cl

O

77

78

79

FIGURE 2.12. MCF or silica gel-immobilized MacMillan catalysts.

Ying and coworkers immobilized 59 onto siliceous and polymer-coated mesocellular forms (MCF), and the resulting polymer-supported organocatalyst was used for asymmetric Friedel–Crafts alkylation and Diels–Alder reaction [122] (Figure 2.12). Polymer-immobilized MacMillan catalysts by polymerization have been reported (Scheme 2.20) [123]. They found that tyrosine was not a very suitable substrate for large-scale preparation of amides, as the phenolic functionality interfered to give rather messy syntheses that necessitated chromatographic purification at some point. A MacMillan catalyst with a hydroxyl group was readily synthesized on a 60-g scale, and the corresponding methacrylic monomer 80 was synthesized. Using a normal suspension polymerization of 80 together with PEG-methacrylates, polymerimmobilized MacMillan catalyst 81 was successfully prepared as practical spherical beads. Asymmetric Diels–Alder reactions of 4-nitrocinnamaldehyde 82 and cyclopentadiene 74 catalyzed by the polymeric catalyst 81 provided product selectivities slightly below the original catalyst, but with the same chemical yield and this time on Poly(alkyl methacrylate)

O O

O N

O

AIBN

N

Toluene, H2O, PVA

N H

N H

80

81 81 (15 mol%)

NO2

HCl or TFA O O2N

82

CHO

+

74

CH3CN/H2O rt, 24 h

+

CHO

84 NO2

83

92% Yield 1.29:1 exo/endo 89% ee (endo)

SCHEME 2.20. Asymmetric Diels–Alder reaction catalyzed by polymer-immobilized MacMillan catalyst 81.

POLYMER-IMMOBILIZED MACMILLAN CATALYSTS

41

a gram scale. The polymeric catalyst with trifluoroacetic acid (TFA) salt was readily reused once. However, in a third and fourth reuse cycle, the enantioselectivities started to drop significantly. Recently, some facile immobilizations of the MacMillan catalyst have been reported. Montrmorillonite clay readily entrapped the MacMillan catalyst and the heterogeneous chiral organocatalyst is used in the Diels–Alder reaction of diene and aldehyde [124]. Silica gel soaked in ion liquid such as 1-butyl-3-methylimidazolium salt was also used for immobilization of the MacMillan catalyst, and the immobilized catalysts were applied to the Diels–Alder cycloaddition [125]. These are noncovalently immobilized MacMillan catalysts (Figure 2.13). The facile synthesis of a polymer-immobilized MacMillan catalyst has also been reported. Using the knowledge that quaternary ammonium sulfonate is stable and that the polymers possessing sulfonate groups can immobilize quaternary ammonium cations through ionic bonding, two methods of the ionic immobilization of MacMillan catalyst have been developed: The first involves the polymerization of the monomer comprising MacMillan iminium moiety 84, and the second is the immobilization of MacMillan catalyst 59 onto a sulfonated polymer through an ionexchange reaction (Scheme 2.21) [126]. Both polymerization and the ion-exchange reaction proceeded smoothly to afford noncovalently polymer-immobilized MacMillan catalyst 85. The methodology of immobilization by ionic interaction has certain advantages because commercially available organocatalysts are directly used for immobilization and the reaction via ion exchange between sulfonated polymer and quaternary ammonium salt proceeded under mild conditions without any side reaction. The catalytic activity of the ionically polymer-immobilized MacMillan catalyst 85 was investigated in the asymmetric Diels–Alder reaction of cinnamaldehyde 73 and cyclopentadiene 74. With 10 mol% of the catalyst, it provided similar enantioselectivity to the analogous MacMillan catalyst with a toluenesulfonate counteranion, full conversion, and the same diastereoselectivity. It is noted that the hydrophilic–hydrophobic balance of the polymer structure is important for the catalyst performance in an asymmetric reaction. Actually, ethylene glycol dimethacrylate (EGDMA) cross-linked PN-isopropyl acrylamide (NIPAM)-immobilized catalyst 86 showed the best performance in the Diels–Alder reaction of cinnamaldehyde and cyclopentadiene. The catalyst can be reused without significant loss of catalytic activity (Figure 2.14). Silicate layer of Montmorillonite

O N

N

N

Bun

PF6

N H2

O

TFA N

H2N

In Silica gel

FIGURE 2.13. Noncovalently supported MacMillan catalysts.

42

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

N

Cl NH2

N

SO3H

O

SO3 NH2

O

59

84

PS Polymerization

Ion Exchange PS

SO3H

+

SO3 NH2

N O

85

SCHEME 2.21. Facile synthesis of noncovalently polymer-immobilized MacMillan catalyst 81.

O

N

0.1

0.02

NH O

O

SO3 NH2

O

0.88

O

NH

O

O

86

FIGURE 2.14. Hydrophilic polymer-immobilized MacMillan catalysts.

2.7 POLYMER-IMMOBILIZED PYRROLIDINE DERIVATIVES Chiral pyrrolidines are one of the most efficient motifs as a chiral organocatalyst. Oriyama and coworkers reported on the utility of chiral pyrrolidine-based ligands as catalysts for kinetic resolution [127, 128]. Janda and coworkers tried to synthesize the polymer-immobilized chiral pyrrolidine, but the Williamson ether formation reactions of Merrifield resin and chloromethyl JandaJel resins with the hydroxyl

POLYMER-IMMOBILIZED PYRROLIDINE DERIVATIVES

43

functionalized chiral pyrrolidine 87 were unsuccessful. An alternative synthetic procedure was used whereby a short spacer unit was introduced to the pyrrolidine derivative before the following coupling reaction (Scheme 2.22) [129]. The kinetic resolution of racemic secondary alcohol 90 using the polymer-immobilized chiral pyrrolidine 89 was performed. The yield of the benzylated product was increased by the amount of 89. When 15 mol% of 89 was used, the benzylated product 91 was obtained in 44% yield with 96%ee, and unreacted alcohol 92 was obtained in 45% yield with 85%ee (S factor was 134). A series of racemic secondary alcohols were resolved using the polymer-immobilized chiral pyrrolidine. Phenyl-substituted cycloalkanols were all resolved with more than 80%ee’s, whereas some fused ring cycloalkanols produced a moderate resolution. The open-chain alcohols such as 1-naphthylethanol and 1-phenylethanol resulted in little or no resolution. Reusability of 89 was tested by performing repeated resolutions of 90 using a 15 mol% catalyst for 6 h. A five-times reuse was accomplished without any loss of either catalytic activity or selectivity. Polystyrene-immobilized chiral pyrrolidines containing triazole were prepared by the copper-mediated 1,3-dipolar cycloaddition between the pyrrolidine derivative with azide and polystyrene resins with alkyne (Scheme 2.23) [130]. The resulting polystyrene-immobilized chiral pyrrolidines 93 and 94 were tested as catalysts for the Michael addition of cyclohexanone 95 to b-nitrostyrene 96. As a general trend, 93 was more reactive but less enantioselective than 94. The adduct 97 was obtained in 87% conversion with 95:5 dr and 89%ee using 94 with 10 mol% DiMePEG in H2O. In addition, a variety of ketones and nitrostyrenes were used in Michael addition under the optimized reaction conditions. All the addition products were obtained in good yields and with excellent diastereo- and enantioselectivities, with no significant dependence on the electronic or steric properties of the substrate. In the reuse test, no decrease was observed in the isolated yield of adduct 97 or in the stereoselectivity after three consecutive uses. 94 was also tested in the Michael addition of aldehydes to nitrostyrene. Quantitative conversions and high diastereoselectivities were obtained for linear aldehydes, although ee’s were only moderate. Similar polymer-immobilized chiral pyrrolidine having triazole 93 was prepared by Wang and coworker [131] (Scheme 2.23). The polymer-immobilized chiral pyrrolidine 93 was also used in the Michael reaction of 95 to 96. The reaction with 10 mol% 93 at 25 C produced the desired product 97 in 99% yield with 99:1 dr and 95%ee. An excellent enantioselectivity (>99%ee) was accomplished when the temperature was decreased at 10 C. 93 was recovered and reused for ten times in consecutive trials without loss of diastereo- and enantioselectivities, but yield was slightly decreased with successive reuse. Polymer-immobilized chiral pyrrolidine with ionic liquids was synthesized by the addition reaction of Merrifield resin with N-Boc–protected chiral pyrrolidine comprising imidazole moiety [132]. Asymmetric Michael addition of cyclohexanone to nitrostyrene without solvent condition at 10 C afforded the adduct 97 in 95% yield with 99:1 dr and >99%ee (Scheme 2.24). The reactions of a variety of nitroolefins with different substituents, ketones, and aldehydes were also investigated. Various styrene-type nitroolefins reacted smoothly with cyclohexanone in high yields with

44

N H

87

N

HO

O N H 88

N

90

Ph

OH

4A MS CH2Cl2, -78 oC, 11 h

89 (15 mol%) BnCl, Et3N

Cl

PS

45% Yield 85% ee

Ph

OH

44% Yield 96% ee

+

N

92

Ph

OBz

89

N H

91

O

O

SCHEME 2.22. Kinetic resolution of racemic secondary alcohol 90 using the polymer-immobilized chiral pyrolidine 89.

HO

PS

45

POLYMER-IMMOBILIZED PYRROLIDINE DERIVATIVES

PS O N N

N

NO2 +

O

N H

O

N

N H

NO2

96

97 87% Conv. d.r. 95:5 89% ee

PS

N N

O

H2O, rt, 24 h

95

93

94 (6 mol%) DiMePEG (10 mol%)

O NO2

93 (20 mol%) TFA (2.5 mol% )

O NO2

+

94

95

96

10 oC, 72 h

97 98% Yield d.r. >99:1 >99% ee

SCHEME 2.23. Enantioselective Michael additions catalyzed by polymer-immobilized chiral pyrrolidines 93 and 94.

excellent diastereo- and enantioselectivities. The polymeric chiral organocatalyst possessed high recyclability, in which the dr and ee values maintained unchanged, while the yield decreased by degrees. Noncovalently polymer-immobilized heterogeneous chiral amine catalysts were reported by Luo and Cheng and coworkers [133]. They used some 1% divinylbenzene cross-linked polystyrene/sulfonic acids as polymeric supports to immobilize PS

N N N H

O NO2

98

98 (10 mol%)

O NO2

neat, rt, 24 h

+ 95

Cl

96

97 97% Conv. d.r. 99:1 99% ee

SCHEME 2.24. Enantioselective Michael additions catalyzed by polymer-immobilized chiral pyrrolidine with ionic liquids 98.

46

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

chiral 1,2-diamine by ionic interaction. The facile immobilization allowed for combinatorial screening of the desired chiral organocatalysts for the asymmetric reaction. The asymmetric direct aldol reaction was selected as a benchmark for testing the catalytic activity. After quick screening of the combination of sulfonated polymers and chiral amines, 98 (1.39 mmol/g of SO3H) and 109 was found to be the best in the direct aldol reaction of cyclohexanone 95 and 4-nitrobenzaldehyde 112. The reaction was carried out in CH2Cl2 at room temperature for 24 h to afford the adduct 113 in 97% yield with 91:9 anti/syn and 97%ee (anti) (Figure 2.15 and Scheme 2.25). The Michael addition of cyclohexanone to b-nitrostyrene was carried out using these types of polymeric catalyst, and the combination of 98 and 105 in toluene at room temperature showed high catalytic activity. However, the reuse experiment revealed that the catalytic reactivity was decreased significantly after six cycles while enantioselectivity was kept (Scheme 2.26). 2.8 OTHER POLYMER-IMMOBILIZED CHIRAL QUATERNARY AMMONIUM SALTS Generally, the immobilization of chiral organocatalysts with a well-designed structure such as a Maruoka catalyst [134, 135] is difficult because the synthetic procedure and functionalization will be a multistep reaction. In addition, there is the possibility that the catalytic activity of a functionalized catalyst is lowered because the structure of the original catalyst is finely tuned. One of the best immobilization methods for these chiral organocatalysts with quaternary ammonium salt at present is using the interaction between ammonium cation and counteranion because the immobilization method can generally be applied to any kind of chiral ammonium salt. The ionexchange reaction of Maruoka catalyst 113 and support polymer comprising sulfonate group 112 proceeded in CH2Cl2-H2O biphasic solvent at room temperature to afford noncovalently polymer-immobilized Maruoka catalyst 114 (Scheme 2.27) [101]. By using 1 mol% of 114 in the alkylation of N-diphenylmethylidene glycine tertbutyl ester 33 with benzyl bromide, the chiral product 34 was obtained in 84% yield with 98%ee. The polymer was fully recovered after the reaction and reused twice to give the same yields and enantioselectivities (for the second and third uses: 84% yield, 98%ee). 2.9 POLYMER-IMMOBILIZED PROLINE DERIVATIVES Proline and its derivatives have been focused as an organocatalyst in intermolecular aldol reaction since List et al.’s report in 2000 [16, 87, 136–138]; even the catalysis of proline was already reported by Eder, Sauer, and Wiechert on the asymmetric synthesis of the Wieland–Mischler ketone via Robinson annulation in 1971 [17, 18]. Proline can be regarded as the simplest “enzyme,” and a tremendous number of

47

99

98

BnO N H

N H

107

101

N

N

BnO

N H

N H

NH

N

109

NH2

N

103: n=1 104: n=2 105: n=3

Chiral amine

108

102

N H

n

106

110

NH2

N

N H

N

FIGURE 2.15. Sulfonated polymers and chiral amines for noncovalent polymer immobilization.

100

SO3H

Linear PS

Sulfonated Polymer

C18H37

SO3H

SO3H

PS

PS

Bu N Bu

NH2

N

111

O

48

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

PS

SO3

N NH2

98+109 O

O 98+109 (10 mol%)

H

+

CH2Cl2, rt, 24 h

NO2 95

OH

O

112

NO2

113 97% Conv. anti/syn 91:9 97% ee (anti)

SCHEME 2.25. Asymmetric direct aldol reaction catalyzed by noncovalently polymerimmobilized chiral amine.

PS

SO3 N N H 98+105 O NO2 + 95

98+105 (10 mol%)

O NO2

Toluene, rt, 24 h 96

97 94% Yield syn/anti 94:6 87% ee

SCHEME 2.26. Asymmetric Michael reaction catalyzed by noncovalently polymerimmobilized chiral pyrrolidine.

49

POLYMER-IMMOBILIZED PROLINE DERIVATIVES

PS

F F

PS

F F

F

Br

F

N

+

SO3

CH2Cl2-H2O, rt, 22 h

N

F SO3Na

F

F

112

113

F F F

114

SCHEME 2.27. Facile synthesis of noncovalently polymer-immobilized Maruoka catalyst 114 via ion-exchange reaction.

papers on the asymmetric reaction, including the aldol reactions [87], Robinson annulations [17], Mannich reactions [139], Michael reactions [137, 140], direct electrophilic a-aminations [141, 142], Diels–Alder reactions [143], Baylis–Hillman reactions [144], aza-Morita–Baylis–Hillman reactions [145, 146], a-selenenylation [147], oxidation [148–150], chlorination [117], and others with use of proline derivatives have been reported. Prolinamide, which is derived from proline, is also one of the efficient organocatalysts [151–155]. Because of the high activities of the prolinamides in the organocatalytic aldol reactions, they are definitely interesting targets for polymer immobilization. The other promising proline-derived catalyst is diarylprolinol developed by Jørgensen and Hayashi and their coworkers independently [156–158]. Polymerimmobilized diarylprolinols have been reported especially for the Corey–Bakshi– Shibata asymmetric reduction [159, 160]. In contrast, polymer-immobilized diarylprolinol silyl esters have emerged only recently. The synthesis of polymer-immobilized prolines 115, prolinamides 116, diarylprolinol silyl esters 117, and their derivatives and the application to asymmetric reactions are described in detail in Chapter 3 (Figure 2.16).

Linker

Linker

R

O N H

115

CO2H

O H N

H N N H

O

116

N H

OH O

117

FIGURE 2.16. Polymer-immobilized proline derivatives.

50

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

PS HN N

O

Linker

O

Linker HN

O O

118

H

119

O

NH R

HO PEGA H N

N NH

O

O

120

TentaGel

O N H CO2H

PS

O HN NH

O

O

121

N H

H N O

H N n H

122

FIGURE 2.17. Polymer-immobilized peptides and poly(amino acid)s.

2.10 POLYMER-IMMOBILIZED PEPTIDES AND POLY(AMINO ACID)S Not only amino acids such as proline but peptides and poly(amino acid)s possess high catalytic activity in an asymmetric reaction (Figure 2.17). A combinatorial approach using a solid-phase synthesis with tripeptide was developed by Wennemers, and this approach was further improved for the discovery of tripeptide 120 as an active catalyst for the asymmetric aldol reaction. Kubo and coworkers developed the immobilization of peptides to PS-graft-PEG, and the polymer-supported peptides such as 121 were used as catalysts for the direct asymmetric aldol reaction in aqueous media. Poly(amino acid)s, e.g., homopolymers of amino acid, have been known as catalysts for asymmetric epoxidation of chalcones to produce highly enantiomerically pure epoxide in good yield thanks to the pioneering work performed in 1980 [161]. The synthesis of polymer-immobilized peptides and poly(amino acid)s and the application to asymmetric reactions are described in detail in Chapter 4. 2.11 POLYMER-IMMOBILIZED CHIRAL ACIDIC ORGANOCATALYSTS Asymmetric dihydroxylation of olefins with hydrogen peroxide catalyzed by Nafion 50 (Ion Power, Inc., New Castle, DE) in water was reported by Sato et al. [162]. trans-1,2-Cyclohexane diol 124 was obtained in 98% isolated yield in the dihydroxylation of cyclohexene 123 with 30% H2O2 and Nafion 50 at 70 C for 20 h (Scheme 2.28). The design and synthesis of chiral acidic organocatalysts have been developed, but the synthesis of polymer-immobilized chiral acidic organocatalyst is quietly limited. Very recently, polymer-immobilized chiral Brønsted acids 125, 126 were synthesized by radical copolymerization [163]. The stick-type polymeric catalyst

HELICAL POLYMERS AS CHIRAL ORGANOCATALYSTS

NafionTM 50 (4 mol%) 30% H2O2

HO

H2O, 70 oC, 24 h

HO

123

51

124 98% yield

SCHEME 2.28. Asymmetric dihydroxylation catalyzed by NafionTM 50. PS

PS O OH P O O

PS O O P O OH PS

125

126

1.25 eq. EtO2C

O N 127

CO2Et N H 128

126 (5 mol%) CHCl3, rt, 16 h

O N H 129 97% Yield 96% ee

SCHEME 2.29. Asymmetric transfer hydrogenation catalyzed by polymer-immobilized chiral Brønsted acid 126.

126 was used in the asymmetric transfer hydrogenation of benzoxazine 127. 127 was asymmetrically reduced to produce an optically pure product 129 in 97% yield with 99% ee. The stick was easily recovered and reused more than ten times (Scheme 2.29). 2.12 HELICAL POLYMERS AS CHIRAL ORGANOCATALYSTS The use of helical polymers as a chiral organocatalyst is challenging. Helical basic polymer 130 was prepared by helical sense-selective anionic polymerization of the corresponding methacrylate monomers with pyridine moiety in the presence of a

52

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

Ph

H N

Ph N O

H n

m

O O

O N

N O 130

O H

SiCl3

+

130 (10 mol%) Excess Pri2EtN

OH

CH2Cl2, 0 oC, 40 h 131

132

133 56%, 19% ee

SCHEME 2.30. Asymmetric addition catalyzed by helical basic polymer 130.

chiral base, followed by treatment of m-CPBA [164]. The polymer was applied to the asymmetric addition of allyltrichlorosilane 132 to benzaldehyde 131. Although the enantioselectivity was low in the reaction, these new types of helical polymer will develop the chemistry of polymeric chiral organocatalysis (Scheme 2.30). Yashima and coworkers have recently reported that optically active, dynamic helical poly(phenylacetylene)s bearing an optically active oligopeptide such as 134 are effective as polymeric organocatalysts for the asymmetric epoxidation of chalcone 57 in toluene/water mixed solvent (Scheme 2.31) [165]. They have also designed and synthesized the functional helical polyisocyanides 136 derived from a helical polyisocyanide while maintaining the macromolecular helicity memory, which exhibits a catalytic activity for the enantioselective aldol reaction of cyclohexanone and 40 -nitrobenzaldehyde. Although the ee value was low (12%ee), this is the example for the transfer of chiral information from the macromolecular helicity memorized in the polymer backbone to an asymmetric reaction [166] (Figure 2.18). Optically active phenylacetylene monomers having L-valine or N-methyl-L-valine moiety were polymerized with a rhodium catalyst to provide the helical poly (phenylacetylene)s. The polymer 137 was used in the asymmetric reduction of aromatic ketimines 138 to afford optically active amine 139 in 98% yield with 26%ee (Scheme 2.32) [167]. In most cases, the predominant chiral configuration of the product was opposite to that obtained by the corresponding monomer. 2.13 CASCADE REACTIONS USING POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYSTS In addition to the asymmetric Enders cascade reaction [168] using a polymerimmobilized chiral organocatalyst, the novel cascade reaction using a polymer-

CASCADE REACTIONS USING POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYSTS

53

C C H

O

L-Ala-L-Ala-L-Ala-ONa

134 O

134 H2O2, NaOH

O

Toluene, 0 oC, 6 days

57

O

135 60% Yield 38% ee

SCHEME 2.31. Asymmetric epoxidation catalyzed by helical poly(phenylacetylene) 134.

immobilized chiral catalyst and star-branched polymer was reported [169]. The concept includes the design of a non-interpenetrating star polymer catalyst to combine iminium, enamine, and hydrogen-bond catalysts in one pot for an asymmetric reaction that generates cascade products with more than one chiral center. Some control experiments were carried out, which demonstrate that the combination of the iminium catalyst, star polymer with sulfonic acid, star polymer with enamine catalyst, and H-bond catalyst is essential for the cascade reaction. The length of arms C C H

O

NH

N H

O 137

N

137 (10 mol%) Cl3SiH (1.5 eq.)

HN

rt, 3.5 h 138

139 98% Yield 26% ee

SCHEME 2.32. Asymmetric reduction of ketimine catalyzed by helical poly(phenylacetylene)137.

54

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

CO2Et t

Bu

N

SO3 NH2

N H

O

Ph Ph OMe

OH Ph

OH

142

Site Isolation

Iminium Catalyst 140 1.2 eq.

1.0 eq.

N

144 + 3.0 eq.

Enamine Catalyst 141 Pr

O

140+141+142 (each 20 mol%)

O

CH2Cl2-iPrOH -30 oC to -40 oC, 7 h then rt, 48 h

143 145

H-Bond Catalyst

O N O

146 89% Yield 100:8 dr >99% ee

SCHEME 2.33. One-pot multi-organocatalyst cascade reactions.

C N

C N

0.97-0.9

0.03-0.1

NH N

CO2H O 136

FIGURE 2.18. Helical poly(phenyl isocyanide) 136.

of the star polymer and the number of arms were also important for the site isolation. In the cascade reaction of 143, 144, and 145 catalyzed by 140, 141, and 142, the desired product 146 was successfully obtained in 89% yield with 100:8 dr and >99% ee under the optimization conditions (Scheme 2.33). 2.14 CONCLUSIONS In this chapter, we have highlighted a variety of polymer-immobilized chiral organocatalysts and the application to asymmetric reactions. The synthetic technique

CONCLUSIONS

55

of polymer-immobilized chiral organocatalysts has been developed with the progress of the chiral organocatalysis. Some useful polymer-immobilized chiral organocatalysts were well investigated, but there is some useful chiral organocatalysts in which immobilization is not reported. One of the new and interesting immobilization techniques is noncovalent immobilization, which allows, in most cases, the preparation of immobilized chiral organocatalysts in a way simpler than that of a conventional immobilization technique, including covalent bond formation, mainly when no modifications of the chiral organocatalyst such as a well-designed organocatalyst are needed to establish the support–catalyst interaction. The catalytic activity of polymer-supported chiral organocatalysts was similar or lower than that of their nonsupported counterparts in most cases. However, the immobilization of chiral organocatalysts is of interest because higher yields and enantioselectivities have been obtained compared with the native organocatalyst in some cases. It is true that the polymer support offers a new microenvironment and possibilities in the asymmetric reaction. The catalytic activity will be determined by the overall catalytic system arranged with the integration of a chiral organocatalyst and polymeric backbone. The suitable design of a support polymer and the arrangement for a good microenvironment will be a guide for a highly effective polymer-immobilized chiral organocatalyst. In the practical sense, the immobilization of chiral organocatalysts onto polymer will play an important role in contributing to further expansion of the applicability of a chiral organocatalyst. Significant progress will be derived from the interdisciplinary contribution development of interdisciplinary contributions from organic, polymer, and material chemists, which can solve the present and future problems. The practical applications of polymer-immobilized chiral organocatalysts will further expand in the future. This will be a result of the continuing improvements brought about by the advancements in the technology of chemical processes and the obvious advantages in the use of a highly efficient and reusable catalyst in terms of cost and impact on the environment. List of Abbreviations AIBN Ala Boc BPO DiMePEG DMAP DMF DMSO DVB EGDMA MCF m-CPBA MS

2,20 -azabis(2-methylpropionitrile) alanine tert-butoxylcarbonyl benzoylperoxide dimethylpoly(ethylene glycol) 4-(dimethylamino)pyridine N,N-dimethylacrylamide dimethylsulfoxide divinylbenzene ethylene glycol dimethacrylate mesocellular form meta-chloroperbenzoic acid molecular sieves

56

POLYMER-IMMOBILIZED CHIRAL ORGANOCATALYST

MTBE NFSI NIPAM PEG PEGA PEO PS PTC TFA THF TMS Ts Tyr

methyl tert-butyl ether N-fluorobenzenesulfonimide N-isopropyl acrylamide poly(ethylene glycol) poly(ethylene glycol)-poly(acrylamide) poly(ethylene oxide) polystyrene phase transfer catalyst trifluoroacetic acid tetrahydrofuran trimethylsilyl toluene sulfonyl tyrosine

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ajera, C. Adv. Synth. Catal. 2004, 346, 1186–1194. [94] Thierry, B.; Plaquevent, J. C.; Cahard, D. Tetrahedron: Asymmetry 2001, 12, 983–986. [95] Thierry, B.; Perrard, T.; Audouard, C.; Plaquevent, J. C.; Cahard, D. Synthesis 2001, 11, 1742–1746. [96] Thierry, B.; Plaquevent, J. C.; Cahard, D. Mol. Divers. 2005, 9, 277–290. [97] Shi, Q.; Lee, Y. J.; Song, H.; Cheng, M.; Jew, S. S.; Park, H. G.; Jeong, B. S. Chem. Lett. 2008, 37, 436–437. [98] Thierry, B.; Plaquevent, J. C.; Cahard, D. Tetrahedron: Asymmetry 2003, 14, 1671–1677. [99] Lv, J.; Wang, X.; Liu, J.; Zhang, L.; Wang, Y. Tetrahedron: Asymmetry 2006, 17, 330–335. [100] Wang, X.; Yin, L.; Yang, T.; Wang, Y. Tetrahedron: Asymmetry 2007, 18, 108–114. [101] Arakawa, Y.; Haraguchi, N.; Itsuno, S. Angew. Chem. Int. Ed. 2008, 47, 8232–8235. [102] Itsuno, S.; Paul, D. K.; Ishimoto, M.; Haraguchi, N. Chem. Lett. 2010, 39, 86–87. [103] Itsuno, S.; Paul, D. K.; Salam, M. A.; Haraguchi, N. J. Am. Chem. Soc. 2010, 132, 2864–2865. [104] Helder, R.; Hummelen, J. C.; Laane, R. W. P. M.; Wiering, J. S.; Wynberg, H. Tetrahedron Lett. 1976, 17, 1831–1834. [105] Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55, 6289–6300. [106] Corey, E. J.; Zhang, F. Y. Org. Lett. 1999, 1, 1287–1290. [107] Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79–87. [108] MacMillan, D. W. C. Nature 2008, 455, 304–308. [109] Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470. [110] Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569. [111] Lelais, G.; MacMillan, D. W. D. In New Frontiers in Asymmetric Catalysis ( Mikami, K.; Lautens, M., Eds.), Wiley, New York, pp. 319–331 (2007).

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[112] Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243–4244. [113] Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874–9875. [114] Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438–15439. [115] Pares, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370–4371. [116] Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172–1173. [117] Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108–4109. [118] Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 6722–6724. [119] Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62, 11413–11424. [120] Benaglia, M.; Celentano, G.; Cinquini, M.; Puglisi, A.; Cozzi, F. Adv. Synth. Catal. 2002, 344, 149–152. [121] Puglisi, A.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, G. Eur. J. Org. Chem. 2004, 567–573. [122] Zhang, Y.; Zhao, L.; Lee, S. S.; Ying, J. Y. Adv. Synth. Catal. 2006, 348, 2027–2032. [123] Kristensen, T. E.; Vestli, K.; Jakobsen, M. G.; Hansen, F. K.; Hansen, T. J. Org. Chem. 2010, 75, 1620–1629. [124] Luo, S.; Li, J.; Zhang, L.; Xu, H.; Cheng, J. P. Chem. Eur. J. 2008, 14, 1273–1281. [125] Hagiwara, H.; Kuroda, T.; Hoshi, T.; Suzuki, T. Adv. Synth. Catal. 2010, 352, 909–916. [126] Haraguchi, N.; Takemura, Y.; Itsuno, S. Tetrahedron Lett. 2010, 51, 1205–1208. [127] Oriyama, T.; Hori, Y.; Imai, K.; Sasaki, R. Tetrahedron Lett. 1996, 37, 8543–8546. [128] Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem. Lett. 1999, 265–266. [129] Clapham, B.; Cho, C. W.; Janda, K. D. J. Org. Chem. 2001, 66, 868–873. [130] Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericas, M. A. Org. Lett. 2007, 9, 3717–3720. [131] Miao, T.; Wang, L. Tetrahedron Lett. 2008, 49, 2173–2176. [132] Li, P.; Wang, L.; Wang, M.; Zhang, Y. Eur. J. Org. Chem. 2008, 1157–1160. [133] Luo, S.; Li, J.; Zhang, L.; Xu, H.; Cheng, J. P. Chem. Eur. J. 2008, 14, 1273–1281. [134] Kitamura, M.; Shirakawa, S.; Maruoka, K. Angew. Chem. 2005, 117, 1573–1575. [135] Kitamura, M.; Shirakawa, S.; Maruoka, K. Angew. Chem. Int. Ed. 2005, 44, 1549–1551. [136] Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975–2978. [137] List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423–2425. [138] Benaglia, M. Cinquini, M.; Cozzi, F.; Puglisi, A.; Celentano, G. Adv. Synth. Catal. 2002, 344, 533–542. [139] List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337. [140] Betancort, J. M.; Barbas III, C. F. Org. Lett. 2001, 3, 3737–3740. [141] Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. N. Angew. Chem., Int. Ed. 2002, 41, 1790–1793. [142] List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657. [143] Thayumanavan, R.; Dhevalapally, B.; Sakthivel, K.; Tanaka, F.; BarbasIII, C. F. Tetrahedron Lett. 2002, 43, 3817–3820. [144] Shi, M.; Jiang, J. K.; Li, C. Q. Tetrahedron Lett. 2002, 43, 127–130.

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[145] Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas III, C. F. Angew. Chem. Int. Ed. 2007, 46, 1878–1880. [146] Vesely, J.; Dziedzic, P.; Co´rdova, A. Tetrahedron Lett. 2007, 48, 6900–6904. [147] Wang, J.; Li, H.; Mei, Y.; Lou, B.; Xu, D.; Xie, D.; Guo, H.; Wang, W. J. Org. Chem. 2005, 70, 5678–5687. [148] Zhong, G. Angew. Chem. Int. Ed. 2003, 42, 4247–4250. [149] Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–10809. [150] Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293–8296. [151] Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. J. Am. Chem. Soc. 2003, 125, 5262–5263. [152] Tang, Z.; Yang, Z. H.; Chen, X. H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. J. Am. Chem. Soc. 2005, 127, 9286–9289. [153] Raj, M.; Maya, V.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097–4099. [154] Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593–2595. [155] Raj, M.; Maya, V.; Singh, V. K. J. Org. Chem. 2009, 74, 4289–4297. [156] Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 794–797. [157] Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296–18304. [158] Hayashi, Y.; Cotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem. Int. Ed. 2005, 44, 4212–4215. [159] Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553. [160] Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925–7926. [161] Juli
a, S.; Masana, J.; Vega, C. Angew. Chem. Int. Ed. Engl. 1980, 19, 929–931. [162] Usui, Y.; Sato, K.; Tanaka, M. Angew. Chem. Int. Ed. 2003, 42, 5623–5625. [163] Rueping, M.; Sugiono, E.; Steck, A.; Theissmann, T. Adv. Synth. Catal. 2010, 352, 281–187. [164] M€uller, C. A.; Hoffart, T.; Holbach, M.; Reggelin, M. Macromolecules 2005, 38, 5375–5380. [165] Maeda, K.; Tanaka, K.; Morino, K.; Yashima, E. Macromolecules 2007, 40, 6783–6785. [166] Miyabe, T.; Hase, Y.; Iida, H.; Maeda, K.; Yashima, E. Chirality 2009, 21, 44–50. [167] Terada, K.; Masuda, T.; Sanda, F. J. Polymer Sci. Part A: Polymer Chem. 2009, 47, 4971–4981. [168] Enders, D.; H€uttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861–863. [169] Chi, Y.; Scroggins, S. T.; Fr
echet, J. M. J. J. Am. Chem. Soc. 2008, 130, 6322–6323.

CHAPTER 3

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES MICHELANGELO GRUTTADAURIA, FRANCESCO GIACALONE, and RENATO NOTO

3.1 INTRODUCTION Until recently, catalytic asymmetric synthesis to obtain enantiopure products has been carried out by the chemist community mainly by following two principal methods, namely organometallic and bioenzymatic catalysis. Although, in the former, transition metal complexes are used, in the latter, the asymmetric catalysis is accomplished using enzymes. Unfortunately, both methods have big drawback being used, including the expense, instability, and being strongly conditiondependent catalysts. However, in the last 10 years, a new method has been born and quickly matured: organocatalysis [1]. In this new field of catalysis, asymmetric reactions are promoted by simple, robust, nontoxic, and often low-cost, metal-free organic molecules in substoichiometric amounts. Although, during the late 19th and early and mid-20th centuries, some organically catalyzed reactions have been described, it was only in the 21st century when organocatalysis’ potential was glimpsed, partially disclosed, and finally largely exploited for enantioselective synthesis. In fact, in 2000, List et al. rediscovered the proline-catalyzed aldol reaction [2], previously reported by Hajos and Parrish [3] and Eder et al. [4], and in the same year, just few months later, MacMillan et al. coined the term organocatalysis [5]. Since then, a huge interest has been devoted to the use of L-proline [6], which can be the simplest “enzyme,” and in addition to the aldol reaction [7], it has been successfully applied to many other reactions such as the Robinson annulation [8], Mannich reactions [9], Michael reactions [10], direct electrophilic a-aminations [11],

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.

63

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ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

FIGURE 3.1. Some proline-catalyzed reactions.

Diels–Alder reactions [12], aza-Diels–Alder reactions [13], Baylis–Hillman reactions [14], aza-Morita–Baylis–Hillman reactions [15], a-selenenylation [16], oxidation [17], a-chlorination [18], and others [19] (Figure 3.1). All of these reactions proceed via the formation of activated enamine or iminium ion intermediates between the carbonyl substrates and the catalyst [20]. However, in such aminocatalytic processes, the covalent binding of substrates normally requires high catalyst loadings in the 20–30 mol% order but in some cases, higher amounts of proline or its derivatives are needed. Although L-proline is an inexpensive natural product, several of its derivatives usually employed as catalysts are not. On the contrary, several derivatives require numerous synthetic steps, including expensive chromatographic purifications, resulting in highly valued catalysts that are not recovered after the reactions. Moreover, these organocatalysts, which are organic compounds, often can represent a complication in the product isolation process, requiring additional purification steps such as acid or base treatments and subsequent extractions. Hence, immobilization of the catalyst on an inert support seems to be the best choice to avoid all the aforementioned complications. In fact, the supported materials are easily recoverable and recyclable for consecutive runs and have a strong impact on catalysts and catalysis costs [21]. This importance is evident both when a less expensive catalyst, such as simple proline, is used in large quantities or when a more expensive catalyst, prepared in multistep syntheses, is used. In this regard, in the last

INTRODUCTION

65

few years, much work has been focused on this topic, which resulted in several review articles [22] and books [23]. The immobilization step may be carried out by covalently linking the properly functionalized catalyst to the support or by noncovalent interactions. In the latter approach, the catalyst may be adsorbed, included, or linked by electrostatic interactions. Although the noncovalent immobilization is a quick and useful approach, it usually does not require any chemical modification on the catalyst chemical structure, and often some leaching may take place, leading to diminished activities, contamination of reaction products, and a loss of the organocatalyst. To remedy the situation, several covalent anchoring strategies have been designed and several different supports such as polymers, silica, magnetite, polyoxometalates, DNA, and dendrimers among others have been successfully employed [21–23] even if the first two classes have been the most widely studied. As stated before, proline is not expensive, and its immobilization and recovery may seem to be a useless chemical exercise because, especially in the covalent immobilization, it requires several additional synthetic reactions employing more expensive starting materials, as is the case for the trans-4-hydroxy-L-proline. In a few words, it does not seem to be cost-efficient to support low-valued compounds on high-valued supports because the latter is rather expensive. However, supported low-cost catalysts may serve as model case studies, paving the way for the immobilization of more complex and expensive catalysts. In addition, other reasons strongly justify immobilization, covalently or not. In fact, immobilization is of interest because the additional morphological properties of heterogeneous supports, such as polystyrene or silica, lead to a changed environment close to the catalyst, which may result in a stereochemical efficiency enhancement for a given reaction. Moreover, the choice of linker between the support and the catalyst may have a crucial importance on the outcome of the reactions also because of the electronic or steric effects as well as the changes of polarity in the reaction environment. Two kinds of spacer may be used: chemically inert, namely an aliphatic chain; or active linker, which can interact with substrates through H-bonds or electrostatic interactions. As a consequence of support and spacer choice, the resulting materials can be modulated in such a way that high stereoselectivities can be achieved and, most important, that new solubility profiles may be studied as well as the influence of the support on catalyst behavior. It is also true that anchored catalysts often show a decreased activity in comparison with their homogeneous versions because of the limited catalyst mobility. In these cases, what is lost in terms of efficiency is gained in terms of practicity (simpler recovery and recycle). Once problems concerning the immobilization procedure have been addressed, instead of regarding the covalent linking of catalyst to the support as an unavoidable and expensive drawback, one has to look at it as an opportunity to improve catalyst performances, having at the same time access to a new reactivity scenario. In the present chapter, we will focus our attention on polymer-supported proline and some of its derivatives such as prolinamides, peptides, pyrrolidines, and prolinols.

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ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

3.2 POLYMER-SUPPORTED PROLINE Soon after the birth of organocatalysis, the high catalyst loading required for the successful outcome of reactions drove chemists to search for catalyst recovery and recycling. In this light, Barbas et al. as early as 2001 attempted to immobilize proline in a silica gel column leaving reactants for aldol reaction incubated for 2 days [7a]. However, even if some result is obtained, the lower activity and optical yield make them have to give up to follow on with this approach. In the following years, another attempt to support noncovalent proline by adsorption on the surface of silica gel modified with a monolayer of covalently attached ionic liquid (IL) has been successfully carried out by Gruttadauria et al. [24]. Nevertheless, in the last 10 years, chemists optimized numerous procedures for the covalent immobilization of L-proline on a polymeric substrate. In this light, until recently, the postmodification strategy has been the most widely used, and since 2009, the bottom-up approach is emerging as a good strategy for the multigram preparation of supported organocatalysts, as we will show later. The choice of postmodification seems to be obvious because at least for the first examples, organic chemists tried to combine the use of commercially available preformed polymers, usually employed for the solid-phase synthesis, with properly functionalized grafting catalysts instead of starting with a tedious and unpredictable synthesis from the bottom. As a starting point, two possible polymers can be used as support: linear solvent soluble polymers and cross-linked polymers. In this regard, the pioneers in preparing and using soluble mono- and bis-proline-end capped polyethyleneglycol (PEG) as an organocatalyst were Benaglia et al. (1 and 2 in Scheme 3.1) [25]. They used such soluble and recyclable catalysts in the enantioselective aldol condensation between acetone or hydroxyacetone and several aldehydes [25a,b], in the synthesis of the Wieland–Mischler ketone, in the Mannich reaction [25b], and in the addition of 2-nitropropane to cyclohexenone [25c]. These catalysts represent an example of monophase catalysis with biphase separation, in which the supported catalyst is working in homogenous conditions and is separated by precipitation by adding a precipitating solvent and filtration in heterogeneous conditions. The best results were obtained in the aldol reaction, in which the supported catalyst behaved similar to the pristine proline, whereas in the other reactions, lower levels of activity and selectivity were achieved. Recycling studies revealed that, after three cycles, ee values are maintained with a low decrease in activity. Some years later, Zhao et al. reported three new PEG-supported proline catalysts that were employed in the asymmetric Michael addition (3a,b-4, Scheme 3.1, reaction c) [26]. In this study, although good diastereoselectivities (up to 98/2 anti/syn ratio) and fair enantioselectivites were observed, the large and expensive synthetic strategy that involves up to eight steps probably does not counterbalance the catalytic activity. Generally speaking, the use of PEG-supported catalysts unfortunately carry some inconvenience on their backs such as the chronic low loadings resulting from the presence of only one or two functionalizable end positions in the polymer. Subsequently, depending on the molecular weight (MW) of PEG chains, large

POLYMER-SUPPORTED PROLINE

O

H N

O O

O

O N H

O

= MeO-(CH2CH2)n-CH2CH2

2: x = 2;

= CH2CH2-(CH2CH2)n-CH2CH2 O

(a)

R-CHO

PMP-NH2

O + R1

R2

Ar

O H S N O

H N

= PEG MW 5000

4:

1 (30 mol%) R

R'

1 (30 mol%)

PMP

DMSO, r.t. 24-72 h

R

NH

NO2

O

3 examples Yield: 10-81% e.e.: 40-96%

3 cycles Yield: 81-64% e.e.: 96-97%

3 or 4 (5 mol%) CHCl3/MeOH r.t. 48 h

COOH N H

5 examples Yield: 8-77% anti/syn: >20/1 e.e.:21->98%

OH O

PMP = 4-CH3O-Ph (c)

= PEG MW 5000

O

solvent, r.t. 20-130 h

O + RCHO +

3b:

+ R'

(b)

= PEG MW 2000

N H

x

1: x = 1;

3a:

COOH

COOH

O

67

O

R1

Ar

R2

NO2

15 examples Yield: 39-94% syn/anti: >98/2 e.e.: <5-86%

SCHEME 3.1. Asymmetric reactions catalyzed by PEG-supported proline 1-4.

amounts of material have to be added to each reaction implying additional practical complications like larger reaction solvent use and larger precipitating nonsolvent wasting. These drawbacks probably make chemists opt for insoluble and highly functionalized cross-linked resins. The first example of supported proline covalently bounded to a cross-linked polystyrene dates back to 1985. Takemoto and co-workers used such a catalyst in a Robinson cyclization reaction with modest results in terms of conversion and enantioselectivity [27], even though the latter was determined by optical rotation (Scheme 3.2). The real explosion of interest in polystyrene-bound proline started in 2006, probably because of the independent and seminal works of Hayashi et al. [28] and Barbas et al. [29] who discovered, respectively, that simple hydrophobic derivatives of proline or pyrrolidines bearing large alkyl chains could catalyze the asymmetric aldol reaction in the presence of water with a high level of stereoselectivity, whereas proline itself did not. The amphiphilic catalyst probably lie organized in the oil– water micellar interface in such a way that only one of the four possible transition states that lead to the four possible diastereoisomers is favored [30]. In this light, in cross-linked, polymer-supported prolines, the polymeric backbone to which the catalyst is bounded to may be regarded as a large and hydrophobic moiety thus, in

68

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

O

O

5a or 5b (40 mol%)

O

DMF, 40° C 5-15 days

O

O

OH

Yield: 20-53% ee: 5-39%

n O 5a: n = 1 5b: n = 7

COOH NH

SCHEME 3.2. Robinson annulations promoted by polystyrene-supported prolines 5a-b.

principle, allowing the exploitation of all benefits deriving from the use of water. One of the most engaged chemists in these studies was Peric
as et al., who prepared and tested several resins obtained mainly by means of Huysgen’s reactions in the key steps [31] (Scheme 3.3). Catalysts 6–10 proved to be very active and selective materials. Catalyst 6 has been used in the aldol reaction between several ketones and arylaldehydes [31a]. The reaction worked nicely in water in the presence of a catalytic amount of DiMePEG to facilitate reactant diffusion to the resin. Comparing the resin results with those

N N N

Merrifield resin

N H

O

(a) R-CHO +

OH

O

OH

H2O, rt

O

R1 + R

R

R1

N

Merrifield resin

N N

Merrifield resin

10:

N H

R2

8:

COOH COOH

6 or 10 (10 mol%)

O

COOH N H

O

Argopore resin

9:

N H PS-PEG NovaBioSyn resin

7:

N N N

O

O COOH

COOH 6:

N N N

PEG

O

R2

R1 R2

N H

Resin 6: 10 examples Yield: 45-97% anti/syn: 58/42-98/2 e.e.: 45-97%

Resin 10 9 examples Yield: 16-99% anti/syn: 84/16-97/3 e.e.(anti) : 94->99% up to 5 cycles

(b) 6 (10-20 mol%)

O + Ph-N=O

R1

O ONHPh

R1

R2

R2

13 examples Yield: 35-86% e.e.: 96-99% up to 3 cycles

(c) O +

R1 R2

HN

PMP COOEt

6 (10-20 mol%) DMF, rt

O

HN PMP

R1

COOEt

9 examples Yield: 40-95% e.e.: 76-99% up to 3 cycles

R2

SCHEME 3.3. Asymmetric reactions catalyzed by resin-supported prolines 6-10.

POLYMER-SUPPORTED PROLINE

69

obtained using a benzyl triazole-substituted proline as a model compound, the authors demonstrated the efficiency of their approach. Resin 6 was the first polymersupported insoluble organocatalyst active in the a-aminoxylation of aldehydes and ketones resulting in a good yield and a high enantioselectivity as well as showing higher reaction rates than those reported with L-proline (reaction b, Scheme 3.3) [31c]. Finally, the same resin has been successfully employed both in batch and in continuous-flow Mannich reactions (reaction c, Scheme 3.3) [31d]. Although donor aldehydes promptly reacted in the 1–3 h range, reactions with the less reactive ketones were efficiently accelerated by employing low-power microwaves (1 W) with no changes in stereoselectivity. With these examples, Peric
as et al. reported the first case in which a resident-supported- organocatalyst is efficiently used in the continuous-flow technique. However, supported-proline 10, despite the hydrophobicity of the polymer backbone, swelled in water and formed a gel-like single phase [31b]. The swollen resin showed a water content of 24% in weight, building in an aqueous microenvironment. This material parallels the effect of essential water on some natural enzymes used in organic media. Indeed, the authors demonstrated that only the water molecules lying in the resin gave catalytic properties to this material. This property developed from the formation of a hydrogen-bond network connecting the proline and the 1,2,3-triazole linker. It is noteworthy that, in all the aforementioned cases, recycle and reuse of the catalyst was accomplished with no losses in either activity or stereoselectivity. A few months later, the first report from Peric
as, et al. immobilized 4-hydroxy-Lproline on a mercaptomethyl-functionalized resin [32]. The anchorage was accomplished efficiently by linking a styrene derivative of hydroxy-L-proline through a thiol-ene coupling reaction [33], leading to catalysts loading as high as 1.4 mmol/g in high yields. Good-to-excellent conversions and stereoselectivities were observed in almost all examined substrates in the asymmetric aldol reaction, and importantly, no additives were required (Scheme 3.4). Recycling studies showed no decrease in yield or stereoselectivity after five cycles. To explain the observed higher stereoselectivity compared with those obtained using nonsupported proline, we hypothesize that hydrophilic proline moieties lie at the resin–H2O interface, which facilitates the formation of a hydrophobic core on the inner surface of the resin (Figure 3.2). Water molecules, lying in the hydrophilic outer region, force hydrophobic aryl aldehydes into the restricted hydrophobic inner pocket. In this way, water promotes the reaction and increases the stereoselectivity. Thus, this material can be considered a better mimic of natural class I aldolase enzymes. It was investigated later whether an inversion of configuration at C-4 of the L-proline unit may have a role in the stereochemical outcome of the reaction [34]. Thus, a new catalyst has been prepared by immobilizing cis-4-hydroxy-L-proline onto a polystyrenic resin and has been checked in the aldol reaction. Although diastereoselectivities were high (94:6 anti/syn), the ee values were 10–12% lower than the supported trans-4-hydroxy-L-proline. Water was also used, albeit as a cosolvent mixed in a 1/15 ratio with dimethylformamide (DMF) and with two novel polystyrene-supported prolines (12 and 13) (Scheme 3.5) in the aldol reaction [35]. The two resins were prepared starting from

70

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

O

S

COOH N H

11 11 (10 mol%)

O R-CHO +

R1 R2

OH O

OH O R1 + R

R H 2O 22-120 h, r.t.

R1 R2

R2

25 examples Yield: 33-99% anti/syn: 68/32->99/1 e.e.(anti) : 66-98% up to 5 cycles

SCHEME 3.4. Asymmetric aldol reaction catalyzed by polystyrene-supported proline 11.

(2S, 4S)-N-Cbz-4-aminoproline methyl ester and 4-hydroxy benzoic acid or terephthaloyl dichloride, which were, in turn, immobilized onto linear chloromethyl polystyrene and aminomethyl polystyrene, respectively. The aldol products were obtained in fair-to-good yields and selectivities employing only 5 mol% of the catalyst even if a large excess of ketone was used (15–36 equivalents). Also of note,

er wat

O

O δ+

N − Oδ δ O H δ+

O

−

R

S S

OH

R hydrophobic pocket

L-Pro

O

FIGURE 3.2. Proposed transition state model for the aldol reaction using resin 35.

X H N

O R-CHO +

N H

12 or 13 (5 mol%)

OH O R

DMF/H2O 15/1 24 h, r.t.

12: 7 examples Yield: 62-72% anti/syn: 87/13-91/9 e.e.(anti) : 86-98% up to 5 cycles

COOH

12: X = O O 13: X = C(O)NH

OH O + R

13: 7 examples Yield: 60-81% anti/syn: 83/17-93/7 e.e.(anti) : 82-95%

SCHEME 3.5. Asymmetric aldol reaction catalyzed by polystyrene-supported prolines 12-13.

71

POLYMER-SUPPORTED PROLINE

catalyst 12 was recovered and reused for another four, cycles resulting in a slowly diminishing yield (61–56%) and comparable ee values (93–88%). However, Portnoy and Kehat have been engaged in the synthesis and study of several polymer-supported dendritic prolines (Scheme 3.6) [36]. Studies were performed using the aldol reaction between acetone and benzaldehyde or 4-nitrobenzaldehyde, showing that first- and second-generation materials gave better yields and ee values than nondendritic material. However, recycling studies, which also included a catalyst, showed that dendronization negatively affected the activity, which dropped after three cycles. Unfortunately, the low-to-fair yield and enantioselectivity displayed, in our opinion, do not justify the very expensive and timeconsuming synthetic strategy that involves up to nine steps. All the aforementioned examples, most of which showed the usefulness of supporting the simple and cheap proline onto a polymeric matrix, in the last years prompted and justified chemists to make efforts toward the synthesis of supported organocatalysts employing the so-called bottom-up approach, hence starting from the monomers reaching to the final resins. As stated before, it is a natural behavior, at least at the beginning, to use known and fast procedures as in the case of the postmodification approach to test new materials in the asymmetric catalysis. Once these preliminary studies showed the feasibility as well as a real interest in such a catalyst, it is time to develop synthetic protocols for the preparation of large-scale amounts of materials. In this light, Kristensen et al. were the pioneers in the research and preparation of suitable and cheaper organocatalyst monomers capable of being polymerized in bead-shaped polymers, paving the way for the preparation of

CHO

O

14-23 (30 mol%)

O

OH

Yield: 6-95% e.e.: 23-85% up to 3 cycles

+ 4-9 days

R

R

R = -H; -NO2

X

X N N N

O

O

COOH

O

NH

Wang Resin G(0) 14

G1(Pro)

O B

O

N N N

N

O

19: X = Y = B O 20: X = Y = C 21 : X = H; Y = B G3(Pro) 23: X = C 22: X = H; Y = C N N N

O

L-Pro

O

G2(Pro)

15: X = Y = A 16 : X = H; Y = A 17: X = A; Y = OPh 18: X = A; Y = D N N N A

X

Y

L-Pro

N

X

O L-Pro

N N N

N O

C

X

L-Pro

O

D

SCHEME 3.6. Aldol reaction promoted by dendritic polymer-supported prolines 14-20

72

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

O

R O n O

O

N H

O O

24a: R = H 25b: R = Me

O

O

COOH

H 2O 24 h, r.t.

O

O

OH O

OH O + R

R

COOH

N H

acrylic resin styrenic resin

27a: 27b:

27a or 28 (10 mol%)

R-CHO +

COOH

N H

26a: by dispersion 26b: by suspension

O

O O

O N H

COOH

O O

O

acrylic resin

28:

8 examples Yield: 7-91% anti/syn: 91/9-97/3 e.e.(anti) : 89-99%

SCHEME 3.7. Bottom-up prepared supported prolines 24-28 for aldol reaction.

industrial interesting low-cost materials [37]. Interestingly, first they thoroughly carried out preliminary investigations on the selective O-acylation of hydroxyproline by means of trifluoroacetic acid (TFA) to avoid expensive and time-consuming protection and deprotection steps as well as chromatographic separations, which would make the whole synthesis less appealing [37a]. Then, they prepared a series of proline-containing polymers, which includes linear high-loaded linear polymers (24a-b), a granulated dispersion copolymerized resin (26a), and beaded suspension copolymerized resins (26b-28) (Scheme 3.7). They obtained multigram amounts of catalysts in only two steps. Once prepared, the catalysts were tested in the asymmetric aldol reaction between cyclohexanone and eight aromatic aldehydes. Interestingly, catalysts 27b and 28, which have inverted stereocenters at C-2, practically gave a mirror stereoselectivity. Moreover, catalyst 27a worked nicely even at 1 mol% loading (for example), resulting in being recyclable for five consecutive runs with an unaffected outcoming. More recently, Gallardo et al. reported the synthesis of two linear and two crosslinked proline–polymers (Scheme 3.8) [38]. Studies on polymers 29a and 30a revealed isoelectric points close to 3, whereas with polymers 29b and 30b, maximum

n

O n

O

O

COOH N H 29a: linear 29b: cross-linked

HN

O

CHO

O

6

O

29a or 30a (30 mol%)

OH

+ O

O COOH N H 30a: linear 30b: cross-linked

O

O

24-64 h NO2

O

O

NO2

Conv.: 11-99% anti/syn: 66/34-89/11 e.e.: 46-88%

SCHEME 3.8. Aldol reaction catalyzed by polyacrylate-supported prolines 29-30.

POLYMER-SUPPORTED PROLINAMIDES

73

swelling degrees of 24 and 11 (g water/g polymer), respectively, were measured at basic pH. Polymers 29a and 30a showed modest-to-good catalytic activity in the aldol reaction in which no recycling was reported. Finally, a series of linear polystyrenes with different amounts of proline has been synthesized by reversible addition-fragmentation chain-transfer polymerization (RAFT) [39]. However, no catalytic studies have been reported. 3.3

POLYMER-SUPPORTED PROLINAMIDES

Recently, several substituted prolinamides have been found to be active and highly stereoselective catalysts for the direct aldol reaction both in organic solvents [40] and in aqueous conditions [41]. Among them, L-proline–based chiral organic molecules that have gem-diphenyl groups showed enhanced performances, including excellent ee for aldols derived from acetone (catalyst loading: 5 mol% –40  C) [40a] or in brine (catalyst loading: 0.5 mol% at –5  C) [41a]. Hence, Gruttadauria and coworkers paired the idea of using an immobilized version of the aforementioned prolinamide organocatalysts with recyclable materials to parallel the outstanding reaction outcome [42]. Once again, the properly modified organocatalysts were anchored to a mercaptomethylic resin through the well-established thiol-ene coupling protocol affording catalysts 31 and 32 (Scheme 3.9). A water/chloroform 1:2 (v/v) mixture was the best reaction medium, and resins were recovered by filtration and reused in the next cycle, which unfortunately show a dramatic drop in activity. The catalysts probably were deactivated by the excess of ketone with the formation of the corresponding imidazolidinone [43]. Therefore, catalysts were regenerated after treating with formic acid to hydrolyze the imidazolidinone [44]. Remarkably, activity and enantioselectivity were restored and regeneration of resins was performed after each cycle, allowing for an astonishing recyclability of both materials up to 12 cycles for 32 and up to 22 cycles for 31. Moreover, the enantioselectivities obtained employing acetone as ketone were the highest achieved with a supported proline- derivative. Interestingly, 31 and 32 worked nicely at room temperature, whereas the excellent results displayed by the S

O O N H

31: X = i-Bu 32: X = Ph

31 or 32 (10 mol%)

O +

X N H

R-CHO CHCl3/H2O 2:1, 22-120 h; r.t.

O

Ph Ph OH

OH

31: 20 examples Yield: 17->99% anti/syn: 91:9-98:2 e.e. : 80-98% up to 22 cycles 32: 29 examples Yield: 35-95% anti/syn: 96:4-98:2 R e.e. : 89-98% up to 12 cycles

SCHEME 3.9. Polystyrene-supported prolinamides 31 and 32.

74

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

analogue, unsupported prolinamides in a homogeneous condition were obtained carrying out the reactions at –5 or –10  C [40a, 41a]. Similar results were later obtained by Hansen and coworkers, preparing analoguesupported prolinamides, although they post-modified resin 27b in the bottom-up approach with the proper aminoalcohol [37b, c]. In addition to resin 33, they also prepared the supported quasienantiomer 34, and both were checked successfully in the aldol reaction between acetone and aromatic aldehydes (Scheme 3.10). The two catalysts behaved more or less identical, with 33 recovered and reused for five cycles with no loss in activity but with some alternating ee results (from 84 to 99%). In 2008, Resmini and coworkers reported the first imprinted organocatalytic nanogel [45]. In this article, the authors prepared a series of nanogels by polymerizing N,N’-methylenebisacrylamide, acrylamide, and the imprinting enaminone 35 (Scheme 3.11). Once prepared, the polymers were hydrolyzed to cleave the templates and subsequently left a series of cavities containing the prolinamide groups. Analogously, control nonimprinted polymers were synthesized using the free-styrene derivative of prolinamide. Interestingly, the imprinted polymers worked with a catalytic constant 18.8 times higher than that obtained with nonimprinted polymers with low catalyst loadings (0.7–3.5 mol%), thus demonstrating the efficiency of this approach. The measured ee in DMF were comparable with those obtained in homogeneous conditions (62%). Recently, Gruttadauria et al. reported supported prolinamide 37 (Scheme 3.12) [34]. This catalyst worked well in water in the asymmetric aldol reaction, with high yields and good enantioselectivities in 5–20 mol% loading. Supported prolinamide 37 showed no appreciable differences in the reaction outcome in four consecutive runs, after which a diminished activity appeared. Fortunately, a simple regeneration step with HCOOH has been sufficient for the resin to recover its original activity. Once again, the fall in activity could be ascribed to the formation of the corresponding imidazolidinone [42]. Interestingly, this study represents one of the few reports in which the supported catalyst works better than its O

O

O

O

O

O

O

O

O

O

O

O Ph

H N N H 33: O

O

Ph

H N

Ph OH

N H

styrenic resin 33 or 34 (10 mol%)

R-CHO + H2 O 24 h, r.t.

O

Ph

Ph OH

styrenic resin

34:

OH O

OH O or

R

Ph

R

6 examples for each resin Yield: 29-90% e.e.: 82-99% up to 5 cycles

SCHEME 3.10. Aldol reaction promoted by supported prolinamides 33-34.

POLYMER SUPPORTED PROLINE-PEPTIDES

75

SCHEME 3.11. Preparation of imprinted nanogel 36.

O O N H

S 37 O

H

N HO

37 (5-20 mol%)

R-CHO + H2O 24 h, r.t.

O

OH R

5 examples Yield: 60-98% anti/syn: 81/19-89/11 e.e.(anti) : 75-86% up to 6 cycles

SCHEME 3.12. Supported prolinamide 37 employed in the aldol reaction.

unsupported version. In fact, 37 displayed both a better activity and a better stereoselectivity than its counterpart in homogeneous conditions. 3.4 POLYMER SUPPORTED PROLINE-PEPTIDES In the next chapter, Kudo and coworkers will discuss supported peptides more in depth, especially focusing on their own work. In this section, we will briefly present proline-based supported peptides and their performances in asymmetric synthesis except for Kudo’s catalysts.

76

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

The use of short peptides as organic catalysts allows for extension beyond the examples of simple amino acids while preserving the advantages of small molecule catalysts. In this regard, shortly after the birth of organic catalysis, chemists disclosed their potential in such a field [6b,14c]. Subsequently, peptide immobilization undoubtedly represents a strategy for the recovery and reuse of these highly valued compounds. The first example dealing with anchored dipeptides and tripeptides was reported in 2005 by Davis [46], who immobilized a series of peptides onto a Novasyn Tentagel resin 38a-j—an amine-terminated PEG polystyrene graft copolymer. These materials were tested in the aldol reaction between acetone and 4-nitrobenzaldehyde (Scheme 3.13). Reactions were carried out in acetone at 20  C for 24 h. Yields ranged from 13% to >99% and ee values from 22% to 77%. Higher enantioselectivities were obtained with tripeptides polymer bound but with lower yields. In 2005, Wennemers and coworkers, after a combinatorial screening of 3375 tripeptides, selected H-L-Pro-L-Pro-L-Asp-NH2, which is a powerful catalyst for the aldol reaction between acetone and aldehydes when used in 1 mol% loading [47]. Shortly after, the versatility of this catalyst was improved by immobilization on a series of solid supports such as polystyrene (39a) (e-amino-caproic acid was used as a spacer between the resin and the peptide), SPAR (polyacrylamide) (39b), TentaGel (polyethylene glycol-polystyrene) (39c) and polyethylene glycol-polyacrylamide (PEGA) (39d) (Scheme 3.14) [47b]. These catalytic materials were evaluated in the reaction between acetone and 4nitrobenzaldehyde. The reactions were performed at room temperature for 18 h with 1 mol% of the catalyst and N-methylmorpholine as base. TentaGel- and PEGA-based catalysts (39c-d) gave comparable results with the nonsupported catalyst. Additional catalytic tests using supported tripeptide 39c gave comparable results with those obtained with nonsupported peptide. Moreover, recycling studies showed that enantioselectivity was maintained for at least eight cycles, whereas activity decreased after three to four cycles.

O N H

HN

[AA1]

Novasyn TG resin

[AA2] N H

38a-j a: H-Pro-NH-TG b: H-Pro-Ala-NH-TG c: H-Pro-Ser-NH-TG d: H-Pro-D-Ser-NH-TG e: H-Pro-Thr-NH-TG CHO O

f: H-Pro-D-Thr-NH-TG g: H-Pro-Cys-NH-TG h: H-Pro-Ser-Phe-NH-TG i: H-Pro-Ser-Trp-NH-TG j: H-Pro-Ser-Tyr-NH-TG OH O

38a-j (13 mol%)

+ 20 °C, 24 h O2N

O2N

Yield: 13-100% e.e.: 22-77%

SCHEME 3.13. Aldol reaction promoted by a series of Tentagel-supported peptides.

POLYMER SUPPORTED PROLINE-PEPTIDES

H N

N NH

O

O

O

77

= a: Polystyrene b: SPAR c: TentaGel d: PEGA

N H CO2H

39a-d O

39c, NMM (5 mol%)

5 examples Yield: 30-93% e.e.: 72-80% up to 8 cycles

OH O

R-CHO + 24 h, r.t.

R

SCHEME 3.14. H-L-Pro-L-Pro-L-Asp-NH2 tripeptide linked to several supports.

A new series of supported di- and tripeptides (40a–h) was reported some years later by Wang and Yan (Scheme 3.15) [48]. Screening of the catalyst library revealed resin 40a to be the most active and selective catalyst for the aldol reaction under neat conditions, which in turn can be reused for seven cycles with only a negligible decrease in activity (2% loss of yield for cycle). In an outstanding work, Kurth and coworkers controled the stereochemistry in the synthesis of optically active spirochromanones (Scheme 3.16) [49]. To do so, they first screened a library of TentaGel-supported peptides 41a–f, focusing their attention on two quasienantiomer di-tert-butoxy-protected hydroxyprolyl-threonine catalysts 41e–f. These catalysts efficiently mediate asymmetric tandem enamine/Michael reactions with a high enantioselectivity and complete diastereoselectivity; the choice of catalyst depends on the desired absolute configuration. It is worth noting that in preliminary assays such catalysts were employed successfully in asymmetric aldol as well as in Michael, Robinson annulation, and Mannich reactions, thus being compatible not only with a variety of substrates and extremely versatile in their use but also highly recyclable. In this regard, the authors claimed more than 40 reuses of the resins. More recently, p-methylbenzhydrylamine (MBHA)-anchored peptides were prepared and used in the aldol reaction of acetone and aryl aldehydes affording products in good yields and with fair-to-good enantioselectivies (Scheme 3.17) [50]. Resin 42i has been employed and recycled for five times with no losses in activity or in selectivity. Finally, in 2009, Gruttadauria et al. reported eight supported dipeptides (43a-h, Scheme 3.18) in which the C-termini was left free to coordinate the substrates eventually in the asymmetric aldol reaction [34]. Good-to-high yields and O O

O N H

HN [AA1] [AA2] N H

40a-h

a: H-Pro-Ala-O-MR b: H-Pro-Phe-O-MR c: H-Pro-Gln-O-MR d: H-Pro-His-O-MR

Merrifield resin

O N H

HN

40a

O e: H-Pro-Pro-O-MR (10 mol%) f: H-Pro-Pro-Ala-O-MR R-CHO + R1 g: H-Pro-Ala-Ala-O-MR neat h: H-Pro-Phe-Phe-O-MR R2 24 h, r.t.

OH O R

R1 R2

14 examples Yield: 52-98% anti/syn: 20/8090/10 e.e.(anti) : 75-95% up to 7 cycles

SCHEME 3.15. Supported di- and tripeptides 40a-h for asymmetric aldol reaction.

78

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

O N H

HN

BuO

TentaGel resin

[AA2] N H 41a-f

[AA1]

a: H-Pro-Phe-TG b: H-Pro-Ile-NH-TG c: H-Pro-Ser(tBu)-NH-TG d: trans-Hyp(tBu)-Ser(tBu)-NH-TG e: trans-Hyp(tBu)-Thr(tBu)-NH-TG f: cis-Hyp(tBu)-D-Thr(tBu)-NH-TG R1

R2

O

t

O

O n

N H

O

BuO

H N N H

41e

O

over to 40 cycles R1

R3 +

MeOH r.t. to 110° C R2

9 examples Yield: 70-94% e.e.: 93-99%

N H OtBu

41f O

9 examples Yield: 71-90% e.e.: 90-97%

N H OtBu

O 41e

t

R1

R3

H N

R3

41f

O

MeOH

OH

O

n r.t. to 110° C

R2

O n

SCHEME 3.16. Tentagel-supported peptides 41a-f for the synthesis of spirochromanones.

O N H

HN

H [AA1] [AA2] N 42a-l

a: H-Pro-Phe-NH-MBHA b: H-Pro-Trp-NH-MBHA c: H-Pro-Met-NH-MBHA d: H-Pro-Cys-NH-MBHA e: H-Pro-Phe-Ser-NH-MBHA f: H-Pro-Trp-Ser-NH-MBHA O

MBHA resin g: H-Pro-Met-Ser-NH-MBHA h: H-Pro-Cys-Ser-NH-MBHA i: H-Pro-Phe-His-NH-MBHA j: H-Pro-Trp-His-NH-MBHA k: H-Pro-Met-His-NH-MBHA l: H-Pro-Cys-Hys-NH-MBHA

42i (25 mol%)

OH O

R-CHO + 24 h, r.t.

R

10 examples Yield: 84-94% e.e.: 66-90% up to 5 cycles

SCHEME 3.17. Aldol reaction promoted by supported-peptides 42a-l.

enantioselectivities were obtained with no need for additives and low temperature. Interestingly, although the second amino acid affects the enantioselectivity of the reaction, the presence of L- or D-amino acid does not influence the configuration of the final product. Furthermore, for the case of resin 43f, it resulted recyclable at least for nine runs with no need for regeneration. 3.5 POLYMER-SUPPORTED PYRROLIDINES The potential use of pyrrolidine derivatives for asymmetric organocatalysis dates back to 2001 when Barbas successfully employed them in the enantioselective direct

POLYMER-SUPPORTED PYRROLIDINES

CHO

O S

O

PS-resin

43a-h a: PS-L-Hyp-L-Ile b: PS-L-Hyp-L-Leu c: PS-L-Hyp-L-Tyr d: PS-L-Hyp-L-Trp

O R

43f (20 mol-%)

2

R

+

O

N H

N H

1

OH

n

H2 O r.t., 24 h

R

e: PS-L-Hyp-L-Phe f: PS-L-Hyp-D-Phe g: PS-L-Hyp-L-Pgl h: PS-L-Hyp-D-Pgl

O

79

OH

R n 9 examples Yield: 34-98% anti/syn: 50/50-97/3 e.e.: 64-99% up to 9 cycles

SCHEME 3.18. Polystyrene-supported dipeptides 43-h for aldol reactions.

Michael additions of ketones [51]. Since then, several pyrrolidines have been described and used as organocatalysts, and some of them have been immobilized onto soluble or insoluble supports [21, 52]. Almost simultaneously, Peric
as et al. [53] and Wang et al. [54] reported the same polystyrene-supported pyrrolidine 44 independently (Scheme 3.19). In addition to supported pyrrolidine 44, the researchers also prepared resins 45 with a Cu-catalyzed 1,3-dipolar cycloaddition between (S)-2-azidomethylpyrrolidine and alkynyl-functionalized Merrifield resins. Then 44 and 45 were used as catalysts in the Michael addition reaction (Scheme 3.19). Peric
as et al. employed resin 45 in 10 mol% at room temperature for 24 h, with water as the reaction medium and DiMePEG (10 mol%) as the additive, with good results [53], but Wang et al. used catalyst 44 in 10 mol% but with a longer reaction time (72 h) and TFA (2.5 mol%) as the additive, obtaining excellent results. No decrease was observed in the isolated yield or in the stereoselectivity parameters after three consecutive uses for 45, whereas only a minor decrease in yield was observed with 44 after ten cycles (from 97% to 89%). In 2008, Wang and coworkers prepared three Merrifield resin-bound, pyrrolidinebased chiral ionic liquids (46a–c, Scheme 3.20) in which the anion was changed [55]. These catalysts were tested in the asymmetric addition of cyclic and acyclic ketones to nitrostyrenes, with 46a performing the most under neat conditions in 10 mol%. This way, very high yields and stereoselectivity were achieved, and in addition, the catalyst was recycled eight times with only 10% erosion of activity. Finally, the same group prepared four different polymer-supported pyrrolidines with the A3-coupling protocol (three-component coupling involving aldehyde,

N N N

N H

O X

44: X = CH2 45: X = C6H4CH2 O + Ar R1

R2

NO2

from ref. 53: Catalyst 45 14 examples Yield: 40-90% syn/anti: 87/13->99/1 e.e.: 26->99% 44 or 45 (10 mol%) r.t.

O

from ref. 54: Catalyst 44 10 examples Yield: 85-97% syn/anti: 97/3->99/1 e.e.: 88->99% up to 10 cycles

Ar NO2

R1

R2

SCHEME 3.19. Asymmetric Michael reaction catalyzed by supported-pyrrolidines 44 and 45.

80

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

N

N H

a: X = Cl b: X = BF4 c: X = PF6

N X

46a-c

O R

NO2

+ Ar

1

R

46a (10 mol%) neat, r.t., 24h

2

24 examples Yield: 69->99% syn/anti: 75/25->99/1 e.e.: 46->99% up to 8 cycles O R

Ar NO2

1

R

2

SCHEME 3.20. Michael reaction promoted by supported-pyrrolidines 46a-c.

N H

O

R N

a: R = H b: R = C6H5CH2 c: R = CH3 d: R = n-C6H13

47a-d O + Ar

NO2

47a or 47c (5 mol%) 25°C, 3d

O

Ar

47a: 8 examples Yield: 40-85% syn/anti: 96/4-99/1 e.e.: 81-97%

47c: 12 examples Yield: 73-92% syn/anti: 92/8-99/1 NO2 e.e.: 73-98% up to 5 cycles

SCHEME 3.21. Pyrrolidine-resins 47a-d employed in the asymmetric Michael reaction.

alkyne, and amine) and tested them in the asymmetric Michael addition (Scheme 3.21) [56]. The reaction generates the corresponding adducts in good yields and stereoselectivities, although in rather large reaction times, catalyst 47c recycled five times without loss in activity or in selectivity. 3.6 POLYMER-SUPPORTED PROLINOL AND DIARYLPROLINOL DERIVATIVES In the past 10 years, prolinol seemed to be a promising candidate for asymmetric organocatalysis [57]. More useful results were obtained from some of its derivatives such as diarylprolinols, which were widely used as organocatalysts in several of asymmetric processes [58]. In the first example we report here, Huang and coworkers used polymer-supported prolinol 48 as an auxiliary in asymmetric Michael addition reactions [59]. After the acylation of the supported prolinol, the corresponding Nenoylprolinols 49 were subjected to a Grignard addition with butylmagnesium bromide followed by treatment with LiOH to yield the desired acids 51 in 78–80% yield, with 20% ee (Scheme 3.22). The authors claimed that higher ee than those observed in homogeneous conditions were thus obtained. In 2009, Peng et al. reported the synthesis and application as a catalyst in the Michael addition of two macroporous sulfonyl chloride resins (MPS)-immobilized prolinol tert-butyldiphenylsilyl ether (52 and 53, Scheme 3.23) [60].

POLYMER-SUPPORTED PROLINOL AND DIARYLPROLINOL DERIVATIVES

O

O

O

N

N

BuMgBr

O

LiOH

N H

49

Bu

R 50

48

+ O

O R

81

Bu R 51

HO

R = Me, Ph yield: 78-80% e.e. 20%

SCHEME 3.22. Michael addition promoted by supported prolinol 48.

A 10 mol% catalyst loading plus a 20 mol% benzoic acid additive were needed to obtain good yields in the Michael reaction of ketones and nitroolefins (up to 100%) and high stereoselectivities (up to 97/3 dr and 93% ee). The resin-bound catalyst 53 was simply separated and recovered by filtration and reused for six consecutive cycles without a significant loss in selectivity, whereas activity fell (from 1.4 days to obtain 92% yield to 4 days to obtain 82% yield). As stated before, major interest was raised in diarylprolinols, particularly diarylprolinol trimethylsilyl ether, also known as the Jørgensen–Hayashi catalyst, because of the high versatility they showed in the asymmetric catalysis. Interestingly, this class of organocatalysts was the last supported, and curiously, the first report focused on a polymer-supported version of the Corey–Bakshi–Shibata asymmetric reduction of ketones [61]. Nevertheless, the same authors, some years later, modified their polymers/monomers and used them in several organic processes. They reported the bottom-up synthesis of polystyrene-beads 54 and 55 prepared by suspension copolymerization from mono- and distyrenic functional monomers, respectively (Scheme 3.24) [62]. In the case of 55, the monomer was used as a cross-linker together with styrene, whereas for 54, styrene and divinylbenzene were mixed. The obtained resins were then tested in an asymmetric epoxidation of cinnamaldehyde with poor conversions. Better results employing organocatalyst 55 in the Michael addition were achieved. Good chemical yields (more than 80%), and excellent diastereomeric ratios (up to 99:1) and enantioselectivities (up to 99% ee) were obtained with 10 mol% of catalyst (Scheme 3.24, reaction a). However, catalysts 54–55 were also tested in a three-component organocatalytic cascade, also called Enders-type triple cascade [63] (Scheme 3.24, reaction b). This time, the pendant-bound catalyst 54 were much more efficient than crosslinked catalyst 55. OTBDPS NH X N H O + Ar

R1 R2

NO2

52: X = NHC=S 53: X = SO2

26 examples Yield: 39->99% syn/anti: 88/12-97/3 e.e.: 74-93% up to 6 cycles

53 (10 mol%) H2O, r.t. 12-72h

O

Ar NO2

R1 R2

SCHEME 3.23. MPS resin-supported diarylprolinols 52-53 for Michael reaction.

82

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

N H

OTMS

N H

54

OTMS

55

(a) 55 (10 mol%)

O NO2

+ Ar

H

O

hexane:benzene 1:1, 7d, 5°C

R

Ar

5 examples NO2 Yield: 80-85% syn/anti: 95/5->99/1 e.e.: 89-99%

H R

(b) O

NO2 O X

+

O

54 or 55 or 56 (20 mol%)

+

H

toluene r.t., 7d

X NO2

54: X = H; Yield: 45% e.e.: 99% 55: X = H; Yield: 15% e.e.: 89% 56: X = Cl; Yield: 32% e.e.: >99%

O O

O O O 56

O

N H

OTMS

SCHEME 3.24. Catalysts employed for Michael and Enders cascade reactions.

The authors ascribed this behavior to the more constrained steric environment near the active sites in 55 when compared with the other catalyst. Unfortunately, recycling of catalysts was not possible because of severe catalyst deactivation, most likely for active sites decomposition. The same organocascade reaction has been successfully carried out by Hansen and coworkers employing the polyacrylic resin 56 (Scheme 3.24) [37c]. They polymerized the acrylic monomer together with methyl methacrylate and ethyleneglycol dimethacrylate, obtaining polymer beads with 0.34 mmol/g catalyst loading. Nothing was said about the recycling of such a resin. In 2008, Wendorff and Studer reported the immobilization of diphenylprolinol TMS ether through an original procedure in which oligostyrene-diarylprolinol conjugates 57a–c were immobilized into a polystyrene matrix by electrospinning [64]. The large surface area fibers obtained were employed in 5 mol% in the Michael reaction between cinnamaldehyde and dimethylmalonate (Scheme 3.25). The fibrous catalysts were recovered and recycled six to nine times, and for 57a, the initial yield of 42% remained for the second run, then decreased and leveled off to 10%. Here, the authors accounted for the deactivation with changes in the macrostructure of the fibrous system, and no leaching of diarylprolinol from the fibers was noticed.

POLYMER-SUPPORTED PROLINOL AND DIARYLPROLINOL DERIVATIVES

57a-c CO2Me (5 mol%) MeO2C

CHO

O

+ N O

Ph

N H

Ph

EtOH r.t., 3 d

CO2Me

OR

57a: Yield: 42% e.e.: 92% 9 cycles

n

57a: R = SiMe3, Mn = 7500 g/mol b: R = Me, Mn 6700 g/mol c: R = Me, Mn 5600 g/mol

Ph

83

CO2Me CHO

57b: Yield: 24% 6 cycles 57c: Yield: 14% 9 cycles

SCHEME 3.25. Catalysts immobilized by means of electrospinning.

Very recently, Peric
as and Alza described a polymer-supported diphenylprolinol silyl ether prepared with postmodification protocol by anchoring the alkyne derivative of the catalyst to the azido-modified Merrifield resin (Scheme 3.26) [65]. To overcome the drawback of the free amine group deactivating copper catalysts, the authors employed a tris(triazolyl)methanol–CuI complex of their invention. Thus, catalyst 58 was tested in the asymmetric Michael addition affording excellent results, with quantitative yields and excellent stereoselectivities (Scheme 3.26, reaction a). Surprisingly, different from the earlier reported results, recycling of polymersupported catalyst 58 was possible only after a reconditioning process. In fact, the deactivated catalyst recovered its activity for at least six cycles once treated with trimethylsilyl N,N-dimethylcarbamate, thus demonstrating that, effectively, some hydrolysis of the silyl ether occurs for these catalysts. The same Jørgensen–Hayashi catalyst, this time anchored to a linear PEG chain, was prepared in 2010 by Zeitler and coworkers (59, Scheme 3.26, reaction b) [66]. The catalyst was then benchmarked in the asymmetric Michael addition of

N N N

(a)

+ Ar

= PS resin

59:

= MeOPEG5000

NO2

R (b)

O + CH3NO2 R

H

N H

58:

O H

O

OTMS

58 (10 mol%) CH2Cl2 r.t., 4-72 h

O

8 examples NO2 Yield: 44-98% syn/anti: 75/25->99/1 e.e.: 90-99% up to 6 cycles

O

7 examples Yield: 48-95% e.e.: 89-95% up to 5 cycles

H R

59 (10 mol%) 0.1 eq PhCO2H MeOH, r.t. 22 h

Ar

R

H NO2

SCHEME 3.26. Supported diaryprolinol silyl ether 58-59 as catalyst for Michael reactions.

84

ASYMMETRIC SYNTHESIS USING POLYMER-IMMOBILIZED PROLINE DERIVATIVES

nitromethane to cinnamaldehydes, affording high chemical yields and enantioselectivities identical to those showed by its homogeneous counterpart. Interestingly, the final products were isolated pures without the need for column chromatography. After diethyl-ether–induced precipitation, more than 95% of 59 was recovered and recycled with unchanged selectivity for five runs but with a significant loss in terms of yields. However, the authors ascribed this loss of activity not to desilylation, as previously noted, but mainly to product inhibition of the catalyst. To corroborate such a hypothesis, they stirred 59 in the presence of cinnamaldehyde (starting material) and observed that the catalyst totally recovered its activity in a second cycle after the reaction product was displaced from the catalyst. For the sake of accuracy, we have to mention that polymer-supported prolinol and diarylprolinol derivatives were employed in other asymmetric reactions beside the Corey–Bakshi–Shibata reduction [61, 67] such as the Diels–Alder reaction [68] and in an asymmetric dialkylzinc addition to aldehydes [69]. The aforementioned catalytic materials were employed for 2–14 cycles. 3.7 CONCLUSIONS AND OUTLOOKS In the present chapter, the advances in asymmetric catalysis, carried out by a polymer-supported proline and its derivatives, have been widely highlighted. In the last 10 years, several researching groups have been developing different strategies to conjugate the advantages of the new emerging and versatile organic catalysts with the well-known practical benefits stemming from solid-phase synthesis. It is fascinating how the immobilization of often simple molecules has stimulated the synthetic creativity of researchers. In doing so, the pioneers chose, under our viewpoint, the “easy way”—namely the postmodification of commercial resins. Such an approach represented the fastest manner to determine whether supported organocatalysts would work under heterogeneous conditions as well as they did in solution phase. Once this strategy was demonstrated to be successful, organic, polymer, and material chemists started developing the “hardest way,” namely the “bottom-up approach,” from monomer-bearing organocatalysts to the final resins. In this manner, multigram amounts of materials have been and can be prepared, especially thanks to Hansen’s group, thus engendering the interest of the industrial community who will benefit from the large-scale preparation of low-cost and metal-free asymmetric catalysts for the syntheses of enantio-enriched compounds. Another possible industrial development for supported organocatalysts may derive from novel studies in regard to the continuous flow methods or to the use of supercritical fluids as reaction media. In this regard, only a few investigations have been carried out on these novel and innovative methodologies dealing with systems in which the catalyst must not be removed from the reaction vessel. In conclusion, although supported-proline materials seldom result in being less effective than their nonsupported homogeneous counterparts, they have the objective advantage of being easily modulated in such a way that higher or “different” stereoselectivities can be achieved by just changing the solvent, the spacer, or the

REFERENCES

85

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Z. H.; Chen, X. H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. J. Am. Chem. Soc. 2005, 127, 9285–9289. (a) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593–2595. (b) Chen, X. H.; Tang, Z.; Luo, S. W.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Chem. Eur. J. 2007, 13, 689–701. (c) Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Org. Lett. 2008, 10, 1211–1214. (d) Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247–1250. (e) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417–4420. (a) Giacalone, F.; Gruttadauria, M.; Lo Meo, P.; Riela, S.; Noto, R. Adv. Synth. Catal. 2008, 350, 2747–2760. (b) Gruttadauria, M.; Giacalone, F.; Mossuto Marculescu, A.; Salvo, A. M. P.; Noto, R. ARKIVOC 2009, 8, 5–15. (a) Gryko, D.; Lipinski, R. Eur. J. Org. Chem. 2006, 3864–3876. (b) Oh, C.-H.;Dong, H.-G.; Cho, H.-W.; Park, S. J.; Hong, J. H.; Baek, D.; Cho, J.-H. Arch. Pharm. Pharm. Med. Chem. 2002, 335, 200–206. Bak, A.; Fich, M.; Larsen, B. D.; Frokjaer, S.; Friis, G. J. Eur. J. Pharm. Sci. 1999, 7, 317–323. Carboni, D.; Flavin, K.; Servant, A.; Gouverneur, V.; Resmini, M. Chem. Eur. J. 2008, 14, 7059–7065. Andreae, M. R. M.; Davis, A. P. Tetrahedron: Asymmetry 2005, 16, 2487–2492. (a) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101–1103. (b) Revell, J. D.; Gantenbein, D.; Krattiger, P.; Wennemers, H. Biopolym. 2006, 84, 105–113. Yan, J.; Wang, L. Synthesis 2008, 2065–2072. Carpenter, R. D.; Fettinger, J. C.; Lam, K. S.; Kurth, M. J. Angew. Chem. Int. Ed. 2008, 47, 6407–6410. Zhang, L.; Ding, W. B.; Yu, Y. P.; Zou, H. B. Chin. Chem. Lett. 2009, 20, 1065–1067. Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, III, C. F. Tetrahedron Lett. 2001, 42, 4441–4444. (a) Gu, Y.; Li, G. Adv. Synth. Catal. 2009, 351, 817–847. (b) Trindade, A. F.; Gois, P. M. P.; Afonso, C. A. M. Chem. Rev. 2009, 109, 418–514. Alza, E.; Cambeiro, X. C.; Jimeno, C.; Peric
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CHAPTER 4

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS KAZUAKI KUDO and KENGO AKAGAWA

4.1 INTRODUCTION Our life activity is based on chemical reactions in our body catalyzed by many kinds of enzymes. Enzymes are naturally occurring, highly sophisticated polymeric chiral catalysts. They catalyze many kinds of biotransformations with very high efficiency and selectivity under ambient conditions in water. Another characteristic of enzymes is their high substrate specificity, which is considered to be a necessary consequence for them because they work in the body of organism where their substrates are buried in a mixture of thousands of chemical species. However, when considering the application of enzymes as synthetic asymmetric catalysts, the substrate specificity, along with a limited reaction scope, turns into a drawback. Therefore, development of asymmetric catalysts, of which the efficiency and the selectivity are comparable with enzymes but are tolerant to kinds of substrates, has long been one of the ultimate goals for organic chemists. In the earlier days, it was believed that enzymes were the only species that could catalyze asymmetric chemical transformation. In fact, some enzymes were used for the synthesis of optically active compounds. For example, a protease a-chymotrypsin was applied to the preparation of chiral a-amino acids by way of kinetic resolution of the synthetic intermediate [1]. Through the structural analysis of the enzymes, the chemists tried to elucidate why the enzymes were so excellent as catalysts. Starting from lysozyme in 1965, the three-dimensional (3D) structure of several enzyme molecules including a-chymotrypsin [2] was unveiled by X-ray crystallography in the following years. They consist of polypeptide secondary structures such as a-helices or b-sheets, just as Pauling et al. had predicted as early as 1951 [3] (Figure 4.1). Then, a combination of indispensable amino acids for the action of a-chymotrypsin, Asp, His, and Ser, or a catalytic triad, was clarified.

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.

91

92

FIGURE 4.1. (a) Crystal structure of a-chymotrypsin [4]. Only the main chain of the polypeptide is shown. Data were obtained from the Protein Data Bank [5]. (b) a-Helix and (c) b-turn found in a-chymotrypsin.

INTRODUCTION

93

This finding inspired the chemists to study the mechanism of enzyme-catalyzed hydrolytic reactions, including the origin of enantioselectivity, in depth and to construct artificial protease molecules having amino acids included in the catalytic triad. However, the catalytic efficiency of such molecules was not so high. This fact made the chemists believe that precise control in the spatial arrangement of specific amino acids is of key importance to realizing an enzyme-like reaction. Later, this stream developed in two ways: (1) biomimetic chemistry, or rational design of a long polypeptide with a controlled 3D structure on the basis of the first principle of the hierarchical structure of protein molecules, and (2) bioinspired chemistry that only mimics a small part of the protein structure to realize some functions by artificial molecules. This chapter mainly concerns the latter. Nevertheless, at roughly the same time as the beginning of this enzyme-mimicking research, investigation on asymmetric molecular catalysts, of which the structure is metal complexes with chiral ligands, started. In 1968, Noyori’s [6] and Knowles’s groups [7] independently proposed the concept of an asymmetric molecular catalyst. In the 1970s, because of better catalytic performance and scalability, the research on asymmetric catalysis began to focus on the homogeneous chiral metal complexes. As a result of this research, many chiral metal catalysts were introduced, for example, Knowles’s rhodium–DiPAMP complex for asymmetric hydrogenation (1975) [8], Sharpless’s titanium–tatrate ester complex for asymmetric epoxidation (1980) [9], and Noyori’s ruthenium–BINAP complex for asymmetric hydrogenation (1980) [10]. During this period, progress in asymmetric catalysts mediated by peptide-related compounds were, in a chronological order, proline-catalyzed asymmetric Robinson annelation (1971) [11], poly(amino acid)-catalyzed asymmetric conjugate addition of thiol to enone (1975) [12], cyclic-dipeptide-catalyzed cyanohydrin formation of aldehydes (1979) [13], enantiomer-differentiating hydrolysis of esters catalyzed by dipeptide derivatives (1980) [14], asymmetric epoxidation of chalcones in the presence of poly(amino acid) catalysts (1980) [15], asymmetric electrochemical oxidation/reduction mediated by poly(amino acid)-coated electrodes (1983) [16], and again enantiodifferentiating hydrolysis of esters by the Z-Phe-His-Leu-OH catalyst in the micellar/vesicular system (1984) [17]. Although they are all interesting and unique reactions, development in the peptide-catalyzed reactions was limited until the latter half of the 1990s. The authors speculate as to the reasons for this delay as follows: (1) The reactions seemed substrate specific just like the enzymecatalyzed ones; (2) in many cases, the reaction was heterogeneous, and for such reactions, a scientifically appropriate mechanistic consideration was hard to make; (3) the preparation/purification of peptides was difficult because of the limited commercial availability of chemicals and the low efficiency of the coupling agents; and (4) related to the previous reason, peptides were not compatible with trial-anderror–based improvement, which was routinely used in the field of chiral metal complex catalysts. Now, problem 3, and hence problem 4, have been resolved thanks to the progress of related fields. Then, a question comes to mind. What can peptides do as catalysts ? To address this question, chemists have to show something unique to peptide catalysts that cannot be attained by conventional catalysts. Definitely, one answer

94

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

is that the peptide catalysts have the possibility of adopting secondary structures. Through the formation of a secondary structure, several parts of the peptide can cooperatively participate in the catalytic process just like the enzymes do. Therefore, peptides that take a secondary (or higher) structure might be promising as a novel catalyst. From this point of view, in this chapter, we will focus on tri- and larger peptides because it is generally considered that at least a three-amino-acid sequence is required for the generation of a secondary structure of peptides. It should be stressed that there is another merit for the peptide catalysts; that is, they can be prepared by the solid-phase synthesis, and hence, they are compatible with the combinatorial approach at the optimization stage of the catalysts. In 2007, Miller and co-workers provided an in-depth, excellent review on the synthetic peptide-catalyzed asymmetric reactions [18]. Although partial overlap with their review is inevitable, in this chapter, we intend to introduce the most recent progress in this field. 4.2 POLY(AMINO ACID) CATALYSTS Poly(amino acid)s (PAAs) are easily accessible compounds for chemists and maybe the oldest synthetic polypeptides applied to asymmetric catalysts. Generally, they are synthesized by amine-initiated, ring-opening polymerization of amino-acid–derived N-carboxyanhydrides (NCAs). In 1975, Inoue et al. first reported on an enantioselective reaction catalyzed by PAAs. Conjugate addition of dodecanethiol to methyl isopropenyl ketone was performed using poly(g-benzyl-L-glutamate) (PBLG) [12], poly(b-benzyl-L-aspartate) [19], and polyalanine [20] as catalysts. The reactions were carried out in either chloroform or chloroform/EtOH (30/1 to 30/2) with several PAAs having a different degree of polymerization (DP). The enantioselective process of this reaction was the protonation to the intermediate enolate, which was formed by the 1,4-addition of thiolate anion to the substrate unsaturated ketone (Scheme 4.1). The PBLG catalyst with a DP of 10 and the trialanine catalyst showed significant enantioselectivity in the presence of ethanol. Inoue et al. explained the experimental results on the basis of both the secondary structure of PAAs and the amino acid chirality; a decamer of g-benzyl-L-glutamate adopts the a-helix, whereas trialanine takes the b-form. The effect of added ethanol was considered to be threefold. First, the ethanol changes the secondary structure of PAAs. Second, the ethanol molecules strongly interact with

H PAA PAA

PAA C12H25 SH +

O

C12H25 S

O

C12H25 S

O

8 mol% catalyst, 20-68 days, 50 – 98 % conversion, up to 47%ee

SCHEME 4.1. The first synthetic-peptide-catalyzed asymmetric reaction [12,19,20].

95

POLY(AMINO ACID) CATALYSTS

the amide groups of PAAs and donate proton to the enolate anion from the same side of the PAA molecule. Last, ethanol can suppress the racemization of the addition product through imine formation. In 1980, Juli
a et al. reported that the polyalanine with a DP of 10 catalyzed oxidation of chalcone by alkaline hydrogen peroxide in a triphasic system of toluene, TABLE 4.1. Juli
a–Colonna reaction of chalcone

Ph

Ph

H2O2, base PAA

Ph

Solvent

O

HOO

1

11 12 13

O

N H

H N O

triphasic, 24 h triphasic, 144 h triphasic, 28 h triphasic, 72 h triphasic,168 h triphasic, 96 h triphasic, 48 h triphasic, 48 h biphasic, 0.5 h biphasic, 0.5 h

3

Yield/% 85 (36) 12 60 76 6 39 66 94 85 80

OMe O

DP is 10 unless otherwise noted. triphasic: toluene/H2O/peptide, H2O2/NaOH, biphasic: THF, urea-H2O2/DBU. c The values in parenthesis are those obtained by a recycled catalyst. d DP ¼ 20. e PS denotes microporous polystyrene resin. f DP ¼ 33. g Tetrabutylammonium bromide. h 3-MeImþ ¼ 3-methylimidazolium. i Sodium percarbonate was used as an oxidant and a base. b

c

ee/% 93 (72) 12 84 95 10 88 93 97 >95 98

triphasic, 20 h, 77 96 100 g scale DME:H2O ¼ 1:1i, 96 95 0.25 h biphasic, 24 h 99 (conv.) 98

O N H

Ph O

3 a

O

O

Conditionsb

poly(L-Ala) PBLG poly(L-Leu) poly(L-Ile) poly(L-Val) poly(L-Val-ran-L-Leu) poly(L-Ala)-PSd,e poly(L-Leu)-PSe, f poly(L-Leu)-PSe H(L-Leu)3.9NHCH2CH2(OCH2CH2)71 NH(L-Leu) 3.9H H(L-Leu)mNHCH2CH2CH2NH(LLeu)nH (m þ n ¼ 78) þ TBABg H(L-Leu)30NHCH2CH2CH2(3MeImþ)Clh

H

Ph

2

Entry PAAa 1 2 3 4 5 6 7 8 9 10

Ph

Ref. c

21 22a 22a 22a 22a 22a 23 23 24 25 28 29 30

96

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

water, and gel-state polypeptide (Table 4.1) [21]. Conjugate addition of hydroperoxide anion and the subsequent intramolecular nucleophilic attack of the resulting enolate anion 2 to the OOH group resulted in epoxide as high as 97%ee. Subsequently, some other poly(L-amino acid)s were applied for this reaction (Table 4.1). This asymmetric epoxidation is now widely known as the Juli
a–Colonna reaction, and several sophisticated reviews have been published [22]. Therefore, here we only briefly mention this reaction mainly from the viewpoint of advancement in the synthetic methodology. In general, the yield and the enantioselectivity were closely related. L-Ala–, L-Leu–, and L-Ile–derived poly(amino acid)s produced a good result, whereas L-Val–, L-Phe–, and g-benzyl L-glutamate–derived ones did not (entries 1–5 in Table 4.1). Concerning random copoly(L-Val-L-Leu), when monomer composition was changed from L-Val: L-Leu ¼ 1:1 to 7:3, the result was worse (14% yield, 39%ee after 192 h) (cf. entry 6 in Table 4.1). Although very high enantioselectivity was attained, the first–generation PAA catalysts have several drawbacks: (1) Because of the presence of the gel phase, the workup is troublesome; (2) a fairly large amount of catalysts (by wt% basis) is required; (3) a long reaction time is needed; (4) applicable to a narrow range of substrates and (5) recycling of the catalyst is of low efficiency. Afterward, improvement from the synthetic viewpoint was reported. In 1990, Itsuno et al. prepared immobilized poly(amino acid)s through the polymerization of NCAs initiated by partially aminomethylated cross-linked microporous polystyrene (entry 7 in Table 4.1) [23]. When immobilized 33mer polyleucine was used as a catalyst, 94% yield and 99%ee were attained (entry 8 in Table 4.1). It is noteworthy that the product of immobilized tetraalanine catalyst showed an enantioselectivity of 88%ee, and this is in sharp contrast to the result with nonsupported pentamer polyalanine, 11%ee. As the catalyst poly(amino acid)s were bound to insoluble polymer resins in spatially separated form, interchain interaction of the poly(amino acid)s was considerably suppressed leading to successful avoidance of gelation. Other merits of these immobilized catalysts were (1) broader substrate scope and (2) high recycling ability (94% yield and 95%ee even after the 12th recycle of immobilized polyleucine). Using the same type of immobilized peptide catalyst, a nonaqueous variant of the Juli
a–Colonna reaction was developed by Roberts’s group; they employed an organosoluble urea–hydrogen peroxide complex as an oxidant and 1,8-diazabicyclo [5.4.0]undec-7-en (DBU) as a base [24]. The reaction proceeded in a tetrahydrofuran (THF)/white paste biphasic system with a much higher rate (entry 9 in Table 4.1). They also developed another type of immobilized PAA on soluble polyethyleneglycol (PEG) resin. A 70mer PEG having polyleucine on both ends showed good catalytic performance even with a shorter length of peptide moiety (entry 10 in Table 4.1) [25]. Other than polymer-immobilized ones, silica gel adsorbed polyleucine [26] and covalently bound polyleucine on aminopropyltriethoxysilanetreated silica [27] were also reported. Continued improvement of the catalyst and reaction conditions enabled a large-scale reaction of up to 100 g of substrate (entry 11 in Table 4.1) [28].

POLY(AMINO ACID) CATALYSTS

97

Only in the last decade have the mechanistic studies on the Juli
a–Colonna reaction been made. From the accumulated experimental and calculation results, the consensus mechanism now widely believed is as follows [18, 22]: (1) The catalyst polyLeu adopts a rigid a-helix conformation; (2) OOH interacts with the peptide catalyst first and then the substrate 1 approaches to from a ternary complex, polyLeu:OOH:chalcone; (3) a fast, reversible conjugate addition of  OOH to chalcone occurs and then a slow ring closure reaction follows; (4) a “correct” enantiomer of the OOH adduct preferentially interacts with the pepetide catalyst with three N-H groups at the N-terminal of the helix that are not involved in the helix forming a hydrogen bond; and (5) in such a complex, the conformation of the intermediate hydroperoxyenolate 2 is fixed to the one in which the overlap between the enolate p-orbital and the s*-orbital of O-OH bond is maximized to allow the epoxide formig process to occur. Recently, Yang and Tang and coworkers demonstrated that polyleucine having imidazolium salt at the C-terminus is a superior, nonsupported catalyst [29]. Epoxidation of chalcone by sodium percarbonate in 1,2-dimethoxyethane (DME) using this catalyst afforded the product in 96% yield with 95%ee in 2 h. It is claimed that the imidazolium moiety serves as a phase-transfer catalyst. This catalyst could be easily separated from the reaction mixture by rapid filtration and could be reused at least six times without any loss in both yield and ee. What is interesting is the reaction rate in the recycled use was much higher (finished in 15 min) than that of the first use. The authors speculated that the catalyst was activated during its first use (entry 12 in Table 4.1). Although not a PAA, a helix peptide containing a de novo designed amino acid, (1S,3S)-1-amino-3-methoxycyclopentanecarboxylic acid (AMC), having a sequence of -(Leu-Leu-AMC)n- was very recently reported by Tanaka’s group as a good Juli
a– Colonna reaction catalyst [30]. A nonamer was proven to be a highly efficient and selective catalyst for this reaction (entry 13 in Table 4.1). Yashima and coworkers prepared helical polyacetylene starting from monomer R-Ala-Ala-Ala-OH, where R is the (4-ethynyl)benzoyl group [31]. The main-chain helicity of the polyacetylene was induced by the chirality of the amino acid units. They applied the polyacetylene having trialanine side chains to the conditions of the Juli
a–Colonna reaction to obtain the chalcone epoxide with up to 38%ee. In 1983, Komari and Nonaka realized electrochemical asymmetric oxidation on a poly(amino acid)-coated electrode surface [32]. He showed that the unsymmetric sulfides can be enantioselectively oxidized to the corresponding chiral sulfoxides (Scheme 4.2). The electrode was first covered with electroconducting polypyrrole; then the whole electrode was dip-coated in the poly(amino acid) solutions. The electrochemical sulfoxidation of tert-butyl phenyl sulfide on a polyvaline-coated Pt electrode occurred in 45% yield with 93%ee to produce (R)-sulfoxide. Less effective were polyleucine (62% yield, 15%ee) and poly(g-benzyl glutamate) (46% yield, 35%ee). The mechanism of asymmetric induction during electrochemical oxidation is not clear. In the case when the PAA-modified electrode was subjected to reuse, the first and second reuse of the electrode produced comparable results with that obtained by a freshly prepared electrode, whereas the enantioselectivity considerably

98

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

PAA-coated electrode Bu4N BF4, CH3CN, H2O S

Ph

S O

electrolysis

Ph

SCHEME 4.2. Asymmetric electrochemical oxidation promoted by poly(amino acid)-coated electrode [32].

decreased after the third reuse. This was explained by the gradual removal of a noncovalently bound PAA layer, and it was revealed that the retreatment of the electrode with PAA solution after each run somewhat improved the result. Nonaka et al. also developed the electrochemical asymmetric reductions. Reductive debromination of prochiral dibromide 4 on a polyvaline-coated graphite electrode produced monobromide 5 in 48% yield and 17%ee [33] (Scheme 4.3). Formal hydrogenation of methylcoumarin 6 resulted in 8% yield with 43%ee [34]. Although the chirality is not derived from amino acid alpha carbon, oligoglycine having a chiral N-(1-phenylethyl) group showed excellent performance in 2,2,6,6tetramethylpiperidine-1-oxyl radical (TEMPO)-catalyzed oxidative kinetic resolution of racemic 1-phenylethyl alcohol [35] (Scheme 4.4). They carried out a positional scanning of the TEMPO and found that the reaction did not proceed in an enantioselective manner when the TEMPO was on the second or the third nitrogen to the N-terminal. Ph

poly(L-Val)-coated electrode

Br

Ph

Br

*

Ph

2e, 2H+

Ph

4

Br + HBr

H 5

O

O

O

poly(L-Val)-coated electrode 2e, 2H+

O

*

6

7

SCHEME 4.3. Asymmetric electrochemical reductions promoted by polyvaline-coated electrode [33,34].

O OH

1 mol%

N

O N H

N O

NaOCl/KBr CH 2Cl2, 0ºC

6

NH 2

O

OH +

s-value up to 5.6

SCHEME 4.4. Oxidative kinetic resolution of 1-phenylethyl alcohol by TEMPO attached on chiral peptoid [35].

TRI- AND TETRAPEPTIDE CATALYSTS

99

4.3 TRI- AND TETRAPEPTIDE CATALYSTS As mentioned in the previous section, trialanine showed ability as an asymmetric catalyst for the conjugate addition. That might be the first tripeptide-catalyzed asymmetric reaction. However, in that work, the peptide was made by NCA polymerization and the polydispersity in DP was inevitable. Inoue’s group was aware of this point, and later they tried the same reaction with monodisperse oligoalanines [36]. The result of the catalytic asymmetric conjugated addition using H-Ala-Ala-Ala-NHPr was proven to be similar to that obtained with the trialanine derived from NCA polymerization. Berkessel and coworkers systematically investigated peptide length effect on the Juli
a–Colonna reaction for TentaGel-supported polyleucines as catalysts. [37] Di-, tri-, and tetraleucine catalysts produced the chiral epoxide with 15, 65, and 90%ee, respectively. Longer polyleucines up to 20mer constantly resulted in >95%ee. They emphasized that the a-helical structure of polyleucine is essential for realizing high enantioselectivity. They also pointed out that the PEG moiety connected at the C-terminus of polyleucine has a role for the “helix surrogate” of the polyleucine. The oldest tripeptide asymmetric catalyst with a nonrepetitive amino acid sequence might be Z-Phe-His-Leu-OH reported by Ueoka and coworkers for the enantiomer differentiating hydrolysis of N-acylphenylalanine 4-nitrophenyl ester in 1984 [17] (Scheme 4.5). This peptide showed surprisingly high selectivity of kL/kD ¼ 71 for the substrate having the N-dodecanoyl group under optimized micellar/vesicular conditions. It took 14 more years until the next efficient tripeptide catalyst was reported by Miller’s group. In 1998, they showed that a tripeptide containing a non-natural amino acid 3-(1-imidazolyl)-(S)-alanine (Ima) is a good catalyst for the kinetic resolution in the acetylation of trans-2-(N-acetylamino)cyclohexan-1-ol with acetic anhydride [38] (Scheme 4.6). They intended to use a minimal b-turn peptide so that the functional groups at two termini cooperatively participated in the catalytic process. A tripeptide having the sequence of Boc-Ima-Pro-Aib-NH-[(R)-1-phenylethyl], of which the Pro-Aib part adopts a b-turn secondary structure, was claimed to catalyze efficiently an enantiospecific acetylation through an N-acetylimidazolium intermediate. The tripeptide was prepared by solution-phase synthesis. The ratio of the rate constants of the peptide-catalyzed acetylation of two enantiomeric substrates, kfast/kslow or s-value, was up to 12.6. In this reaction, initially, the catalyst 9 O C11H23CONH CH C O CH2

Z-Phe-His-Leu-OH NO2 (C14H29)2NMe2 Br (C16H33)NMe3 Br

O H C11H23CO N CH C OH + HO CH2

NO2

kL/kD = 71

Tris buffer (pH 7.6), rt

SCHEME 4.5. Tripeptide catalyzed hydrolytic kinetic resolution under micellar/vesicular conditions [17].

100

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

O OH NHAc

peptide Ac2O

OAc

N

NHAc

BocNH

Toluene, 0°C

O

N H HN

O

N

8

9 N

>90% yield, 84% ee, s-value = 12.6

SCHEME 4.6. Tripeptide catalyzed kinetic resolution by esterification [38].

and the substrate 8 were dissolved in chloroform, and then toluene was added to provide white suspension. The reaction is essentially heterogeneous. Miller’s group pointed out that the chirality of the 1-phenylethyl group is important for the efficient kinetic resolution, and when the epimer having a (S)-1phenylethylamine unit was used as catalyst, the same product was obtained with 53% ee, or s-value ¼ 3.5. They extended this research to the b-turn tetrapeptide catalyst using p-(methyl)histidine (Pmh) instead of Ima. A sequence Boc-Pmh(L or D)-Pro-Aib-Xaa-OMe was optimized for Xaa ¼ (L or D)-Phe, (L or D)-Val, and Gly [39]. Through an analysis of proton nuclear magnetic resonance spectrum they found that the peptide having D-Pro-Aib moiety has a stronger tendency to adopt a type II b-turn conformation, and this tendency was reflected on the higher differentiating ability for the racemic alcohols compared with its analog having a L-Pro unit. With this catalyst, the ee of unreacted starting alcohol was higher compared with the corresponding acetate, and the Boc-Pmh-D-Pro-Aib-L-PheOMe–catalyzed reaction produced the intact alcohol with 99%ee and the acetate with 73%ee, which equals s-value ¼ 28, at 58% conversion. Through the two studies mentioned, they found that when the peptide-catalyzed reaction is faster, it is also more selective. On the basis of this fact, they proposed a screening method for the effective peptide catalysts [40]. On the resin beads used for the preparation of peptides, a 9-(1-piperidinylmethyl)anthracene derivative was introduced (Figure 4.2). This compound is photochemically inert because of efficient quenching of the excited state of anthracene by the electron transfer from amino nitrogen. Once this amino group is protonated, it can no longer participate in the electron transfer process, resulting in the fluorescence from the excited anthracene. The peptide library was constructed on the one-bead-one peptide basis. In the peptide-catalyzed acylation of alcohols with acetic anhydride, one equivalent of AcO peptide

N HN

H N

peptide HN

O

O Non-fluerescent

fluerescent

FIGURE 4.2. Fluorescent sensor for acylation reported by Miller’s group.

101

TRI- AND TETRAPEPTIDE CATALYSTS

O

2.5 mol% Bn N N

N H HN

N O Boc

O

NH 10

O

O

O

N

R

O N

TMS-N3, t BuCOOH Toluene, -10ºC

N3 R

up to 90% yield up to 92% ee

SCHEME 4.7. Tripeptide catalyzed asymmetric conjugate addition of azide anion [41].

acetic acid is released during the progress of the reaction. This acid will protonate the nearby nitrogen on the piperidine ring, and then the fluorescence is observed. The usefulness of this selection method was found in the process of seeking penta- and higher peptides, which will be mentioned later. As for the tripeptide catalyst, Miller and Guerin had also developed azidation of a,b-unsaturated imides [41] using peptide catalyst 10 (Scheme 4.7). This reaction includes controlled formation of hydrazoic acid (HN3) by mixing trimethylsilyl azide and pivalic acid in the reaction flask and the subsequent amine-catalyzed conjugate addition of an azide anion in an enantioselective manner. Another line in peptide-catalyzed asymmetric acylation research has been reported by Schreiner’s group. They applied tetrapeptide 11 to the kinetic resolution of cyclic trans-1,2-diols [42] (Scheme 4.8). They had tested racemic 5-, 6-, 7-, and 8-membered substrates and obtained very high efficiency for the enatioseparation with an s-value > 50 for 6-, 7-, and 8-membered substrates. The enantiomeric excess of an unreacted substrate was high.

O O

N H

O

O

H N

N H

O 11

OH n OH

N

1-2 mol% peptide 11 5.3 equiv Ac2O Toluene, -20 to 0ºC

H N

O O

N Me

OAc

OH +

n OH

n OH

n = 1-4

SCHEME 4.8. Tetrapeptide catalyzed kinetic resolution of trans-1,2-cycloalkanediols [42].

102

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

OH

1 mol% peptide 11 5.3 equiv Ac2O 5.3 equiv DIEA

OAc

OH

Toluene, -40ºC, 48 h

OH

TEMPO m-CPBA Bu4NBr

OAc

rt, 1 h

O

81% GC yield 88% ee

70% yield 88% ee

SCHEME 4.9. Tetrapeptide catalyzed desymmetrization of cis-1,2-cyclohexanediol [44].

Sunoj and Shinisha rationalized the mechanism of the kinetic resolution of cyclohexanediols by peptide 11 through density functional theory (DFT) calculation of the substrate–catalyst complex [43]. They successfully reasoned for the preferential isomer of the acylation of trans-1,2-diols and predicted that the desymmetrization of cis-1,2-cyclohexanediol would also proceed in a highly enantioselective manner by using the same catalyst 11. This was experimentally verified again by Schreiner’s group [44]. Although monoacylated products derived from cyclic cis-1,2-diols easily racemize as a result of intramolecular transesterification, rapid oxidation of the monoacetate by catalytic TEMPO and excess m-CPBA was proven to be effective for the suppression of the racemization (Scheme 4.9). Miller et al.’s b-turn peptide catalyst was not limited to functional group manipulation, but it was also applicable to a C-C bond forming reaction. Intramolecular asymmetric C-C bond formation through a Stetter reaction was demonstrated. For this reaction, thiazole moiety behaves as an activator of the formyl group [45] (Scheme 4.10). Miller et al. had also extended their tetrapeptide catalyst to an asymmetric aza-Baylis–Hillman–like reaction of allenoate ester with imines [46] (Scheme 4.11). Here they introduced the non-natural amino acid, 3-pyridylalanine. Sophisticated extension of the b-turn tripeptide catalyst with completely different machinery was reported by Miller et al. They used the tripeptide 12 having Asp moiety for asymmetric epoxidation of allyl phenylcarbamates through the intermediacy of in situ formed percarboxylic acid of the aspartate side chain [47] Scheme 4.12. The corresponding homoallyl carbamate was not a good substrate

O 20 mol% CHO R

N H S

BnO H N O

N

N H

Boc O OtBu

I

OtBu

O O

Diisopropylethylamine CH2Cl2, rt, 48 h

R

O

O

39-45% yield 64-76% ee

SCHEME 4.10. b-Turn peptide catalyzed asymmetric Stetter reaction [45].

TRI- AND TETRAPEPTIDE CATALYSTS

103

O 10 mol%

N H HN

N N

O

O

O XR

N

+

NH R

R2

O

Boc

2

O

NMe2

R1

NH O

O R1

Toluene

XR

X = O, S up to 88% yield up to 90% ee

SCHEME 4.11. Tetrapeptide catalyzed asymmetric aza-Baylis-Hillman-type reaction [46].

for the enantioselective reaction. Later they clarified the importance of each part of the peptide catalyst structure through control experiments with the catalysts in which the amide bond was isosterically displaced by alkenes [48]. In 2000, List et al. reported that L-proline, a simple amino acid, catalyzes the direct asymmetric aldol reaction [49]. Although the asymmetric Robinson annelation including intramolecular asymmetric aldol reaction step was known to be catalyzed by proline, as mentioned in Section 4.1 [11], its expandability to the intermolecular version only recently has been investigated. Therefore, their finding opened a new possibility for proline derivatives including prolyl peptides as asymmetric catalysts. As a pioneer of the proline catalyst, List and Martin first examined the catalytic performance of N-terminal prolyl peptides [50]. They tried eight dipeptides and two tripeptides in the “benchmark” aldol reaction of acetone with 4-nitrobenzaldehyde (4NBA). Some gave better yield compared with the proline catalyst; however, the enantioselectivities were either equal to or less than that of the proline-catalyzed reaction (entries 2 and 3 in Table 4.2). After that, many groups tried out this reaction with peptide catalysts. Some of them, including our group used an immobilized peptide as a catalyst. The results with such resin-bound peptide catalysts other than ours should be found in the previous chapter. O 10 mol% N O PhHN

HOOC O

Boc

O

N H HN

NH

O O PhHN

O

12 O Diisopropylcarbodiimide aq. H 2O2, DMAP CH2Cl2/H2O

up to 97% yield up to 92% ee

SCHEME 4.12. Asymmetric epoxidation catalyzed by tripeptide through peracid formation of side chain carboxy group on N-terminal Asp residue [47].

104

H-Pro-OH (30) H-Pro-Gly-Gly-OH (30) H-Pro-His-Ala-OH (30) H-Pro-D-Ala-D-Asp-NH2 (10) H-Pro-Pro-Asp-NH2 (1) H-Pro-Pro-Asn-NH2 (10) H-Pro-Pro-Glu-NH2 (1) H-Pro-Pro-D-Asp-NH2 (18) H-Val-D-Pro-Gly-Leu-OH (20) þ PhCOOH (40) H-D-Pro-Tyr-Phe-TentaGel (20) þ ZnCl2 (20) H-Pro-~-Pro-OHb (20)

1 2 3 4 5 6 7 8 9 10 11

+

n.m. n.m. D D D D D N D N

Prep.a

O

O OH

NO2

DMSO, rt, 4 h DMSO, rt, 18 h DMSO, rt, 18 h Acetone, rt, 24 h Acetone, rt, 4 h Acetone, rt, 24 h Acetone, rt, 18 h Acetone, rt, 18 h MeOH, rt, 48 h Acetone/H2O/THF ¼ 1/1/1, 0 C, 20 h Acetone/H2O ¼ 10/1, rt, 24 h

Conditions

peptide

b

a

Preparation method of a peptide catalyst: D ¼ solid-phase synthesis, N ¼ solution-phase synthesis, n.m. ¼ not mentioned. For symbol ~, see Figure 4.3.

Catalyst (mol%)

Entry

O2N

CHO

TABLE 4.2. Aldol reaction of acetone with 4-nitrobenzaldehide catalyzed by peptide

68 68 85 73 99 39 81 46 58 99 89

Yield (%)

76 (R) 53 (R) 56 (R) 70 (R) 80 (S) 54 (S) 64 (S) 33 (S) 95 (R) 71 (S) 78 (R)

ee (abs. config)

49 50 50 51 51 52a 52a 52b 53 57 55

Ref.

TRI- AND TETRAPEPTIDE CATALYSTS

105

The first peptide catalyst that exceeded both the yield and the selectivity of the proline-catalyzed reaction was the one reported by Wennemers’s group [51]. They used a combinatorial method for the search of a catalytically active tripeptide along with their original “substrate-catalyst co-immobilization” approach. Elements for the tripeptide library H-AA1-AA2-AA3-NHR (R = resin or H) made by Wennemers’s group are as follows: AA1, AA3: X, D-Val, L-Ala, L-Leu, D-Phe, L-Tyr, D-Arg, D-Asp, L-Glu, D-Asn, L-Gln AA2: X, L-Val, D-Ala, D-Leu, L-Phe, D-Tyr, L-Arg, L-Asp, D-Glu, L-Asn, D-Gln. X ¼ {Gly, D-Pro, L-Pro, D-His, L-His} They successfully picked up two tripeptides from a 153 ¼ 3375–sized library (entries 4 and 5 in Table 4.2). One of them, H-Pro-Pro-Asp-NH2, was found to be effective, and the reaction was completed within 4 h in the presence of only 1 mol% of catalyst. When the reaction was performed at a lowered temperature, the aldol product was obtained in 98% yield and 90%ee. It is very interesting that this peptide produced (S)-aldol as a major product, whereas the reactions catalyzed by other peptides having L-proline at N-terminal proceeded in an (R)-selective manner. This means that the stereochemistry of the aldol reaction catalyzed by H-Pro-Pro-Asp-NH2 was controlled by the 3D structure of the whole peptide rather than by the point chirality of the proline at the N-terminal. Computational calculation of this molecule showed that the Pro-Pro has a turned conformation. Related peptides having an N-terminal Pro-Pro sequence, including those containing D-proline, were thoroughly surveyed by Wennemers’s group, but a catalyst with better performance was not found (entries 6 to 8 in Table 4.2) [52]. Da et al. demonstrated that tetrapeptides having a b-turn structure are also enantioselective catalysts for the aldol reaction (entry 11 in Table 4.2) [53]. When cocatalyzed with benzoic acid, H-Val-D-Pro-Gly-Leu-OH produced the product with 95%ee, although the yield was moderate. When the benzoic acid is absent, the enantioselectivity reduces to 66%ee. In our body, enzymes catalyze many kinds of reactions in water. As the enzymes are polypeptides in their chemical structure, it is expected that the peptide can also catalyze the reaction under aqueous conditions. However, the addition of water to the proline-catalyzed aldol reaction of acetone with 4NBA brings about lowering of the enantioselectivity [54]. For example, the proline-catalyzed aldol reaction in acetone/ H2O ¼ 10/1 (v/v) proceeds with entirely no enantioselectivity [55]. Development of a water-tolerable version of a proline-related asymmetric catalyst would open a new horizon to organic synthesis. Great progress in this field has been achieved mainly by prolinol-derived catalysts [56]. However, it would be desirable that such a catalytic reaction can also be realized by peptides because the peptide catalyst can be optimized for a variety of substrates through “fine-tuning” of its sequence. Kudo and coworkers have developed the prolyl peptide catalyst from this viewpoint by employing a tripeptide D-Pro-Tyr-Phe covalently immobilized on

106

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

O

H2 N

O

COOH

(+)-cis-β-ACC,

O

H2 N

O

COOH

(-)-cis-β-ACC,

FIGURE 4.3. Structure of Reiser’s amino acids having a cyclopropane skeleton.

amphiphilic polyethyleneglycol-polystyrene (PEG-PS) resin, or TentaGel, as a catalyst (entry 10 in Table 4.2) [57]. Nearly quantitative yield and good enantioselectivity was attained for the reaction in the solvent system of acetone/H2O/ THF ¼ 1/1/1. The same reaction in the presence of water was also reported by Reiser’s group [55]. They designed 2c,3t-2-amino-3-methoxycarbonylcycropropanecarboxylic acid (b-ACC) as a turn-inducing element (Figure 4.3). Both antipodes of this chiral b-amino acid were prepared and incorporated into the peptide sequence to find the optimal catalyst, which is shown in Table 4.2, entry 11. The presence of 10 vol% of water was essential for high enantioselectivity. Kudo’s group extended their research to a one-pot sequential reaction including the enantioselective process [58]. In general, acid catalysts are not compatible with base, and vice versa. If the acidic and basic sites are spatially separated, they might independently work without perturbing each other [59]. In the presence of an acidic ion-exchange resin Amberlite and the resin-supported D-Pro-Tyr-Phe peptide, the deprotection of acetal 13 and the subsequent asymmetric aldol reaction of generated aldehyde 14 with acetone occurred successively in one pot (Scheme 4.13). The mixture of these two kinds of resin-supported catalysts could be reused six times without significant loss in catalytic activity. Another synthetically useful sequential reaction, an oxidation of primary alcohols to aldehydes followed by the asymmetric aldol reaction, was found by the same group (Scheme 4.14). The oxidation was performed by a combination of TEMPO and a copper salt using air as an oxidant [60]. Resin-supported TEMPO was used to avoid possible amine-mediated C-O bond formation between acetone and TEMPO [61]. The triglycyl peptide between TEMPO and the resin was proven to absorb the Cu complex, leading to the enhancement of the oxidation process [62].

OCH3 H3CO O2N 13

Amberlite HO3S 20 mol% D-Pro Tyr Phe H2O/Acetone/THF = 1/1/1 rt, 24 h

O

OH

OHC + O2N

O2N 14

15

13 : 14 : 15 = 10 : 1 : 89 ee of 15 = 73%

SCHEME 4.13. One pot sequential deacetalization-asymmetric aldol reaction catalyzed by an acidic Amberlite resin and a basic resin-supported tripeptide [58].

107

TRI- AND TETRAPEPTIDE CATALYSTS Cu-complex adsorbed on 20 mol% TEMPO (Gly)3 O 20 mol% D-Pro Tyr( tBu) Phe HO O2N 16

air, DMF, rt, 24 h

O

OH

OHC +

buffer (pH 7.8) O2N 0°C, 24 h

O2N 14

15

16 : 14 : 15 = 0 : 13 : 87 ee of 15 = 85%

SCHEME 4.14. Sequential primary alcohol oxidation and asymmetric aldol reaction of the resulting aldehyde catalyzed by a copper ion/immobilized TEMPO couple and a resinsupported tripeptide [62].

In 2005, Co´rdova and coworkers showed that several nonproline amino acids, such as alanine, valine, and aspartate, catalyze the aldol reaction of cyclohexanone with 4NBA in a highly diastereoselective (anti/syn up to 37/1) and exceptionally enantioselective manner of 99%ee or higher [63]. This finding can be regarded as another breakthrough in the amino acid organocatalysis, and it is also significant from the viewpoint of an industrial application. Then, just as many chemists did after the finding of the proline catalyst, the catalytic ability of the related peptides was investigated by Co´rdova’s group [64]. Although several dipeptides including H-Ala-Ala-OH showed a comparable result with amino acid catalysts, a tripeptide H-Ala-Ala-Ala-OH was proven to be less efficient (entries 2–4 in Table 4.3). It is noteworthy that N-terminal prolyl peptides are a good catalyst for the asymmetric aldol reaction of acetone but not so for the reaction of cyclohexanone, and vise versa, although some exceptions to the consensus were introduced recently. A peptide-catalyzed aldol reaction of hydroxyacetone with aryl aldehydes was reported by Gong and coworkers in 2004 [65] (Scheme 4.15). When the reaction was performed in aqueous media, the C-C bond formation occurred preferentially at the 3-position of hydroxyacetone. The reaction took days to obtain affordable yield, and the stereoselectivity was high. They had synthesized the peptide catalysts in gram scale by liquid-phase reaction and had purified the N-protected precursor of the target peptide through recrystallization from ethanol. What is interesting is that their catalyst 17 was not only stereoselective but regioselective as well. When chemists discover a certain good catalyst, they will try to use that catalyst for another reaction. That is true for peptide catalysts. Peptide catalysts for aldol reaction have been widely examined as catalysts for Michael addition, which is another important C-C bond forming reaction. Co´rdova and coworkers had extended their simple di- and tripeptide catalysts to asymmetric Michael addition, and they found that the reaction of a 6-membered ketone with b-nitrostyrene (BNS) proceed in a highly enantioselective manner [66] (Scheme 4.16). Catalytic efficiency was in the order of H-Ala-Ala-OH > H-Ala-AlaAla-OH > H-Ala-OH, whereas enantioselectivity was close to each other. It is interesting to add that, for the reaction, H-L-Ala-D-Ala-OH was more potent compared with the parent H-L-Ala-L-Ala-OH. As shown in the aldol reaction, the reaction of the acyclic ketone did not produce a good result.

108 NO2

peptide

75

Yield (%)

NO2

+

Ketone/H2O ¼ 10/1, rt, 24 h

anti

OH

95 73 90 42 87

O

DMSO, 10eq. H2O, rt, 3 days DMSO, 10eq. H2O, rt, 48 h DMSO, 10eq. H2O, rt, 48 h H2O, SDS (1 eq), rt, 120 h MeOH, rt, 76 h

Conditions

All peptides were prepared by solution-phase synthesis.

a

6

H-Ala-OH (30) H-Ala-Ala-OH (30) H-Ala-Ala-Ala-OH (30) H-Ala-Ala-Ala-OH (30) H-Val-D-Pro-Gly-Leu-OH (20) þ PhCOOH (40) H-Pro-~-Pro-OH (20)

1 2 3 4 5

a

Peptide Catalyst (mol%)

+

OHC

Entry

O

TABLE 4.3. Peptide-catalyzed aldol reaction of cyclohexanone with 4NBA O

6/1

15/1 8/1 1/2 2/1 36/64

anti/syn

syn

OH

NO2

95

99 91 81 75 95

anti

ee (%)

99

51

syn

55

63 64a 64a 64b 53

Ref.

109

TRI- AND TETRAPEPTIDE CATALYSTS

20 mol% O

NH

N H

H N

O

O

O

N H

O

17 R

CHO +

OH O

O OH

OH O OH + R

R

THF/H2O, 0ºC

OH

up to 88% yield up to 96% ee

minor

SCHEME 4.15. Tetrapeptide-catalyzed regioselective asymmetric aldol reaction of hydroxyacetone [65].

The Michael addition of the same combination of substrates was also repoted by Tsogoeva’s group. The reaction was carried out “on water,” which means that the substrate is not water soluble and the reaction occurs at the oil/water interface [67]. The result of the Michael addition of cyclohexanone to BNS with dipeptide catalyst H-Pro-Phe-OH was better (99% yield, syn/anti ¼ 95/5, 68%ee) compared with the tripeptide catalyst H-Pro-Phe-Phe-OH (70% yield, syn/anti ¼ 96/4, 56%ee). Wennemers’s group had also succeeded in finding a good catalyst for Michael additions. In the previous study on the structure-activity relationship of the peptide catalyst for an asymmetric aldol reaction, her group had tried a several of tripeptides that are structurally related to the parent catalyst H-Pro-Pro-Asp-NH2. They had surveyed that tripeptide library for the Michael addition shown in Scheme 4.17 and had found that H-D-Pro-Pro-Asp-NH2, a diastereomer of the parent compound, was a good catalyst for the Michael addition of aldehydes to b-substituted nitroolefins [68]. They explained the high performance of the catalyst by the “double activation” mechanism, namely, enamine formation by proline and nitro group activation by a carboxylate of Asp side chain in a fixed turn conformation. After additional 30 mol%

H N

H 2N

O OH

O or 45 mol% H 2N

O + R1

H N

R2

Ar

NO2

O OH

O

Ar

O 10 equiv H 2O DMSO/NMP

NO2 R1

R2

up to 95% yield up to 36:1 dr up to 98% ee

SCHEME 4.16. Peptide-catalyzed diastereo- and enantioselective conjugate addition of ketones to b-nitrostyrenes [66].

110

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

0.1-0.4 mol%

H N

O NH2

N O O NH

OHC

+ R1

R2

R2

COOH

NO 2

OHC 0.1-0.4 mol% NMM CHCl3 /iPrOH, rt, 48 h

NO2 R1

up to 98% yield up to 98:2 dr up to 98% ee

SCHEME 4.17. Peptide-catalyzed diastereo- and enantioselective conjugate addition of aldehydes to b-nitrostyrenes [69].

screening, they found that H-D-Pro-Pro-Glu-NH2 is an even better catalyst [69], and they applied this Michael reaction to the production of g 2-amino acids [70]. Through kinetic study of this reaction, they found that the catalyst loading can be decreased to as low as 0.1 mol% when dried solvents, substrates, and glassware were used [71]. 4.4 LONGER PEPTIDES WITH A SECONDARY STRUCTURE Longer peptide catalysts, provided that they have an ideal 3D structure, will interact with substrates more efficiently compared with shorter ones; hence, the higher activity/ selectivity is expected for them. However, the challenge of finding a longer peptide catalyst is associated with an increased risk because chemists have to widen the field of search and that takes more time and money with no guarantee of hitting any target. In the combinatorial approach, the number of possible sequences increases in the manner of geometric progression with an increase in the peptide length. If the elements were limited only to the proteinogenic 20 L-amino acids, the number of combinations is 3.2  106, 6.4  107, 1.3  109, and 2.6  1010 for penta-, hexa-, hepta-, and octapeptides, respectively. As has been shown in the previous section, it is effective to add D-amino acids to the elements for the library. In that case, even pentapeptide has 9.0  107 possible combinations. In addition, chemists sometimes want to try a couple of other non-natural amino acids. This situation makes it impossible to apply an orthodox combinatorial approach. Instead, a biased library containing an affordable number of members (maybe at most 106 order) that consist of only selected amino acids might be of practical use. Moreover, it should be mentioned that the larger peptide catalyst had lower versatility because of the limitation in the production of peptide. This situation requires the longer peptide catalyst at least one of the following: (1) the catalytic reaction is so unique and cannot be achieved by any other catalysts, (2) the catalytic ability of the peptide is exceptionally high, (3) the catalyst can be recycled and used repeatedly. Since 2001, efforts toward finding good penta- and longer peptide catalysts have been made by Miller and coworkers. They first applied their combinatorial approach to the peptide catalyst optimization for a kinetic resolution of secondary

LONGER PEPTIDES WITH A SECONDARY STRUCTURE

111

alcohols [72a]. Unlike the substrate 8 used in the tri- or tetrapeptide-mediated kinetic resolution, simple chiral secondary alcohols having no functional groups other than hydroxyl group, 1-phenylethanol, for example, are obviously more difficult to differentiate. The peptide catalyst with a longer chain will be required to realize efficient recognition of the substrates. Accordingly, they began a quest in the octapeptide space. N- and C-termini of the peptide were fixed to be Pmh and L-Ala, respectively, and the rest of hexapeptide region was screened using 14 kinds of amino acids, D-Val, D-Phe, D-Pro, L-Ile, L-Tyr(tBu), L-Gln(Trt), L-Ala, L-Asn(Trt), Gly, Aib, L-Asp(tBu), L-Trp(Boc), L-His(Trt), and D-Glu(tBu) (Aib ¼ 2-aminoisobutyric acid). After screening the library with the size of 146 ¼ 7.5  106 for the acetylation of ()-1-phenylethanol in toluene at room temperature, they picked up one peptide, Pmh-L-Asn(Trt)-D-Val-L-His(Trt)-D-Phe-D-Val-D-ValL-Ala (18), with an s-value of 8.2. Then they made a second-generation library that is directed to the peptide 18. The directed library is a library that is designed so that the peptide sequence of the member is similar to the parent peptide 18. Then they selected eight new peptide catalyst candidates, and subjected them to the solution-phase assay. Although “on resin” and “in solution” results was not identical, they could find the most effective octapeptide, Pmh-L-Tyr(tBu)-D-ValL-His(Trt)-D-Phe-D-Val-L-Tyr(tBu)-L-Ile (19), which showed an s-value of 20. The scope of this peptide for the kinetic resolution of secondary alcohols was checked with nine substrates. For all the substrates, the catalyst 19 was proven to be effective. Two of them, 1-(1-naphthyl)ethanol and trans-2-phenylcycloheanol, produced an s-value of >50. Even 2-butanol could be resolved with an s-value of 4.0. Their method was successfully applied to the development of a substrate-specific peptide catalyst for a synthetic intermediate of mitosane 22 [72b] (Scheme 4.18). They screened a 152-membered b-turn peptide library and concluded that pentapeptide 20 was the best catalyst. The optical resolution was achieved starting from 0.25 g of racemate using 13 mg of the peptide catalyst to produce 0.12 g of the recovered alcohol with 90%ee. Single recrystallization resulted in an enantiomerically pure compound with the total yield of >40%. The same strategy was applied for the phosphorylation of myo-inositol to seek the kinase analog from the peptide library [73] (Scheme 4.19). The targeted reaction was desymmetrization, that is, site-selective phosphorylation of meso-triol, 2,4,6-triO-benzyl-myo-inositol. It should be noted that both the 1-position selective catalyst 23 and the 3-position selective catalyst 24 were successfully found after intense screening. For the selection of the latter catalysts, screening was carried out three times in a gradually focusing manner. They had also succeeded in fishing out a good acylating peptide catalyst for desymmetrization of a linear substrate, 2-protected glycerol [74]. Later, they showed that the desymmetrization reactions of meso-diols can also be achieved through the sulfonylation with 4-nitrophenylsulfonyl chloride. For the catalyst, 24-related tetrapeptide in which the C-terminal Try(tBu)-Phe-OMe is changed to Leu-OMe was used [75]. Then, they tried how far they can go. Desymmetrization of a prochiral bisphenol 25, of which the two hydroxy groups are separated by nearly 1 nm, was challenged [76]

112

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

O

O OH

O

2 mol% peptide 20 Ac2O

O OAc

O OH

O

O

+ Toluene

N Boc

N Boc

Me N

N Boc

N

O

Boc

21

N H HN

N

NH

O

O NH

O

6 steps, 27% yield

20

O

O

21

O N

NH

22

SCHEME 4.18. Application of peptide-catalyzed kinetic resolution toward the total synthesis of mitosane [72b].

(Scheme 4.20). A hexapeptide library having N-terminal Pmh was designed to have efficient interaction with the substrate. Starting from 138 peptides, repetitive screening, truncation, and final C-terminal modification of the peptide produced the best catalyst 26. OBn HO

O O P(OPh)2

1

2 mol% peptide 23

BnO

OBn OH

OBn HO

OH 3

1

BnO

65% yield >98% ee

Cl-P=O(OPh)2, Et3N Toluene, 0ºC

OBn

O (PhO)2P O

OH 2.5 mol% peptide 24

OBn OH 3

BnO

OBn OH

56% yield >98% ee Trt

NH O

O Me N N

H N

HN O Boc

NH

O HN

N O

N Bn

O O

23

O

N H

Me N N

O N O

Boc

NH

N H HN

O

O NH

O

O

O

O

O 24

SCHEME 4.19. Controlled phosphorylative desymmetrization of myo-inositol-derived meso-diol by peptide catalysts [73].

LONGER PEPTIDES WITH A SECONDARY STRUCTURE

113

2.5 mol% peptide Ac2O HO

CHCl3, -30ºC

OH

HO

OAc

25 iBu

Me N Boc

X= N H

O

H N

N H

O

H N O

O X

OMe

68% yield, 72% ee

Bn

Ph X=

O

O

HN

O

O

H N

N

80% yield, 95% ee

Ph

HN

HN Trt

HN

(26) Ts

SCHEME 4.20. Desymmetrization of prochiral bisphenol by peptide catalyst [76].

Then, they extended their chemistry to site-selective acylation of an unsymmetrical polyol compound. By using erythromycin 27 as a substrate, they demonstrated that the peptide catalyst can override the inherent reactivity order of the hydroxy groups [77]. When acylation was performed using N-methylimidazole as a catalyst, site a acetylated product and site b acetylated product were obtained in a ratio of a:b ¼ 4:1, whereas the value was 1:5 for the reaction catalyzed by peptide 28, which was screened out of 137 candidates (Figure 4.4). Such a site-selective acylation is useful for the study of the structure-activity relationship of bioactive compounds [78]. This methodology was extended to site-selective deoxygenation of diols through a thionocarbonate intermediate (Scheme 4.21). The peptide 31 preferentially produced compound 29 with the ratio of 29:30 ¼ 11.7:1, whereas that of the reaction mediated by the peptide 32 in the presence of FeCl3 cocatalyst was 1:6.6. Both products were successfully deoxygenated by the action of tin hydride [79]. Peptide-catalyzed kinetic resolution is also applicable to racemic amines [80] (Scheme 4.22). Boc protection of the amide nitrogen of thioformamide of chiral 1-phenylethyl amine. Without using the library approach, they could obtain b O OH

O OH HO O

O O

Me N

NMe2

OH

O O

O

N

OMe

a

N O Boc

NH

N H HN

O

O NH N O Boc

OH

28 O

27

FIGURE 4.4. Structure of erythromycin and its acylation site.

114

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

N

S OPh

Cl

(1.5 equiv) O Ph O O HO HO OMe

(2 equiv) Ph

catalyst

O O HO

O O O O HO OMe S OPh

Ph

O + O OMe

CH2Cl2, rt, 1 h S

OPh

29

30

O Me Me N N

N H HN

N O Boc

N N

O

Boc

NH

O

H N

N H

O

NH N O Boc

Ph

31

O N H O

H N

O N H

O

O

O N H

O

O

H N

O

O

N N Trt

32

O

H N

SCHEME 4.21. Controlled site-selective thionocarbonate formation by peptide catalysts. [79].

significantly an enantiospecific peptide catalyst 33. The Boc-protected thioformamide was easily converted to the corresponding Boc-protected amines. Other than for functional group transformation, Miller’s group tried to find a peptide catalyst for C-C bond forming reactions. An asymmetric Baylis–Hillman reaction of electron-deficient aryl aldehydes with methyl vinyl ketone in the presence of cocatalyst L-Pro [81] (Scheme 4.23). Starting from 19%ee for a single amino acid, Boc-NH-Pmh-OMe, they went as far as the octapeptide 34 shown in Scheme 4.23 to achieve the ee of 78%. The precise method for the screening was not shown; however, they claimed that rough optimization could lead to acceptable enantiosO

5 mol% Me N N

N O Ac

NH

N H HN O

NH

33 R1 R2

O O

S N H

O

R1 R2

H Boc2O (0.6 equiv) CHCl3, 25ºC, 24 h

R1

S N H Boc

+

R2

S N H

~50% conversion s-value up to 43.7

SCHEME 4.22. Kinetic resolution of thioformamides by peptide-catalyst [80].

H

115

LONGER PEPTIDES WITH A SECONDARY STRUCTURE

O R

OH

10 mol% peptide 10 mol% proline

CHO +

O

R

CHCl3 /THF, 25ºC up to 95% yield up to 81% ee

H N

O O

H N

Boc

N H

O

H N

N H

O

H N

Trt O

O

H N

O

N H

N

O O

O

N N Me

34

SCHEME 4.23. Octapeptide-catalyzed asymmetric Baylis-Hillman reaction [81].

electivity. It should be noted that the combinatorial approach that has been used in the acylation chemistry is not applicable to this reaction. That is also the case for conjugate addition of highly enolizable alpha-nitro ketone to enones. Instead of a combinatorial approach, they carried out a mechanism-driven catalyst design to find the best peptide 35 [82] (Scheme 4.24). When the phenyl group of the Michael donor is replaced by the cyclohexyl group, the enantioselectivity reduces to 0%. Kudo and coworkers took a totally different approach. Again they targeted the asymmetric reactions under aqueous conditions. They used amphiphilic resinsupported 30mer peptides that are “chimeras” of PAA and the b-turn peptide [83–85]. O

O NO2

R1

+

2

O

2 mol% peptide R3

R

O

R1

R3 R2 NO2

Toluene, 4ºC

up to 85% yield up to 74% ee O O O NH2 S N N H O

N O O

NH

N H HN

O

O NH N

N Bn

O 35

O

SCHEME 4.24. Asymmetric conjugate addition of a-nitroketones to enones catalyzed by rationally designed peptide [82].

116

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

Pro D-Pro Aib Trp Trp (Leu)25.4 catalytically active site

(36)

hydrophobic chain

FIGURE 4.5. Structure of “chimeric” peptide catalyst by Kudo’s group.

The catalyst 36 consists of the N-terminal pentapeptide Pro-D-Pro-Aib-Trp-Trp, which adopts the b-turn structure, and the a-helical polyleucine chain. This highly hydrophobic peptide is attached to the amphiphilic PEG-PS resin (Figure 4.5). In the molecular design, the polyLeu moiety was expected to behave as a hydrophobic sink for organic compounds in aqueous media, which enhances the reaction by raising the local concentration of substrates around the reaction center. The catalyst was prepared through the polymerization of Leu-NCA initiated by the amino residues on the TentaGel resin and the subsequent orthodox Fmoc solid-phase peptide synthesis. Catalyst 36 promotes the asymmetric transfer hydrogenation [83], the asymmetric Friedel–Crafts-type alkylation [84], and the asymmetric a-oxyamination [85] efficiently and enantioselectively in aqueous media (Scheme 4.25). The former two reactions proceed through the iminium ion formation, whereas the mechanism of the last reaction involves an enamine intermediate. It is worth noting that a single peptide catalyst was effective in mechanistically different reactions. Transfer hydrogenation

O

O

EtO 20 mol% TFA • 36, R

CHO

OEt N H

CHO

R

THF/H2O = 1/2, rt

up to 76% yield up to 96% ee

Friedel–Crafts-type alkylation

R

CHO + Ar-H

20 mol% TFA • 36

Ar

NaBH4 R

THF/H2O =1/2 (or H2O), rt

OH

up to 88% yield up to 94% ee

α -Oxyamination O R

CHO +

N

20 mol% 36 30 mol% FeCl 2 • 4H2O 30 mol% NaNO2, air THF/H2O = 1/2 rt, 1 h

TEMPO

R NaBH4

OH O N

up to 87% yield up to 93% ee

SCHEME 4.25. Catalytic asymmetric reactions of aldehydes by a common resin-immobilized chimera peptide 36 [83–85].

LONGER PEPTIDES WITH A SECONDARY STRUCTURE

20 mol% catalyst FeCl3 (1 equiv)

O N

CHO +

OH

D-Pro

O N

NaBH4

THF/H2O = 1/2 rt, 3 h catalyst

Pro

Aib

Trp

Trp

Pro D-Pro Aib

(Leu)25.4 Trp

Trp

yield (%)

ee (%)

(36)

57

89

(37)

8

39

Pro

D-Pro

Aib

Trp

Trp

(Ile)26.5

(38)

20

13

Pro

D-Pro

Aib

Trp

Trp

(Val)26.3

(39)

21

14

D-Trp

(Leu)26.5

(40)

14

-23

D-Pro

117

Pro Aib

D-Trp

SCHEME 4.26. Asymmetric a-oxyamination of aldehyde catalyzed by immobilized peptides [82].

As expected, the hydrophobic polyLeu moiety significantly enhanced the reaction. More interestingly, the polyLeu part considerably affected the enantioselectivity for the reactions. The case of asymmetric a-oxyamination is illustrated in Scheme 4.26. When peptide 37 without a hydrophobic segment was used as a catalyst, the reaction hardly proceeded and the enantioselectivity dramatically decreased. The reaction catalyzed by the peptides having hydrophobic, but non– a-helical, polyisoleucine or polyvaline moieties were slow, and low enantioselectivities were observed. Replacing the part of the terminal five residues with their antipode (catalyst 40) also resulted in a poor reaction rate and selectivity. A brief molecular mechanical study showed that one enantiotopic face of the reaction intermediate, regardless of whether it is iminium ion or enamine, is effectively shielded by the peptide chain; hence, the enantioselectivity was attained. Infrared spectroscopic observation revealed that the polyLeu moiety assists the formation of a b-turn structure at the N-terminus even in the highly polar reaction media [83]. As mentioned in the previous section, if the chiral-amine–catalyzed organocatalytic reactions of aldehydes can be coupled by preceding in situ oxidation of the precursor primary alcohol, it would be synthetically useful. Catalyst 36 could be applied to the one-pot sequential reaction including the oxidation of alcohols to aldehydes by the TEMPO/Cu system and the following peptide-catalyzed asymmetric a-oxyamination (Scheme 4.27) [86]. This one-pot reaction was unique to peptide catalysis in aqueous media, and it could not be attained by a homogeneous catalyst. It was also demonstrated that the resin-supported peptide had high reusability, affording the product without significant loss in yield and enantioselectivity even after repeated use. Finally, the same group has recently found an asymmetric epoxidation catalyzed by the immobilized peptide. After screening the peptide sequence starting from the lead catalyst 36 (73%ee for the reaction in Scheme 4.28) through to elongation/

118

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

O R

OH

N

+

20 mol% 36 30 mol% CuCl 30 mol% 2,2'-bipyridine

R

OH O

NaBH4

N

O2, THF/H 2O = 1/2 rt, 36 h TEMPO

yield: up to 85% ee: up to 93%

SCHEME 4.27. One-pot sequential aerobic primary alcohol oxidation and aldehyde aoxyamination catalyzed by a copper complex and an immobilized peptide in the presence of TEMPO [86].

D-Pro

Ach (Ala(1-Pyn))3 (Leu)28.6

CHO + O2N

H2O2 1.5 equiv

(41)

H2N

COOH

H2N

Ach

20 mol% 41 THF/H2O = 1/2, 0°C, 24 h

COOH

Ala(1-Pyn)

NaBH4 O2N

O OH 78% yield trans/cis = 98/2 91% ee (trans)

SCHEME 4.28. Asymmetric epoxidation of enal by hydrogen peroxide in the presence of immobilized peptide catalyst [87].

truncation of the amino acids and displacement of targeted positions, they found that peptide catalyst 41 was the best [87]. Catalyst 41 contains hydrophobic and bulky pyrenylalanines. These amino acids should effectively shield the one face of the intermediate iminium ion from the attack of the small nuclephile, OOH. 4.5 OTHERS Although we focused on peptide catalysts consisting of more than three amino acid residues, it should be noted that there are excellent dipeptide asymmetric catalysts. Besides the ones hitherto mentioned, cyclo-Phe-(S)-a-amino-g-guanidinobutyryl for an asymmetric Strecker reaction [88], and H-Pro-Phe-OH [89], H-Pro-Trp-OH [90], H-Ala-Phe-OH, H-Val-Phe-OH, H-Val-Val-OH, and H-Val-Ala-OH [65] for an asymmetric aldol reaction are notable. Dipeptide H-Pro-Val-OC12H25 having a long alkyl chain was reported to form hydrogel at a lower temperature [91]. The aldol reaction of cyclohexanone with 4NBA catalyzed by this peptide hydrogel was considerably improved (18%ee to 88%ee) by changing the temperature from 25 C to 5 C. It is interesting that this small difference in the temperature brought about considerable increase in the enantioselectivity.

CONCLUSIONS AND OUTLOOKS

119

Several groups concentrated on the development of an asymmetric metal catalyst having a peptide as a chiral ligand. This kind of catalyst is of interest in relation to naturally occurring metalloenzymes. Gilbertson’s group prepared non-natural amino acids having metal-coordinating units and applied them to peptide ligands having a secondary structure [92]. Hoveyda’s group developed two kinds of tripeptide ligands having the metal-binding site at the N-terminal. Both the Cu-catalyzed asymmetric conjugate addition of dialkylzinc [93] and the Al-catalyzed asymmetric TMSCN addition to ketones [94] underwent with very high ee. Meldal and coworkers made immobilized peptidyl P-N and P-S ligands and applied them to Pd-catalyzed asymmetric allylic substitution [95]. Chiral surface modification of a heterogeneous catalyst Pt/Al2O3 by Trp-Gly-Gly was reported by Baiker et al. and used for asymmetric hydrogenation [96]. 4.6 CONCLUSIONS AND OUTLOOKS The last decade seems to have been a “renaissance” in the peptide catalyst: Miller et al.’s histidine derivatives, N-terminal prolyl peptides, mentioned in this and other chapters; Co´rdova et al.’s nonhistidyl/nonprolyl simple peptides; and so on. New knowledge is accumulating at a pace never seen before. This situation is expected to lead to the creation of a database of a peptide catalysts, and to “in silico” optimization of the peptide catalyst in the future. However, now we are still in the stage of collecting more experimental facts. The combinatorial approach is promising for the exploration of a good peptide catalyst. Obviously, a “full-scale” library is not realistic, and appropriate design of a library with selected “correct” components is the key to success. As observed in the result of both Miller’s and Wennemers’s group, incorporation of both D- and L-isomers seems important. Needless to say, development of an efficient assay method is of critical importance. So what will be the future of peptide catalysts? As shown by Miller’s group for site-selective acylation, the peptide catalyst has expandability to hitherto unrealized differentiation of functional groups. The goal toward this direction might be the usage of a peptide catalyst in the key reaction of multistep synthesis of a target compound with a highly complex structure, such as highly bioactive natural products. Even a complete peptide-catalyzed multistep synthesis without using any protective group can be expected. Furthermore, development of a good peptide catalyst for large-scale production of chiral compounds such as a synthetic intermediate of drugs is also expected. Thus, a major breakthrough in peptide preparation method is coming. Another aspect of the peptide catalyst is its relevance to the biological system. It sounds exciting that simple peptides, or even amino acids, can catalyze the aldol reaction, which is related to the formation of sugar molecules [97]. The progress of research toward this direction is scientifically interesting. We believe that peptide catalysts can be a tool in the chemical biology field. The possibility of the large-scale production of catalytic peptides based on biological machinery is yet another probability.

120

PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

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en, H.; Ibrahem, I.; Co´rdova, A. Adv. Synth. Catal. 2006, 348, 418–424. Freund, M.; Schenker, S.; Tsogoeva, S.B. Org. Biomol. Chem. 2009, 7, 4279–4284. Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem. Int. Ed. Engl. 2008, 47, 1871–1874. Wiesner, M.; Neuburger, M.; Wennemers, H. Chem. Eur. J. 2009, 15, 10103–10109. Wiesner, M.; Revell, J.D.; Tonazzi, S.; Wennemers, H. J. Am. Chem. Soc. 2008, 130, 5610–5611. Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J. Am. Chem. Soc. 2010, 132, 6–7. (a) Copeland, G.T.; Miller, S.J. J. Am. Chem. Soc. 2001, 123, 6496–502. (b) Papaioannou, N.; Evans, C. A.; Blank, J. T.; Miller, S. J. Org. Lett. 2001, 3, 2879–2882. Sculimbrene, B.R.; Morgan, A.J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 11653–11656. Lewis, C.A.; Sculimbrene, B.R.; Xu, Y.; Miller, S.J. Org. Lett. 2005, 7, 3021–3023. Fiori, K.W.; Puchlopek, A.L.; Miller, S.J. Nature Chem. 2009, 1, 630–634. (a) Lewis, C.A.; Chiu, A.; Kubryk, M.; Balsells, J.; Pollard, D.; Esser, C.K.; Murry, J.; Reamer, R.A.; Hansen, K.B.; Miller, S.J. J. Am. Chem. Soc. 2006, 128, 16454–16455. (b) Lewis, C.A.; Gustafson, J.L.; Chiu, A.; Balsells, J.; Pollard, D.; Murry, J.; Reamer, R.A.; Hansen, K.B.; Miller, S.J. J. Am. Chem. Soc. 2008, 130, 16358–16365. Lewis, C.A.; Miller, S.J. Angew. Chem. Int. Ed. Engl. 2006, 45, 5616–5619. (a) Lewis, C.A.; Merkel, J.; Miller, S.J. Bioorg. Med. Chem. Lett. 2008, 18, 6007–6011. (b) Lewis, C.A.; Longcore, K.E.; Miller, S.J.; Wender, P.A. J. Nat. Prod. 2009, 72, 1864–1869. Sanchez-Rosello´, M.; Puchlopek, A.L.; Morgan, A.J.; Miller, S.J. J. Org. Chem. 2008, 73, 1774–1782. Fowler, B.S.; Mikochik, P.J.; Miller, S.J. J. Am. Chem. Soc. 2010, 132, 2870–2871. Imbriglio, J.E.; Vasbinder, M.M.; Miller, S.J. Org. Lett. 2003, 5, 3741–3743. Linton, B.R.; Reutershan, M.H.; Aderman, C.M.; Richardson, E.A.; Brownell, K.R.; Ashley, C.W.; Evans, C.A.; Miller, S.J. Tetrahedron Lett. 2007, 48, 1993–1997. (a) Akagawa, K.; Akabane, H.; Sakamoto, S.; Kudo, K. Org. Lett. 2008, 10, 2035–2037. (b)Akagawa, K.; Akabane, H.; Sakamoto, S.; Kudo, K. Tetrahedron: Asymmetry 2009, 20, 461–466. Akagawa, K.; Yamashita, T.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2009, 50, 5602– 5604.

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Akagawa, K.; Fujiwara, T.; Sakamoto, S.; Kudo, K. Org. Lett. 2010, 12, 1804–1807. Akagawa, K.; Fujiwara, T.; Sakamoto, S.; Kudo, K. Chem. Comm. 2010, 46, 8040–8042. Akagawa, K.; Kudo K. Adv. Synth. Catal. 2011, 353, 843–847. Iyer, M.S.; Gigstad, K.M.; Namdev, N.D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910–4911. Shi, L.; Sun, Q.; Ge, Z.; Zhu, Y.; Cheng, T.; Li, R. Synlett 2004, 2215–2217. Lei, M.; Shi, L.; Li, G.; Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron 2007, 63, 7892–7898. Rodr
ıguez-Llansola, F.; Miravet, J.F.; Escuder, B. Chem. Comm. 2009, 7303–7305. (a) For example, Gilbertson, S.R.; Pawlick, R.V. Angew. Chem. Int. Ed. Engl. 1996, 35, 902–904. (b) Gilbertson, S.R.; Collibee, S.E.; Agarkov, A. J. Am. Chem. Soc. 2000, 122, 6522–6523. (c) Christensen, C.A.; Meldal, M. Chem. Eur. J. 2005, 11, 4121–4131. (d) Xu, G.; Gilbertson, S.R. Org. Lett. 2005, 7, 4605–4608. Degrado, S.J.; Mizutani, H.; Hoveyda, A.H. J. Am. Chem. Soc. 2001, 123, 755–756. Deng, H.; Isler, M.P.; Snapper, M.L.; Hoveyda, A.H. Angew. Chem. Int. Ed. Engl. 2002, 41, 1009–1012. Benito, J.M.; Christensen, C.A.; Meldal, M. Org. Lett. 2005, 7, 581–584. Mondelli, C.; Vargas, A.; Santarossa, G.; Baiker, A. J. Phys. Chem. C 2009, 113, 15246–15259. (a) Co´rdova, A.; Ibrahem, I.; Casas, J.; Sund
en, H.; Engqvist, M.; Reyes, E. Chem. Eur. J. 2005, 11, 4772–4784. (b) Weber, A.L.; Pizzarello, S. Proc. Natl. Acad. Sci., U S A 2006, 103, 12713–12717.

CHAPTER 5

CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS SANTIAGO V. LUIS and EDUARDO GARC
IA-VERDUGO

5.1 INTRODUCTION A distinct feature of the 21st century is that scientists and technologists are confronted simultaneously with the need to achieve significant scientific and technological breakthroughs and with the requirements derived from applying the concepts of sustainable development [1]. In the case of chemistry, the term “green chemistry” was coined by Paul Anastas and John Warner to describe a series of techniques, methodologies, and approaches that could allow for the development of new, more efficient chemical processes not only taking into account classical parameters such as those of yield, purity, or selectivity but also considering, for the overall equation, the environmental and hazard costs [2]. Thus, a new green chemistry process should be one that can provide a given chemical product with chemical efficiency and economic viability but, at the same time, produce less waste and less energy consumption, with less associated risks as well as generating and handling less toxic compounds than classical, known processes. In this regard, the use of functional polymers in organic synthesis is, indeed, playing a fundamental role. In addition to discussing the immobilization of functional moieties into a solid support, we will concentrate on polymeric supports capable of acting as reagents, scavengers, or catalysts producing some important advantages related to this issue. First, the use of a reagent or catalyst anchored to a phase that is different from the one containing the substrates and products greatly facilitates the separation and work-up protocols, leading to increases in yields and important savings in solvents, energy, and labor time. The same factors also simplify the reuse and recycling of the

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.

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CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

spent supported reagents and catalysts, which is a key issue for sustainability. Moreover, immobilization of toxic or volatile compounds on a solid matrix will significantly reduce the hazards and “inconveniences” derived from their use [3]. Taking into account the former considerations, the immobilization of a chiral moiety onto a solid matrix (polymeric matrix) allows for maximizing some of the afore mentioned advantages [4]. Chiral reagents and catalysts often contain complex organic fragments that need to be prepared through costly multistep synthetic procedures. In this case, the potential for recycling and reuse is a critical factor for assessing the feasibility of the process under consideration. An additional factor that can contribute to implementing the sustainability of a chemical transformation is the substitution of batch processes by flow processes [5]. Advantages associated with flow systems include improvement in mass and heat transfer; significant intensification of the process, making available systems working 24 h a day, 7 days a week; and easier optimization through adjustments of simple parameters such as flow, pressure, or temperature. Additionally, the scale-up of flow processes is generally attained more easily than for batch processes via different approaches such as scale-out or number-up [5]. Although the advantages of flow chemistry were soon realized by the bulk chemistry industry, the situation is different in the fine chemicals and pharmaceutical industries. Most industrial petrochemical processes, and others for the preparation of bulk chemicals, are carried out in flow, but batch processes still dominate in other industrial areas and a high pressure is currently being exerted to introduce flow processes there. If we consider that many commercialy important chemical products, in terms of added value, for the fine chemicals industry are chiral [6], there is no doubt that we can expect a dramatic increase in the next few years in the number of industrial applications for the preparation of chiral compounds of commercial interest under flow conditions. In fact, the last few years have experienced the introduction of new developments in the field of applying flow processes in complex organic syntheses [7]. Nevertheless, applying these approaches to asymmetric synthesis has been, to date, much more limited [8]. Two main methodologies can be considered in this regard. The first method involves the use of microreactor technologies with the use of either homogeneous or supported systems [9]. The second method is based on the use of what can be called minireactors, with dimensions being an order of scale larger than the microreactors [10]. Insoluble polymeric matrices containing the appropriate functionalities are particularly well suited for the development of flow reactors and, accordingly, flow systems predominantly for catalytic applications. This kind of material, however, has been exploited more in the field of minireactors than in the area of microreactors. In this chapter, we will mainly concentrate on those flow applications with minireactors derived from insoluble functional polymers and involving asymmetric transformations. Many different types of insoluble matrices have been used to immobilize supported asymmetric reagents or catalysts. Specific advantages have been claimed for each support, but those, necessarily, always need to be explicitly evaluated for each application. In the case of insoluble organic polymers—those that are of interest

INTRODUCTION

recycle

pumps mixer Reagents and solvents

pressure Reactor

BPR collection

heat cool Microreactors

127

analysis Mini-reactors

FIGURE 5.1. General scheme of the experimental setup for continuous flow processes using either micro reactors or mini reactors for the catalyst immobilization.

for this chapter—materials derived from many different monomeric compositions have been studied (Chart 5.1), but the use of polystyrene-based polymers has clearly dominated. This is based on two fundamental factors. First, it is because of the easy functionalization of the polymeric matrix that takes advantage of the chemical reactivity of the aromatic rings derived from styrene (or divinylbenzene) [11]. Second, it is a result of the “inert” chemical nature of the rest of the matrix, as the absence of any other organic functionality reduces potential interference for the chemical transformation to be carried out. This is essential in the case of asymmetric, particularly enantioselective, transformations. In this case, differences in energy between the transition states leading to two isomers (enantiomers) can be small and affected by minor changes [12]. In general, but most importantly in the case of flow applications, the morphology of the functional polymers can be as important as the chemical functionality present in the support [13]. The morphology of the matrix will determine the accessibility of the functional sites under a given set of conditions, both in batch and in flow, but will also determine the fluidodinamic regime taking place under some given flow conditions (Figure 5.3) [14]. In this sense, two main classes of insoluble polymers can be described: microporous and macroporous. In the case of microporous or gel-type polymers, the resin in the dry state does not contain any permanent porosity.

128

n

m

1

PS

O O k

O

R' p

O

m

R'

3

R

O

n

n

R'

X

m

CHART 5.1. General structures of some common polymeric matrices.

= Functional moities

= Polymeric Backbone

p

p

TG

2

PA

INTRODUCTION

129

FIGURE 5.2. Optical microscope images of a gel-type resin in the dry state (left) and swollen using a good solvent (right).

Nevertheless, in the presence of a good solvent for the polymeric chains (a good swelling agent), the originally collapsed structure is expanded and the functional sites located on the polymeric chains become accessible (see Figure 5.2). Most gel-type polymers are prepared in the form of different-sized beads, with the most classic example being Merrifield’s resins originally used for solid-phase peptide synthesis [15]. For those microporous polymers, the volume and the accessibility, and accordingly, the reactivity, are dramatically dependent on the nature of the solvent used. Thus, in the case of the most common polystyrene-divinylbenzene (PS-DVB) resins, the use of good solvents such as dichloromethane, Tetrahydrofuran (THF), dioxane, or N,N0 -dimethylformamide (DMF) is critical to obtain good results, On the contrary, the use of solvents like methanol or water can lead to sluggish kinetics or to a complete lack of reactivity. The situation is different for macroporous polymers. For those resins, polymerization is carried out in the presence of a porogenic agent, which is entrapped in the polymeric matrix information and, on removal, produces a permanent porous structure in the dry state [16]. Here, the swelling is a less critical parameter. Modifications in the solvent used do not affect, to the same extent, the accessibility of the functional sites. Moreover, as the formation of macroporous polymers involves the use of high cross-linking degrees, even the use of a good backbone solvent has no appreciable effect on the volume of the polymer. A concomitant advantage is that functional sites can also be accessed in the presence of that do not swell very well agents. A potential drawback is the possibility of obtaining some functional groups, which because they are buried in a highly crosslinked region would not be accessible for more reactions. It is our experience, however, that this last factor can be regulated through an appropriate selection of the polymerization conditions, particularly the chemical nature of the porogenic agents, to locate functional sites on the accessible surfaces [17]. As mentioned previously, the most common presentation of polystyrene resins is in the form of beads. This has been, for years, the typical presentation of PS-based ion exchange resins, which can be considered one classical application of functional polymers in chemistry [18]. Achieving an appropriate packing of beads in a column to obtain stable and reproducible fluidodinamics is not, however, a simple matter, as it has been known for years in the field of chromatography. Thus, the preparation of macroporous polymers in the form of monoliths with the required shape and size is an attractive approach. This kind of material has been developed for different applications including chromatography and catalysis [19]. In the case of monolithic catalysts, the corresponding functional monomers can be polymerized inside a stainless steel or glass column in the presence of adequate porogens to afford tubular minireactors.

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CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

Mini-reactors based on PS-DVB polymers

Gel-type polymer

Monolithic polymer

Acetonitrile

(no-swelling) 2.5

non-swollen (CH3CN) swollen (Toluene) monolithic

E (t)

2.0 1.5 1.0 0.5 0.0 0

2

4

6

time (min)

8

10

Toluene

(swelling)

FIGURE 5.3. E(t) curves for either gel-type or macroporous monolith chlorometylated PS-DVD resins for some given flow conditions (0.5 mLmin1) and solvent.

A related approach is the one used by Kirsching to prepare the so-called PASS-flow (polymer-assisted solution-phase synthesis in the flow-through mode) reactors [20]. In this case, the polymerization takes place inside the porous of a fitted glass to cover the glass surfaces with a polymer layer. When using monolithic polymers, the use of flow reactors involves the application of a forced flow produced by a peristaltic pump or a high-performance liquid chromatography (HPLC) pump (Figure 5.4). In general, careful control of the monomeric composition, porogenic volume, chemical nature, and polymerization conditions (initiator and temperature) allows for obtaining quantitative yields for the corresponding mass polymerization [21]. Particular care is needed, however, to ensure an appropriate size and distribution of the pores (in the range of ca. 1000 mm) and to avoid the presence of wall effects that would lead to the formation of preferential channels and a nonhomogeneous flow through the column. For bead polymers, either micro- or macroporous, different minireactor assemblies are possible (Figure 5.5) [10, 22]. The simplest one is the gravity flow (type I). A flow of solvents and substrates/reagents is fed to the top of a column packed with the corresponding functional beads. The solution flows downward because of gravity,

INTRODUCTION

131

FIGURE 5.4. Preparation of monolithic columns by bulk polymerization.

and the products and unreacted substrates/reagents are collected at the bottom of the column. A similar assembly is present in the second case (forced flow), but in this system, a pressurized flow is supplied by a pump and the flow can be either upward or downward. A different approach is used for the third type, in which a flow of solvents and substrates/reagents is fed into the bottom of the column containing the resin, and

TYPE I

Substrates/ reagents

TYPE II

Substrates/ reagents

TYPE III Product Substrates/ reagents

Substrates/ reagents

or

Product

Product

Product

Packed bed reactor

Monolithic reactor

FIGURE 5.5. Different reactor assemblies for catalytic flow processes based on functionalized polymeric materials.

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CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

membrane

BPR

catalysts

Solution Product (AB) stirrer

pump pump

Solution Reagent (A)

Solution Reagent (B)

FIGURE 5.6. General assembly for a membrane reactor.

the flow of solvents and products is collected from the supernatant solution on the top of the column. In this case, the overall assembly is reminiscent of a fluidized-bed reactor [23]. When gel-type resins are used for any of those flow-through assemblies, it is important to take into account the increase in volume that will occur when the polymer comes into contact with the solvent used for the corresponding reaction. Although we will not concentrate on membrane reactors here, this has been an additional approach to developing flow reactors based on functional polymers (Figure 5.6) [24]. In the specific case of asymmetric/enantioselective reactions, it is often mentioned that the immobilization of an efficient reagent or catalyst usually ends in supported systems with a decreased efficiency, particularly in terms of enantioselectivity. Fortunately, this is not always the case, and we have found different examples in which the immobilization process produces heterogeneous systems that are more active, more stable, or more selective/enantioselective that the related homogeneous ones [25].

5.2 ASYMMETRIC POLYMER-SUPPORTED, METAL-BASED CATALYSTS AND REAGENTS 5.2.1 Enantioselective Additions to C¼O Groups 5.2.1.1 Addition of Dialkylzinc Reagents to Aldehydes. This reaction represents one of the first examples of an enantioselective transformation carried out under flow conditions with the help of a polymer-supported chiral catalyst. In the early 1990s, Fr
echet and Itsuno reported the use of polymers functionalized with some amino alcohol derivatives (1 and 2) and their use as enantioselective catalysts for adding diethyl zinc to aldehydes (Figure 5.7) [26]. A complete analysis of the influence of structural parameters such as the degree of cross-linking and

ASYMMETRIC POLYMER-SUPPORTED, METAL-BASED CATALYSTS AND REAGENTS

CHO PS

Ph

CH2O H 2N

Ph

E t2Zn

Cl

OH 90% Yield 94% ee (S) o 0C

1

PS

133

Ph Ph

CH2O N

OH

R 2

OH

Cl

FIGURE 5.7. Enantioselective addition of diethyl zinc to benzaldehydes catalyzed by supported aminoalcohols under flow conditions developed by Fr
echet and Itsuno.

functionalization was performed using bead-type resins. Using a fixed-bed configuration and working at 0 C, excellent yields and enantioselectivities could be achieved in optimal cases. After this seminal work, Hodge et al. was involved in a systematic study of this process, taking into consideration a large variety of variables, including the nature and morphology of the polymer, structural variation in the chiral moiety, flow parameters, and so on [27]. This allowed the authors to optimize the system to obtain yields and enantioselectivities as high as 98% with resin 3 (Figure 5.8). For this purpose, the authors used a fluid-bed configuration (type II system). It is important to note that one significant finding of this work was the observation of the key role played by the concentrations and flow rates not only on the yield of the reaction but also on the selectivity and enantioselectivity [27]. The use of a flow system was also demonstrated to favor the recovery and reuse of the polymer greatly. In the case of supported aminoalcohol 4, they continuously ran the system for 275 (6 mL/h) with 95% yield and 97%ee for benzaldehyde [27]. It must be mentioned that experiments can be efficiently carried out under flow conditions even with gel-type resins with low cross-linking degrees (0.2). The fragility of these materials hampers the catalyst recovery and recycling limiting their used under batch conditions. The problems associated with the fragility of many bead resins and with the proper packing of the reactor can be overcome by using monolithic systems [28]. Thus, the monolithic polymer 5, containing a chiral amino alcohol moiety derived from the waste industrial material from the synthesis of Ramipril at Aventis [29], was easily prepared inside a stainless steel column [30]. This allowed for the direct use of this column as a minireactor under flow conditions through the connection to a HPLC pump. Excellent enantioselectivities were obtained (99%ee) and high yields (85%) could be achieved when the system was maintained in a recirculation loop mode for 24 h (Figure 5.9). The system could be recycled for consecutive cycles without any

134

CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

OH +

ArCHO

ZnR2

Ar

Ph PS

CH2 N

PS

N CH2 OH

Ar= C6H5, R= Et 98% Yield 98% ee (R) 10 mL/h, 20 ºC

OH 3

4

FIGURE 5.8. Enantioselective addition of diethyl zinc to benzaldehydes catalyzed by supported efredine and aminoborneol derivatives.

decrease in performance. It is worth mentioning that the enantioselectivity observed for this system under flow conditions was significantly higher than the enantioselectivity obtained in batch experiments using either a gel-type resin containing the same functional group or a related homogeneous catalyst (89 or 87%ee vs 99%ee). This remarkable result illustrates that polymer-supported systems can be more

H

H

N

PS 5

HO

H Ph Ph

Ar= C6H5, R= Et 85% Yield 99% ee (R) 1 mL/h, r.t.

A rCHO + ZnR2

OH Ar

FIGURE 5.9. Continuous flow addition of diethyl zinc to benzaldehyde using a supported aminoalcohol related to Ramipril. Some commercial devices can be found, see, for instance: www.syrris.com, http://thalesnano.com, www.vapourtec.co.uk, www.uniqsis.com, www.micronit.com, www.chemtrix.com.

ASYMMETRIC POLYMER-SUPPORTED, METAL-BASED CATALYSTS AND REAGENTS

135

efficient than the homogeneous analogues, even in terms of enantioselectivity, when the proper set of parameters (functionalization, morphology, etc.) are optimized; additionally, flow conditions can often favor the obtention of higher enantioselectivities for this kind of process. It is generally considered that, under flow conditions, the actual catalyst/substrate ratios inside the flow reactor are significantly higher than those under batch conditions favoring an increase in both activity and enantioselectivity, particularly when the reaction can also occur to some extent in the absence of the catalyst. The polymer-supported amino alcohol 6 has been exploited by Pericas for different enantioselective addition processes involving alkyl and aryl zinc reagents. In this case, gel-type bead resins were used to immobilize chiral moiety. To set up the system for the work under flow conditions, the swollen resin was packed in a lowpressure chromatographic column and a type III configuration was used [31]. One remarkable result of this work was the obtention of high yields with short residence times (2.8 min). The same system has been used to prepare diaryl methanols using PhZnEt instead of ZnEt2 [32]. A different approach for the enantioselective addition of ZnEt2 to aldehydes was carried out using polymer 7. Although chiral aminoalcohols represent the most important family of chiral ligands for this transformation, Ti-TADDOLates like 7 have also been studied in detail for this process, both under homogeneous conditions or supported on polystyrene resins [33]. When polymer 7 was prepared as a monolith OH Ar

R

OH Ph Ph N

6

H Ph

Ar= C6H5, R= Et 99% Yield 93% ee (R) 0.24 mL/min

N PS

Ar CHO

ZnR2

FIGURE 5.10. Addition of alkyl and aryl zinc derivatives to benzaldehyde using swollen gel-type resins for the packing.

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CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

A r Ar O

PS

O

O

O 7

Cl

Ti

O

Ar

Ar= C6H5 , R= Et 85% Yield 99% ee (R) 1 mL/h, r.t.

A rCHO

+

ZnR2

Cl

Ar

OH Ar

FIGURE 5.11. Monolithic Ti-TADDOLates for Et2Zn addition.

inside a stainless steel column, the setup to work under flow conditions was again very simple. The activity of the supported catalyst required, like in the case of 5, recirculation of the solution through the column for 2.5 h, resulting in excellent yields and enantioselectivities (99%ee) (Figure 5.11) [34]. 5.2.1.2 Enantioselective Cyanation of Benzaldehyde. Titanium-salen complexes are known to catalyze the enantioselective addition of cyanide to benzaldehyde. Nevertheless, the active species is a dimeric catalytic species [35, 36]. This can represent a drawback for immobilization under conditions for which pseudodilution effects can apply. To overcome this issue, Moberg prepared a chiral salen ligand attached to macroporous divinylbenzene beads modified with a hydrophilic coating to prepare the corresponding Ti catalyst (8). This illustrates how the appropriate support design can combine design elements that favor the mechanical stability (macroporous polymer) as well as other parameters appropriate for flow conditions and design elements to generate the suitable catalytic species. In this case, the flexible space arms were introduced to allow for the formation of the required Ti-salen dimeric catalytic species. The results obtained under flow conditions showed an excellent conversion with moderate-togood enantioenantioselectivities under flow conditions (Figure 5.12) [37]. 5.2.2 Diels–Alder and Related Cycloaddition Reactions Luis et al. and Seebach et al. have shown the importance of morphology and properties of the polymeric backbone in regard to the activity, selectivity, and enantioselectivity when using polymer-bound chiral catalysts [38, 39]. This is particularly well illustrated in the case of polymer-supported Ti-TADDOLates like 7 that also have been shown to act as enantioselective catalysts for the

ASYMMETRIC POLYMER-SUPPORTED, METAL-BASED CATALYSTS AND REAGENTS

137

CHO +

N

N

OH HO

N

TMSCN

OR

N Ti

O

O

O

O 9 2% Yield 7 2% ee (S) 0.8 μL/h, 20-25ºC O

O

O

N

N Ti

O

O

O O

O

PS

Ti 8

O

N

O O N O TMS CN

FIGURE 5.12. Enantioselective cyanation of benzaldehyde with Ti-salen complexes.

Diels–Alder reaction between cyclopentadiene and 3-crotonoyl 1,3-oxazolidin-2one (Figure 5.13) [13]. A comprehensive study was carried out using a variety of supports for this reaction. Some observations from those experiments allow for illustrating the advantages that can be associated with monolithic systems. Besides facilitating the work under flow conditions, these systems can modify the selectivity of the processes and provide catalytic material with an outstanding long-term stability. In this regard, one remarkable result was a clear reversal in the topicity of the major isomer when the substituents at the a position of the TADDOL were 3,5-dimethyl phenyl groups. Thus, when the process was carried out under batch conditions using gel-type–supported or homogeneous catalysts, the major isomer had a (2R,3S) configuration, whereas it had a (2S,3R) configuration if the reaction was carried out with the monolith-supported catalysts using a stop-flow approach. It should to be mentioned that different groups have reported an increase in enantioselectivity when the chiral fragment are incorporated with the polymeric matrix through polymerization instead of grafting [25a, 40]. Although, in most cases, the enantioselectivities achieved were only moderate, they were comparable or higher than the ones obtained with the corresponding homogeneous catalysts [34]. A second remarkable observation was the long-term stability of the catalytic monoliths. The appropriate columnar catalytic minireactors could be kept active (without any appreciable loss of properties) for more than 1 year. Nevertheless, once the catalytic sites are deactivated by a reaction with water/moisture, the resulting polymers could not be efficiently regenerated for their use in the Diels–Alder reaction. Rather

138

CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

O

N

+ O

O

A Ar Ar O

PS

O

O

O 7

Ar= 3,5-dimethylphenyl25% Yield, 2.8 endo/exo 19% ee (2S, 3R) 0.04 mL/min

Cl

Ti

O

Ar

Cl

Ar

N O

O O

FIGURE 5.13. Diels–Alder reactions catalyzed by supported Ti-TADDOLates.

interestingly, those regenerated polymers could be applied efficiently as enantioselective catalysts for the ZnEt2 addition to benzaldehyde. In fact, they presented the same activity and enantioselectivity as newly prepared supported catalysts and could be used for several successive runs [34]. In general, Diels–Alder reactions are catalyzed by a large variety of Lewis acids. Boron derivatives represent a common alternative to Ti complexes. In this field, Itsuno et al. has prepared and studied a variety of boron derivatives. The best results were obtained for polymers containing supported N-sulfonyl amino acids, obtained from the polymerization the corresponding functional monomers, from which the corresponding borane complexes were prepared (9) [41]. For flow application, the authors used a simple gravity flow setup to catalyze the Diels–Alder reaction between methacrolein and cyclopentadiene in dichloromethane (DCM). This work involves another example of the need to design the polymeric matrix to accomplish two different conditions simultaneously. A relatively high cross-linking degree (10%) was used to favor mechanical stability and flow applications, but a rather flexible cross-linker containing an oligoethylene glycol fragment was also introduced to facilitate the accessibility of the catalytic sites. Excellent yields and endo/exo selectivities were observed along with moderate-to-good enantioselectivities (Figure 5.14).

ASYMMETRIC POLYMER-SUPPORTED, METAL-BASED CATALYSTS AND REAGENTS

139

CHO +

O PS

SO2 N

95% Yield 71% ee (R) 10 mL/h, -30 ºC

O B

9

H

CHO *

CHO

+

*

FIGURE 5.14. Enantioselective Diels–Alder reactions catalyzed by boron derivatives of supported N-tosyl aminoacids.

Up to 20 g of product could be obtained by scaling out the process (running the reaction for long periods of time), highlighting the potential of flow application for this purpose. Salvadori et al. studied the carbonyl ene reaction catalyzed by polymer-supported chiral Cu complexes [42]. The corresponding complexes (10) were prepared by reacting Cu(OTf)2 with an immobilized bis(oxazoline) derivative that has a relatively long aliphatic spacer to facilitate the separation between the catalytic site and the polymeric surface. Also, in this case, the polymeric matrix was selected containing a high cross-linking degree. The corresponding reaction between ethyl glyoxalate and a-methyl styrene (Figure 5.15) was accomplished under flow conditions in good yields and enantioselectivities, and up to five successive runs could be completed maintaining the global efficiency of the catalysts. 5.2.3 Enantioslective Cyclopropanation Reactions Copper-catalyzed cyclopropanation reactions of alkenes is an important C-C forming reaction in which two C-C bonds are formed with the potential simultaneous generation of up to two stereogenic centers. Cu-box and related complexes are probably the most studied catalytic systems for this reaction. Thus, it is not surprising

140

CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

O Ph

PS

+ H

O

10 O O

78% Yield 88% ee 0.0 15 mL/h, 0ºC

O N

Ph TfO

Cu

N OTf Ph

OH O

Ph O

FIGURE 5.15. Glyoxal-ene reactions catalyzed by supported Cu-Box complexes.

that the immobilization of bisoxazoline ligand (box) and related species such as pybox or azabox ligands has been studied in detail by different groups [43]. To study the corresponding reaction under flow conditions, Luis et al. prepared different monolithic polymers functionalized with bisoxazoline subunits by polymerization of the corresponding functional monomers (11). A variety of different conditions were studied, including the presence or absence of additional comonomers such as styrene, divinylbenzene, or others. The cyclopropanation of styrene using ethyl diazo acetate was selected as the benchmark process (Figure 5.16). The results gathered in this study revealed that all those parameters are of great importance for the final outcome and that important differences can be found when those results are compared with those of related batch processes [44]. Thus, the flow rate was a critical parameter to be controled in terms of conversion and selectivity. Quantitative conversions were achieved using DCM as the solvent for low flow rates (2 mL/min), leading to high residence times (350 min). The chemoselectivity defined as the cyclopropanes [cyclopropanes þ fumarate þ maleate]  100 ratio) was clearly reduced when changing from batch (90%) to flow (76%) conditions. Surprisingly, no change in this parameter was observed for variations in the flow rates.

ASYMMETRIC POLYMER-SUPPORTED, METAL-BASED CATALYSTS AND REAGENTS

+

Ph

PS O N R TfO

Cu

11, R= -Ph 61% Yield 71% eetrans, 55% eecis 0.2 µL/min

N OTf R

12, R= -CH(CH3)2 53% Yield 79% eetrans, 48% eecis 20 µL/min

PS X 12 O

O

N N

R

N2CH2CO2Et

PS

O

11

141

Ru X

X

N R Ph

CO2Et

FIGURE 5.16. Supported bisoxazolines and related systems.

The flow rates had, however, a distinct impact on the enantioselectivity of the reaction, and a simple optimization of the process could be achieved in this regard. In general, better enantioselectivities could be observed for the lower flow rates. A 20% increase in enantioselectivity can be obtained by reducing the flow by two orders of magnitude (from 200 to 2 mL/min) for the trans isomer. Rather unexpectedly, the cis isomer did not show such dependence and the enantioselectivity remains essentially constant for the different flow rates studied at ca. 55%. The data reveal that, in this case, the supported systems can be more efficient, particularly in terms of enantioselectivity, than the related homogeneous catalytic systems. In this case, a proper control of the flow parameter is required, but after a simple optimization, at least a 10% increase in enantioselectivity can be achieved, either for the trans (62 vs 51%ee) or for the cis (56 vs 40%ee) isomers. The cyclopropanation reactions of styrene with ethyl diazoacetate are usually carried out using an excess of styrene to favor the desired reaction over the competing alternative routes for consuming the diazoacetate. This, and the use of supported systems—particularly working under flow conditions—opens up exploration of the reaction under solventless conditions, providing processes that are much more environmentally friendly as they allow for the suppression of the use of a solvent of environmental concern such as DCM. For this purpose, different styrene: ethyl diazoacetate (EDA) ratios were assayed in the flow processes, with the best results attained for a styrene:EDA ratio of 4 at a flow rate of 20 mL/min. When using those

142

CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

conditions, a large increase in productivity was obtained (33 g of cyclopropanes vs 11 g of cyclopropanes [g Cu]1 h1) without significantly reducing the enantioselectivity of the reaction. The use of polymer-supported pybox systems (12) afforded similar results, although for those ligands, Ru is the catalytic metal [45]. As in the former case, productivity increased almost an order of magnitude when working in flow under solventless conditions (TOF values 0.3–0.7 vs 3.3–4.3 moles [mol pybox]1 h1). Eliminating of the use of DCM produced, in this case, is an important increase of the chemoselectivity. Another improvement of those flow processes could be obtained using supercritical fluids [46]. Both catalysts derived from box (11) and pybox (12) were studied in flow processes using scCO2 (40 C, 8 MPa [44, 45]. Again, a significant improvement in the productivity was achieved when going from conventional to supercritical conditions with the same reactor (up to a 20-fold increase in the productivity) without compromising the selectivity and the enantioselectivity of the process. However, the use of scFs allows for the introduction of additional parameters (temperature and pressure in addition to flow) to control and optimize the reaction. Also, in the case of box and pybox systems, the results obtained have demonstrated that, when using the appropriate polymeric matrix, functional moieties, and reaction conditions, the conversion, chemoselectivity, selectivity, and enantioselectivity obtained with supported systems can be comparable with or even slightly superior to those found for homogeneous systems or under batch conditions with the same catalysts. 5.2.4 Reduction Reactions A large variety of processes involving the hydrogenation of organic substrates using silica- or alumina-supported catalysts have been reported under flow conditions [47], as well as the continuous asymmetric transfer hydrogenation of ketones using chiral Ru-amino alcohol complexes immobilized on silica [48]. In this review, however, we will solely concentrate on the systems supported in organic polymeric matrices. In this regard, just a few examples of asymmetric continuous reduction reactions using polymer-supported catalytic systems have been reported. In this regard, the seminal work by Itsuno et al. must also be mentioned. In those experiments, the polymer-supported borane-amino alcohol complexes were used to reduce prochiral ketones (Figure 5.17) [49]. Resin 1 is a characteristic example of the structures used. For the flow process, a fluid-bed reactor was used (type III assembly) in such a way so that diborane and ketone were fed to the bottom of the column, and the solution containing the products was collected by overflow. Excellent enantioselectivities of up to 93% were achieved for residence times of 30–60 min. An example of a continuous-flow system for asymmetric hydrogenation has been recently described by Ding et al. [50]. For this purpose, they use the concept of selfsupported chiral catalysts in which an organometallic polymer is obtained through self-assembly of chiral multitopic ligands and reactive metal anions [51]. In the case considered, hydrogenation was carried out by the intermediacy of Ru complexes (13), whereas the chiral ligands contain phosphoramide subunits derived from

ASYMMETRIC POLYMER-SUPPORTED, METAL-BASED CATALYSTS AND REAGENTS

143

BH3.THF H

OH

O Ph Ph

PS

Ph Ph

CH2O 1

H2N

OH

0.47mL/min BH3/THF 0.09mL/min Ketone/THF 93% ee, rt

FIGURE 5.17. Enantioselective reduction of ketones using B2H6 and supported amino alcohols.

1,10 -bi-naphtol (BINOL). A mixture of the “self-supported catalyst” with an inert packing material (MgSO4, activated carbon, TiO2, etc.) was used to improve the flow properties of the column and the productivity of the system. The different catalysts were tested for the asymmetric hydrogenation of a-dehydroamino acid methyl esters (Figure 5.18). The best catalyst was run continuously for 144 h, achieving a conversion >99% with selectivities of 97%ee (Figure 5.18). Some leaching of Ru was observed, which could limit the long-term use of those catalysts. 5.2.5 Oxidation Reactions Epoxidation is, most likely, the most widely studied asymmetric oxidation reaction. Salen catalysts containing a variety of metal centers have been studied for this purpose. Different strategies have been used to approach the immobilization of salen ligands and complexes onto solid supports and, particularly, onto polystyrene– divinylbenzene resins. The most general approach is the introduction on the aromatic ring, particularly in position 4 relative to the hydroxyl group of a functionality allowing for anchoring to the support. In fact, one main problem to be overcome is often the preparation of an unsymmetrical salen that will react with a single site in the polymeric matrix, avoiding the problems that can be associated with difunctional ligands (uncomplete reaction or increase in cross-linking). One such example is shown in Figure 5.19. In this case, one aromatic ring has a hydroxymethyl functionality instead of a second t-butyl group in the 4 position. Although many examples of supported salen catalysts have been reported—providing excellent results under batch conditions—the number of examples dealing with the use of such catalysts under flow conditions is rather scarce. The example shown in Figure 5.19 is also useful for illustrating the application of membrane reactors in flow processes. In

144

13

N P OO

n

[Rh] m

Tolue ne

self-supported catalyst

NHAc

O CH3

R

O

NHAc

H2

OCH3

R= CH3, 99% conv. 96-97% ee sustrate: 0.05 mL/min H2: 3 mL/min

FIGURE 5.18. Enantioselective hydrogenation using “self-supported catalysts.”

OO P N [Rh]

N O P O

R

O

ASYMMETRIC POLYMER-SUPPORTED, METAL-BASED CATALYSTS AND REAGENTS

145

O

NC NMO, m-CPBA

dendrimeric catalyst 70% yield, 92% ee, 7 mL h-1, 0 ºC H

H N

membrane

N Mn

O PG

O Cl

14

O

NC O

FIGURE 5.19. Application of a dendrimer-supported Mn salen catalyst for the asymmetric epoxidation of chromene under flow conditions.

catalyst 14, the support is a soluble, star-shaped hyperbranched polymer derived from glycerol, whereas an MPF-50 membrane is used for the retention of the catalyst in the first compartment [52]. The system has been applied to the enantioselective epoxidation of a chromene using m-CPBA/NMO as the oxidizing reagent. A flow of 7 mL/h1 was established to achieve a constant conversion of 70% after 12 residence times, with enantioselectivities of up to 92%ee. The space–time yield for this assembly was 458 g L1 d1. Unfortunately, batch experiments revealed that some metal leaching occurs, leading to decreased maximum conversions and enantioselectivities for successive batches. The enantioselective dynamic kinetic resolution of racemic epoxides is partly related to the former reaction. This process has been described by Kirschning et al. using the so-called PASSflow system. In the general approach followed by Kirschning et al. polymerization of the appropriate monomeric mixture is carried out in the interior of a column containing porous glass. The polymerization on the surface of the porous glass directly produces a columnar reactor for flow applications. Although numerous useful applications have been reported for those systems, only a few of them involve enantioselective transformations [20]. The enantioselective dynamic kinetic resolution of racemic epoxides shown in Figure 5.20 represents one such example. The catalytic site (15) also involves, in this case, the use of an unsymmetrical salen ligand. In the presence of water, the corresponding cobalt complex can

146

O

O

15

O O

N Co O

N

H

OH

OH

76–87% yield, 91–93% ee, 20h each cycle

Br

H 2O O

Br

FIGURE 5.20. Continuous dynamic kinetic resolution of epibromohydrin using a Co-salen complex supported on a PASSflow system.

PAS S

O

H

147

POLYMER-SUPPORTED ASYMMETRIC ORGANOCATALYSTS

catalyze the conversion of epibromohydrin into the corresponding (R)-diol with yields of 76–87% after 20 h of reaction (1 mmol scale) and with enantioselectivities of 91–93% [53]. Because of the slow kinetics of the process being studied, the process needs to be carried out in a recirculation model to afford good conversions.

5.3 POLYMER-SUPPORTED ASYMMETRIC ORGANOCATALYSTS Organocatalysis is probably one area of research that experiences a faster growing these days [54]. In this regard, it is obvious that many attempts to attach the corresponding homogenous organocatalysts to solid supports (to obtain the benefits of heterogeneous catalysis) have been reported [55]. Nevertheless, most known examples deal with the work under batch conditions, and only a few examples can be found in the literature for which a continuous flow approach has been studied. One of the first examples to be reported in this field, if not the first, is the work by Hodge et al. on the use of supported chincona alkaloids as organocatalysts for the Michael addition [56]. The chiral fragment was anchored onto a PS-DVB polymer via a sulfide linkage. The structure of the final organocatalyst (16) and the reaction under study are shown in Figure 5.21. To attain high conversions and yields (up to 96%), long residence times were necessary with low flow rates (5 mL h1, 6 h). Nevertheless, the enantioselectivities obtained were only moderate (ca. 50%ee) There is no doubt that proline plays a central role in the area of organocatalysis, and indeed, many efforts have been reported for the efficient immobilization of such a simple subunit into a large variety of supports [55]. In this regard, Pericas and coworkers have reported on the use of a PS-DVB-supported proline, anchored via O O

* +

O

O

O

H3 C

O

O

O

PS

97% Yield 51% ee 5.0 ml h-1, 50ºC

S

H

N OH

N

H

16

FIGURE 5.21. Continuous flow Michael addition using a polymer-supported cinchona derivative as organocatalyst.

148

CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

NHPMP

O

+ CO2Et

N N PS

N O

17

N H

dr> 97:3, >99% ee 0.02mL/min

CO2H

O

NHPMP CO2Et

FIGURE 5.22. Polymer-supported proline for the continuous Mannich reaction.

“click” chemistry (17), as an organocatalyst for the continuous flow Mannich addition between aldehydes and ethyl glyoxalate imine (Figure 5.22) [57]. Using residence times of 6.0 min with flow rates of 0.2 mL min1, conversions of up to 95% were observed with productivities of 1.42 mmol h1 g1. Letcka and coworkers have studied different approaches to the enantioselective preparation of organic compounds using different organocatalysts. One of the first examples reported involves the a-chlorination of acid chlorides. As in the case of Hodge et al. the immobilization of cinchona alkaloid-derived fragments is a critical step. Here, a different approach is used to attach to polystyrene matrixes with the use of a terphtalic acid spacer (18, Figure 5.23) [58]. This supported organocatalyst seems to play a double role. Adding the acid chloride acts as a dehydrochlorinating agent to afford an intermediate ketene then reacts with 2,2,3,4,5,6-hexachloro-3,5cyclohexa-dien-1-one to produce the expected a-chlorinated ester. For the last step, the organocatalyst can efficiently control the enantioselectivity. Thus, a yield of 50–61% and enantioselectivities of 88–94% can be obtained. The use of this methodology could be applied to the synthesis of the metalloprotease inhibitor BMS-275291 [59]. This system presents some clear advantages over the classical homogeneous and/or batch work-up. First, it is not necessary to isolate or manipulate reactive ketenes. Numerous reuses are possible (more than 100), and the

149

O O

O

N

Cl

Cl

R

+

O O

Cl

Cl

Cl

Cl

Cl

A rCl5

R= Ph, CH2OPh, 1 -Np, 4-Cl Ph, 4Tol

40-61% Yield 88-94% ee 0.1 mL/min, 0 oC

Cl

O

O

N

O N CH3

CH3

CH3

FIGURE 5.23. a-chlorination of acid chlorides under flow conditions using a resin-bound cinchona-derived organocatalyst.

PS

O

N

OMe

R

O

150

CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

flow conditions avoid any mechanical degradation of the polymeric beads. Finally, the reaction time is significantly reduced and the system can be easily automated. Another step in this area was provided by the same group in their multistep continuous synthesis of enantiopure b-lactams (Figure 5.24) [60]. For this purpose, several columns containing different polymer-supported reagents, scavengers, and catalysts were coupled. In the first step, an acid chloride was converted in the corresponding ketone by using a polymer-supported base (resin-bound 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), 19). The addition of this ketene to a N-tosyl ethyl imine glyoxate in the presence of the same cinchona-derived chiral organocatalyst used before (18) produced the corresponding b-lactam. The final step involves using a scavenger resin (20) to remove the excess or reagents to afford the essentially pure desired b-lactam with yields of ca. 60% and Cl

R

SP Base

O

PS

N N

P

But

NH

19

H

N

Ts N

EtO2C

N N

SP Catalyst

OMe

O PS O

NH2 18

PS

20 Ts

O N

SP Scavenger

EtO2C

R

FIGURE 5.24. Multistep continuous system for the enantioselective preparation of b-lactams.

POLYMER-SUPPORTED BIOCATALYSTS

151

enantioselectivities of 90%ee. The process maintains its efficiency after 60 runs, with the appropriate protocols of washing and regeneration after each run.

5.4 POLYMER-SUPPORTED BIOCATALYSTS The high efficiency of biocatalysts and particularly for enantioselective transformations has prompted numerous studies involving their immobilization onto a diverse variety of solid supports, including polymeric matrixes [61]. Although most examples involve batch processes, many different examples of continuous biocatalytic processes are known [62]. If we do not consider membrane reactors in detail, then packed-bed reactors represent the most common assembly used for polymersupported biocatalysts. One advantage for those reactors is that, as the substrates and product flow continuously through the bed, product inhibition can be avoided. The enzymatic kinetic resolution of racemic alcohols is the best studied reaction in this field. The preparative-scale kinetic resolution of different racemic secondary alcohols has been reported by Csajagi et al., with the use of CALB (Candida antarctica lipase B) immobilized on an acrylic resin affording optimal results [63]. A second important advantage of the flow processes involves the possibility of using fluids above their boiling point simply by including a retention valve at the exit of the reactor. This has allowed for the use of this kind of reactor with supercritical fluids, particularly, scCO2 [64]. Taking into consideration the excellent compatibility of scCO2 and many ionic liquids (ILs) and polymeric matrixes as well as the efficient stabilization reported for numerous enzymes in ILs [65], the immobilization of ionic liquid-like moieties onto PS-DVB surfaces by covalent attachment (supported ionic liquid-like phases, SILLPs) makes possible the simultaneous immobilization and stabilization of enzymes onto polymeric matrixes [66, 67]. Thus, the immobilization of CALB into monolithic SILLPs allowed for the preparation of efficient flow bioreactors for the esterification of alcohols using vinyl propionate as the acyl donor and scCO2 as the mobile phase [66]. The resulting supported enzymes showed not only an excellent productivity but also a thermal stability significantly higher than that displayed by other related systems including commercial supported CALB. A thorough study has been carried out to establish the influence of the support and different polymers, either monolithic or in the form of beads, containing different monomeric compositions and IL-like loadings [68]. The resulting polymeric materials were specifically designed for optimal performance in terms of the stabilization and activation of the biocatalyst and for an optimal fluidodynamic behavior under the flow conditions to be tested. The dynamic kinetic resolution of secondary alcohols has also been assayed with some of those materials. Excellent results were achieved using scCO2, with ca 50% yield and 99.9% ee values. The same results were maintained, under flow conditions for 6 days at 50 C and 10 MPa. To improve the yields, the columnar flow reactor was coupled with a second acidic reactor capable of facilitating the racemization of the unreacted enantiomer. The connection of this acidic catalytic reactor to a second bioreactor has allowed for increasing the yields up to 75% without compromising the enantioselectivity of the

152

CONTINUOUS FLOW SYSTEM USING POLYMER-SUPPORTED CHIRAL CATALYSTS

OH

O +

Cl PS

N

CA L-B Bu

O

92% Yield, scCO2 99.9 % e e 10.6 mo l/min, 50 ºC, 10MPa

N

Zeolite CP811E/ [BMIM][P F6]

O O

OH +

FIGURE 5.25. Multistep continuous enzymatic kinetic resolution of alcohols catalyzed by CALB supported on SILLPs and using scCO2 as the mobile phase. Zeolite CP811E (Figure 5.25) covered with [BMIM][PF6] was used as the acid catalyst.

process. As the acidic catalytic reactor, different alternatives were studied, but better results were observed with the use of a column filled with zeolite CP811E. 5.5 CONCLUSIONS It is commonly accepted than the immobilization of a catalytic moiety onto a polymeric matrix provides some specific advantages, particularly for the recovery and reuse of the catalytic system. The importance of those factors is greatly increased when the catalytic sites involve the construction of a chiral environment to carry out enantioselective transformations. Hence, the cost and effort required to prepare the chiral ligand, in the case of organometallic catalysts, the corresponding chiral organocatalysts, or biocatalysts, clearly justify the immobilization. Many reports in this field, however, have reported that enantioselective reactions carried out using supported catalysts tend to be less efficient and, particularly, less enantioselective than their homogeneous counterparts. Fortunately, this is not always true, and today, many examples are known in which the supported system can be even more active, selective,

REFERENCES

153

and enantioselective than the homogeneous analogue. A careful study is still required for each case to understand the critical factors determining such behaviors, but it seems clear now that a precise simultaneous design of the polymeric matrix, linker, and spacer as well as the catalytic site is required to develop more efficient and attractive systems with the capacity to achieve practical applications. Another improvement in this area comes from the use of those catalytic systems under flow conditions. Many different approaches can be used for this purpose, but the preparation of columnar reactors is becoming the most common alternative. In this regard, columnar reactors of different sizes and characteristics can be assembled either by filling an empty column with the appropriate functional resin or by polymerization inside the column of the corresponding monomeric mixture to obtain the desired functional monolith. The main advantages associated with the use of continuous flow conditions involve a higher mechanical and long-term stability of the supported catalysts, the achievement of much higher space–time yields and productivities, and the potential to work under a broad range of conditions, including the use of neoteric solvents, a field that is expected to grow significantly for the next few years. This potential is of great industrial interest as it allows for a much simpler optimization of the entire process through an appropriate adjustment of process variables such as flow, concentration, temperature, pressure, and so on. Within this context, it is worth mentioning that, in some instances, the work under flow conditions has been revealed to produce processes that are more enantioselective than the ones being carried out with the same systems under batch conditions. Thus, the development of enantioselective catalytic processes under flow conditions represents a key target for the fine chemicals industry worldwide, and the capacity to adapt a given catalytic system to those conditions will be an essential test in the future to assess its potential for practical applications.

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echet, J. M. J.; Irgum, K. Chem. Mater. 1996, 8, 744. (b) Okay, O. Prog. Polymer Sci. 2000, 25, 711. (c) Santora, B. P.; Gagne, M. R.; Moloy, K. G.; Radu, N. S. Macromolecules 2001, 34, 658. (d) Marti, N.; Quattrini, F.; Butte, A.; Morbidelli, M. Macromol. Mater. Eng. 2005, 290, 221. (a) Kirschning, A.; Jas, G. Top. Curr. Chem. 2004, 242, 209. (b) Hodge, P. Ind. Eng. Chem. Res. 2005, 44, 8542. Lapkin, A. A.; Pawel, K. P. In Chemical Reactions and Processes under Flow Conditions, RSC, London, U.K., pp. 44–86 (2009). Muller, C.; Nijkamp, M. G.; Vogt, D. Eur. J. Inorg. Chem. 2005, 4011. (a) Altava, B.; Burguete, M. I.; Garcıa-Verdugo, E.; Luis, S. V.; Vicent, M. J.; Mayoral, J. A. React. Funct. Polym. 2001, 48, 25. (b) Burguete, M. I.; Fraile, J. M.; Garcia-Verdugo, E.; Luis, S. V.; Martinez-Merino, V.; Mayoral, J. A. Ind. Eng. Chem. Res. 2005, 44, 8580.

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CHAPTER 6

CHIRAL SYNTHESIS ON POLYMER SUPPORT: A COMBINATORIAL APPROACH DEEPAK B. SALUNKE and CHUNG-MING SUN

6.1 INTRODUCTION Since the beginning of the 19th century, organic chemist has been practicing chemical reactions in homogeneous media. It took around 100 years to create the first completely synthetic polymer and an additional 50 years to put forth the revolutionary concept of performing organic reactions on a polymer support. The organic synthesis on polymer support was initially developed to prepare peptide and oligonucleotide libraries [1]. Later, with more advances, chemists designed and synthesized small molecules on a polymer support [2]. During this revolution, as required by the pharmaceutical industry, organic chemists learned the significance of solid-supported parallel and combinatorial synthesis required for the lead generation to accelerate the drug discovery process. By employing various new methodologies for high-throughput synthesis, combinatorial chemistry has developed a new paradigm for the chemical synthesis of small molecules [3]. It has changed the way in which drug discovery was conducted in a pharmaceutical industry [4]. Many pharmaceutically active compounds contained a chiral core inside the structure. Recent findings also revealed that both the complexity as well as the presence of chiral centers in the molecule correlate with success as compounds transition from discovery, through clinical testing, to drugs [5], which demands the design of enantioselective combinatorial libraries. This new approach of synthesizing chiral combinatorial libraries on polymer support will lead to a breakthrough in modern drug discovery. Enantioselective synthesis of polymer support can be designed in various ways (Figure 6.1). Figure 6.1(a) describes a polymer-supported enantioselective catalysis

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.

157

158

CHIRAL SYNTHESIS ON POLYMER SUPPORT

A

P

B

CC

S

P

CP

S

CP

C

D P

CS

P Polymer Support CP Chiral Product

CP

CA

CC P

CC Chiral Catalyst CA Chiral Auxiliary

S

CP

S

Substrate

CS Chiral Substrate

FIGURE 6.1. Chiral synthesis on polymer supports.

in which the polymer-supported chiral catalyst can be used in a routine solution phase synthesis. Several highly reactive polymer-supported chiral catalysts and reagents have recently been developed for a variety of reactions, and excellent enantioselectivities in many asymmetric reactions have been obtained by using these catalysts [6]. The other way to perform enantioselective synthesis is to use polymer-supported chiral auxiliaries [Figure 6.1(b)]. A chiral auxiliary is temporarily incorporated into an organic synthesis so that it can be carried out asymmetrically with the selective formation of one of the enantiomers. It actually serves as an anchoring group and allows for diastereoselective transformations on the immobilized building blocks. This classic approach was well executed using polymer-supported auxiliaries [7]. Kindly refer to Chapters 2 and 3 in this book for more details about approaches A and B. Approach C is the straightforward technique of performing asymmetric synthesis on a polymer support and closely resembles the chiral pool synthesis. In this approach, a chiral starting material is manipulated through successive reactions using achiral reagents while retaining its chirality to obtain the desired target molecule. Whereas, approach D is the polymer-supported version of the widely recognized asymmetric catalysis. During the last 10 years, several research groups have demonstrated the use of asymmetric catalysts for the total synthesis, suggesting that the asymmetric synthesis on a solid-phase support is possible and that results comparable with solution-phase methods can be obtained [8]. The use of polymer supports in organic synthesis is becoming well established as demonstrated by the massive increase in the number of publications referring to Organic Synthesis on Polymeric Supports. A key advantage of solid-phase synthesis is the faster and simplified purification procedures for the generation of numerous compounds in a short time. Most solid-supported synthesis reported today was carried out using polystyrene (PS) cross-linked with 1–2 % divinyl benzene (DVB) as the resin matrix. Such resins are stable and exhibit high compatibility and good swelling characteristics with a wide range of nonpolar solvents. However, they fail when polar solvents are required and distancing of the

INTRODUCTION

159

reaction sites from the hydrophobic PS-DVB resin core becomes necessary. For such reactions, various modified resins are designed that swell in a wide variety of polar and nonpolar solvents [9]. Another key consideration in the design of a solidphase chemical route is the proper choice of suitable linkers. Linkers provide attachment sites for different functional groups onto the resin, and their proper choice is crucial for a solid-phase synthesis to be successful. Access to various linkers is key to allowing for flexibility in the design of polymer-supported chemical reactions [10]. With several such advantages, solid-phase organic synthesis (SPOS) became a core technology of combinatorial chemistry and received much attention for its application in generating diverse screening libraries [11]. It offers benefits in easy, fast purification in the separation of excess reagents and side products from the desired compounds attached to the insoluble carrier. However, few disadvantages were noted as well by using solidphase chemistry, such as heterogeneous reaction conditions, reduced rate of reactions, solvation of the bound species, and mass transport of reagents. The range of chemistry that can be applied to the solid-phase synthesis is also limited. Furthermore, it is difficult to monitor reaction progress in a solid-phase reaction. To overcome some of these limitations, another technique has emerged, namely liquid-phase combinatorial synthesis (LPCS). LPCS, in which soluble polymer supports are used to immobilize the substrates during the reactions, has been well documented in recent years [12]. Unlike an insoluble matrix, the soluble polymer support remains homogenous during the reaction in many organic solvents and tends to precipitate in diethyl ether or ethanol. When the reactions are complete, the products remain covalently bound to the support. After precipitation with diethyl ether or ethanol, products are purified simply by filtering and washing away the unwanted material. The large excess of reagents typically used in solid-support synthesis are normally not required in liquid-phase synthesis. This method combines the strategic features of classic solution-phase chemistry and solidphase synthesis. Furthermore, this method allows for routine analytical methods [(e.g., 1 H-nuclear magnetic resonance (NMR), 13C-NMR, infrared (IR), and thinlayer chromatography (TLC)] to monitor the progress of the reaction transformations and to determine the structures of compounds directly attached to the polymer support. Because liquid-phase reactions can be carried out in homogeneous solution, the wealth of known chemical transformations available to solution-phase chemistry may be applied directly, and the reaction optimization time also should be reduced. It is beyond the scope of this chapter to discuss the type of resin selection for the combinatorial synthetic design. This chapter describes the developments made over 10 years in regard to the combinatorial synthesis of chiral, complex, and polyfunctional natural product-like molecules on a polymer support using principles of both solid-phase as well as solution-phase combinatorial techniques. The use of asymmetric catalysts for the enantioselective library generation on a polymer support is also included in this chapter. The pictorial representations for the various organic supports mentioned in this chapter are included in Figure 6.2.

160

CHIRAL SYNTHESIS ON POLYMER SUPPORT

Sasrin resin (PS-SAS)

Merrifield resin (PS-Merrifield)

x x

y

y

Wang resin (PS-Wang) x

z

y

z

z

cross-linker

M

O

x

Cl

O

x

Cl

x

Hydroxymethylated Merrifield resin (PS-HM Merrifield)

O S

x

y

OH

OH

W

OH

OH

z Poly(ethylene glycol) (PEG) HO

M

OH x

OH

HO

PEG

O

O

O n

OH

OH

FIGURE 6.2. Various organic supports mentioned in this chapter.

6.2 CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT Approximately half of the drugs currently in clinical use are of natural product origin and have a complex polyfunctional framework with chiral core structures [13]. Recent findings revealed that both the complexity as well as the presence of chiral centers in the molecule correlate with success as compounds transition from discovery, through clinical testing, to drugs [5]. In recent years, various protocols for the construction of such complex polyfunctional molecules via polymer-supported strategies have been developed. This section will describe a few combinatorial approaches for the synthesis of these chiral molecules. 6.2.1 Spirocyclic Compound Libraries The spiroketal is the underlying structural motif of numerous natural products that provide a rigid scaffold that can display a variety of ligands in fixed-geometry formats [14]. Many structurally simplified spiroacetals derived from natural products retain biological activity; as a result, this scaffold has become an extremely attractive target for combinatorial chemistry [15]. The first synthesis of a small set of symmetrically substituted spiroketal libraries using a polymer-supported ketal protection group was reported by Ley et al.’s research group [16]. In their work, acid-catalyzed cleavage and spirocyclization of poly(ethylene glycol) (PEG) supported ketal 2 was carried out using acidic ion-exchange resins in acetone (Scheme 6.1). This was one of the rare examples of the designed interaction of two polymer-supported species. During the development of novel, drug-like molecules, Bartlett and Trump [17] designed a solid-supported protocol for the synthesis of a spirocyclic ketal-lactone

161

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT SO3H PEG O O

OH

X

X

O

R

1

O

Amberlite IRA-118H

OH

O

O R

Acetone

R

R

+

O

2

O

3

O 4

SCHEME 6.1. Acid-catalyzed cleavage and spirocyclization of PEG-supported ketal 2.

framework 10 amenable to diversified combinatorial chemistry. As shown in Scheme 6.2, the appropriate building blocks are sequentially immobilized on the polymeric support. Commercially available polystyrene resin with 4-hydroxymethylbenzoic acid (HMBA) linker 5 was used as a polymeric support to build an electron-deficient, benzyl ester anchored substrates 9 to implement the cyclative release of the desired products. The readily available amino acids and amino alcohols were used in this strategy to synthesize previously unreported chiral spirocyclic lactones. Later, Sommer and Waldmann [18] demonstrated the use of a double internal hetero Michael addition reaction to synthesize unsymmetrically substituted spiro [5.5]ketals 16 and 17 on polystyrene resins and translated their strategy to the construction of compound libraries (Scheme 6.3). The key step in their synthesis was the acetal formation (14 ! 15) via the conjugate addition of two alcohol functionalities generated in situ to the alkynone functionality in a traceless fashion. To facilitate this conjugate addition in one pot, they have selected an acid-labile linker to attach to the solid support and an acid-sensitive protecting group for the Linker R1 M

M

OH

H N

BrCH2COOH

1) TFA/CH2Cl2 2) IBCF, NMM

R2 R1

O

N Ts

O

H N

O

Br O

R3 M

HO

O O

R4

R1 O

NaI, DIEA

R2 N

Linker

O

N O Ts HO

R1

Ts R3

TMG

N

R2 N R3

O O

R4

R4

O

9

10

Amino alcohols O

H2N

H N

O

H2N

O

O

H2N

O HO

O

H N * HO

*

O NHBoc

O

1) Amino acids 2) TsC l

N Ts 7

Amino acids

O

R1 O

Br

8

H2N

Linker

6

Linker

3) CH2N2 4) HBr

M

O O

HMBA Linker

M

O

H2N

O

DIC/DMAP

O

5

Linker

HN *

O

O O

H2N O

O

H2N O

HO (S) and (R)

(S)-Me / (S)-Ph (S)-Me / (R)-Ph (R)-Me / (S)-Ph (R)-Me / (R)-Ph

SCHEME 6.2. Amino acid and amino alcohols derived from spirocyclic ketal lactones.

162

CHIRAL SYNTHESIS ON POLYMER SUPPORT

THPO BzlO

OMe BzlO

OH

R

W

OBzl

O

12

OTHP

14

1) EtMgBr, THF 2) IBX, DMSO/THF

OMe

1) MeSO3H, CH2Cl2 2) MeOH & Toluene

OMe

OBzl

HO

17

OBzl

O 15 β-Hydroxyesters

OH R

OH *

O O

16

Homoallylic alcohols

OH

NMe3BH4 MeOH

O O

+ OBzl

HO

OMe

OMe

O O

OBzl

(R) and (S)

OH

(R = Ph), (R = Cy) (R = nBu), (R = i-Pr) (R = (CH2)2Ph), (R = (CH2)2OBzl)

Alkynes THPO

O

H

O

11 Homoallylic alcohol

O

W

13 Alkyne

HO

CO2Et

Me

Me

*

CO2Me

(R) and (S)

OMe * OR1

R1 = Me: (R) and (S) or R1 = Bzl: (R) and (S)

OTHP

*

THPO

(R) and (S)

THPO

R2O

Me R1 = Me or Bzl O

THPO

O

SCHEME 6.3. Double internal hetero Michael addition reaction for the synthesis of unsymmetrically substituted spiro[5.5]ketals.

acetylenic builing block 13. In a typical process, chiral homoallylic alcohol 11 was immobilized on Wang resin and transformed to an aldehyde 12. (The anchored chiral aldehydes also were synthesized from b-hydroxyesters.) The construction of intermediate alkynone 14 was achieved by adding chiral alkynes 13 on a polymerbound aldehyde 12. The release of alkynone 14 from the solid support was achieved by treatment with methanesulfonic acid in dichloromethane. Upon successive exchange of the solvent to toluene and methanol, the acid-labile tetrahydropyranyl (THP) protecting group was cleaved and initiated the double intramolecular conjugate addition to furnish spiroketal ketones 15 as a single stereoisomer. These are purified and reduced to epimeric alcohols 16 and 17 by means of polymer-bound borohydride reagent. The use of several building blocks in a library fashion yielded 147 spiro[5.5]ketals in a seven-step sequence with high overall yields and purity. The representative synthetic sequence and the structures of various building blocks are shown in Scheme 6.3. Both Bartlett (Scheme 6.2) and Waldmann (Scheme 6.3) used the readily available chiral building blocks in their strategy to synthesize chiral spirocyclic compound libraries.

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

163

For the synthesis of natural product spongistatin, a well-developed chemistry of boron enolates [19] bearing chiral substituents at the boron atom was effectively and independently applied to the solid-phase synthesis of a library of spiro[5.5]ketals by Waldmann et al. [20] and Paterson et al [21]. During the synthetic process in Waldmann’s group (Scheme 6.4), the immobilized aldehyde 21 was built on a polystyrene resin 18 with a Wang linker, and the preformed Z-enolate 22 was reacted to result in the enantioenriched aldol adduct 23 (only the more favored syn addition product was formed via transition state 28) in two cycles with six equivalents of the chiral reagent 22. For the construction of protected bis-b-hydroxyketone framework 26, and to control the consecutive antiselective aldol reaction (transition state 29) with a set of aldehydes (25), a stereocontrolled formation of a boron-E-enolate 24 on the solid phase was carried out using chlorodicyclohexylborane and triethylamine in two cycles. The final products 27 were obtained upon release from the carrier by oxidative cleavage of the p-alkoxybenzyl ether groups. In general, the desired spiroketal 27 was obtained in a 12-step, solid-phase synthesis with an overall yield of 16 %, which corresponds to an average yield of 86% per step. To understand the efficiency of this solid-supported stereoselective synthesis, a similar solution-phase synthesis was repeated starting from p-methoxy benzyl alcohol 19. The spiroketal obtained from the solid-phase synthesis had the same configuration as that obtained from the solution-phase synthesis, which is evidence that both aldol reactions on the polymeric support proceed by full analogy with the corresponding asymmetric transformations in solution.

O TBSO 20

OH O

TBSO

O O

18

H

O H

TBSO

O

B(cC6H11 )2

O

1) 22 (6 eq.), DCM 23 -78 oC to 0 oC then 2) H2O2, DMF/MeOH (buffer, pH 7) (each 2 cycles) 3) TBSCl

21

19, used for solutionphase synthesis

O (c-C6H11) 2BCl

22

OH O

B(lpc)2

OH

TBSO

OPMB 25

O

OTBS

O

O

O

O

O

26

24 DDQ, DCM (buffer, pH7)

O

H B

O O

H B

O O

O

TBSO O O

PMBO Z enolate 22 favored syn product 23 28

E enolate 24 favored anti product 26 29

TBSO

lpc = Isopinocamphyl group

27

SCHEME 6.4. Enantioselective aldol reactions on Wang resin.

164

CHIRAL SYNTHESIS ON POLYMER SUPPORT

The similar enantioselective protocol for the synthesis of spiroketal 43 on a hydroxymethylene modified Merrifield resin 31 was reported by Paterson et al. (Scheme 6.5) [21]. In the first step, chiral homoallylic alcohol 30 was attached to a polymeric support with a diisopropylsilyl linker to furnish 32; this material on continued oxidative cleavage resulted in a resin-bound chiral aldehyde 33. The stereocontrolled construction of the pseudo-C2-symmetric chain (40, 41, and 42) with desired b-hydroxy ketone functionality was achieved using sequential, twodirectional, and asymmetric boron-mediated aldol couplings of acetone with polymer-bound chiral aldehyde 33 using (-)-diisopinocampheylboron chloride (Ipc2BCl). The subsequent cleavage of this linear fragment from the resin, selective removal of the protecting groups, and concomitant spiroacetalization was achieved in one pot. The diversification of this two-directional asymmetric aldol approach was demonstrated at the second aldol coupling as shown in Scheme 6.5. The authors also suggested possible extension of this methodology to access many different spiroacetal scaffolds using different homoallylic alcohols and aldehydes. Overall, this section on the synthesis of spirocyclic compound libraries demonstrates excellent examples for the proper choice of suitable linkers in a polymersupported synthetic design. As per the synthetic requirements and the presence of functional groups or protecting groups, acid- or base-sensitive linkers are used and iPr iPr SiCl 2 2

OH

OBn

imidazole

iPr

Si

O

iPr iPr

O

O OBn

M

30

OH 31

Si

O

Me2CO (-)-Ipc2BCl Et3N

O

H

iPr iPr

O

O

OH

O OBn

OBn

34

33

32

Si

TBSCl, DMF Imidazole iPr iPr

Ipc2BO

Si

OTBS O

(-)-Ipc2BCl Et3N

O

iPr Pr Si O OTBS O i

O

OBn

OBn 36

TIPSO

O

35

OTES O

BnO

H

37

38 OTIPS

OTIPS HO

1) HF-pyr, THF 2) PPTS, MeOH/CH2Cl2

O O

HO

5% over 7 steps

TBSO

OBn HO

OTES O OSiiPr2O

40

OBn HO OTES O OSiiPr2O

OTES O OSiiPr2O TBSO

TBSO OBn 43

OTES O

39 ent-38

H

TBSO

OBn

OBn 41

42

OBn

SCHEME 6.5. Enantioselective aldol reactions on hydroxymethylene-modified Mrrifield resin via a diisopropylsilyl linker.

165

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

the final products are cleverly knocked out in a traceless manner. These linkers also provided an additional flexibility to the anchored substrates for the ease of enantioselective chemical transformations. 6.2.2 Macrocyclic Compound Libraries Macrocyclic natural products often display remarkable biological activities, and many of these compounds or their derivatives are used as medicines. The chemical diversity of these compounds is immense and may provide inspiration for innovative drug design [22]. Therefore, to understand a structure–activity relationship better in these important molecules, it is necessary to develop strategies for the high-speed synthesis, leading to the focused combinatorial libraries. For example, a solid-phase synthesis of Epothilone A, reported by Nicolaou et al. in 1997 [23], showed how to generate large combinatorial libraries of various natural product analogues using polymer supports. An appropriate retrosynthetic analysis to identify the requisite fragments as well as the selection of suitable reaction sequences were the key factors in designing such processes. The coupling of fragments 47, 48, and 49 via Wittig olefination, an aldol reaction, and esterification produced polymer-bound precursor 50 (Scheme 6.6). The RCM macrocyclization was achieved in a traceless fashion in which desired macrocycles 51 were released spontaneously from the resin-bound olefinic compound 50. During macrocyclization, the described protocol furnished four different isomers in 3:3:1:3 ratios with 52% total yield. On continued purification using high-performance liquid chromatography (HPLC) or preparative-layer silica gel chromatography followed by the removal of silyl protection and epoxidation in solution phase, epothilone A (70%) and its diastereoisomer (45%) were furnished. The a-epoxy isomers of these compounds were also obtained during these

O O

O 45 OR

O

Cl

44

Merrifield resin 0.3 mmol g-1

PPh3

H

46

R = TBS

47 O

OR

S

OH O

N

OR O

HO

48 N

O

N S

S

HO

HO O O

O

OR 52

49

O O O CF3

O

OR

O

51 Four isomers (3:3:1:3)

H

O

Ph PCy3

Cl Ru Cl Cy3P

S HO

N O

CH2Cl2, 25 0C O

OR

O 50

SCHEME 6.6. Total synthesis of epothilone A on a solid phase by Nicolaou et al.

166

CHIRAL SYNTHESIS ON POLYMER SUPPORT

epoxidation reactions. The biological screening of this small library demonstrated that more potent microtubule binding analogues than the parent epothilones can be obtained by chemical synthesis. A solid-phase, high-speed strategy for the synthesis of a natural product-like macrosphelide library was demonstrated by Takahashi et al. [24]. Their process involved the attachment of the secondary alcohol 53 to a polymer support (Scheme 6.7); this was additionally elongated in two directions—in one side by esterification with 54 and on the other side with chemoselective carbonylation of the vinyl iodide in unit 53 with alcohol 55 containing a vinyl bromide moiety. The resulting polymer-bound intermediate 56 on continued carbonylative macrolactonization and cleavage from the polymer support furnished the desired macrosphelides 57. Based on this solid-phase strategy, they have constructed a 122-member macrosphelide library using radio frequency encoded combinatorial (REC) chemistry with a split-and-pool method. The various chiral building blocks used for this library synthesis are summarized in Scheme 6.7. The final preparative HPLC purification using silica gel afforded 0.2–1.5 mg of the desired compounds with 54–99% purities. The 1 H and 13 C spectral data as well as optical rotations of the synthetic Macrosphelide A and E exactly matched with those published for the natural products. This confirmed the high enantiopurity of the generated library. To synthesize a natural product like molecules, a library of ten/nine-membered biaryl-containing rings, in parallel on solid phase was synthesized by Schreiber

carbonylative esterification

C

O

HO attachment

PS-DHP

I

HO A 53

55 Br A

O HO 54

B

I

OTBS

HO OTBS

56

B

OMEM

Br

HO

OMEM

Br

HO

O

carbonylative macrolactonisation

B

O

O

57

I

(b)

OMEM

Br

O OMPM

OMEM

Br

O OMPM

HO

O HO

OMPM

HO

O OTBS

HO

O

HO

HO OTBS

P1 and P2 are the protecting groups

(c) HO

O

A

Br

OH

polystyrene

I

HO

CO

O

I

HO

HO

O

OP2

PS-DHP = polystyrene-dihydropyran resin (a)

C O

O

cleavage

OP1

esterification

O

C O

HO

OMPM

O O Br

HO

O Br

HO

HO

Br

Br

SCHEME 6.7. Takahashi’s strategy for the combinatorial synthesis of a macrosphelide library.

167

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

et al. [25]. The solid-phase supports were used to take advantage of the power of split pool synthesis and resulted in a predominantly single compound on each individual bead. Larger “macrobeads” (diameter of 500 mm; capacity of 100 mmol per bead), functionalized with a diisopropylsilyl group and ideal for alcohol attachment, were used to construct the desired macromolecules (Scheme 6.8) [26]. The amino alcohol building blocks were attached by reductive amination, which was conducted by soaking the macrobeads in a solution containing an excess of amino alcohol to form the oxazolidine, which was reduced by adding NaBH4 to afford 62. The reductive alkylation of the polymer-supported secondary amine by using 2-bromobenzaldehyde and borane-pyridine complex as a reductant followed by O-alkylation with 2bromobenzyl bromide by potassium hexamethyldisilazane (KHMDS) furnished the cyclization precursor 65. A lithium halogen exchange followed by the transmetalation and oxidation of intermediate bis-aryl organocuprates resulted in the formation of the desired ten-member ring 66 on support with remarkable diastereoselectivity. The representative biaryl-containing ten-member 68–70 as well as nine-member ring compounds 71 and 72 [25c] are shown in Scheme 6.8.

OH 1) TfOH 2) R-OH

Si

* 58 *

OMe

Si

* 59

Ph

1) O3 2) Me2S

O

Si

*

3

O

61

H

NH2 Si

NaBH4

O

3

60

OH Ph

*

NH

O 62

= 500-560 μm polystyrene resin Br OH

O

Ph

63 Si

BH3-pyr

*

Si

*

1) KHMDS 2) 63

N

Ph Si

O

*

64

O Ph

O

Br

Ph

N Si

O

*

66

1) t-BuLi 2) CuCN-2LiBr 3)1,3-DNB

Br

N

55 % 6:1 dr (P:M)

O 65

O

150 oC, 24 h

P

Br

M

O

HF-pyr

N HO

O 67

M

Ph

N

68 65 %, 1:7 dr (P:M)

O Ph

O N O

O

P

N

Ph

OH 69 86 %, 7:1 dr (P:M)

N MeO

M N

M

P

Ph N

O

O N

Ph

3 OH OMe 70 74 %, 1:8 dr (P:M)

OH

Ph 71 80 %, >20:1 dr (P:M)

OH 72 91 %, >20:1 dr (P:M)

SCHEME 6.8. Diversity-oriented stereoselective synthesis of biaryl-containing medium rings.

168

CHIRAL SYNTHESIS ON POLYMER SUPPORT

6.2.3 Heterocyclic Compound Libraries Most biologically relevant chemical space is explored by heterocyclic structures [27]. The presence of heterocyclic cores is directly linked to some bioactivity, and such motifs are frequently found in “privileged structures” [28]. Thus, it is not surprising that, in recent years, to speed up the drug discovery process, various protocols for the construction of heterocyclic compounds via solid-phase strategies have been developed [29]. There are several reports on building libraries of biologically relevant and structurally diverse heterocyclic scaffolds [30]. This practice has unimaginable ends because each scaffold with its pharmacophoric residues occupies unique chemical space. The incorporation of tetrahedral carbon atoms in aromatic ring systems can disrupt the typical one-dimensional planarity of these skeletons, creating multidimensional concave and convex surfaces in the molecule, and can make these scaffolds privileged structures to design high-affinity ligands for future drug discovery [5]. This can be achieved by incorporating any chiral center in the cyclic molecules. Based on these data, the present section will describe few synthetic attempts for building chiral complex heterocyclic compound libraries on polymeric supports. A combinatorial solid-phase synthetic strategy was used by Zechel et al. [31] to develop structure activity relationship (SAR) around the lead structure 73, identified earlier as aVb3-receptor antagonists, to manage various metabolic disorders. The desired N-substituted amino-pyrimidinone scaffold 79 was synthesized on chlorotritylchloride resin [32] in six steps starting from chiral a-Z-b-Fmoc-diaminopropionic and b-Z-x-Fmoc-diaminobutyric acids (Scheme 6.9). The first diversity

O N C

A

N

OH

N

O NHZ

N

O

n NH

B

N

O N

N H

Fmoc

O

Z

77

B

N

O

O

O

Piperidine

O

Z

N

n NH

74 (n = 1 or 2)

S

O N

HNR2R3 S

CN

O O

Z

N

n NH

R1

78

O HO

N

R1

BrCN

NH

R1

76

O n NH

O

S 75

Z

73 IC50 = 1μM Initial lead compound

O

H N

R1

Acid N R3

R2

C

O

Z

N

N

n NH

R1

79

N R3

N HN

NH

HN

N

N H

O N

N

H

N NH

N

H

O N

N

N

S

O

NH N H

N

N H

H N

N H

N

B = Me, n = 0 : IC50 = 1.3nM

SCHEME 6.9. Four-Amino-pyrimidinone–based avb3-receptor antagonists.

R2

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

169

element was introduced using appropriate enamine derivatives 75 during the construction of thiouracil moiety 76 on the polymer supported primary amine end [33]. The thio-carbonyl functionality of 76 was then converted to thiocyanate leaving the group (77) using cyanogen bromide and substituted with various secondary amines to build appropriate SAR. This lead optimization study furnished various highly potent derivatives with a 1000-fold increase in potency (IC50 reduction from 1 mM to 1 nM). The chiral center on the starting material was kept untouched throughout this synthetic process to maintain the required chirality in the final molecules. A small library of unsaturated 3-substituted piperazine-2,5-diones 84 on a solid support was reported by Li and Yang [34]. This skeleton was constructed on Wang resin starting from commercially available L-amino acids (Scheme 6.10). The Wang resin was first activated with p-nitrophenylchloroformate. The activated resin 80 was then additionally elaborated to acid 81. Resin-bound acid 81 on treatment with 1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride (EDC) resulted inoxazolone 82. The key transformation includes conversion of resin-bound oxazolones 82 to required piperazine diones 84 using appropriate aldehydes through Z-azalactone intermediate 83 in a traceless fashion. The desired three-point diversity was achieved using various commercially available amino acids, aldehydes, and alkyl halides. A new strategy to create diversity in a dihydropyrimidine scaffold was reported by Rana and Zhang [35] using the Biginelli reaction [36]. They used a typical N,N’diisopropylcarbodiimide (DIC) coupling condition to synthesize Wang resin-linked aminoesters 85 (Scheme 6.11). The 1,3-diketone unit (87) required for the Biginelli reaction was built on the N-terminal end by acetoacetylation with diketene 86. Solidphase Knoevenagel condensation of polymer-bound b-acetoacetamide derivatives 87 with a set of aldehydes produced the desired polymer-bound enones 88. The resulting immobilized material 88, after treatment with 2-benzyl-2-thiopseudourea hydrochloride 89, furnished resin-bound 1,4-dihydropyrimidine 90 in which the a-Lphenylalanine was linked to the 5-position via a carboxamido bond. Because of the chiral amino acids, the present Biginelli reaction produced two diastereomers. A new R1 O

4-nitrophenyl chloroformate

OH

W

O

R2

N H

OLi O

O O

O 80

Wang Resin

OLi

H2N

R1 N R2

H N

O OH

EDC

O 81

O O

R1

O O

NO2

N R2 82

N

R3

O O

O H

O

R1

R1 R3

N

N R2

O 83

TFA

H CH2Cl2 O

R2

N H H

R3

N O

H O

Et3N toluene

O R1

H N N R2 84

SCHEME 6.10. Regioselective synthesis of three-substituted piperazine-2,5-diones.

R3 H O

170

CHIRAL SYNTHESIS ON POLYMER SUPPORT O

R1 HO

R1

NHFmoc O

O OH

W

O

NH2

O

N H

O

O

1. DIC 2. piperidine

O

O

R2

N H

O

O

87

85

R

H R2 piperidine

O

R1

O 86

O 88

NH H2N

R

SBn

O

89

Cs2CO3

O

R1

O H R2 N

N H 90

TFA/H2O/TIPS

HO O

N H

O H R2 N H

N N H

S

S

91

SCHEME 6.11. Solid-phase parallel synthesis of substituted 1,4-dihydropyrimidines.

chiral center at the four position of the heterocycle was produced but no diastereoselectivity was achieved during this transformation, and both diastereomers are formed in approximately equal amounts. As a part of our ongoing efforts in the combinatorial drug discovery, we reported the synthesis of several chiral small molecules on a PEG support using the liquidphase combinatorial technique [12]. Although this method combines the important features of classic solution-phase chemistry and solid-phase synthesis, the proper selection of reaction conditions to take care of any problems related to the instability of the most common ester linkage is crucial in the synthesis design. In the last 20 years of searching for novel combinatorial methodologies with synergistic applications of several techniques [37], we have synthesized many compound libraries using this liquid-phase combinatorial protocol. Throughout this process, we successfully demonstrated the stability of PEG support and the linker ester functionality for various reagents and reaction conditions such as conventional high-temperature heating, microwave irradiation, and sonication. In various synthetic processes, the linker ester functionality was cleverly used to furnish the desired molecules in a traceless fashion. Traceless synthesis of a small library of chiral piperazinediones 94 is one of our earlier examples of successful chiral synthesis on a soluble polymer support using the principles of LPCS [38]. As depicted in Scheme 6.12, the prolineanchored polyethylene glycol monomethyl ether 92 underwent dipeptide formation with different Fmoc-amino acids in the presence of dicyclohexylcarbodiimide (DCC) to furnish 93. Deprotection of Fmoc accompanied with the cyclative cleavage from the polymer support resulted in piperazinediones 94 in good yield and purity. To monitor the progression of the reaction, a small portion of the reaction mixture was pulled out, the compound was precipitated and washed with cold ether and dried, O MeO

PEG 92

O

Fmoc N piperidine Amino acids

O MeO

PEG

O

R

O N

N Fmoc H piperidine

O R

N

HN 93 O 94

SCHEME 6.12. Traceless liquid-phase synthesis of piperazinediones.

171

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

Two-Step PEG Supported Synthetic Process Conventional versus Microwave XX

XX

10 h A

MW 5 min

YY

24 h

B

B

MW 10 min

C

XX : In-pot reaction time, YY : Reloading time - Convntional heating, MW - Microwave irradiation Over all in-pot reaction time : ( ) = 34 h and (MW) = 15 min

FIGURE 6.3. In-pot and reloading reaction time.

and the proton NMR spectrum was recorded. Upon completion of the reaction, the polymer-bound compound mixtures were purified by precipitation and washing with cold ether to remove excess reagents and dried under vacuum. The crude product obtained was used as is for reloading the next reaction mixtures. Using this PEGsupported protocol has drastically reduced the reloading time. To accelerate our library synthesis, the PEG supported synthetic process was also demonstrated using microwave irradiation to reduce the in-pot reaction time (Figure 6.3) [37]. The microwave-assisted method for the liquid-phase combinatorial synthesis of 3,5-disubstituted thiohydantoins 97 was also developed in our group [39]. To increase the resin loading, both ends of the PEG support were used in this process. Fmoc-protected amino acids 95 were coupled with polymer support and then deprotected to produce primary amines (Scheme 6.13). In the next step, the PEG-bound primary/secondary amines were incorporated with various isothiocyanates to yield thiourea intermediates 96 and the concomitant cyclization/cleavage step was carried out under mild basic condition to furnish chiral thiohydantoins 97 in 88–99% yield, based on the initial loading to the support and 81–99% purity, assessed by HPLC. Various heterocyclic scaffolds were reported from our group using 4-fluoro-3nitrobenzoic acid (FNBA) 98 as a template [12, 40]. Microwave-assisted chiral synthesis of quinoxalinones is one typical example in which three different functionalities on a phenyl ring are expertly used to construct the desired molecules on support [41]. As depicted in Scheme 6.14, the acid functionality of FNBA was

O

H N

PEG O

Fmoc

R1

95

R2

O

2

piperidine R2-NCS MW

H N

PEG O R1

96

H N

K2CO3

R2

N

O

NH

MW

S 2

SCHEME 6.13. Traceless liquid-phase synthesis of thiohydantoin.

R1

97

S

172

CHIRAL SYNTHESIS ON POLYMER SUPPORT O

HO

PEG

PEG

O

O NO2

OH + HO

F

DCC DMAP MW

PEG O

F

98

NO2

O

Amno acid methyl esters

NO2

NH

MW

99

100

O Zn, NH4Cl MeOH MW

PEG

O

NH2

O

H N

PEG O

CH3ONa CH3OH

O

NH

O 101

N H

OCH3

R

2

OCH3

R

2

O O

oC

25 10 h

R 2

102

O

H N N H 103

2

O R

SCHEME 6.14. Microwave-assisted chiral synthesis of quinoxalinones.

hooked to a PEG support using microwave-assisted dehydrative esterification by DCC and a catalytic amount of N,N-(dimethylamino)pyridine (DMAP) in dichloromethane. The resulting PEG-bound o-fluoronitrobenzene 99 was subjected to ipsofluoro displacement with various L-amino acid methyl ester hydrochlorides under microwave irradiation. This polymer immobilized o-nitrophenylamino ester 100 in a one-pot reductive cyclization using Zn/NH4Cl, which furnished the desired chiral quinoxalinones 102 on support. Finally, the polymer support was cleaved in CH3ONa/MeOH solution at room temperature to produce the target molecules 1,2,3,4-tetrahydroquinoxalin-2-ones 103. The maintenance of chiral integrity of the molecules throughout all synthetic steps could not be monitored unless the polymer support was detached. A small amount of racemization (10%) was observed in some products, whereas the molecules with the bulky substituents were obtained as a single enantiomer without losing any chirality. In addition, using this similar methodology, recently, the enantioselective synthesis of benzimidazolyl quinoxalinones 107 was also accomplished on a PEG support [42]. The present enantioselective synthesis on PEG support using microwave irradiation provided rapid access to the desired chimeric quinoxalinone scaffolds. The basic synthetic methodology was planned using two molecules of 4-fluoro-3-nitrobenzoic acid (Scheme 6.15). The functional groups on FNBA were sequentially used to construct benzimidazole 106 followed by quinoxalinone 107. The first diversity element was introduced during the N-substituted benzimidazole synthesis using appropriate primary amines. Chiral quinoxalinone moiety was built using commercial amino acids with a similar methodology as shown in Scheme 6.14. The final cleavage of the soluble polymer support was achieved by 1% KCN in methanol at room temperature to obtain polymer free benzimidazolylquinoxalinones 107. High enantiomeric excesses of final cleaved compounds were observed in most cases, showing an insignificant loss of chirality during the three-step reaction on the polymer support in microwave (MW) harsh conditions. Apart from the chiral pool approach discussed, the nonracemic heterocyclic compound libraries are also synthesized using classical asymmetric synthesis of polymer-immobilized prochiral substrates. This approach has not been explored much for the combinatorial library generation, but based on the future need of

173

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

O 99

PEG

1o amines

NH2

O

Zn, NH4Cl MeOH

NH 2 R1

104

FNBA 118 DCC DMAP MW

F O

O

TFA MgSO4

NO2

PEG

NH

O

NH R1

2

105 O PEG

N

O

NO2

HN R2

N

O

F N R1

O

O

3-steps Scheme 16

NH N R1

2

107

106

SCHEME 6.15. Enantioselective synthesis of benzimidazolyl quinoxalinones on soluble polymer support using focused microwave irradiation.

unsaturated skeletons in the drug discovery process [5], it will be an important tool for generating rapid nonracemic compound libraries. Among the various ringforming reactions, the enantioselective 1,3-dipolar cycloaddition reaction [43] was well investigated in solid-phase synthesis. Jiang and Zou reported a solid-phase asymmetric 1,3-dipolar cycloaddition of a Wang resin-bound aromatic nitrile oxide 108 with allylic alcohol using EtMgBr as base and (-)-diisopropyl tartrate as chiral auxiliary [44]. A set of chiral isoxazolines 109 were synthesized in their study using substituted hydroxyl benzaldehydes in approximately 63–78% yield with enantiomeric excess (ee) of up to 95% (Scheme 6.16). A plausible transition state 110 was predicted by the authors for this solid-phase asymmetric 1,3-dipolar cycloaddition reaction based on the similar solution phase reaction, which was carried out by Et2Zn as a base [45]. The number of biologically active agents contained a chiral isoxazoline ring as a pharmacophore [46]. This methodology can be well used for the combinatorial decoration around this chiral skeleton using appropriate building blocks. To achieve the required stereochemical diversification in various pathways of diversity-oriented synthesis [47], Schreiber et al. have successfully used the enantioselective [3þ2] and [4þ2]-cycloaddition reactions for the synthesis of pyrrolidine- and dihydropyran-based chiral libraries, respectively (Scheme 6.17).

O N

OH Cl

N

HC

OH

OH W

W O 108

EtMgBr (-)-DIPT -50 oC

O

C

110

Mg O

C H

H

C

O

H

H

109

C Mg

O

H C

O

O

Et

H N

W

O

O O

Et H

SCHEME 6.16. Solid-phase asymmetric synthesis of isoxazolines.

H O

174

CHIRAL SYNTHESIS ON POLYMER SUPPORT COOtBu i-Pr2NEt3 AgOAc (10 mol%)

COOMe N

CHOOMe HN

H

*

Si

*

N

O

PPh2

111 112 (S)-QUINAP (10 mol%)

*

Si

R1

O

Si

R2

*

114

R2

O

O

O

O R1

O

O

R

R3 115

OEt O

Si

OAllyl O

O Si

113

O

EtO O

CHOOtBu

O

Final detached products diastereoselectivity (endo:exo >20:1) and enantioselectivity (>90% ee)

* O

R3

*

Si

*

Si

*

Si

EtO O

R2

O O

R

O

O N

N Cu 2 OTf

R3 EtO O

R2

O

O R

O

116 117, R = OAllyl

R3

N R4 118, R = R5

SCHEME 6.17. Schreiber’s stereochemical diversification approach using enantioselective cycloaddition reactions.

In the first approach, they subjected an immobilized aromatic azomethine ylide 111 to a silver acetate/(S)-(-)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline (QUINAP) catalyzed [3þ2] cycloaddition with electron-deficient tert-butyl acrylate to furnish an optically pure pyrrolidine ring 113 with up to four tetrahedral centers [48, 49]. Under these conditions, regardless of the electronic property of the aromatic ring, the reaction showed excellent levels of diastereoselectivity (>20:1) and enantioselectivity (94–96% ee) for the endo products, which proved the applicability of this method to library synthesis. In another approach, they succeeded in the synthesis of a 4320-member library via an enantioselective inverse– electron-demand hetero Diels–Alder reaction (Scheme 6.17) [50]. The transformation of a set of immobilized enol ethers 114 required 20 mol% of the C2-symmetric bisoxazoline ligand 116 for the enantioselective cycloaddition with different heterodiens 115. Compounds were obtained with an enantiomeric excess varying from 80% to more than 96%. Cleavage of the allyl esters in 117 and subsequent coupling to a set of primary and secondary amines led to a collection of dihydropyran carboxamides 118. To analyze the purity of members of this huge library, two macrobeads from each pool were removed, arrayed, and treated with HF-pyridine, and fractions of the eluted products were assayed by liquid chromatography-mass spectrometric (LCMS) analysis. Overall, the final products were obtained in high purity, 95% in 72% of the analyzed examples. Both of these libraries are synthesized on high capacity, 500–

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

AllylO

O

O

O 115

O R2

1 eq. 121

AllylO

119

O

O

R1

R1

175

N Cu 2 OTf 121

N

O R2

O O O 120 endo/exo >10:1 up to 98% ee

commercially available LanternTM (trademark of Mimotopes Pty, Ltd.) was used as a polymeric support

SCHEME 6.18. Enantioselective cycloaddition reactions on Lantern using Inda-Box.

600-mm polystyrene macrobeads, using a one bead/one stock solution technology platform [26, 51] that produced a sufficient quantity of compounds per bead to perform hundreds of assays. note that both enantiomers of the new catalyst systems (QUINAP 112 as well as bisoxazoline 116) were prepared from commercially available reagents and their use was successfully demonstrated. Using this similar methodology, Kurosu et al. synthesized several cycloadducts 120 [52] in which one equivalent of the newly designed catalyst Inda-Box 121 was required in the solid-phase reaction studies (Scheme 6.18). To demonstrate the similar enantioselectvity in solution phase, use of 5 mol% of the ligand was sufficient to furnish the desired product with up to 95% yield in >95% enantiopurity. The synthesis of diarylheptanoids 126 consisting of a chiral tetrahydropyran core structure on a polymeric support was reported by Waldmann et al. [53]. An enantioselective oxa Diels–Alder reaction [54] was employed in their process to generate a collection of 2,4,6-trisubstituted tetrahydropyrans. To execute this crucial enantioselective hetero-Diels–Alder reaction on the solid support, chromium catalysts 127 [55] and 128 [56] were investigated. The best results were obtained by 5 mol% of the chiral chromium catalyst 127. Resin-bound aldehydes 122 (Scheme 6.19) were treated with the Danishefsky’s diene 123 in the presence of a chiral chromium catalyst 127 to furnish the immobilized chiral cycloadducts 124.

OTMS O

MeO O

R1

R2

123

R2

W

R1

W

O 122

3 eq. 123 5 mol% 127

N H

N Cr

O

O O Ph Ph

124 O TFA/DCM

BF4

127 HO

R1

R2

HO H

O

CH3

R1 R2

R3

H

O

125

126 OH

N O

O Cr O Cl

SCHEME 6.19. Enantioselective oxa Diels–Alder reaction on polymeric support.

128

176

CHIRAL SYNTHESIS ON POLYMER SUPPORT

These polymer-bound chiral dihydropyrans 124 were subjected to additional transformations to yield the highly enantioenriched final products 126. The intermediate pyrones 125 were also cleaved from the support in good overall yield with enantiomeric ratios up to 99%. 6.2.4 Natural-Product–Inspired Compound Libraries Natural products (NPs) have extensive past and present use in the treatment of many diseases. Several new drugs that were launched recently in the market originate from the natural resources [57]. NP framework provides a privileged structure in the search for useful biological activity and by synthesizing compound collections based on their highly complex core structures; it will be easy to spot the regions of biologically relevant chemical structure space. To develop the NPs as potential drug candidates, it is important to design high-throughput synthetic methods for library synthesis. Based on these data, several research groups have synthesized such natural-product–inspired compound libraries with multistep reaction sequences in a combinatorial fashion [58]. This section will describe the asymmetric syntheses of compound collections based on natural-product scaffolds on the solid support. With the understanding that natural products have played a key role in pharma research [59], we undertook the challenge to develop enantioselective polymersupported synthetic methods in solution phase to obtain fast access to complex, natural-product–like compound libraries in a high-throughput manner. In our efforts to develop combinatorial methods for the synthesis of natural-product–inspired compound libraries, we were particularly attracted to 1,2,3,4-tetrahydro-b-carboline pharmacophore. It is an important structural element of several tryptophan-derived, natural-product alkaloids such as yohimbine, ajmalicine, reserpine, fumitremorgin, tadalafil, jafraine, manadomanzamine, and eudistomin [60]. Numerous compounds from this class have received considerable attention because of their broad spectrum of pharmacological activities [61]. A tetrahydro-b-carboline template that has multiple sites for structural modifications encouraged us to develop novel methodologies for its combinatorial elaboration. One-pot cyclocondensation of polymerbound tryptophan 130 with a variety of aldehydes and ketone under microwave irradiation provided easy access to immobilized 1,2,3,4-tetrahydro-b-carboline derivatives 131 [62] (Scheme 6.20). This was the first report from our laboratory in which an application of microwave technology in liquid-phase combinatorial synthesis facilitated rapid library generation. This methodology resulted in the formation of cis and trans diastereomeric tetrahydro-b-carbolines 132. It was important to notice that no epimerization of the stereocenter at C-1 was detected during the cleavage and that the mixtures were predominantly enriched with the trans isomers. In addition, the anchored 1,2,3,4-tetrahydro-b-carboline derivatives 131 were successfully used for the stereoselective synthesis of tetracyclic tetrahydrob-carbolinehydantoin 133 [63], tetrahydro-b-carbolinethiohydantoin 134 [64], and diketopiperazine-fused b-carboline 135 [65] libraries. We also demonstrated this stereoselective protocol on a fluorous support using 3-(perfluorooctyl)propan-1-ol 136 [66]. Recently, a novel ionic liquid 137 supported green synthetic protocol was

177

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT MeO

PEG

OH

HO

PEG

OH

Rfh

OH

IL

OH

O

F

NH2 130

IL

NH O

pTSA or TFA O O

F

O

NH

P 129

Rfh F

O

SS

anchoring on support

HO HN

Nitrogen Protection: P = Boc or Fmoc SS Soluble Supports used for the synthesis

C1

KCN MeOH

HN

R1

HN

N H R1 R2

R3-NCO Et3N

132 O R3 N O

R2

R1

N R2 H

131

F

F F

F

F

F

F

OH

O

F

OH

F OH

F

F

136

BF4 N

N

OH

O Cl

Cl

O

F

F

137

O

SS

F

R3

N N

R3-NH2 O

R3-NCS Et3N

N H R1 R2 135

O N R1

R3 N N R2 H 133

S

N

N H R1 R2 134

SCHEME 6.20. Liquid-phase combinatorial synthesis of chiral tetracyclic tetrahydrob-carbolines.

developed for the synthesis of a three-dimensional combinatorial library of oxo and thio hydantoin analogs tethered with tetrahydro-b-carboline by the use of focused microwave irradiation [67]. A concise and biomimetic retrosynthetic route for the total synthesis of a pyrazino-quinazoline-dione skeleton of several alkaloid natural products from the dehydration of appropriate peptide precursors was proposed and demonstrated by several researchers [68]. Using this biomimetic path, an efficient four-step synthesis of (-)-fumiquinazoline G and (-)-fiscalin B alkaloids 143 was reported by Wang and Ganesan [69]. They also demonstrated the successful use of this route for combinatorial solid-phase synthesis on Wang resin [70]. Using the standard Fmoc-chemistry of solid-phase peptide synthesis (SPPS), the Wang resin-bound L-Tryptophan 138 in sequence was condensed with anthranilic acid and Fmoc-protected acid chloride of glycine to produce the corresponding triamide 140 on solid support (Scheme 6.21). This triamide precursor was intramolecularly dehydrated with Ph3P/I2/DIEA, subsequently deprotected, and cyclized with concomitant detachment from the solid support to afford the desired product (þ)-glyantrypine 143 (R ¼ H) in 51% overall yield. To demonstrate the scope of this protocol, a small library of unnatural analogs were also prepared by the authors via parallel synthesis using L-alanine, L-leucine, and L-phenylalanine in place of L-tryptophan. A set of five anthranilic acids and D-or L-amino acid chlorides were used for additional elongation followed by final coupling to yield the desired cis products. Approximately 10% of the trans diastereomers were also observed during the final cyclative cleavage. By replacing the a-amino acid chlorides with acid chloride of b-alanine, Ganesan et al. also

178

CHIRAL SYNTHESIS ON POLYMER SUPPORT Fmoc NH R O

W

H N

O

H2N

O Fmoc

NH

O

N H

O O

O NH

Ph3P/I2/DIEA

NH

anthranilic acid EDC

140

NH

139 R *

R N H2N

O O

Fmoc-Gly-Cl pyridine

O

138 Fmoc

HN

H N

piperidine

O

*

O O N

piperidine O

R N

*

HN N

MeCN ClCH2CH2Cl

H N

O

O NH 141

N

* N

O NH

NH

143

142

SCHEME 6.21. Solid-phase synthesis of quinazoline alkaloids.

demonstrated the formation of seven-member ring products. Adapting this protocol and starting from suitably protected L-glutamine anchored to Sasrin resin, Sim and Wang demonstrated the first total synthesis of quanazoline alkaloids verrucine A, B, and anacine [71]. However, these multistep procedures suffered from the use of a large excess of reagents, long reaction time, as well as low yield. To overcome these limitations, a total synthesis of pyrazino[2,1-b]quinazoline-3,6-diones on solid support recently was reported by Chu and Tseng [72]. Their protocol involves the synthesis of the same triamide intermediate 140 on Wang resin using commercially available L-amino acids and anthranilic acid. Based on a key double cyclodehydration step facilitated by zinc triflate, this anchored intermediate is transformed into the unnatural quinazoline alkaloid skeletons in a traceless fashion. Using this Lewis acid catalyzed protocol, a library of 12 unnatural analogues was synthesized in good yield (overall yield up to 97%). Unlike the earlier report, the trans isomers were obtained as major products (up to 15:85 cis-to-trans ratio). The combinatorial synthesis of various drug like substituted benzopyrans [73] and indolines [74] were reported by Nicolaou’s research group using novel polystyrenebased selenenyl bromide resins 145. These resins are capable of loading substrates through electrophilic cyclization reactions and were prepared from commercial polystyrene by lithiation followed by treatment with dimethyl diselenide and subsequent oxidation with bromine (Scheme 6.22) [75]. The loading of o-prenylated phenols 146 through a 6-endo-trig cyclization resulted in resin-bound benzopyrans 148 linked to the resin through a selenoether, whereas, substituted o-allyl anilines 149 cycloloaded onto this selenenyl bromide resin via a 5-exo-trig cyclization afforded resin-bound indoline scaffolds 150. From this step onward, the authors have elaborated both the benzopyrans 148 as well as the indoline scaffolds 150 as per the SAR requirement or to establish the natural products or natural-product–resembling

179

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT OAc O

AcO AcO

AcO AcO

O O

OAc O

AcO AcO

syn-Elimination

O OAc 152

OAc O O AcO AcO

O

MeO

R1

H

O

O H

O

Br2

(MeSe)2

EtOH

Elaboration & Oxidation

Se

Se

Br 145 cycloloading R1 5-exo-trig

NH R2

Se

Elaboration

153 X Cyslization cleavage H N

R3 N R3 R2 150 Elaboration Radical followed by rearrangement cleavage

H

O H

R3 = H R1

Representative example is shown single diastereomers with relative stereochemistry as shown

155

O 148

R3

149

R3 = H

R1 6-endo-trig

147

R3

Se N

OH

Se

144

R1

R1

cycloloading

Se Me

Polystyrene

146

SeBr

Se

OAc O MeO 151 Representative example is shown

OH

nBuLi

154

O

OAc

N R2

Elaboration followed by oxidative cleavage

R1 N R2

R3 = H 157

Traceless cleavage R3 = H

R1 156

N R2

SCHEME 6.22. Nicolaou’s strategy for the solid-phase synthesis of substituted benzopyrans and indolines.

structures. For example, the total synthesis of macrophylloside D 152 and naturalproduct–mimicking polycyclic indole skeletons 154–157 are shown in Scheme 6.13. The functionalized benzopyran derivatives are released from solid support by H2O2 oxidation of the selenide to the corresponding selenoxide followed by spontaneous syn-elimination at room temperature. The resin-bound indoline scaffolds are further diversified to various interesting structures 154–157 with additional complexity using the ability of this selenium tether to generate a carbon-centered radical upon cleavage. During the exploration of the concept that natural products can be regarded as biologically validated starting points for the development of compound libraries, Waldmann et al. [76] synthesized a series of analogues of the antitumor phosphatase inhibitor dysidiolide 166 (Scheme 6.23). It was assumed that, for the libraries designed and synthesized around a given natural product, a higher hit rate can be expected for the identification of biologically relevant leads. To deliver new potent biologically active compounds using this concept, the authors developed a highfrequency complex multistep reaction sequence on a solid phase. A broad range of transformations with widely different requirements were demonstrated in this

180

CHIRAL SYNTHESIS ON POLYMER SUPPORT I

O H

159 O EtPPh3I nBuLi

O

O

O

O 162

TMSOTf

160

158 O O

TMSOTf

Dysidiolide

164

O

H

pTSA

161

1) pTSA 2) olefin metathesis

O

6

olefin metathesis

6-epi-Dysidiolide and analogues

OH

OHC

O HO

166 O

O

H

163

165

via 162 via 161 endo:exo = 91:9 endo:exo = 83:17 endo:endo' = 81:19 endo:endo' = 95:5

SCHEME 6.23. Enantioselective total synthesis of dysidiolide analogs on solid support.

11-step, polymer-supported process. A key transformation of the synthesis is the asymmetric Diels–Alder reaction (160 ! 164) of resin-bound chiral diene 160 with chiral dienophile 162. Initially, the polymer-bound diene 160 was subjected to a Diels–Alder reaction with tiglic aldehyde 161 in the presence of a TMS-triflate, and the cycloadduct 163 was obtained as a mixture of four isomers that were formed in the ratio endo/endo’/exo/exo’ ¼ 67:16:16:1, with the desired endo isomer predominating. The isomer ratios were determined by 1 H-NMR spectroscopy after the release of the cycloadducts from the solid support by olefin metathesis. To increase the stereoselectivity and to achieve a more efficient stereochemical steering of the cycloaddition, tiglic aldehyde 161 was replaced by a quasi-C2-symmetric chiral acetal 162, which produced the cycloadduct 164 in high selectivity (endo/endo’/exo/ exo’ ¼ 87:4:9:0.1) and then converted it to aldehyde 163 by acetal hydrolysis. The aldehyde functionality in conjugate 163 was elaborated to resemble dysidiolide analogs closely that were released from the solid support by ring-closing metathesis. The use of achiral aldehyde 161 instead of chiral acetal 162 was also proposed for the construction of diastereomer libraries for preliminary biological investigation. This process convincingly demonstrated that the multistep enantioselective total synthesis of natural products on polymeric supports can be achieved. Lee et al. developed a method to collect khellactones 172, a compound class exhibiting a broad range of biological activities, including antifungal, antitumor, and antiviral effects [77]. The khellactone ring skeleton was constructed on a polymer support by Knoevenagel condensation between ethyl malonate bound to the Wang resin (167) and o-hydroxyarylaldehyde 168. The immobilized coumarin derivative 169 (Scheme 6.24) was subjected to the Sharpless asymmetric dihydroxylation

181

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT O H O

HO

O

O

O KO W

OH

O

O

EDC.HCl

ArgoGel Wang resin

168

O

O

O O

piperidine pyridine

O 167

O

O

K2CO3 methane sulfonamide

169 O

O O 1) RCOOH DIC O

HO

O

O O

O

HO 170

2) DIEA DMAP

OH

OsO4 (DHQ)2-PHAL K3[Fe(CN)6]

O

O

50% TFA/CH2Cl2

O

R

O

O

O

O

R

HO

O

O R

O

O HO

O

R

RCOOH O

O O

172

O

171

O

O HO

O

O HO

HO

O HO

O O

SCHEME 6.24. Asymmetric hydroxylation on solid support for khellactone library synthesis.

conditions using (DHQ)2-PHAL as ligand and catalytic OsO4. Additional functionalization of this newly generated hydroxyl group was carried out by esterification with a set of in situ generated anhydrides of a set of acids to yield the target compounds 172. The resulting products displayed an enantiomeric excess of up to 91%. This was the first report in which an asymmetric dihydroxylation was carried out on a polymeric support to generate compound libraries. Earlier asymmetric dihydroxylation of solid support-bound olefins was systematically investigated by Janda and Han [78] to study the influence of the immobilizing material and the solvent polarity during the reaction. However, Berkessel et al. [79] studied this reaction both in solution as well as in solid phase with three different substrates and concluded that only those substrates that react in high enantioselectivity in solution are more suited to the solid-phase variant of the reaction. As an alternative for drug discovery and amore direct entry to high throughput synthesis (HTS), the concept of stereocombinatorial synthesis leading to libraries with stereochemically diverse monosaccharides was reported by Armstrong and Sutherlin [80]. Using this concept and by iterative carbon-chain elongation, Fessener and Mullenmeister envisioned synthesizing all stereoisomeric deoxy hexopyranoses starting from a noncarbohydrate material such as glycolaldehyde (Figure 6.4). This stereocombinatorial synthesis principle was tested by the authors both in solution and on solid support [81]. In their process, the polystyrene resin was linked to a tetrahydropyranyl linker (173) and functionalized to a glycol aldehyde analog 175 by substituting it with allyl alcohol followed by ozonolysis (Scheme 6.25). The resin-bound aldehyde 175 was treated with a ten-fold excess of vinylmagnesium bromide, the intermediate OH-group was acetylated, and the double bond was

182

CHIRAL SYNTHESIS ON POLYMER SUPPORT O OH Glycolaldehyde O

O OH OH D(+)-Glycerinaldehyde

HO OH L(+)-Glycerinaldehyde

O OH

O

HO OH L(-)-Erythrose

O

OH L(-)-Threose

O

OH OH

O

HO

OH OH

HO

HO HO

HO

OH 2-DeoxyL-glucose

O OH

HO HO

OH 2-DeoxyL-allose

OH 2-DeoxyL-gluose

O

HO OH D(-)-Erythrose

OH D(-)-Threose

O

HO HO HO

O HO HO

O

O

OH HO OH OH OH OH OH OH 2-Deoxy2-DeoxyD-glucose D-allose

OH 2-DeoxyL-galactose

O

OH

HO HO

HO OH OH 2-DeoxyD-gluose

OH OH 2-DeoxyD-galactose

FIGURE 6.4. Stereo-combinatorial synthesis of 2-deoxy hexopyranoses.

cleaved by ozonolysis to yield the protected a-hydroxy-aldehyde 176, which was extended by vinylation/ozonolysis. Tetraallyl stannane was used as an allylation reagent for additional elongation. Final ozonolysis resulted in the resin-bound 2deoxyhexopyranoses 178. The corresponding 2,4-dideoxyhexopyranoses were formed by two allylation steps with tetraallyl stannane, with each followed by ozonolysis. Waldmann’s stereocomplimentary synthetic methodology [82] for the naturalproduct–derived compound collection on a solid phase resulted in easy access to stereoisomer libraries (Figure 6.5). Using enantioselective, reagent-controlled carbonyl allylation on a solid support and employing chiral allylboranes, the authors demonstrated combinatorial synthesis of all eight isomers 187–194 of the naturalproduct cryptocarya diacetate 179 (Scheme 6.26, 6.27). O

O

PPTS

HO

O

O

1) O3 2) Me2S

O

+

O 175

173

MgBr 1) 2) Ac2O/Pyr 3) O3 4) Me2S

PS-DHP 174

O HO HO

O

1) O

178

OH

2) O3 3) Me2S

Sn 4

OAc

OH 1)

O

O OH 177

MgBr

2) O3 3) Me2S

O

O 176

SCHEME 6.25. Stereo-combinatorial synthesis of 2-deoxy hexopyranoses on solid support.

183

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

R,R,R; R,R,S

R,R R,S

R Starting material

OAc OAc O

S,R,R; S,R,S

S,R S,S

S

O

R,S,R; R,S,S

179

S,S,S; S,S,S

FIGURE 6.5. Synthetic path for stereoisomer libraries and cryptocarya diacetate 179.

W

OH B

OH COOEt 180

1) Cl3CCN, DBU BF3-OEt2

O

O

182 H

2) DIBAL-H 3) IBX

181 O O

1) 182 (I-IpcBAII)

2

O

then H2O2

O

O O

OTBS O

1) TFA

179

2) Ac2O

(2 cycles)

2) acryloyl chloride Et3N/DMAP

OTBS

184 H

183

20 mol% of Grubbs II catalyst

OTBS O

O

1) TBSCl 2) O3, PPh3

OH

185

186

SCHEME 6.26. Enantioselective synthesis of cryptocarya diacetate on a solid support.

To synthesize cryptocarya diacetate 179, enantiomerically pure b-hydroxy ester 180, was immobilized on Wang resin and converted to the corresponding aldehyde 181 (Scheme 6.26). Homoallylic alcohol functionality was built on the resin via asymmetric Brown allylation using diisopinocampheylborane 182. This asymmetric transformation resulted in homoallylic alcohol 183 in a diastereomeric ratio of 85:15 (determined after release from the resin). The secondary hydroxy function was W

O

O H

181 a b

OTBS O

187 40%, >80:<5:13:2

O OH

OTBS O

OTBS O

191 42%, >85:<5:7:3

O OH

188 50%, 18:67:1:14

by analogy from ent-181 O OH

b

b

O OH

a

b

OTBS O

OTBS O

192 65%, 27:63:6:9

OH

189 57%, 13:2:77:8

O OH

O OTBS O

190 60%, 2:13:5:80

O OH

OTBS O

193 50%, 13:2:63:22

O OH

OTBS O

194 42%, 2:13:10:75

a: asymmetric Brown allylation, TBS protection, ozonolysis b: 2nd asymmetric Brown allylation, acryloyl chloride acylation, ring closing metathesis, oxidative release (DDQ)

SCHEME 6.27. Enantiocomplementary solid-phase synthesis of eight stereoisomers based on cryptocarya diacetate.

184

CHIRAL SYNTHESIS ON POLYMER SUPPORT

protected as a silyl ether, and the terminal alkene was cleaved with ozone, which generated new aldehyde functionality 184 upon reductive work-up. A second Brown allylation, followed by acylation with acryloyl chloride, led to the cyclization precursor 185, and ring-closing metathesis with Grubbs II catalyst furnished the a,b-unsaturated d-lactone 186. Release from the resin with consecutive cleavage of the silyl group was achieved by treatment with trifluoroacetic acid. The final acylation using acetic anhydride yielded a mixture of four stereoisomers from which the natural product cryptocarya diacetate 179 (all-syn isomer) was isolated as a major product in 11% overall yield. Using the combination of both enantiomers of the b-hydroxy ester and the two enantiomeric allylation reagents, and following the synthetic sequence shown in Scheme 6.26 [compounds were released using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)], a collection of all diastereomers 187–190 and their enantiomers 191–194 were generated by the authors with a high degree of selectivity and in 40–60% overall yield (Scheme 6.27). 6.2.5 Libraries Through Combinatorial Decoration of Natural Products Natural products have an excellent source of novel chiral structures that can cover a different chemical space than most synthetic libraries [83]. High hit rates in the biological screening are expected from the compound collections based on their biologically prevalidated core structure [84]. In principle, there are two distinct options to synthesize such libraries. The ideal approach is to select the ready template available from the natural resources, immobilize it on a polymeric support, and carry out the additional transformations as per the SAR requirement using combinatorial techniques [85]. The other approach is to design a scaffold amenable for additional decoration or elaboration in a solution-phase followed by its anchoring on support and to construct natural-product–resembling libraries using a diversity-oriented approach. The historical and modern aspects of influence of natural products in drug development have been reviewed by Newman et al. [86], whereas several benefits of natural products as medicinal drugs were highlighted by Hall et al. [87] in a comprehensive review on strategies for the design, synthesis, and screening of libraries based on natural-product templates. A few of the characteristic and recent approaches on the combinatorial decoration of natural products are discussed here. A complex molecular structure like Taxol was manipulated on solid supports by Xiao et al. [88]. A Taxol template was derived from commercial baccatin III 195 in a solution phase and a resin-trapping method was used to immobilize this template onto the solid support (Scheme 6.28). A reversed-loading method was devised as the template was derived from expensive starting material baccatin III. Using the REC strategy and solid-phase synthetic techniques (split-pool method), a 400-member taxoid library was generated. The various building blocks used in this taxoid library are shown in Scheme 6.28. The quantity obtained for each compound in the library ranged between 2 mg and 4 mg and purity ranged between 50% and 100%. The synthesis of a library of naltrindole derivatives from noroxycodone 198 was reported by Takahashi et al. [89] (Scheme 6.29). Noroxycodone 198 was immobilized on the resin through phenolic hydroxyl functionality under Mitsunobu reaction

185

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT Microreactor

porus membrane OH

O

O MocFHN AcO

R1

AcO

O O R2

NH

O

O OH

O

HO

O H OBz OAc

HO

AcO NH

O

HO 196

O O

O

H OBz OAc

O MeO

O

2

A

O

B

O

N

F

HN

O D

O2 N

F F

O

O

C

O

NH E

O

N

N

F

G F

O

O

I

SMe

N

M

O

N

N

O

K

O

L

N N

O

S N

O

J

N

O2N

O

O

S O

Q

O

P

O

N

S

R

N

O

O

N

Br

F

O

H R2 HO 197 OBz OAc a: Excess 2-chlorotrityl resin, DIEA b: Distribution of resins in 400 microreactors c: further modifications

195, Baccatin III R1

O O R2

O

a,b,c

HO

O

O

H N

2-chlototrityl resin Rf tag

O2N

O N

O

O

S

T

S

O

S

O

U

O

U O

R2 Building blocks A, C, D, F, G, I, J, K, L, M, N, P, R, S for R2 are the same as for R1

H H

E O

O

Q

O

O T

O

SCHEME 6.28. Synthesis of a Taxoid library using radio-frequency–encoded combinatorial chemistry.

R1

O

OH

H2N

OH

HN

HN O

O

O

R2

OH

N H

R1

N

R2

1. A, NaBH3CN 2. B, 4 Ao MS, AcOH

O

N O H

3. 10% TFA/CH2Cl2 OMe

O

198

OH 200

199

(a)

(b) CHO CHO

CHO

CHO

CHO

CHO

H N

H N NH2 H N

NH2

H N

NH2

HN

O

SCHEME 6.29. Synthesis of a naltrindole library on solid support.

NH2

NH2

186

CHIRAL SYNTHESIS ON POLYMER SUPPORT

conditions. To demonstrate the one-pot cyclization and cleavage reaction for the solid-phase synthesis, a Wang linker on a hydroxymethylphenoxyethyl resin was used as a polymer support. Six aldehydes (A, Scheme 6.29) for N-substitution and five hydrazines (B, Scheme 6.29) for Fischer indole synthesis were used for additional elaboration of the anchored product 199 to yield a 30-member naltrindole analogs 200. Sarcodictyins are a class of natural products that have received much attention by synthetic chemists because of their structural complexity and Taxol-like antitumor activity [90]. To understand the structure–activity relationships in this new structural class of compounds, a small 22-member library was synthesized by Nicolaou et al. [91] (Scheme 6.30) and was subjected to biological evaluation with regard to tubulin polymerization and cytotoxicity. The chiral core structure 202, earlier synthesized in solution phase during the total synthesis of Sarcodictyins A 203 [92], was expertly used to carry out additional modifications on three different reactive entities to obtain the required diversity at the specific sites. This molecular diversification was carried out on a solid support with an acid labile linker. The modified

O OH

O

Side chain is crucial for activity N

Both the nitrogens are important

N

HO O

OTBS

O OH OTIPS

201

O

202

O

OAc 1) O

M

203

PPh3

205

R1

O

OH

3

Ketal substitutions are tolerated OH O Esters are prefered over amides

O

O

2) NaOMe O

4 O

O L

O

R1

R1

O

O

O R2 208

R3

O O

O,N

R1

O

O O

M

TIPSO 207

TIPSO 206

TIPSO 204

O L

M

O

R4 209

O

R3 HN R5

210

SCHEME 6.30. Synthesis of a sarcodictyin library on solid support.

R3

187

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

Merrifield resin 205 with phosphorane functionality was specially synthesized to improve the yields (>95%) during the substrate loading. The synthesized sarcodictyin library was screened for the induction of tubulin polymerization using the filtration colorimetric assay. In their library of 22 derivatives, an excellent structure– activity relationship was established. During this study, they found that the replacement of a side chain with acetate, phenyl carbamate, or cynamoyl ester is not tolerated; replacement of the substituted imidazole heterocycle by a pyridine, thiazole, or oxazole led to reduced activity; methyl and ethyl ketals are well tolerated, whereas propyl or trifluoroethyl ketals are not; esters are more active than the corresponding amides; substitution of the ester group is well tolerated, and the reduction of the ester to the alcohol and derivatives thereof are not tolerated (SAR shown in 203, Scheme 6.30). They also identified compounds with biological activities superior to those of the parent structure. A similar approach of synthesizing the core structure in solution and then elaborating it on solid supports for additional diversification was reported by Waldmann et al. (Scheme 6.31) [93]. Enantioselective synthesis (98% ee) of the 4-amino–substituted tryptophan derivative 213 using N-TIPS (triisopropylsilyl)protected gramine 211 was carried out in solution phase (H2O/MeOH, 92:8) via enzymatic enantioselective hydrolysis of an N-acylated derivative of racemic amino acid 212 with penicillin G acylase as one key step. The second stereocenter characteristic of the indolactam nucleus was introduced on amino alcohol 214 by alkylation of the aromatic amine with different a-hydroxy acid ester triflates 215. Subsequent hydrogenolytic removal of the Z-protecting group and the benzyl ester functionality followed by amide formation yielded nine-membered lactams 216. This chiral core structure 216 was then anchored on a Merrifield resin with a tetrahydropyran (THP) linker and diversified to a 31-member library of analogs 218 of the protein kinase C (PKC) activator indolactam V 219. A cell-based assay was

R1 NHBoc

NHBoc

NHBoc

penicillin G N TIPS acylase 212 98 % ee O

NHZ 1)

NH2

NHPhac N TIPS 211

OH

COOH

COOH

N

213 O

N TIPS

214

O

R1

NH OH

HN

216

N H

O

O

R1

O 1) R2CHO, NaBH(OAc)3 2) I2, pyridine/1,4-dioxane

217

N H

3) R3CCH, [(PPh3)2PdCl2 CuI, Et3N 4) TFA/H2O

O 12

NH

NH

HN

2) H2, Pd/C, H+ 3) TBTU, NMP, HOBt

N TIPS

M

O R1

OBzl TfO 215 O 2,6-lutidine

11 N 13

OH

N R2 N H O 218

9

OH

3

5

R3

10

NH 14

7

N1 H

219, (-)-Indolactam

SCHEME 6.31. Synthesis of an indolactam library on solid support.

188

CHIRAL SYNTHESIS ON POLYMER SUPPORT

developed to quantify the activation of PKC by various modulators. In the present study, all tested compounds induced a striking activation of PKC, which was slightly less efficient than indolactam V itself. 6.2.6 Divergent Synthesis of Small Molecular Libraries The macromolecules that carry out many biological functions have an enormous structural diversity. A similar massive diversity was also found in natural products that have provided several new drugs. This suggests that complementary levels of structural diversity will be needed in the collection of small molecules to identify the lead structures for future drug discovery [94]. To achieve this goal, diversity-oriented synthesis (DOS) has emerged to synthesize a collection of small molecules efficiently that are capable of perturbing any disease-related biological pathway [48]. A key strategy in DOS is designing a molecular skeleton that has multiple reactive sites with potential for orthogonal functionalization, which can be elaborated to diverse skeletons using novel combinatorial techniques. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are reviewed by Schreiber [95]. A few attempts for the synthesis of chiral complex libraries using DOS are discussed subsequently. The stereoselective synthesis of a compound library that has structural features reminiscent of natural products was reported by Schreiber et al. [96], who put forth a concept of diversity-oriented synthesis [95]. During this highly efficient and multistep synthesis, an enantiomerically pure substrate 221 was synthesized from shikimic acid 220 and then immobilized on a poly(ethyleneglycol)-polystyrene copolymer (Tentagel-S-NH2) linked through a photocleavable linker (Scheme 6.32). This resin-bound epoxycyclohexenol derivative 222 on being exposed to various nitrone carboxylic acids under esterification conditions yielded a tetracyclic compound 223 with complete regio- and stereoselectivity via tandem acylation and 1,3-dipolar cycloaddition reaction sequences. The chiral, rigid, and densely functionalized tetracyclic scaffold 213 was designed to introduce a variety of functional groups easily around the central octahydrobenzisoxazole structure without the use of protecting groups. On treatment with a variety of organic and organometallic reagents, this template was diversified to highly functionalized bicyclic and tricyclic derivatives 224–232, which were elaborated via complex split-pool synthesis using various alkynes, amines, and acid building blocks to yield more than 2 million distinct, spatially separated, and encoded chemical entities that have rigid, stereochemically defined, and structurally diverse skeletons common to many natural products. The authors achieved the controlled release of compounds from the individual 90-m supports into nanodroplets containing engineered cells. The specially designed miniaturized cell-based assays were used to screen this library for cell permeability and various protein-binding activities. As a result, several molecules activating a reporter gene in mink lung cells were identified. Arya et al. have developed an interesting approach for the synthesis of enantiopure natural-product–like compound libraries [58a,97]. Based on the widespread

189

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

O

O HO

HO

OH

HO

OH

PyBOP DIPEA

O

OH

O

O HO

NH2

O O 222

H

O

N I

H

HN

H

O

O

O

H

224

N

O H N

O

O

O H N

O

225

O

H O

H O

O

O

S 226

232 I

O

O

R

H N

H

H

N O H N

O

O 227

MeO O

O

O H N H O

O

NH

H

O

H O

O H N H O

N

O O

S

O H N

230

H O

I

N O

N O HO

H

I

NH H MeO

O H N O

O NH 231

MeO

N

H

223

H

H

O HO

H O

OMe

NH

O H N

O

HO

I

N

O

H

MeO

H

H

O H N

HO

O

H N

H

HO HO

O

O H N

O

O HO

223

I

O

NH

R

HATU DIPEA, DMAP

221

220

O N

HO

228

O

O 229

SCHEME 6.32. Schreiber’s diversity-oriented approach for a natural-product–resembling compound libraries.

occurrence of indoline and tetrahydroquinoline substructures in many natural products, a synthesis program aimed at designing these functionalized skeletons was launched to build various polycyclic architectures. In this process, as a first step, a practical enantioselective synthesis of many appropriately functionalized/protected indolines 234–237 and tetrahydroquinolines 238–241 were achieved in a solutionphase chemistry using commercially available 5-hydroxy-2-nitrobenzaldehyde 233. The scaffolds were designed to have the anchoring site (R1, Scheme 6.33) and various functionalized residues for additional elaboration based on the DOS platform. These enantioenriched scaffolds 234–241 were then attached to polystyrene resins. The chiral anchored units were elaborated to build different architectures leading to natural-product–like compounds 242–247 and compound libraries 248, 249 (Figure 6.6) using a diversity-oriented approach on a solid support.

190

CHIRAL SYNTHESIS ON POLYMER SUPPORT R2 N

R2 N

COOEt

R1O

R1O 235

R2 N

R2 N

NHR3

236

OH NHR3

R1O OR3

R1O

237

NO2

234 HO

R2 N

CHO 233

R2 N

OR3

R1O

R1O

OR4

R2 N

241

O

R1O

R1O

OR3

240

R4

238

R2 N

N R3

COOEt O

O

239

NH

COOEt O

R1 = Anchoring site for solid-phase synthesis; R2-R4 = Diversity sites for further elaboration

SCHEME 6.33. Enantioselective synthesis of appropriately functionalized indolines and tetrahydroquinolines in solution-phase chemistry.

A representative process for the synthesis of an indoline-derived natural product resembling a small molecular library is shown in Scheme 6.34 [98]. Phenolic hydroxyl protection followed by carbon homologation of 5-hydroxy-2-nitrobenzaldehyde resulted in olefinic compound 250. This Wittig product on asymmetric aminohydroxylation resulted in N-Cbz-protected chiral amino alcohol 251 in 80% yield and 92% ee. The aminoindoline 252 was obtained from 251 in several steps that involved the reduction of the carboxylate ester, benzoyl-protection of the primary alcohol, tosylation of the secondary alcohol, selective reduction of the nitro

O

O

SPh

Alloc N H

SPh N N

H OH

O H OAc

O

O

O

243

242

OH O

H

OH

COOEt

244 O

O O N

OTBS

N

O O

O 245

O

O

O

HN

H

246 O

R1

N

N COR2

COOEt H NHCOR3

O 248

Ph N

COOEt O O

H O

O

O O 247

H

O NH O

Ph O N O

O 249

OAc

H OCOR1 NHCOR2

FIGURE 6.6. Arya’s natural-product–resembling compound libraries.

COOEt

191

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT OH

(DHQ)2PHAL K2OsO2(OH)4 BnOCONClNa

OMEM

CHO

COOEt

NO2 233

NO2 250

O

NHFmoc COOEt

O NHAlloc 253

H N

COOEt 3) TsCl, DMAP HO 4) H2, Lindlar cat. NO2 NHCbz

OBz

NHCbz 252

R1

N Si

1) LiBH4 2) BzCl, pyridine

OH

251 O

*

80 % ee > 90 %

OH

O

R1

N

NH

20% piperidine asymmetric hetero-Michael addition

O

248

COOEt H NHAlloc

O 254

SCHEME 6.34. Stereocontrolled solid-phase synthesis of a library of indoline-alkaloid–like polycycles.

group, and cyclization under mild basic conditions. For library generation, this scaffold was elaborated to 236, immobilized on (4-methoxyphenyl)diisopropylsilylpropyl polystyrene beads through a three-carbon spacer to improve the loading yield, and elaborated to adduct 253 ready for an asymmetric hetero-Michael addition reaction. Conjugate 253, on being exposed to 20% piperidine, underwent an in situ conjugate hetero-Michael reaction in a stereoselective manner preferably through a b-face attack. These alkyl-silyl-linker-based macrobeads 254 were used to generate a library of 90 compounds by split-and-mix type combinatorial technology. Shaw and Mitchell reported the synthesis of an enantioselective pilot library of 529 complex natural products mimicking compounds via a linear synthetic sequence and by employing a folding process [99] on a polystyrene macrobeads [100]. From a single, solid-phase starting material 262, compounds with a comparable level of structural diversity 263–266 were synthesized (Scheme 6.35). The first key transformation was the enantioselective Suga–Ibata reaction for the addition of a polymer-bound methoxy-substituted oxazole 255 to an appropriately substituted aromatic aldehyde 256. For this transformation, several aluminum complexes were examined by the authors, and a triflate (OTf) complex 257 offered the best overall performance to yield the chiral oxazolines 258 with up to 99% ee and 91:9 diastereomeric ratio based on a comparison with racemic reference compounds prepared in solution. Additional alkylation of the oxazoline intermediates 258 was achieved in high yield and diastereoselectivity (>94%) using strong, neutral phosphazene bases (tert-butylimino-tri(pyrrolidino)phosphorane, BTPP 260 or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, BEMP 261) and reactive electrophiles. The final fused and spirocyclic lactams were obtained by employing a reduction/cyclization sequence under Staudinger-type conditions from the oxazolines with strategically placed azide and ester functional groups in 262. Additional diversification was achieved by mix-and-split alkylation of the lactam amide NH functionality on all core structures. The library compounds are planned to screen in a series of biological assays. In the preliminary screening experiments, several compounds modulated the cellular process of both yeast and human cancer (HeLa) cells.

192

CHIRAL SYNTHESIS ON POLYMER SUPPORT O

R1

R2

H Si

*

OMe

O

O 3O

Br

256

N

(R)-257, LiClO4 3Ao MS

=

BTPP or BEMP Bu4NI, MNP

N O

Enantioselective Suga-Ibata Reaction

255

COOMe N

Enolate Alkylation

R1

O R1

258

262

tBu

tBu N N P N N

tBu TfO

R2

259

COOMe

BTPP 260

O N Al O N

tBu

tBu N N

257

N P

BEMP 261

N

tBu

NH N

O

R1 = H R2 = N3

R1 = H R2 = CH2N3

a

a

O

N O 265

264

N O

O NH

R1 = CH2N3 R2 = H

O O

COOMe

263 Ph

R2

NH N

Ph

R1 262

a

R1 = N3 R2 = H

N

a

O

reduction/cyclization sequence under Staudinger-type conditions

O NH

266

a: Me3P/DBU, Dioxane/H20

SCHEME 6.35. A structurally diverse library of polycyclic lactams resulting from systematic placement of proximal azide and ester functionalities.

6.2.7 Chiral Molecules Through Sequential Use of Polymer-Supported Reagents The use of polymer-immobilized catalysts or reagents offer numerous advantages such as simplification of product work-up as well as separation, isolation, and reuse of the catalysts [101]. These polymer-bound reagents were used in solution phase library production and proved their importance in high-throughput chemistry. Advances in these strategies have allowed for the multistep synthesis of many novel compound libraries without conventional purification, providing a straightforward alternative to solid-phase organic synthesis. Since the introduction of such catalysts and reagents on solid support, a new advancement in designing multistep reaction sequences, high-throughput purification, and combinatorial synthesis has emerged– namely the continuous flow system [102]. A representative example is included in this section. Kindly refer to Chapter 3 for more details about this approach. The first total synthesis of the amaryllidaceae alkaloid plicamine 276 using solidsupported reagents and scavengers in a multistep sequence of reactions is one

193

CHIRAL SYNTHESIS OF COMPLEX POLYFUNCTIONAL MOLECULES ON POLYMER SUPPORT

representative example for the orchestrated application of immobilized reagents for the rapid synthesis of complex molecules using the chiral pool approach [103]. The synthesis starts from the conversion of optically pure 4-hydroxyphenylglycine 267 to amide 268 (Scheme 6.36). In this step, Amberlyst 21 was used as a scavenger for hydrochloric acid produced during the formation of an intermediate methyl ester on treatment with TMSCl/MeOH. In the next step, the polymer-supported borohydride reagent was used for the reductive amination. The amine formed was immediately acylated with trifluoroacetic anhydride to yield the protected amine 269. Polymersupported aminomethylpyridine in the presence of polyvinylpyridine were used as the catalysts in this transformation. To proceed, the polymer-supported hypervalent iodine reagent was used to convert 269 into spirodienone 270, which was then converted into a pentacyclic core structure 271 using fluorosulfonic acid resin as a catalyst. Another key transformation was the stereo and regioselective reduction of keto functionality in 271, which was accomplished using a resin-bound borohydride reagent. The sterically hindered intermediate alcohol was then methylated by treatment with trimethylsilyl diazomethane and sulfonic acid resin. The subsequent trifluoroacetate protecting group was removed by Ambersep 900 in methanol in a OH O OH

OH

O

1) TMSCl/MeOH 2)

O

O

3) NH2Me H2N

H

1)

NEt2 2)

CO2H

O

H2N

267

NMe3BH4

NHMe CF3

O 269

3) (CF3CO)2O, DCM

NHMe

O

N

O

OAc

N I

268 N

OAc

N O

O H

MeO H O

SO3H

N H

O

271

O N

O 270

CF3

NHMe O CF3

NEt3 (NaCO3)

1)

PPh2 HO Br

274 SH

MeO H

1) CrO3

N

O

OH HO

H N

2)

O

273

Br2

R2

MeO

H N N

N

H

O

2)

SO3H

3) clay scavenger 275

OH

277

N O

R3

NHR5

O N S O

278 clean 5-step process R5 5 independent libraries Final library with 5 point diversity

N

O

R1

R1

H O

O O

CF2SO3H

O N H O

O

NMe3 OH

3)

H

272

O

2) TMSCHN2 O

O

N

NMe3BH4

1) N

O 276 OH

SCHEME 6.36. Total synthesis of the (þ)-Plicamine using solid supported reagents and scavengers in a multistep sequence of reactions.

194

CHIRAL SYNTHESIS ON POLYMER SUPPORT

sealed tube microwave reactor to furnish free amine intermediate 272. Compound 272 was then functionalized and transformed into 275 in three steps all involving immobilized reagents and scavengers. The final oxidation was achieved using CrO3 and 3,5-dimethylpyrazole in which the Amberlyst 15 resin was used as a scavenger to remove the contaminating unoxidized amine and the pyrazole. The chromium salts were efficiently removed by filtration through the mixed-bed column Chem Elut CE 1005 packing material and Montomorillonite K10 clay to yield (þ)-plicamine 276. Throughout this process, work-up of the reaction mixture was greatly facilitated requiring only the simple operation of filtration to remove excess reagents followed by evaporation to afford the products. The entire route, including optimization was reported to be completed in just 6 weeks, without needing to rehearse the reactions using conventional solution-phase reagents or requiring separation methods. Although no library synthesis was reported, the present synthetic protocol can be easily used to synthesize (þ)-plicamine library with four-or-five–point diversity as shown in Scheme 6.36. Overall, this represents a unique and powerful example of multistep synthesis of complex natural products using polymer-supported reagents and scavengers to avoid conventional chromatographic purifications and easy adaptability to combinatorial library synthesis. The power of this orchestrated use of polymersupported reagents was also demonstrated by the authors for the combinatorial synthesis of various heterocyclic systems and natural-product libraries [101a,b]. Preparation of bicyclo[2.2.2]octane 278 via tandem Michael addition reactions and their subsequent combinatorial decoration is one prominent example for the application of this technique in combinatorial chemistry [104].

6.3 CONCLUSIONS The synthesis of chiral compound collection on polymeric support has broad applications in the drug discovery process. Among the possible options of chiral synthesis, a chiral pool approach has been enormously explored for such library synthesis. At the same time, during last 20 years, several research groups have demonstrated the use of asymmetric catalysis for the total synthesis on solid support, and a few of these enantioselective reaction types were used for chiral library synthesis. We have observed the application of an asymmetric boron-mediated aldol coupling reaction, asymmetric 1,3-dipolar cycloaddition reaction, asymmetric dihydroxylation reaction, enantioselective Suga–Ibata reaction, enantioselective Diels– Alder, and oxa-Diels–Alder reactions for such a chiral compound collection. The asymmetric Michael addition and alkylation of polymer-bound chiral substrates was also used to generate the diastereoselective combinatorial library. Apart from these reactions, there are a few other examples of the enantioselective synthesis on solid support. Namely, asymmetric crotyl transfer to immobilized aldehydes using chiral silanes [105], asymmetric catalytic hydrogenation using chiral rhodium catalysts [106], enantioselective alkylation of immobilized imines [107], and enantioselective cyanohydrins synthesis [108] have great potential to be used in combinatorial library synthesis or in diversity-oriented synthesis for the possible

REFERENCES

195

diversification of resin-bound substrates. This approach has not been explored much for the combinatorial library generation, but based on the future need of unsaturated skeletons in the drug discovery process, it will be an important tool for generating rapid nonracemic compound libraries.

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CHAPTER 7

SYNTHESIS AND APPLICATION OF HELICAL POLYMERS WITH MACROMOLECULAR HELICITY MEMORY HIROKI IIDA and EIJI YASHIMA

7.1 INTRODUCTION Inspired by the fascinating biological helices in DNA and proteins, the design and synthesis of artificial helical polymers with a controlled helical sense (right- or lefthanded helix) has become one of the emerging research areas in polymer chemistry and supramolecular chemistry as well as in the materials sciences for their wide variety of possible applications as chiral materials for separating enantiomers and enantioselective catalysis. Nowadays, a great number of helical polymers with optical activity have been synthesized and the details, including the historical background of helical polymers and its recent progress, have been thoroughly reviewed elsewhere [1–15]. Optically active polymers can be prepared by the polymerization of optically active monomers. However, it proves difficult if their optical activities were mainly derived from an excess of a one-handed helical conformation, in other words, if the polymers could possess a helical structure or not. Circular dichroism (CD) and/or optical rotation are often used to describe possible helical structures, but these methods are not straightforward for proposing an unambiguous helical structure. Convincing evidence that a stable helical conformation in solution can be synthesized was first reported by the groups of Nolte and Okamoto (Figure 7.1a). Nolte et al. successfully resolved poly(t-butyl isocyanide) (1) into enantiomeric right- and left-handed helices by chiral liquid chromatography in 1974 [16]. Later, Okamoto et al. polymerized an achiral vinyl monomer with a bulky substituent, triphenylmethyl methacrylate (TrMA), using chiral anionic initiators, resulting in a fully isotactic polymer (2) with a large, specific rotation in 1979 [17]. These discoveries 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.

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FIGURE 7.1. Three methods for helical polymer syntheses and representative structures (a and b).

obviously reached the conclusion that optically active polymers whose optical activity is solely a result of preferred-handed macromolecular helicity can be indeed synthesized during the polymerization under total kinetic control. Okamoto et al.’s method is called helix-sense-selective polymerization, resulting in the formation of static helical polymers and has become a powerful tool for the synthesis of other optically active helical polymers, such as polychloral (3) [18, 19], poly(quinoxaline2,3-diyl)s (4) [10], and polyguanidines (5) [20].

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In addition to these static helical polymers, Green et al. discovered a unique helical polymer, that is, a dynamic helical polymer in 1988 [21]. They found that a deuterium-substituted polyisocyanate (6) (Figure 7.1b) showed a remarkably large, specific rotation ([a]D –444
), whereas the monomer has a negligibly small, specific rotation ([a]D þ 0.65
). Green et al. experimentally and theoretically revealed the principle observed for this noticeable amplification of the chirality. Polyisocyanates consist of a mixture of interconvertible right- and left-handed helical segments separated by the rarely occurring mobile helical reversals. Because of the very low helix inversion barrier together with an extremely long helical persistent length, a small chiral bias at the pendants is significantly amplified with a high cooperativity, resulting in a large helical sense excess of the entire helical polymer chain under thermodynamic control. Therefore, the copolymerization of an achiral isocyanate with a small amount of an optically active isocyanate (less than 1 mol%) [22, 23] or polymerization of nonracemic isocyanates with a very low enantiomeric excess (ee) can produce helical polyisocyanates with an excess one-handedness; these phenomena are termed the “sergeants and soldiers” effect and “majority rule,” respectively. A large number of other optically active polymers, such as polysilanes [9, 13], polyacetylenes [11, 12, 14, 15, 24, 25], and poly(carbodiimide)s [26] (for example, 7, 8, and 9, respectively) belong to this category. Taking advantage of the noncovalent bonding interaction, which is a key technique for constructing molecular assemblies in supramolecular chemistry, we succeeded in developing a facile method for constructing dynamic helical polyacetylenes with an excess of one-handedness via noncovalent bonding interactions using specific optically active guests. In addition, the preferred-handed helicity induced in dynamically racemic helical polyacetylenes was successfully “memorized” after the complete removal of the optically active guests (Figure 7.1c) [11, 12, 15]. In this chapter, we focus on this unprecedented memory effect on helical chirality discovered in our laboratory and describe the recent progress in the synthesis of helical polymers with a macromolecular helicity memory together with their applications in asymmetric catalytic reactions.

7.2 MACROMOLECULAR HELICITY MEMORY 7.2.1 Macromolecular Helicity Memory in Solution An optically inactive cis-transoidal stereoregular poly(phenylacetylene) (PPA) bearing a carboxy group (10) is one of the dynamic helical polymers that forms a complex with optically active amines through an acid–base interaction. As a result, a preferredhanded helical conformation is instantaneously induced on the polymer through such noncovalent bonding interactions with chiral amines (Figure 7.2a) [27, 28]. The predominantly one-handed helix formation can be proven by the appearance of a characteristic induced circular dichroism (ICD) in the ultraviolet (UV)–visible region of the p-conjugated polymer backbone. The preferred-handed macromolecular helicity is not static, but dynamic in nature. Therefore, the ICD generated from the

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FIGURE 7.2. (a) Schematic illustration of a helicity induction in 10–13 with (R)-14, and loss and memory of the induced helicity after removing of (R)-14 and replacement by achiral amines (15–20), respectively. (b) Memory efficiencies of macromolecular helicity of 10 induced by (R)-14 using a series of achiral amino alcohols and amines 15–20. Memory efficiencies (%) were estimated on the basis of the CD intensities of the second Cotton effect ([q]2nd), just after the fractionation of the 10-(R)-14 complex solution in the presence of amino alcohols and amines in DMSO as the mobile phase. (c) Storage of the induced helicity or helicity memory by asymmetric esterification with diazomethane.

helical sense bias immediately disappears when the amines are removed by exposure to a stronger acid, such as trifluoroacetic acid (TFA). Interestingly, the helical conformations of 10–13 induced by nonracemic amines, such as (R)-14, are memorized after the chiral amines are removed and completely replaced by achiral amines, e.g., 15 and 18 in dimethyl sulfoxide (DMSO) [29–32]. This unique memory of the macromolecular helicity is not transient, but it is retained for a long time with a half-life time of more than 2 years for 10, indicating that the dynamic helical conformation with an excess handedness assisted by nonracemic amines that is first

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induced under thermodynamic control, is locked and transforms into a kinetically controlled static one after replacement with the achiral amines. The mechanism of the preferred-handed helix induction and subsequent memory of the helical chirality of 10 was thoroughly investigated using UV–visible, CD, and infrared (IR) spectroscopies [30]. A one-handed helical sense is cooperatively induced on 10 to form the ion pair between the carboxy groups of 10 and the optically active amines in which the bulkiness of the chiral amines plays an important role in biasing an excess of the one-handedness. In addition, the free ion formation is essential for the helicity memory of 10 after the replacement of the chiral amine by achiral amines, because the intramolecular electrostatic repulsion between the neighboring negatively charged carboxylate ions of 10 contributes to reducing the helix inversion of 10 [30]. The memory efficiency was found to be dependent on the small structural changes in the achiral amino alcohols and amines used, whereas the weak basic and bulky amines (17, 20) showed no memory effect (Figure 7.2b) [29, 30]. The helical chirality induced and memorized in dynamic helical polyacetylenes provides a specific chiral field for further transfer of chiral information. A similar preferred-handed helicity induction and memory is possible for a dynamic PPA bearing a phosphonic acid mono ethyl ester as the pendant group (12). The pendant group can be converted into its methyl ester using diazomethane, which results in the generation of a phosphorus stereogenic center with optical activity (21 in Figure 7.2c) [33]. Interestingly, the esterification enantioselectively proceeds when 12 has a preferred-handed helical conformation induced by (R)- or (S)-14 or a macromolecular helicity memory assisted by the achiral ethylenediamine. This means that a dynamic helicity memory induced or memorized in the polyacetylene has been stored. Upon complexation with various chiral amines and amino alcohols in DMSO, a PPA bearing a carboxybiphenyl group as the pendant (22) also exhibited a characteristic ICD in the UV–visible region as a result of the predominantly one-handed helix formation of the polymer backbone as well as an excess of a single-handed, axially twisted conformation of the pendant biphenyl groups (Figure 7.3) [34]. The induced macromolecular helicity in the polymer backbone and the twisted biphenyl chirality in the pendants were further memorized after the chiral amine was replaced with the achiral 18 in DMSO. However, the helicity memory of 22 with the achiral 15 occurred with inversion of the axial chirality of the biphenyl groups followed by memory of the inverted biphenyl chirality. As a result, the diastereomeric helices of 22 with an opposite axial chirality at the biphenyl units could be successfully prepared by the different amines. The noncovalent helicity induction followed by the helicity memory provides a facile method to produce either a right- or a left-handed helical conformation with an excess one-handedness. However, the helical sense (right- or left-handed helix) is determined by the chirality of the enantiomeric amines used, so that the helicity memory with the opposite handedness requires the opposite enantiomeric amine before the replacement with achiral amines. Recently, we found that both enantiomeric helices with a mirror-image to each other can be produced with a high memory efficiency from a helical PPA (23) induced by a single enantiomer (Figure 7.4) [35].

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FIGURE 7.3. Schematic illustration of a helicity induction in 22 upon complexation with (R)-14, memory of macromolecular helicity and axial chirality of the biphenyl units of 22 induced by (R)-14 assisted by interactions with achiral 18 and 15.

This so-called dual memory of enantiomeric helices was achieved by taking advantage of the temperature-dependent inversion of the macromolecular helicity, that is, one of the most unique features of dynamic helical polymers. The PPA 23 formed a preferred-handed helical conformation induced by (R)-14 at 25
C in DMSO. Upon heating, the helix sense inverted at 65
C, as evidenced by the Cotton effect inversion. These diastereomeric right- and left-handed helices of 23 formed at 25
C and 65
C can be further memorized using an achiral diamine, such as 24, at these temperatures, resulting in the formation of enantiomeric helices of the 23–24 complexes that exhibited the perfect mirror-image Cotton effects in their patterns and intensities accompanied by the identical absorption spectra. Subsequent replacement of the nonracemic 14 with the achiral 24 afforded the enantiomeric helices of 23 with an excess single-handedness. For the memory of the macromolecular helicity in dynamic helical PPAs, the use of achiral amines is essential; otherwise the memory will be immediately lost just after removing chiral amines used for the helicity induction in the polymers. However, poly(4-carboxyphenyl isocyanide) (25) with an excess single-handed helix induced by (S)-26 in water was found to memorize its helicity even after complete removal of the (S)-26 (h-25b), whereas that induced in DMSO and DMSO–water mixtures containing less than 30 vol % water could not maintain its optical activity after removal of the chiral amines (25a) (Figure 7.5a) [36]. The helix induction mechanism with chiral amines and the memory of the macromolecular helicity in water and

MACROMOLECULAR HELICITY MEMORY

207

FIGURE 7.4. (a) Schematic illustration of an induced one-handed helicity in optically inactive 23, helix inversion with temperature, and subsequent memory of the diastereomeric macromolecular helicity at different temperatures. (b) These diastereomeric helices of 23 are memorized at different temperatures by replacement of the (R)-14 with achiral 24, resulting in the formation of the enantiomeric mirror image helices of 23.

a DMSO–water mixture were comprehensively studied by various spectroscopic measurements, theoretical calculations, and persistence length measurements together with X-ray diffraction (XRD) measurements [37]. The as-prepared achiral 25 folded into a rigid preferred-handed 10/3 helical structure in the presence of chiral amines in water. This process is accompanied by transformation of an imino configurational mixture of syn- and anti-25 into one of a single configuration, and this selective and specific configurational isomerization, driven by hydrophobic and chiral ionic interactions in water, plays a crucial role in forming an excess of a one-handed helical structure (h-25b) [37]. Therefore, the induced helix seems to be kinetically controlled and can be maintained after removal of the chiral amines. The as-prepared 25 also folded into a preferred-handed, semirigid 9/5 helix with an excess helical sense upon complexation with chiral amines in DMSO (25a), probably due to the similar syn–anti configurational isomerization. In sharp contrast to h-25b, however, the resulting 9/5 helical 25a has a dynamic characteristic and its helical conformation instantly racemizes after removal of the chiral amines, as observed for the dynamic racemic polyacetylenes. Therefore, the induced helix in 25 is formed under thermodynamic control in DMSO. After standing in solution for an extremely long time, the as-prepared 25 and h-25b changed their structures to the 25a, suggesting that the 25a structure seems to be the thermodynamically most stable structure. We also measured the persistence length (q) of the corresponding methyl esters (25-Me) and found that the q-value of the as-prepared 25-Me significantly increased from 59 to 88 nm when a preferred-handed helicity

208

SYNTHESIS AND APPLICATION OF HELICAL POLYMERS

FIGURE 7.5. (a) Possible structures of 25, 25a, and h-25b and their mutual interconversions via a helicity induction in 25 in DMSO and water with (S)-26 and subsequent removal of (S)-26. The macromolecular helicity induced in water is memorized after complete removal of (S)-26 (h-25b), whereas that induced in DMSO cannot be memorized (25a). (b) Modification of the pendants and the application to asymmetric polymer catalyst with macromolecular helicity memory.

is induced and memorized (h-25b-Me). In contrast, the q-value of the methyl ester, which lost its optical activity (25a-Me), decreased to 43 nm. Consequently, the optically inactive 25 can change its structure into either a static or a dynamic helical conformation upon complexation with chiral amines in water or organic solvents, respectively, accompanied by selective configurational isomerization around the C¼N double bonds, and these different helical conformations can be interconvertible [37]. This unprecedented helix-sense-selective synthesis through specific noncovalent chiral interactions, resulting in a polyisocyanide with a static helicity memory,

MACROMOLECULAR HELICITY MEMORY

209

has a significant advantage over the memory effect observed in the helical PPAs because achiral amines are no longer required to retain the helicity in the polyisocyanide. Therefore, additional modifications of the side groups are possible without loss of the macromolecular helicity memory, thus affording a variety of helical polyisocyanides with functional pendant groups, such as 27, 28, and 29 that may be aligned along the helical polymer backbone (Figure 7.5b) [38, 39]. The static polyisocyanides with a macromolecular helicity memory are likely a promising scaffold for the development of diverse chiral materials, such as asymmetric polymer catalysts and chiral stationary phases (CSPs), for highperformance liquid chromatography (HPLC). In fact, the modified helical polyisocyanide with achiral piperazine (29) could be used as a polymeric organocatalyst for the asymmetric aldol reaction, and the observed enantioselectivity was solely derived from the preferred-handed macromolecular helicity memorized in the polyisocyanide (see Section 7.3) [39]. The macromolecular helicity of polyisocyanides plays an important role in the chiral recognition of enantiomers when used as a CSP for HPLC (Figure 7.6) [40]. We prepared diastereomeric left- and right-handed helical polyisocyanides with a different molecular weight and a narrow molecular weight distribution (M-30(–) and P-30(þ)) by the living polymerization of an enantiomerically pure phenyl isocyanide bearing an L-alanine pendant using the m-ethynediyl Pt–Pd complex [41, 42] as the catalyst, which could be further isolated into the diastereomeric helical polyisocyanides via fractionation with acetone [43]. After block copolymerization with a protected carboxylic acid (31) using M-30(–) and P-30(þ) as a macroinitiator, the obtained polymers (M-30(–)-b-31 and P-30(þ)-b-31) were immobilized on silica gel via chemical bonding (Si-M-BP(–) and Si-P-BP(þ)) and their optical resolution abilities were evaluated as CSPs [40]. The CSP consisting of the left-handed Si-M-BP(–) resolved the racemic cyclic ether and carbonyl compounds and the cyclic dianilides and dibenzamides, whereas the right-handed Si-P-BP(þ) showed a complementary chiral recognition ability and specifically resolved the racemic metal acetylacetonate complexes, which were not separated on the former CSP at all. In addition, the elution order of some enantiomers was reversed on the CSPs, indicating that not only the pendant alanine residues but also the macromolecular helicity of the L-alanine-bound-polyisocyanides contributed to the enantioselectivity and elution order of the enantiomers. The helicity memory effect has also been observed in supramolecular helical systems (Chart 7.1). Trialkyl-1,3,5-benzenetricarboxamides (32 and 33) formed a helically twisted columnar structure by self-assembly through a threefold intermolecular hydrogen bonding in apolar solvents [44, 45]. The sorbyl residues introduced at each achiral 32 unit preferentially 1,4-polymerized under UV light irradiation within the columnar assembly, thus producing an optically active linear polymer while maintaining its supramolecular helical columnar structure after removal of the chiral template 33 in specific solvents [46]. A zinc (II) meso–meso-linked porphyrin oligomer (34) formed a predominantly one-handed helical conformation upon complexation with 35 in the presence of the chiral diamine (S)-36) [47]. A chiral memory effect was observed when an equimolar amount of the opposite (R)-36 was added to

210

SYNTHESIS AND APPLICATION OF HELICAL POLYMERS

Si-M-BP(–)

i)

31 M- 30(–)

TBAF

M- 30(–)-b- 31

THF

Diastereomeric Helices

THF

DMT-MM Pyridine ii) CH2N2

Block Copolymerization

Immobilization on Silica Gel

i)

31

TBAF

THF

P -30(+)

P-30(+)-b-31

PEt 3 Pt Cl PEt 3

PEt3 Cl Pd C n PEt3 N

THF

DMT-MM Pyridine ii) CH2N2

Si-P-BP(+)

PEt3

PEt 3

C Cl Pd x PEt3 N

Pt Cl

C n N

C m-x N

PEt3

M-30(–) P-30(+) O

O

NH

NH O

OMe O

NH O

O OC10H21 C

Si O O O

N

OC10H21

Si-M-BP(–) Si-P -BP(+)

Silica Gel O Si O

O

31

Silica Gel

O Si (CH2)3NH2 O

FIGURE 7.6. Schematic illustration of the helix-sense-selective living block copolymerization of 31 using diastereomeric left-handed M-30(–) and right-handed P-30(þ) as the macroinitiators obtained by acetone fractionation of the as-prepared 30 and immobilization of the resulting block-polymers onto silica gel through amidation reaction (Si-M-BP(–) and Si-P-BP(þ)).

a solution of 34–35 and (S)-36. A supramolecular ladder-shaped polymer with an excess handedness was also constructed using the saddle-shaped porphyrin 37 as a building block in the presence of the optically active Pd complex (38) or achiral Pt complex with the optically active mandelic acid [48, 49]. The helical chirality translated into the saddle-shaped chirality of the monomer porphyrin was further memorized upon depolymerization of the ladder polymer in the presence of achiral acetic acid. A dynamically racemic helical oligopeptide composed of achiral amino acids with a single intramolecular side-chain cross-link (39) was prepared [50]. Noncovalent chiral interactions occurred at the N-terminal amino group with a chiral carboxylic acid (L-40) that induced a helix-sense bias in the entire oligopeptide chain,

211

MACROMOLECULAR HELICITY MEMORY

32: R 1 = C8H17

R1 O

N

R2 = O

H

H R1

N

O O

H

N

H3C

5 O

CH3 O CH3

O H3C

N

33: R 1 = R2 =

H3C

R2

N

CH3 NH

N

R

R N

HN

H3C Ar

N

Ar =

H3C O

H3C

N N Ar

N N Zn N N

CH3

CO2H OC12H25

HO2C

Zn N N Ar 7

CH3 O CH3

N

37a: R = OC 12H25 37b: R = H

H C4H7

N

C4H7

N

O Ar

34

H

35 Ph2 P PPh2

Ph P Ph

P Ph Ph

Pd O(CH2)2NH2

H2N(H2C)2O

TfO

DPPP

OTf 38

(S)-36

O

O N

H N

H2N O

O N H

H N O

N

O N H

H N O

O N 2H

39

H N O

O

O OCH3 2

H N

O OH

O H L-40

CHART 7.1.

which was successfully memorized after the side-chain cross-linking at i and i þ 3 in a 3/10-helix. The PPAs bearing the bulky diisopropylaminomethyl group (41) and aza-18crown-6-ether (42) as the functional groups are soluble in acidic and neutral water and can serve as a novel template for the formation of supramolecular helical aggregates of achiral porphyrin and cyanine dyes, respectively (Figure 7.7). The positively charged PPA (41-HCl) can trap a hydrophobic chiral guest, (S)-1,1’-bi-2naphthol (S)-43), within the hydrophobic helical cavity in water, which induced an excess one-handed helix in the PPA. The achiral porphyrin with opposite charges (H4TPPS2) self-assembled on the outer side of the induced helical 41-HCl as a template to form supramolecular J-homo-aggregates in a preferred-handed helical array as evidenced by the appearance of an intense ICD in the J-aggregated porphyrin chromophore region (Figure 7.7a) [51]. The supramolecular chirality of the porphyrin

212

SYNTHESIS AND APPLICATION OF HELICAL POLYMERS

FIGURE 7.7. Schematic illustration of the induction of a preferred-handed helicity in 41-HCl (a) and 42 (b) upon complexation with (S)-43 and D-Trp, respectively, subsequent formation of supramolecular helical aggregates of achiral H4TPPS2- and 44, and memory of the supramolecular chirality after inversion of the helicity of the polymer backbone by addition of excess (R)-43 and L-Trp, respectively.

J-aggregates retained its optical activity after the addition of an excess opposite enantiomer (R)-43 [51]. However, an excess single-handed helical conformation was induced in the water-soluble neutral 42 in the presence of chiral amino acids, such as the L- or D-tryptophan (Trp), through specific host–guest complexations in the exterior crown ether residues [52]. The helical 42 could trap an achiral cyanine dye, 3,3-diethyloxadicarbocyanine iodide (44), within its hydrophobic helical cavity in acidic water, resulting in the formation of supramolecular J-aggregates with a preferred-handed helical array along the helical backbone of 42 after annealing, thus showing an ICD in the achiral cyanine chromophore region (Figure 7.7b) [53]. In addition, the supramolecular chirality induced in the cyanine aggregates can also be memorized after inversion of the macromolecular helicity of the template 42 by the addition of excess Trp with the opposite configuration [53]. An amidinium–carboxylate salt bridge that has a well-defined geometry originating from double hydrogen bonding and high association constants even in polar solvents has been widely used as a versatile structural motif for constructing several supramolecular assemblies, including double helices [54–57]. A platinum containing

MACROMOLECULAR HELICITY MEMORY

213

double helix consisting of an achiral amidine (45) and carboxylic acid strands (46) with chiral phosphine ligands (R)- or (S)-2-diphenylphosphino-2’-methoxy-1,1’binaphthyl (R)- or (S)-MOP) on the Pt(II)-acetylide linkers (R)- or (S)-4546 was recently designed and synthesized [58]. The double helix takes a dynamic helical structure induced by the chiral ligand MOP and exhibits temperature-dependent Cotton effect changes in the metal-to-ligand charge transfer (MLCT) region of the Pt (II) complex linkers (Figure 7.8a). Surprisingly, the helical sense in chloroform was inverted in toluene. Taking full advantage of this unique helix inversion in different solvents and the helicity induction and memory effect together with the specific interstrand ligand exchange reaction by an achiral diphosphine with one methylene spacer, bis(diphenylphosphinomethane) (dppm), both enantiomers of the bridged double helix (47) were successfully synthesized, in other words, memorized using a single enantiomer of MOP by changing the solvents (Figure 7.8b). The optically active bridged double helices (47) with a helicity memory can accommodate metal ions such as Cu(I) in a tweezer-like fashion (Figure 7.8c), and the complex catalyzed the asymmetric cyclopropanation reaction of styrene with ethyl diazoacetate, thus producing an optically active product up to 85%ee. The free radical polymerization of a bulky vinyl monomer bearing optically active groups, 2,5-bis[(4’-alkoxycarbonyl)phenyl]styrene, produced an optically active polymer (48). Interestingly, after the optically active alkyl chains were removed by chemical reaction (49) followed by methylation using dimethyl sulfate (50), the optical activity of the polymers remained presumably via the memory effect (Scheme 7.1) [59]. 7.2.2 Macromolecular Helicity Memory in a Gel and a Solid The preferred-handed helicity induction and subsequent memory of the macromolecular helicity can also be applied to a commodity polymer, such as syndiotactic poly(methyl methacrylate) (st-PMMA). st-PMMA forms a thermoreversible physical gel in aromatic solvents, such as toluene and chlorobenzene, in which the st-PMMA is reported to take a helical structure with a sufficiently large cavity of about 1 nm, and the solvent’s molecules are encapsulated in the cavity [60]. We anticipated that one of the helices might be induced in the st-PMMA with chiral additives during the gelation and, at the same time, encapsulation of fullerenes. In fact, in the presence of an optically active alcohol, such as (S)- or (R)-1-phenylethanol (51) and fullerenes in toluene, st-PMMA folds into a preferred-handed helix accompanied by gelation, and encapsulated fullerenes, such as C60, C70, and C84 within its helical cavity, thus producing a robust, processable, peapod-like crystalline complex (Figure 7.9a) [61]. As expected, after removal of 51, the st-PMMA gel complexed with C60 exhibited vibrational CD (VCD) and ICD signals in the PMMA IR regions and in the encapsulated C60 chromophore regions, respectively, although C60 itself is totally achiral. The optically active, fullerene-encapsulated st-PMMA with a macromolecular helicity memory can be further used as a template for inclusion of the complementary isotactic PMMA (it-PMMA) through replacement of the encapsulated C60 molecules, resulting in a practically versatile PMMA stereocomplex [62–64] with optical activity (Figure 7.9a) [65].

214

SYNTHESIS AND APPLICATION OF HELICAL POLYMERS

FIGURE 7.8. (a) Enantioselective synthesis of complementary double-helical molecules. Schematic illustration of the diastereomeric double-helix formation from complementary molecular strands (45 and 46) containing Pt(II) acetylide complex moieties through amidinium carboxylate salt-bridge formation; the chiral phosphine ligand (MOP) induces diastereomeric double helices. (b) Removal of the chiral ligands by ligand exchange on the Pt(II) with achiral diphosphine ligands (dppm) generates the enantiomeric double helices 47 with controlled helicity; the right- and left-handed double helices can be controlled by the type of solvent used. (c) Application to the optically active ligand for Cu-catalyzed asymmetric cyclopropanation.

The helical st-PMMA showed a preferential binding capability to C70 over C60. When equal amounts of C60 and C70 were mixed in toluene with st-PMMA, st-PMMA preferentially encapsulated C70 over C60 with an almost perfect selectivity (99.8%) (Figure 7.9b) [66]. The higher fullerenes were also selectively extracted

MACROMOLECULAR HELICITY MEMORY

*RO

CH

CH2

RO n

CH

BBr3

CH2

215

n

48 OR*

OR

49

R* =

R=H

CD active 50

(CH3)2SO4

R = CH3

CD active

SCHEME 7.1.

from the carbon soot (a commercially available fullerene mixture) composed of the C60/C70/higher fullerenes (64.0:27.2:8.8%), and the higher fullerene content significantly increased to 95.4% from 8.8% in the feed by single extraction with st-PMMA. Furthermore, an optically active st-PMMA with an excess single-handed helix induced

FIGURE 7.9. (a) Schematic illustration of a helicity induction in st-PMMA in the presence of C60 with (S)- or (R)-51, memory of the induced helicity after removal of 51, and subsequent “optically active” stereocomplex formation after the addition of it-PMMA, resulting from replacement of the encapsulated C60 molecules by it-PMMA strands. (b) Schematic illustration of the preferential encapsulation of C70 over C60 by st-PMMA and (c) selective extraction and resolution of higher fullerenes by helical st-PMMA with the induced helicity.

216

SYNTHESIS AND APPLICATION OF HELICAL POLYMERS

by a chiral amine (S)- or (R)-52) was found to enantiomer-selectively extract chiral fullerenes (Figure 7.9c) [66]. A series of optically active fullerenes (C76, C84, C86, C88, C90, C92, C94, and C96) was extracted from carbon soot, and each higher fullerene was isolated by preparative HPLC. The optically active C76 of ca 4%ee was obtained by a single extraction from the carbon soot. Dynamic helical polymers with a low helix inversion barrier readily racemize in solution; thus, the memory effect cannot be expected in the absence of chaperoning molecules that assist in retaining the helicity. However, such a memory of helicity may be possible in the solid state in which the helix inversion may very slowly proceed. The optically active poly(diphenylacetylene) (53) and poly(phenylacetylene)s (54 and 55) having chiral p-(dimethylpinanylsilyl) pendant groups were reported to maintain their optical activities after removal of the optically active pinanylsilyl groups in the solid state and exhibited ICDs in the p-p* main-chain chromophore regions (Scheme 7.2a) [67]. Using the recently developed layer-by-layer (LbL) assembly technique [68], the macromolecular helicity memory of a PPA (12) in water has been achieved [69]. A negatively charged dynamic helical 12 with a helical sense bias induced by (S)-26 showing a full ICD in water was first deposited on a quartz substrate. To this was LbL assembled the hydrochloride of poly(allylamine) (PAH) with positive charges. The (S)-26 molecules were simultaneously removed during the LbL assembly process, and repeating the alternative deposition cycle resulted in optically active multilayer thin films with a helicity memory (Scheme 7.2b). When a positively charged, induced helical 12-HCl was used instead, the similar LbL assembly with an achiral vinyl polymer with opposite charges produced an optically active thin film with a helicity memory [69].

(a)

(b) C

C

C H

n

53

Pi

C

54: R = -OPi 55: R = -CH2OPi

R

Depinanylsilylation with CF3CO2H

NH3+ NH3+ Amino-modified NH3+ quartz plate

n

Pi =

12—(S)-26 complex

Me Si Me

n PAH

C

C

n

C H

C

n

NH3Cl LbL assembly

de-54: R' = -OH de-53 CD active

R' de-55: R' = -CH2OH CD active

SCHEME 7.2.

(S)-26

LbL films with helicity memory

217

MACROMOLECULAR HELICITY MEMORY

Exposure of nonracemic volatile molecules, such as (R)- and (S)-limonene (56) and carvone, to the d-form syndiotactic polystyrene (st-PS) films induced an intense ICD in the aromatic region of the st-PS (Figure 7.10a) [70–72]. Interestingly, the ICDs were retained after complete removal of the guests or successive absorption of other racemic or nonracemic guests. A detailed investigation suggests that the chiral memory effect may not be associated with the molecular structure of the st-PS but derived from the formation of nonracemic supramolecular crystalline structures induced by nonracemic guests [72]. The electrochemically polymerized emeraldine base form of polyaniline (57) exhibits an ICD in the polymer main-chain regions in solution or in the film when doped with optically active strong acids, such as (R)- or (S)-camphorsulfonic acid (CSA), presumably as a result of the helical conformation with an excess handedness [73, 74]. The film retained its optical activity after removal of the dopants [75]. The (R)-CSA dedoped polyaniline thin films possessed an interesting enantioselective discrimination ability to the chirality of L- and D-phenylalanine (58) enantiomers and showed a different color change (green versus blue) in the presence of the L- and D-58 [76]. a

(a)

b

Exposure to (R)- or (S)-56

Extraction with supercritical CO 2

(R)- or (S)-56

(R)- or (S)-56

Helicity induction and memory

δ -Form st-PS film

CD active

O

(R)- or (S)-56

(b) H N

Doping

De-doping

(i)

(ii)

N N H

n

green film

(R)-CSA

Helicity induction and memory

blue film

D-58

L-58

O

SO3H O

(R)-CSA

N

57

Ph

OH

(iii)

(iv)

NH2

(R)-CSA

L- or D-58

blue film

green film

FIGURE 7.10. (a) Schematic illustration of a chirality induction in st-PS upon exposure to chiral molecules (R)- or (S)-56) and subsequent memory of the chirality after removal of 56 in d-form st-PS film. (b) Schematic illustration of the enantioselective discrimination of D-and L-58 by chiral polyaniline (57) thin films: (i) a green (R)-CSA doped 57 thin film; (ii) a blue (R)-CSA de-doped 57 thin film; (iii) a de-doped 57 thin film turns green after exposure to L-58; and (iv) a de-doped 57 thin film stays blue after exposure to D-58. (Reproduced with permission from Ref. 71 and 76. Copyright 2008 The Royal Society of Chemistry and 2003 Wiley-VCH.)

218

SYNTHESIS AND APPLICATION OF HELICAL POLYMERS

7.3 ENANTIOSELECTIVE REACTION ASSISTED BY HELICAL POLYMERS WITH HELICITY MEMORY Polymeric chiral catalysts are generally prepared by the immobilization of small molecular chiral ligands or organocatalysts on achiral polymers via polymer reactions or by the polymerization of the corresponding styrene or methacrylate monomers bearing the chiral ligands as the pendant groups. Accordingly, the polymer main chains just work as supports and the immobilized chiral ligands or catalysts contribute to the enantioselectivity during asymmetric reactions [77, 78]. However, if the support polymers could adopt a helical conformation with an excess of onehandedness, an intriguing synergistic effect derived from the ligand chirality as well as the helical chirality on the enantioselectivity could be anticipated, leading to a more efficient asymmetric polymeric catalyst than the chiral ligand itself, although successful examples are rare [79–84]. Reggelin et al. reported that the one-handed helical polymethacrylates bearing one or two pyridyl groups as a chiral polymeric ligand prepared by the helix-sense-selective polymerization catalyzed the asymmetric allylic alkylation reaction when complexed with palladium, producing the product up to 60%ee [85, 86]. An analogous polymethacrylate bearing pyridyl N-oxide groups with a predominantly one-handed static helical conformation was also found to work as a polymeric organocatalyst for the asymmetric alkylation of benzaldehyde, affording the corresponding allylated product up to 19%ee [87]. Optically active helical poly(quinoxaline-2,3-diyl)s (4) bearing metal-binding phosphino pendant groups prepared by the helix-sense-selective living polymerization are excellent helical polymer catalysts when complexed with palladium that catalyzed the asymmetric hydrosilylation of substituted styrenes, showing a remarkably high enantioselectivity up to 87%ee [83]. More interestingly, a poly(quinoxaline-2,3diyl)-based helical polymer exhibits a unique solvent-dependent helix-sense inversion and produced the S- or R-hydrosilylated products of the opposite configurations (> 93%ee) in each solvent [84]. As described, the “helicity induction and memory” effect is a useful tool for the synthesis of optically active static helical polymers with the macromolecular helicity, and the method was applied to the design for enantioselective polymeric organocatalysts. After the excess one-handed helicity induction and its memory in poly(4-carboxyphenyl isocyanide) (25, Figure 7.5), the side groups of the optically active h-25b were partially modified with achiral piperazine to obtain an optically active helical polymer catalyst (29a), which is devoid of any additional chirality except for the macromolecular helicity memory (Scheme 7.3) [39]. The helical polymer catalyzed the asymmetric direct aldol reaction in which the bifunctional secondary amino and carboxylic acid pendants, arranging in a preferred-handed helical array along the polymer backbone, likely play an important role in the catalytic activity and enantioselectivity. Although the observed enantioselectivity was low (up to 12%ee), this is the first example of the transfer of chiral information from the macromolecular helicity, memorized in the polymer backbone, to the asymmetric transformation. Further rational design and synthesis of helical polyisocyanides bearing functional pendants will provide a

REFERENCES

219

O OH

O

O

H O2N

O2N

29a DMSO, 0 °C

C N

29a

12% ee

C

x

N

1-x n

OH O

N

NH

O

SCHEME 7.3.

new class of asymmetric catalysts based on helical polyisocyanides with the helicity memory.

7.4 CONCLUSIONS In this chapter, the synthesis of optically active polymers with a macromolecular helicity memory and the application of the optically active helical polymers to enantioselective polymeric catalysts are mainly described. The “memory of helical chirality” developed during the intensive studies on the dynamic helical polyacetylene derivatives has been proven to be a unique and useful method for preparing novel helical polymers and oligomers. This methodology has a significant advantage from a practical viewpoint such that a preferred-handed helical polymer can be obtained from commodity polymers such as PMMA. The applications of various synthetic polymers and oligomers with memory of the helical chirality to advanced chiral materials including enantioselective catalysts will be an interesting and important challenge, although the development is still in its infancy.

REFERENCES Okamoto, Y.; Nakano, T. Chem. Rev. 1994, 94, 349–372. Farina, M. Top. Stereochem. 1987, 17, 1–111. Wulff, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 21–37. Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.; Lifson, S. Science 1995, 268, 1860–1866. [5] Pu, L. Acta Polymer, 1997, 48, 116–141. [6] Rowan, A. E.; Nolte, R. J. M. Angew. Chem., Int. Ed. 1998, 37, 63–68. [7] Nakano, T.; Okamoto, Y. Chem. Rev. 2001, 101, 4013–4038. [1] [2] [3] [4]

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SYNTHESIS AND APPLICATION OF HELICAL POLYMERS

[8] Cornelissen, J. J. L. M.; Rowan, A. E.; Nolte, R. J. M.; Sommerdijk, N. A. J. M. Chem Rev. 2001, 101, 4039–4070. [9] Fujiki, M. Macromol. Rapid Commun. 2001, 22, 539–563. [10] Suginome, M.; Ito, Y. Adv. Polymer Sci. 2004, 171, 77–136. [11] Maeda, K.; Yashima, E. Top. Curr. Chem. 2006, 265, 47–88. [12] Yashima, E.; Maeda, K. Macromolecules 2008, 41, 3–12. [13] Fujiki, M. Chem. Rec. 2009, 9, 271–298. [14] Liu, J.; Lam, J. W. Y.; Tang, B. Z. Chem. Rev. 2009, 109, 5799–5867. [15] Yashima, E.; Maeda, K.; Iida, H.; Furusho, Y.; Nagai, K. Chem. Rev. 2009, 109, 6102–6211. [16] Nolte, R. J. M.; Van Beijnen, A. J. M.; Drenth, W. J. Am. Chem. Soc. 1974, 96, 5932–5933. [17] Okamoto, Y.; Suzuki, K.; Ohta, K.; Hatada, K.; Yuki, H. J. Am. Chem. Soc. 1979, 101, 4763–4765. [18] Corley, L. S.; Vogl, O. Polymer Bull. 1980, 3, 211–217. [19] Ute, K.; Hirose, K.; Kashimoto, H.; Hatada, K.; Vogl, O. J. Am. Chem. Soc. 1991, 113, 6305–6306. [20] Tang, H.-Z.; Novak, B. M.; He, J.; Polavarapu, P. L. Angew. Chem. Int. Ed. 2005, 44, 7298–7301. [21] Green, M. M.; Andreola, C.; Munoz, B.; Reidy, M. P.; Zero, K. J. Am. Chem. Soc. 1988, 110, 4063–4065. [22] Green, M. M.; Reidy, M. P.; Johnson, R. J.; Darling, G.; Oleary, D. J.; Willson, G. J. Am. Chem. Soc. 1989, 111, 6452–6454. [23] Jha, S. K.; Cheon, K.-S.; Green, M. M.; Selinger, J. V. J. Am. Chem. Soc. 1999, 121, 1665–1673. [24] Aoki, T.; Kaneko, T.; Teraguchi, M. Polymer 2006, 47, 4867–4892. [25] Rudick, J. G.; Percec, V. New J. Chem. 2007, 31, 1083–1096. [26] Schlitzer, D. S.; Novak, B. M. J. Am. Chem. Soc. 1998, 120, 2196–2197. [27] Yashima, E.; Matsushima, T.; Okamoto, Y. J. Am. Chem. Soc. 1995, 117, 11596–11597. [28] Yashima, E.; Matsushima, T.; Okamoto, Y. J. Am. Chem. Soc. 1997, 119, 6345–6359. [29] Yashima, E.; Maeda, K.; Okamoto, Y. Nature 1999, 399, 449–451. [30] Maeda, K.; Morino, K.; Okamoto, Y.; Sato, T.; Yashima, E. J. Am. Chem. Soc. 2004, 126, 4329–4342. [31] Onouchi, H.; Kashiwagi, D.; Hayashi, K.; Maeda, K.; Yashima, E. Macromolecules 2004, 37, 5495–5503. [32] Hasegawa, T.; Maeda, K.; Ishiguro, H.; Yashima, E. Polymer J. 2006, 38, 912–919. [33] Onouchi, H.; Miyagawa, T.; Furuko, A.; Maeda, K.; Yashima, E. J. Am. Chem. Soc. 2005, 127, 2960–2965. [34] Maeda, K.; Tamaki, S.; Tamura, K.; Yashima, E. Chem. Asian J. 2008, 3, 614–624. [35] Miyagawa, T.; Furuko, A.; Maeda, K.; Katagiri, H.; Furusho, Y.; Yashima, E. J. Am. Chem. Soc. 2005, 127, 5018–5019. [36] Ishikawa, M.; Maeda, K.; Mitsutsuji, Y.; Yashima, E. J. Am. Chem. Soc. 2004, 126, 732–733.

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CHAPTER 8

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S, AND RELATED HELICAL POLYMERS USED AS CHIRAL POLYMER CATALYSTS IN ASYMMETRIC SYNTHESIS YUUYA NAGATA and MICHINORI SUGINOME

8.1 INTRODUCTION The use of polymers as catalysts or ligands for asymmetric synthesis is highly attractive because of the ease of separation of the catalysts from the reaction mixtures. The easy separation is also advantageous in the recovery and reuse of the precious chiral catalysts. Small chiral units such as BINAP, BINOL, and chiral aminoalcohols have been immobilized to common polymers such as polystyrene for the development of practical catalysts for asymmetric synthesis. In this type of molecular design, the polymer scaffolds are expected to be transparent in terms of steric interaction to avoid any unfavorable or conflicting effects of the polymer scaffolds on the chiral reaction sites. In addition, polymer-based catalysts in which the small chiral units are incorporated into polymer main chains have also been developed. These polymer catalysts are dealt with in other chapters of this book. There is a highly contrasting molecular design for the polymer-based chiral catalyst in which the main-chain structures of the polymer create an asymmetric reaction environment. They are highly attractive in that the created asymmetric reaction environment can be different from those created by the corresponding small chiral molecules. Moreover, macromolecular conformational change of the polymer main chain by external stimuli may allow for fine tuning of the chiral reaction environment or even for dramatic change of the enantiodiscrimination. Those

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.

223

224

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

polymer-based chiral catalysts possessing helical main-chain structures are dealt with in this chapter. Prior to the discussion of the chiral polymer catalysts for asymmetric synthesis, synthesis and properties of helical poly(isocyanide)s and poly(quinoxaline-2,3-diyl)s are described as a basis of the discussion. Those polymers have no chiral stereogenic centers in their polymer main chain and thus have only sp2-carbon chains that form helical structures. An induction of the helical sense has been made kinetically or thermodynamically with the use of a chiral end group as well as with chiral side chains. They are treated separately in the following sections.

8.2 ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S Isocyanides are readily prepared from primary amines and used in organic synthesis [1]. In particular, isocyanide-based, multicomponent, carbon–carbon–bond-forming reactions such as Passerini and Ugi [2] reactions are regarded as a powerful strategies for the diversity-oriented synthesis and complex organic molecules. During attempts to explore reactions of isocyanides, most isocyanides bearing no bulky group often form “tars” or “resins” on distillation or storage. These residues were not structurally characterized until the late 1960s. Millich and Sinclair succeeded in the polymerization of isocyanides using finely ground glass coated with sulfuric acid [3]. Yamamoto et al. then found that some cobalt and nickel complexes polymerized cyclohexyl isocyanide efficiently [4]. Recent progress in polymerization of isocyanide has largely relied on transition-metal complexes as polymerization promoters or initiators. There have been numerous efforts to develop the polymerization techniques for isocyanides, and the detailed pioneering works were reviewed and discussed by several authors. In a series of studies originating in 1973, Nolte et al. reported a general and reliable procedure, which uses nickel complexes such as NiCl2 and Ni(acac)2 to polymerize isocyanide in ethanol [5]. The other significant contribution by Nolte et al. in this area was the discovery of a single-handed helical structure of poly(isocyanide)s. Optical resolution using a chiral high-performance liquid chromatography (HPLC) technique or asymmetric polymerization led to the isolation of optically active polymers, whose chirality was supposed to be solely a result of the main-chain helicity. The efforts in the research area concerning chiral helical poly (isocyanide)s will be discussed in this section. 8.2.1 Synthesis of Poly(isocyanide)s Bearing Chiral Side Chains 8.2.1.1 Early Studies on the Polymerization of Chiral Isocyanides. Although it has been suggested from space-filling models that the backbone of poly(isocyanide)s has the conformation of a tightly coiled helix, a nonracemic helical conformation in poly(isocyanide)s was not reported until 1969. Millich and Baker carried out homopolymerizations of d- and l-1-phenylethyl isocyanide in the presence of an acidic-ground glass catalyst (Scheme 8.1) [6]. With the acid catalyst system, each optically active monomer yields an optically active

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

Ph H Me

acidic ground glass NC heptane, O2, 50 °C, 3 d

(S)-(–)-1 [α]27D = -40.4 (neat)

225

Ph Me N H C n (–)-2

60%, Mn = 14.9 × 104 [α]27D = -382 (toluene) Ph

Ph Me H

acidic ground glass NC heptane, O2, 50 °C, 3 d

(R)-(+)-1 [α]27D = -39.5 (neat)

N C

H Me

n (+)-2 55%, Mn = 11.5 × 104 [α]27D = +329 (toluene)

SCHEME 8.1. Polymerization of (S)-(
)-1 and (R)-(þ)-1 in the presence of an acidic ground glass catalyst.

polymer that has a specific rotation of the same sign as the monomer, with ten-fold increased values. Such enhanced optical activity indicated that a nonracemic helical conformation was induced in the main chain. After 10 years, nickel-catalyzed polymerizations of optically active isocyanides have been extensively studied by Nolte et al [6–9]. This catalytic system using NiCl2 had a high tolerance for a wide variety of functional groups, allowing for the production of wide varieties of poly(isocyanide)s. The polymerization of l-1phenylethyl isocyanide in the presence of a nickel catalyst was reported and compared with the corresponding acid-catalyzed polymerization. Both polymerizations yielded poly(isocyanide) (
)-2, whose specific rotations are almost ten times larger than those of the starting isocyanide (S)-(
)-1. Deming and Novak later developed a modified nickel catalyst for the highly efficient polymerization of isocyanides [10]. The polymerization of isocyanide (S)-(
)-1 was carried out with h3-allylnickel trifluoroacetate as a catalyst, yielding a polymer showing identical optical rotations to those obtained in the NiCl2 and acid-catalyzed polymerization (Scheme 8.2) [11]. These results suggest that the helix sense selectivity is not dependent on the polymerization mechanism but is determined by the thermodynamically favored structure of the polymer [12]. These reports on the synthesis of optically active poly(isocyanide)s prompted additional studies on the detailed helical structures. In 1980, Nolte et al. applied circular dichroism (CD) spectroscopy to chiral poly(isocyanide)s. The CD measurements revealed that poly(isocyanide) (
)-2 possesses an M-helical backbone as judged from its positive Cotton effect. The screw sense of the polymers can be predicted from the structure of the chiral isocyanides [9]. Chiral isocyanides ((S)(M)(L)C-NC, where S, M, and L stand for the smallest, medium, and the largest substituents), which have no coordinating substituents, polymerize to P-screw (right-handed helix) if the sequence S > M > L,

226

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

Ph H Me

NC

Ph Me N H C n (–)-2

NiCl2 •6H2O neat, 0–5 °C, 5 d

(S)-(–)-1 [α]27D = -40.9 (MeOH)

90%, Mv = 9.4 × 104 [α]20D = -350 (CHCl3)

SCHEME 8.2. Polymerization of (S)-(
)-l in the presence of nickel chloride.

as viewed from the nitrogen atom to the stereogenic carbon center, is clockwise. For those bearing a coordinating group (Y), such as the ester group, the P-screw-senseselective polymerization is supposed to be preferred if the sequence S > Y > L, as viewed from the nitrogen atom to the stereogenic carbon center, is clockwise (Scheme 8.3). The optical rotation data for ten representative chiral isocyanides and their polymers verify this rule in their report. 8.2.1.2 Synthesis of Poly(isocyanide)s Bearing Amino Acid and Peptide Side Chains. Peptides that have free amino groups can easily be converted into peptide-based isocyanides. A series of the peptide-based isocyanides were successfully polymerized by Ni(II) catalysts. Several solvent systems were used in the polymerization of the peptide-based isocyanides, depending on the solubility of the isocyanides. As mentioned earlier, the use of alcohols as a solvent or cosolvent can accelerate the polymerization. The ester, hydroxy, and imidazole groups on peptides were protected to avoid undesirable reactions, and these protective groups were finally removed to yield poly(isocyanide)s bearing unprotected peptide side chains. In 1978, the synthesis and catalytic activity of imidazole-containing poly(isocyanide)s such as poly(carbylhistidine) 5, which could be a model for hydrolytic enzymes, were revealed (Scheme 8.4) [13, 14]. However, 5 was not obtained in an optically active form because the starting monomers suffered from a rapid racemization at the isocyano-bound carbon atom. This finding may result from the electronwithdrawing nature of the isocyano group. This racemization problem therefore could be avoided by using dipeptide monomers 6, which consisted of histidine and other amino acids as shown in Scheme 8.5 [15]. The protective group was modified to p-toluenesulfonyl (Tos) group from the benzyl (Bn) group for facile deprotection. The esterolytic enzyme chymotrypsin possesses a so-called charge relay system in its active site. This system consists of an imidazolyl, a carboxyl, and a M L

Y NC or L

NC

NiCl2 •6H2O

P-helices

S S S: small group, M: medium group, L: large group, Y: coordinating group

SCHEME 8.3. Prediction of helical screw sense of poly(isocyanide)s.

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

O CN

227

O NiCl2•6H2O CF3COOH

O N Bn N 3

C N

O

n N Bn

MeOH

N 4 O C N

OH

Na, liq. NH3

n

NH N 5

SCHEME 8.4. Synthesis of imidazole-containing poly(isocyanide) 5.

hydroxymethyl group. Therefore, it would be worthwhile to synthesize polymers that combine these groups. A series of tripeptide-modified poly(isocyanide)s, which contain imidazolyl, carboxyl, and hydroxymethyl functions, were also reported (Figure 8.1) [16]. The CD spectra reveal that the polymers derived from 9a (L-Ala-LHis-L-Ser) and 9b (L-Ala-L-His-D-Ser) had right-handed helical configurations. The pKa values of the imidazolyl and carboxyl groups in the polymers have increased as compared with L-histidine and L-serine. This finding suggests that strong electrostatic interactions exist between these groups. Copolymers functionalized with dipeptides at the side chains were also prepared to obtain poly(isocyanide)s containing imidazolyl, carboxyl, and hydroxymethyl functions [17]. Optically active isocyanides were synthesized from the dipeptides L-Ala- L-Ser, and L-Ala-L-His by converting the amino groups of these compounds into isocyano groups. These isocyanides were mixed in various ratios and polymerized with catalytic amounts of nickel(II) chloride. The titration curves indicated that copolymers 10 have two H N

CN O

O NiCl2•6H2O

O

O

H N

C N

O n

O

CHCl3 / MeOH N Tos

N Tos

N 6a: L-Ala, L-His 6b: D-Ala, L-His

N 7a: L-Ala, L-His 7b: D-Ala, L-His NaOH aq.

H N

C N

O

O

OH n NH

N 8a: L-Ala, L-His 8b: D-Ala, L-His

SCHEME 8.5. Synthesis of imidazole-containing poly(isocyanide)s 8 using dipeptide monomers.

228

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

O

H N

C N

OH N H

O

C N

OH k

O

OH O NH

O

H N

NH

n H N

N 9a: L-Ala, L-His, L-Ser 9b: L-Ala, L-His, D-Ser 9c: D-Ala, L-His, D-Ser

N O

C N

OH

m n OH 10: L-Ala, L-His / L-Ala, L-Ser O

FIGURE 8.1. Structures of poly(isocyanide)s 9 and 10 bearing imidazolyl, carboxyl, and hydroxymethyl groups.

different imidazol groups, which had pKa(ImHþ) values of approximately 7 and 9.5. The latter imidazole groups may strongly interact with neighboring carboxylate ions. Highly ordered arrangements of the side chains in the peptide-based poly(isocyanide)s have been reported [18, 19]. The polymers obtained from LL-11 and 13 exhibit b-helix structures, in which the L-Ala-L-Ala as well as L-Ala-L-Ala-L-Ala side chains are organized in a b-sheet-like fashion. In this b-helix structure, the rigid helical backbone of the poly(isocyanide)s may act as a director for the suitable spatial arrangement of the side chains (Scheme 8.6). They form stable b-helical architectures stabilized by the intramolecular hydrogen-bonding networks formed between the peptide side chains n and (n þ 4) (Figure 8.2). During these studies, it was discovered that the isocyanide monomer LD-11 rapidly polymerizes and yields polymer LD-12 even without a nickel(II) catalyst (Scheme 8.7) [20]. The resulting polymer had exactly the same composition and conformation as polymer LD-12, which was prepared by using a nickel(II) catalyst. To obtain more insight into the stereospecificity of this acid-catalyzed polymerization, kinetic studies were performed with trifluoroacetic acid (TFA) in dichloromethane. When 0.15 molar equivalents of TFA, with respect to a monomer, were used, after a short induction period, polymerization (Route A, Scheme 8.8) followed H N

CN

O O

O

EtOH / CH2Cl2

LL-11: L-Ala, L-Ala DD-11: D-Ala, D-Ala LD-11: L-Ala, D-Ala H N

CN O

C N

O O

13: L-Ala, L-Ala, L-Ala

O O n

O LL-12: L-Ala, L-Ala DD-12: D-Ala, D-Ala LD-12: L-Ala, D-Ala

O N H

H N

Ni(ClO4)2•6H2O

Ni(ClO4)2•6H2O EtOH / CH2Cl2

C N

H N

O N H

O O 14: L-Ala, L-Ala, L-Ala

O n

SCHEME 8.6. Synthesis of poly(isocyanide)s 12 and 14 exhibiting b-helix structures.

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

N

H N

O

H N

O

N

H N

O

O O

N H

O N

O

N H

O

O O

N H

O

229

O

FIGURE 8.2. Schematic image of the intramolecular hydrogen bonding networks in the side chains of polyisocyanide bearing L-Ala-L-Ala-L-Ala side-chains.

first-order kinetics with respect to the monomer. Evaluation of the kinetic data in an Eyring plot revealed that the polymerization displayed a large negative entropy of activation (DSz of
170 J mol
1 K
1), which implies a high degree of organization in the transition state. At higher acid concentrations ([TFA]/[LD-7] > 0.15), spectroscopic studies indicated that a side reaction begins to compete with the polymerization reaction. This side reaction is the hydration of the isocyanide through the formation of a cyclic imidazolone to form the corresponding formamide (route B, Scheme 8.8). The stereochemical course of the polymerization was studied at a low acid concentration ([TFA]/[LD-7] < 0.15) to negate the side reaction. Polymer LD-12 prepared with TFA maintains its polymerization activity and can be used as a macroinitiator for additional block copolymerizations. Upon the addition of monomer LD-11, block copolymerization takes place as expected. In contrast, no block copolymerization of the opposite enantiomeric monomer DL-11 took place. It is also remarkable that the polymerization of LD-11 was suppressed in the presence of 1% of the “wrong” monomer DL-11. Because monomers LD-11 and DL-11 could be copolymerized with a Ni(II) catalyst, it is likely that a highly organized

CN

H N

O

O O LD-11: L-Ala, D-Ala

CN

H N

O

H N

CF3 COOH O

O LD-11: L-Ala, D-Ala

CH2 Cl2

C N

O

Polymerization proceeded

O

O

n

LD-12: L-Ala, D-Ala CN

H N

O

Polymerization stoped

O O DL-11: D-Ala, L-Ala

SCHEME 8.7. Acid-catalyzed polymerization of isocyanides LD-11 and DL-11.

230

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

O

H N

C N

H+

HC N

O

O LD-11

O

O

H N

+

O

+

HN

O

O

N

H2O O

-

O

O

H N

N H

H+

O

O

Route B

Route A O

H N

O

O

O

H N

O O

NR C+

+

N C

C N

Folding

RN C H

n

N CH O

RN C H

O

H N

N

O

O

RN

Helical template

NR C N C+ NR

RN

NR

O

O

H N

RN

H N O

N

O

H N

O

C-C bond formation RN

O O

RN C H

O

RN

H N

+

NR C N C NR

O

N

O

H N

O O O

O

RN

Supermolecular complex

SCHEME 8.8. A proposed polymerization mechanism of LD-11.

“supramolecular complex” in Scheme 8.8 plays a critical role in the TFA-initiated stereospecific and enantiomer-selective polymerization. The TFA-initiated polymerization of tripeptide monomer 13 was carried out [21]. In the polymerization of monomer 13, the entropic barrier probably can be overcome by an enthalpic gain through the formation of a more extended hydrogen-bonding network. Polymer 14 formed by acid-initiated polymerization had the same conformation as polymer 14 prepared by a nickel-(II)-catalyzed polymerization, but the former had a higher molecular weight (Mw ¼ 1374 kg mol
1 for TFA-catalyzed polymerization and Mw ¼ 221 kg mol
1 for nickel(II)-catalyzed polymerization). Helical poly(isocyanopeptide)s 15 and 16 derived from b-amino acids were synthesized (Figure 8.3) [22]. Like their a-amino acid analogs, the helical conformation in these polymers is stabilized by internal hydrogen-bonding arrays. Interestingly, the flexibility of the b-peptide side arms results in a rearrangement of the initial macromolecular architecture, leading to a more stable helical structure possessing a better defined hydrogen-bonding pattern, as was indicated by infared (IR) and temperature-dependent circular dichroism studies. Based on these results, a dynamic helical model was proposed for the b-amino-acid–derived

O C N

O

N O H 15: βhAla, βhLeu

O C N n

O

N N H H 16: βhAla, βhAla, βhLeu

O O n

FIGURE 8.3. Structures of poly(isocyanopeptide)s 15 and 16 derived from b-amino acids.

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

231

poly(isocyanopeptide)s. This model is apparently in contrast to the kinetically stable helical macromolecules that are formed after the polymerization of a-amino acid-based isocyanopeptides. These poly(isocyanopeptide)s are attractive scaffolds for the three-dimensional alignment of functional groups. Inspired by natural light-harvesting antenna, polyisocyanide 17, with arrays of porphyrins attached to a rigid polyisocyanide backbone, has been synthesized and its physical and optical properties studied (Figure 8.4) [23]. Each polymer strand contains four columns of approximately 200 stacked porphyrins and has an overall length of 87 nm as judged from atomic-force microscopy. The chromophores are arranged in a left-handed helical fashion along the polymer backbone. Resonance light-scattering measurements showed that at least 25 porphyrins within one column are excitationally coupled. Poly(isocyanide)s bearing perylene diimide (PDI) groups as side chains were prepared using a similar approach (Figure 8.4) [24, 25]. Recently, great attention has been paid to PDI derivatives because of their high absorptivity, fluorescence quantum yield, stability, and electron affinity. In the fluorescence measurements of 18a, a broad red-shifted band is observed. The quantum yield has decreased (F ¼ 0.11), and the fluorescence decay is multiexponential with a minor contribution from a decay time equal to that of an isocyanide monomer of 18a (t1 ¼ 3.9 ns) and a major contribution from a much longer decay time (t2 ¼ 19.9 ns). These properties demonstrate that fluorescence emission mainly results from an an intramolecular excimer-like species in the polymer as known as a phenomenon in stacks of perylene molecules. Remarkably, the polymer 18a formed fibers up to 1 mm in length, containing several thousands of perylenediimide molecules. Photovoltaic devices OC12H25

H N

C N

N

O

HN OC12H25

NH

O

N

17: L-Ala OC12H25 H N

C N O

O

O

N

N

R R O 18a: L-Ala, R = C2H5 18b: L-Ala, R = C6H13

O

FIGURE 8.4. Structures of poly(isocyanopeptide)s 17 and 18 bearing porphyrins or perylene diimide groups.

232

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

O

H N

C N

O

O

C N

PMDTA

n

N

O

O

19: L-Ala, L-Ala

R=

O

H N

R-N3, CuBr

20: L-Ala, L-Ala

O

O

N

N

O

O

O

O

C6H13 O

C6H13

N n N R OH

4

SCHEME 8.9. Functionalization of the acetylene-containing poly(isocyanide)s by click reaction.

using polymer 18b, which is modified by longer alkyl chains to improve solubility, have been demonstrated [26]. Prototypical photovoltaic devices containing blends of polyisocyanide 18b with common semiconducting polymers readily showed an order of magnitude improvement in power conversion efficiency, as compared with analogous blends of the semiconducting polymers with a perylene isocyanide used for the synthesis of polyisocyanide 18b. Poly(isocyanopeptide) containing acetylene functionalities 19 was reported (Scheme 8.9) [27]. Incorporated terminal alkynes were converted to various functional groups by a click reaction with azides in the presence of copper(I) bromide and N,N,N0 ,N0 ,N00 -pentamethyldiethylenetriamine (PMDTA). By using perylene azide and ethylene glycol azide, chromophoric water-soluble polymeric nanowires were formed. The incorporation of multiple chromophores was also demonstrated by the reaction of the acetylene-containing polymers with both perylene azide and coumarin azide. A blue-shifted emission of the coumarin was observed because of the interaction with the coupled perylene molecules. Poly(isocyanopeptide) containing azide groups 21 was also prepared (Scheme 8.10) [28]. The azide-functionalized polymer 21 exhibited excellent water solubility because of the sodium carboxylate structures, and their reaction could be H N

C N O

H N

C N

O N H

R

N3 n

O

O

CuSO4 , Ligand sodium ascorbate

O-Na+

O

H N

C N

H N

C N

O N H

N N N

O

n

O-Na+

O

m

R

m

21

22 N O O

R=

O

O ClN+

Ligand =

O

N N N

N 3

SCHEME 8.10. Functionalization of the azide-containing poly(isocyanide)s by click reaction.

233

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

carried out in aqueous media. An acetylene-functionalized rhodamine dye was successfully introduced to polymer 21 by click chemistry. The ultraviolet (UV)visible spectrum of polymer 22 showed the characteristic absorption peaks of a rhodamine dye at 539 and 559 nm. The fluorescence spectrum of 22 showed a broad emission with a maximum at 579 nm. The CD spectrum showed that 22 has the same characteristic Cotton effect indicating a well-defined helical polymer. As shown in these examples, the click chemistry based on the copper-catalyzed [3 þ 2] Huisgen cycloaddition is a useful and reliable reaction for the modification of poly(isocyanide)s, which were functionalized with terminal alkynes or azides. Similarly, the thiol group is also readily functionalized by a reaction with maleimides, iodoacetamides, thioesters, and so on under mild reaction conditions. Poly(isocyanide)s 23 bearing cysteine as side chains were reported (Scheme 8.11) [29]. Pyrene derivatives were introduced through thio specific reactions leading to arrays of stacked chromophores with excimer-like emissions. A water-soluble polyisocyanide that has cystine side chains was also synthesized, and biotins were introduced to the polymer backbone with a thioclick reaction. The biotins on the polymer interacted efficiently with streptavidins. These results revealed that poly(isocyanide)-bearing thiol groups were promising scaffolds for the assembly of bioactive molecules.

O

H N

O C N

N H

O

N Pyr

n

S

24a

O

7

O N O

O H N

C N O

I

O N H SH

N H

Pyr

H N

C N

7

N H

O

n

Pyr O

O HN

O S

H N O

C N

Pyr =

N H

O 24c

Pyr

O

H N

Pyr

n

S

24b

23

7

7

n

S O HN

O Pyr

SCHEME 8.11. Functionalization of the thiol-containing poly(isocyanide)s by thio-click reaction.

234

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

8.2.1.3 Synthesis of Poly(isocyanide)s Having Chiral Aryl Pendants. In the polymerizations presented above the chiral moiety determining the screw-sense selectivity is connected directly or closely to the isocyanide groups. The existence of chiral groups in close proximity to the main chain allows for the effective induction of a nonracemic helical structure. In contrast, screw-sense induction with aryl isocyanides bearing stereogenic carbon centers distant from the polyisocyanide backbone has been reported [30]. Polymerization of the chiral isocyanide monomer (R)-25a in the presence of a nickel catalyst afforded poly(isocyanide) (R)-26a (Scheme 8.12). The obtained polymer (R)-26a exhibited a clear Cotton effect, and the helical sense was assigned to M. Monomer (S)-25a, which is an opposite enantiomer of (R)-25a, resulted in a P-helical polymer (S)-26a. Although a similar asymmetric helix induction was observed in the polymerization of monomers 25a-g, no CD signal was observed for polymer (R)-26h, which has chiral carbon centers further from the isocyano group. The polymerization of achiral monomer 25i resulted in an optically inactive polymer 26i. The relationship between the configuration of the side chain and the helical chirality is summarized in Scheme 8.12. The M-helical structure is preferred when the methyl group is located at the front side, and the P-structure is preferred with the methyl group at the back side. The effect of rod-like spacers between an isocyanide group and a chiral substituent on the screw-sense selectivity of the polymerization of these monomers has been studied (Scheme 8.13) [31]. A series of analogues of polymer (R)-26b with varied spacer groups were prepared by nicked-catalyzed polymerization, and the chiral induction was monitored using CD spectroscopy. Except for polymer 28b, similar chiral inductions were observed for all chiral poly(isocyanide)s, and the semirigid spacer group seemed to be essential. Interestingly, polymer 28f showed significant optical activity resulting from a polymer main chain despite of the large linking group, which separates the chiral carbon center from the polymer backbone by  approximately 21A. Takahashi et al. have shown that the dinuclear Pd-Pt m-ethynediyl complex 29 promotes successive living polymerizations of aryl isocyanides (Scheme 8.14) [32]. O NiCl2•6H2O

CN O

R

O C N O

MeOH / CH2Cl2

25 O

O C6H13

(R)-a: M-Helix

R n

26 O C5H11

(R)-b: M-Helix

O

O

O

O

(S)-f: P-Helix

(S)-h: racemic

OC4H9 (R)-c: M-Helix

(S)-d: M-Helix

R= O

O C6H13

(S)-a: P-Helix

O

O

C5H11

OC4H9

(S)-b: P-Helix

(S)-c: P-Helix

O

O

Cl OC7H15

(S)-e: M-Helix

(R)-g: M-Helix

C8H17 i: racemic

SCHEME 8.12. Synthesis of a series of poly(isocyanide)s bearing stereogenic carbon centers distant from the backbone.

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

CN

NiCl2•6H2O

X O C5H11

28

C N

235

X O

MeOH / CH2Cl2

C5H11 n

29 O

a: Δε363= +0.52

O c: Δε363= +0.90

b: Δε363= 0

X= O

O

O

O

O

O

d: Δε363= -1.51

O O

e: Δε363= +0.78

f: Δε363= +0.30

SCHEME 8.13. Synthesis of 26a-h with varied spacer groups as analogs of polymer (R)-26b.

NC

PEt3 PEt3 Cl Pd C C Pt Cl PEt3 PEt3 29 THF, reflux

PEt3 Cl Pd PEt3

C N

PEt3 C C Pt Cl PEt3

COOR* 30: p-substituted 31: m-substituted

n COOR* 32: p-substituted 33: m-substituted

iPr iPr iPr iPr 32a: Δε = +13.0 32b: Δε = -12.0 32c: Δε = -13.2 32d: Δε = -12.8 33a: Δε = +2.8 33b: Δε = -2.9 33d: Δε = +3.4

R* = 32e: Δε = -9.8

C6H13

C5H11

C2H5

32f: Δε = -9.7 33f: Δε = -0.6

32g: Δε = -9.8

32h: Δε = -8.5 33h: Δε = -0.2

C2H5 32i: Δε = +0.3

C2H5 32j: Δε = ~0

SCHEME 8.14. Polymerizations of chiral aryl isocyanides in the presence of dinuclear Pd-Pt m-ethynediyl complex 29.

236

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

New families of optically active poly(isocyanide)s were synthesized by this unique polymerization system.[33] Aryl isocyanides 30 and 31 were smoothly polymerized in the presence of a Pd-Pt m-ethynediyl complex in refluxing tetrahydrofurane (THF) for 20 h to yield brownish-yellow polymers 32 and 33 in quantitative yields. Polymer 32a-e bearing chiral mentyl groups showed intense Cotton effects at 364 nm because of the stable one-handed helical conformation of their main chains. Polymers 32f-h also exhibited intense Cotton effects despite the smaller chiral groups. The intensities of the Cotton effects of polymers 32i and 32j were lower than those of polymers 32fh. This result suggests that the distance between a chiral center and the main chain is closely related with the screw-sense selectivity. However, polymer 33, synthesized from m-substituted aryl isocyanides, showed relatively weaker Cotton effects than polymer 32 prepared from p-substituted monomers. Screw-sense selective polymerizations of achiral isocyanide were achieved using oligomeric 32a, which has an active end-group [Pd(PEt3)2Cl] as a chiral initiator [34]. The relationship between the length of the achiral chain and the value of the optical rotation suggests that a screw-sense selective polymerization of the achiral isocyanide occurs at the initial stage of the reaction and that the selectivity gradually falls as the degree of polymerization increases. The loss of selectivity in the propagation step might be ascribed to a rather weak steric interaction between the achiral substituents. This problem was successfully solved by using bulkier isocyanides, such as 3,5-di(propoxycarbonyl) phenyl isocyanide, to increase the steric interaction. The polymerization mediated by Pd-Pt m-ethynediyl complex 29 has a wide substrate scope. Poly(isocyanide)bearing porphyrins, which are sterically bulky substituent groups, as a pendant groups were readily prepared (Scheme 8.15) [35]. PEt3 PEt3 Cl Pd C C Pt Cl PEt3 PEt3

O C OR*

1) 40 eq CN

2) 20 eq CN

O C OTPP

3) 40 eq CN

O C OR*

29

PEt3 Cl Pd PEt3

C N

C N

C O OR*

C O OTPP

C O OR*

40

20

i

Pr a: P-Helix

i

Pr b: M-Helix

C6 H13 e: M-Helix

i

Pr c: M-Helix

i

Pr d: M-Helix

40

t

34

R* =

PEt3 C C Pt Cl PEt3

C N

Bu

N

HN t

TPP = NH

Bu

N

C2 H5 f: M-Helix

t

Bu

SCHEME 8.15. Synthesis of poly(isocyanide) block copolymer 34 bearing porphyrin side chains using 29 as an initiator.

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

237

Incorporated porphyrin units were regularly arranged, which provided interesting optical properties. However, it is well known that the CD sign resulting from a couple porphyrins is a useful tool to assign the absolute configuration of chiral molecules. A series of tribrock copolymers 34a-f, in which porphyrin units were introduced as pendant groups in the central part of the main chain, were prepared by living polymerization in the presence of a Pd-Pt m-ethynediyl initiator 29 [36]. The Cotton effects of the exciton coupling resulting from the Soret band were clearly observed by subtracting a spectra of chiral homopolymers from that of copolymers 34a-f. Thus, the helix sense of copolymers as well as homopolymers could be determined. Ferrocene-containing poly(isocyanide)s 35a and 35b were also prepared with dinuclear Pd-Pt complex 29 (Scheme 8.16) [37]. Although the electrochemical properties of polymer 35a were investigated by cyclic voltammetry, the results suggested that the deposition of an oxidized polymer onto the electrode occurred because of the low solubility. To improve the solubility of the polymer, long and flexible alkyl groups were introduced as side chains. This polymer 35b showed good solubility and a completely reversible redox cycle. Interestingly, the CD spectrum reversed because of an electrical stimulus, suggesting that the helical structure of the polymer could be controlled by the electrical stimulus. A unique helix sense–controlled polymerization of the enantiomerically pure aryl isocyanides bearing L-alanine residues with a long alkyl chain with a NiCl2 catalyst has been reported [38, 39]. The measurements of the CD spectra revealed that the polymer 37a obtained by the polymerization of 36 at room temperature in THF or at 100  C in toluene possessed a left-handed helix (Scheme 8.17). However, polymer 37b yielded at room temperature in nonpolar solvents, such as toluene or CCl4, had a right-handed helix. This significant difference of the helix sense of the polymers 37a and 37b, depending on the polarity of the solvents and the reaction temperature, could be explained by the intermolecular hydrogen bonding between monomer 36 and the reactive end group of the polymer. It is assumed that the polymerization was kinetically controlled by strong hydrogen bonds in a nonpolar solvent at low temperature. In contrast, polar solvents or high temperature weakened the hydrogen bonds, leading to the formation of a thermodynamically favored helical sense. This R

O O

PEt3 PEt3 Cl Pd C C Pt Cl PEt3 PEt3

Fe 100 eq

NC

PEt3 Cl Pd PEt3

PEt3 C C Pt Cl PEt3

C N

THF, reflux

R

29

O

O

Fe 100 35a: R = -CH3 35b: R = -C21H43

SCHEME 8.16. Synthesis of poly(isocyanide)s bearing ferrocenyl groups using 29 as an initiator.

238

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

C N

O

C N

NC NiCl2•6H2O

NiCl2•6H2O

THF at rt or toluene 100 °C

CCl4 or Toluene at rt

NH

O

NH

O OC10H21

O

NH

O

O

OC10H21

n

37a: M-Helix

OC10H21

n

37b: P-Helix

36

SCHEME 8.17. Screw-sense-selective polymerization of isocyanide monomer 36.

hypothesis was supported by nuclear magnetic resonance (NMR) and IR spectra of 37 measured in polar and nonpolar solvents as well as by the fact that polymerization of an analogous isocyanide, in which the amide group is replaced by an ester group to exclude the contribution of hydrogen bonding, showed no such solvent-dependant induction of helical sense [39]. Size-exclusion chromatography with multiangle light scattering (SEC-MALS) measurements and atomic force microscopy (AFM) measurements of these polymers, and it was revealed that a related polymer 38, in which the amide group is replaced with ether group, was to be more flexible than the original polymer 37, probably because of the lack of hydrogen bonding (Figure 8.5) [40]. Polymerization of 36 in the presence of a dinuclear Pd-Pt complex 29 was studied (Scheme 8.18) [41]. Interestingly, diastereomeric M- and P-helical polymers 37c and 37d showed different molecular weights and were successfully separated by solvent fractionation with acetone. P-helical polymer 37d was more soluble in acetone, whereas M-helical polymer 37c was not soluble in acetone. The structures of these polymers including helix sense, helical pitch, and main-chain length were directly determined by high-resolution AFM. A series of optically active polyisocyanides bearing chiral mono- (39), di- (40), or tri-alkoxy chains (41) were synthesized by a nickel-catalyzed or by a Pt-Pd complexpromoted polymerization (Scheme 8.19) [42]. The CD spectra were significantly C N

O

O O OC10H21 38

n

FIGURE 8.5. Structure of polymer 38 as an analog of polymer 37.

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S PEt3 PEt3 PEt3 Cl Pd Cl Pd C C Pt Cl PEt3 PEt3 PEt3

NC

PEt3 Pt Cl PEt3

C N

29 THF, 55 °C O

Separation

NH

O

NH

O

O

OC10 H21

OC10 H21

36

239

37c: M-Helix, High Mw Insoluble in Acetone 37d: P-Helix, Low Mw Soluble in Acetone

n

Mixture of M-Helix and P-Helix

SCHEME 8.18. Synthesis and separation of M- and P-helical poly(isocyanide)s 37c and 37d.

dependent on the number of chiral pendants and on the position of stereogenic center. The polyisocyanide bearing a single alkyl chain showed no Cotton effect in the polymer main-chain region regardless of the position of the stereocenter (39a and 39b). Weak Cotton effects were observed in the spectrum of the polyisocyanide that has dialkoxy chains with a stereogenic center in the proximity to the main chain (40b). Polyisocyanides 41 bearing three chiral alkoxy chains exhibited intense Cotton effects regardless of the position of the stereogenic center. A clear odd– even effect was found for the di- and trialkoxy derivatives. It was also revealed that helical polyisocyanides 41 form the thermotropic liquid crystal. 8.2.2 Nonracemic Poly(isocyanide)s Without Chiral Pendant Groups The first example of nonracemic helical poly(isocyanide)s without chiral side chains was obtained by chromatographic resolution of poly(tert-butyl isocyanide)s by using a chiral stationary phase made with one-handed helical poly(isocyanide)-bearing NiCl2•6H2O or PEt3 PEt3 Cl Pd C C Pt Cl PEt3 PEt3 29

NC

R1

R3 R2

39a, 40a, 41a: R* = 39b, 40b, 41b: R* =

C N n

R1

R3 R2 39: R1 = R3 = H, R2 = R* 40: R1 = H, R2 = R3 = R* 41: R1 = R2 = R3 = R*

O O

SCHEME 8.19. Synthesis of poly(phenyl isocyanide)s bearing chiral mono-, di-, or trialkoxy groups on the phenyl rings.

240

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

1st fraction

N C

t-Bu

Column Chromatography

n 42 racemic

Et N C

Me H

n Chiral Stationary Phase

N C

t-Bu

n (+)-42: [α]20578 = +5.2

4th fraction

N C

t-Bu

n (–)-42: [α]20578 = -5.5

SCHEME 8.20. Chromatographic resolution of poly(tert-butyl isocyanide)s by using chiral poly(isocyanide) as a chiral stationary phase.

chiral side chains (Scheme 8.20) [43, 44]. A racemic mixture of P- and M-helical poly(tert-butyl isocyanide) 42 was successfully separated on the column packed with poly ((S)- or (R)-sec-butyl isocyanide). With poly ((S)-sec-butyl isocyanide) as a supporting polymer, a partial resolution has been obtained of poly(tert-butyl isocyanide), which exhibited significant optical rotation þ5.2 for the first fraction and
5.5 for the fourth fraction. The specific optical rotation of 42 was increased up to
16 after fractioning three times by the chiral column. Successful asymmetric polymerization was achieved using a dicationic isocyanidenickel(II) complex with enantiopure primary amines [45]. The polymerization of tert-butyl and tert-pentyl isocyanide 47 by the isocyanide-nickel(II) complex 43 with optically active amines 44, such as (S)-l-phenylethylamine, yielded helical poly(isocyanide)s (Scheme 8.21). In the initial step, a chiral amine attacks an isocyanide ligand on the nickel center to form a diaminocarbene complex 46. The polymerization begins with the migration of the chiral carbene group to one of the two diastereomeric neighboring isocyanide groups stereoselectively. The subsequent migration of the living polymer terminus proceeds with the same direction in a R* R H2 N N R*-NH 44 2 C C (Optically active amine) R N C Ni C N R R N C Ni C N R 2+ 2+ C C 45 43 N N R R R R R* N R* N C R-NC NH C NH 47 R N C Ni C C R N C Ni C 2+ NH C 2+ N NH C N R R n N R R R 46 48: Optically active R

N

SCHEME 8.21. Asymmetric polymerization using isocyanide-nickle(II) complex with chiral primary amines.

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

N C

(R)-49, (S)-50 or (S)-51

t-BuNC

241

t-Bu

n [α]20D = +12 for (R)-49 [α]20D = -12 for (S)-50 [α]20D = -18 for (S)-51

OMe F3C Ph

CF3 MeO Ph

O Ni O

O Ni O

O Ni O

O Ni O

Ph

OMe CF3

Ph

CF3 OMe

(R)-49

(S)-50

O F3C

N H O Ni O

O Ni O H CF3 N O

(S)-51

SCHEME 8.22. Asymmetric polymerization using p-allylnickel initiators bearing chiral ligands.

revolving manner, leading to the selective formation of a one-handed helical structure [46]. A helix-sense induction by chiral ligands coordinated to p-allylnickel complex has also been reported by Deming and Novak (Scheme 8.22) [47]. Optically active carboxylato ligands were used in this asymmetric polymerization. The polymerization of tert-butyl isocyanide in the presence of (R)-49 proceeded under aerobic conditions. Poly(tert-butyl isocyanide) (Mn ¼ 880) was obtained in the reaction and had a specific rotation of [a]20D ¼ þ12, which could be assigned to an M-helix based on the previous study. The use of the enantiomeric initiator (S)-50 produced a P-helical polymer exhibiting a specific rotation of [a]20D ¼ þ12. In the polymerization of tert-butyl isocyanide using (S)-51, a polymer with a specific rotation of [a]20D ¼ þ18 (Mn ¼1100) was obtained. Based on the specific rotation of the completely resolved poly(tert-butyl isocyanide) ([a]20D ¼ þ26), a screw-sense excess was determined as 46% ee for (R)- and (S)-50 and as 69% ee for (S)-51. The addition of cyanide ion such as tetrabutylammonium cyanide also enhanced the screw-sense selectivity of the obtained poly(isocyanide)s. In 1995, Okamoto et al. developed a novel method to induce nonracemic screw-sense through noncovalent bonding interactions with chiral guest molecules [48]. The first report on the helicity induction to poly(acetylene)s was followed by the application to a wide variety of dynamic helical polymers including poly (isocyanide)s [49]. An achiral water-soluble poly(phenyl isocyanide) 53 was prepared by hydrolysis of the precursor polymer 53-Et, which was synthesized by a nickel-promoted polymerization (Scheme 8.23) [50]. This polymer folds into a one-handed helix on treatment with optically active amines in water. Interestingly, this induced helicity is efficiently memorized after the complete removal of the chiral amines, which are used to induce single-handed helix

242

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

NC

O

NiCl2 H2O / MeOH CH2Cl2, rt, 1d

OEt

52

C N n 1) sat. NaOH aq / THF

•6

C N n

2) HCl aq O

C N n

Chiral Amine R*-NH2 Helicity Induction

OEt

O

53-Et

OH

O

+ NH4R* O-

h-53: Optically active

53

SCHEME 8.23. Screw-sense induction to polyisocyanide 53 through noncovalent bonding interactions.

(Scheme 8.24) [51]. Although the memory of macromolecular helicity was also observed in poly(acetylene)s in the presence of the achiral amines to fix the helicity in the polymer [52], there is an apparent advantage of helicity memory of poly(isocyanide), which does not require such amines and could be readily modified with a variety of functional groups without losing their helical chirality. As shown in Scheme 8.25, the esterification by diazomethane [51] and the amidation using primary and secondary amines with a condensation agent [53] were successfully accomplished to yield optically active polymers h-53-Me and h-53-N, respectively. The amidation with bifunctional achiral amines resulted in the formation of hydrogel that maintain their helicity memory even at 90  C [54]. The anionic polymer h-53-Na successfully induced nonracemic helical conformation to positively charged racemic polyacetylene 54 in water [55]. The backbone structure of polymer 53 was transformed into a single-handed helix after complexation with optically active amines in dimethyl sulfoxide (DMSO) and water (Scheme 8.26). Moreover, the macromolecular helicity induced in water and a DMSO–water mixture (more than 50% DMSO by volume) could be memorized even after removal of the chiral amines (h-53, memory efficiency ¼ 80–99%), whereas that induced in DMSO and in a DMSO–water mixture (less than 30% DMSO by volume) could not be maintained after the removal of the chiral amines (53’, memory efficiency ¼ 0.5–2%) [56]. The helix induction with chiral amines and the solvent-dependent memory of the macromolecular helicity were extensively studied [57] by spectroscopic measurements, theoretical calculations, persistence length measurements, and Xray diffraction (XRD) measurements of the oriented films prepared from the nematic C 1) N n

NH2

C N n

OH (S)-56 in water

2) Removal of (S)-56 O ONa 53-Na

O ONa h-53-Na Helicity Induction & Memory

SCHEME 8.24. Induction and memory of helical chirality of poly(isocyanide) 53-Na.

ASYMMETRIC SYNTHESIS OF POLY(ISOCYANIDE)S

O

CH2N2

C N OMe n

h-53-Me C N n

O

NHR'R''

C N

DMT-MM

NR'R'' n

h-53-N H 2N O

MeO

NH2

R

Cross-linked Hydrogel

ONa DMT-MM

h-53-Na

243

NMe N+ N Cl-

N

O

MeO DMT-MM

n

NH+Cl54

Replication of macromolecular helicity

SCHEME 8.25. Chemical modifications of side chains of h-53-Na with retention of helical chirality in the main chain.

"As prepared" Polymer C N n in solution at room temperature

Δ

Δ R*NH2

O

in DMSO C N n

53: q = 59 nm

R*NH2

Memory efficiency ≤ 1% R*NH2

O OH 53' q = 43 nm Dynamic 9/5 helix Polymer without Helicity Memory

R*NH2

OH

in water R*NH2

Memory efficiency ∪ 90%

C N n

R*NH2

in solution at room temperature

O OH h-53 q = 88 nm Rigid and stable 10/3 helix Memorized Helical Polymer

SCHEME 8.26. Summary of structural characteristics of helical poly(isocyanide) 53.

244

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

and cholesteric liquid crystals after conversion into the corresponding methyl esters. From the data for polymers 53, h-53, and 53’, the configurational isomerization around the C¼N double bonds occurs during the helicity induction process. Based on the XRD analyses, the helical structure of 53’ was suggested to be a 9/5 helix, and that of h-53 was suggested to be a 10/3 helix. The density functional theory (DFT) calculations at the B3LYP/MIX level of 14mer helical poly(phenyl isocyanide) afforded a 7/2 helix as the most probable helical structure, which is in agreement with the XRD results. Furthermore, the persistence length measurements revealed that these structural changes accompany a significant change in the main-chain stiffness. The structural information and their interconversions were summarized in Scheme 8.26.

8.3 ASYMMETRIC SYNTHESIS OF POLY(QUINOXALINE)S 8.3.1 Polymerization of 1,2-diisocyanobenzenes In the beginning of 1990s, Ito et al. reported the oligomerization of a 1,2-diisocyanobenzene derivatives using Grignard reagents as initiators (Scheme 8.27) [58]. Treatment of 1,2-diisocyano-3,4,5,6-tetramethylbenzene 55 with Grignard reagents in THF at 0  C afforded a variety of quinoxaline oligomers. These oligomers were separated and isolated by preparative thin-layer chromatography (TLC) on silica gel and/or recycling preparative gel permeation chromatography (GPC). The methyl groups on the 3,6-positions of 1,2-diisoxyanobenzene were essential for the stability of the monomer. Grignard reagents were not an efficient initiator for the polymerization of 1,2-diisocyanobenzene derivatives and just yielded oligomers up to hexamer. The aromatizing oligomerization and the polymerization of monomer 55 were efficiently promoted by organopalladium complexes (Scheme 8.28) [59]. As the ratio of 55 to the palladium initiator decreased, the polymerization degree increased linearly. The living oligomers bearing an active palladium end group were stable and isolable by preparative GPC or silica gel chromatography. The isolated oligomers were still active in extended polymerization. The 1,2-diisocyanobenzene derivative 59 bearing trimethylsilylmethyl groups was also used as a monomer (Scheme 8.29) [60]. The polymerization resulted in a high molecular weight polymer 60, which showed good solubility in common organic solvents. Monomer 59 was also polymerized with organonickel complexes [60]. A stoichiometric reaction between monomer 59 and trans-o-TolNiPMe3 was carried

NC NC 55

1) RMgX, dioxane 0 ºC 2) H2O

N

R

N

H n

56: n = 1~6

SCHEME 8.27. Oligomerization of a 1,2-diisocyanobenzene derivative using Grignard reagents as initiators.

ASYMMETRIC SYNTHESIS OF POLY(QUINOXALINE)S

trans-MePdL2Br (L = PMe 2Ph)

NC

N

THF, reflux

NC

Me

N n

55

245

PdL2Br

57 N

Me3SiCH2MgCl

Me

CH2SiMe3 n 58: Oligomers (n=1~8) and higher polymer N

SCHEME 8.28. Oligomerization and polymerization of 1,2-diisocyanobenzene derivative 55 using a trans-methylpalladium initiator. R NC NC R 59

R

1) 0.05 equiv trans-MePdL2Br (L = PMe 2Ph) THF, reflux

N

Me

N Me n R 60: Mn = 4830 (VPO) Mw/Mn = 1.08

2) MeMgBr

R= SiMe3

SCHEME 8.29. Polymerization of 1,2-diisocyanobenzene derivative 59 bearing trimethylsilymethyl groups.

out to synthesize a quinoxalinylnickel complex 61, which is isolable by preparative TLC (Scheme 8.30). A controlled living polymerization was promoted by organonickel complex 61, yielding a high molecular weight polymer with a narrow molecular weight distribution. R NC

trans-(o-Tol)NiL 2Cl (L = PMe 3)

R

NC R 59 1) 15 equiv 59 2) MeMgBr

N

o-Tol

N

NiL2Cl

R 61

R N N

o-Tol R= Me n

SiMe3

R 62: Mn = 4980 (VPO) Mw/Mn = 1.10

SCHEME 8.30. Polymerization of 1,2-diisocyanobenzene derivative 59 using a nickel initiator.

246

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

RO RO

NC NC

63a: R = n-C3H7 63b: R = n-C5H11 63c: R = n-C7H15

1) trans-MePdL2Br (L = PMe 2Ph) THF, reflux 2) MeMgBr

RO RO

N

Me

N

Me

64a: R = n-C3H7, n = 10, 20, 30, 50, 70, 100 mesophases were observed for n ≥ 30 64b: R = n-C5H11 , n = 30, 50, 70, 100 mesophases were observed for n ≥ 50 64c: R = n-C7H15, n = 30, 40, 50, 70, 100 mesophases were observed for n ≥ 70

SCHEME 8.31. Synthesis of poly(quinoxaline)s bearing various alkyl chains with a varied degree of polymerization.

Poly(quinoxaline)s have rigid main chains and therefore are expected to be liquid crystalline materials [61]. Poly(quinoxaline)s bearing various alkyl chains were prepared by a living polymerization in the presence of a organopalladium initiator with a varying degree of polymerization (Scheme 8.31). The phasetransition behavior of the poly(quinoxaline)s was investigated by an optical polarized microscope with a hot stage. It was proven that the poly(quinoxaline) s with a sufficient high molecular weight could exhibit the mesophase at temperatures above 120  C. However, the low molecular weight polymers did not show any mesophase. The critical points of the degree of polymerization depended on the length of the alkoxymethyl side chains. The liquid crystallinity of the poly (quinoxaline)s seemed to be underpinned by a fine balance between the rigidity depending on the degree of polymerization and the flexibility resulting from the side chains. 8.3.2 Preparation of Nonracemic Poly(quinoxaline)s Nonracemic poly(quinoxaline)s were initially synthesized via optical resolution of the living oligomer with a single-handed helical chirality. 1,2-Diisocyanobenzene 65 (4 equivalent) bearing bulky p-tolyl groups was oligomerized in the presence of the palladium complex 66 bearing a chiral phosphine ligand (Scheme 8.32) [62]. The crude product, which was a mixture of oligomers, was separated by preparative GPC to yield pentamer 67. The particular chiral phosphine ligand has almost no ability to control the helical sense in the polymerization. The pentamer was a mixture of diastereomers (þ)-67 and (
)-67, which had an opposite screw sense (Pand M-helix) with the same chirality (S configuration) at the phosphine ligand. These diastereomers could be separated by preparative HPLC on silica gel, and the CD spectra of these products showed almost a mirror image. After the substitution of the chiral palladium moiety by the Grignard reagent, the CD spectra of the resultant polymers showed a perfect mirror image of each other. These diastereomeric pentamers were still active as initiators for the polymerization of 1,2-diisocyanobenzene derivatives. Each diastereomerically pure pentamer ((þ)-67 and (
)-67) was employed in the polymerization of 63a (Scheme 8.33) [63].

247

ASYMMETRIC SYNTHESIS OF POLY(QUINOXALINE)S

p-Tol

1) 0.25 equiv trans-MePdL*2Br (66) THF, reflux

NC NC

N

Me

N

2) preparative GPC

p-Tol 65

p-Tol

5

p-Tol

PdL*2Br

67 preparative GPC p-Tol

p-Tol N N p-Tol

N

Me

5

Me

N

PdL*2Br p-Tol

(+)-67: [α]D = +233

5

PdL*2Br

( –)-67: [α]D = -343 Ph P

L* =

SCHEME 8.32. Synthesis of nonracemic poly(quinoxaline)s using diastereomerically pure oligo(quinoxaline) pentamer 67.

After removal of the chiral palladium moieties, optically active poly(quinoxaline)s (
)-68 and (þ)-68 were obtained, which exhibited symmetrical CD spectra. This result indicated that polymers (
)-68 and (þ)-68 have helical structures that were mirror images of each other.

R

NC

R

NC

p-Tol N

p-Tol N

Me

N

63a N 5

p-Tol

PdL*2Br

then MeMgBr

Me

NC

R

NC

N 5

PdL*2Br

then MeMgBr

( –)-67: [α]D = -343 L* =

N

R

n

p-Tol

Me 63a

p-Tol

R

(–)-68: [α]D = -171 R

N N

N 5

p-Tol

(+)-67: [α]D = +233

p-Tol

Me

Me

N p-Tol

N

R

N

R

5 Me

n

(+)-68: [α]D = +165 Ph P

R = -CH2OCH2CH2CH3

SCHEME 8.33. Polymerization of monomer 63a using diastereomerically pure oligo (quinoxaline) pentamers (þ)-67 and (
)-67 as initiators.

248

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

R

R

R

N

Me

N

PdL*2Br

n L* =

69a: R = Me, n = 6 69b: R = Pr, n = 5 69c: R = Pr, n = 6 Diastereomerically pure

MeMgBr

Ph P

R

N

Me

N

Me

n

70a: R = Me, n = 6, Ea = 100 kJ mol-1 70b: R = Pr, n = 5, E a = 106 kJ mol-1 70c: R = Pr, n = 6, E a = 133 kJ mol-1

SCHEME 8.34. Synthesis of quinque- and sexi(quinoxaline)s 70a-c.

The chiral ligand on the terminal palladium atom was replaced by an achiral ligand PPhMe2 before subsequent polymerization to exclude the influence of the ligand chirality for the induction of helical chirality during polymerization [64]. The oligomeric initiator bearing no chiral auxiliary could successfully induce the screw-sense selective polymerization. The polymerization of 1,2-diisocyanobenzene was not controlled by the chirality of the phosphine ligands but by the chirality of the helical secondary structure of the helical backbone. Detailed research focusing on the racemization of the oligo(quinoxaline)s has been reported [65]. Pentameric and hexameric oligomers 69a-c with a palladium terminus were stable in solution at room temperature for several days without any detectable decrease in diastereomeric excesses (Scheme 8.34). Although oligomers without palladium terminus underwent racemization, its rate depended on the bulkiness of the substituents at the 5,8-positions of the quinoxaline rings and on the number of quinoxaline units in the oligomer chain. For instance, the activation energy values for the racemization were 100 and 106 kJ mol
1 for the hexamer 70a with smaller substituents and for the pentamer 70b bearing bulkier substituents, respectively. The hexamer 70c with sterically bulky substituents showed a larger activation energy, 133 kJ mol
1, which corresponds to a 10,000-fold increase in the half-life time at ambient temperature. The chiral helical structure of the hexameric (oligoquinoxalinyl)palladium complex (
)-69a bearing p-tolyl groups on the 5,8-positions was sufficiently stable in the transformation at the palladium-carbon bond as shown in Scheme 8.35 [66]. Methylation with methyl Grignard reagent, reduction with NaBH4, and bromination with N-bromosuccinimide (NBS) led to the formation of (
)-70a, (
)-71, and (
)-72, respectively, with retention of the helical sense of (
)-69a. The terminal bromine

249

ASYMMETRIC SYNTHESIS OF POLY(QUINOXALINE)S

p-Tol

p-Tol N

N

Me MeMgBr

N p-Tol

p-Tol

Me 6

(–)-70a: [α]D = -430

N

Me

N

PdL*2Br

6

p-Tol

NaBH2 N

Me

N

Ph2PLi p-Tol N

H

Me

N

6

p-Tol

6

( –)-72: [α]D = -287

Ph P

L* =

Br

N p-Tol

(–)-69a: [α]D = -468

p-Tol

Me

NBS

p-Tol

( –)-71: [α]D = -462

6

PPh2

( –)-73: [α]D = -418

SCHEME 8.35. Transformations of diastereomerically pure sexi(quinoxaline) (
)-69a.

moiety was readily converted to a diphenylphosphino group with lithium diphenylphosphide at
78  C. These results suggest that the optically active oligo(qunixaline)s are promising chiral scaffolds for producing new functional compounds. In contrast to the optically active helical poly(quinoxaline)s obtained through a resolution of the racemate by HPLC, asymmetric synthesis of poly(quinoxaline)s using chiral initiators have been developed. Chiral binaphthyl-based organopalladium initiators were initially used for asymmetric polymerization of 1,2-diisoxyanobenzene derivatives [67, 68]. Chiral initiators 74a-d were prepared from enantiopure binaphthyl iodide and 1,2-diisocyanobenzene 65. Polymerizations of the diisocyanide 65 and 63a were carried out in the presence of chiral organopalladium initiator 74a-d (Scheme 8.36) [68, 69]. All polymerization reactions yielded the corresponding poly(quinoxaline)s 75 and 76 in good yields with narrow polydispersity indexes (Scheme 8.37). The screw-sense selectivities depended on the structure of the binaphthyl moiety. In the polymerization of monomer 63a, the p-Tol Nap I

1) Pd(PPhMe2)n

p-Tol

N

Nap

N 2) CN

NC (PPhMe2)2IPd

p-Tol

p-Tol 74a-d

65 (1 equiv) Nap =

OSiMe2tBu

OMe (S)-74a

(S)-74b

(S)-74c

OMe (S)-74d

SCHEME 8.36. Preparation of chiral palladium initiators 74 with various binaphthyl moiety.

250

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

CN

p-Tol

NC

p-Tol

p-Tol 65

1) 74a-d 2) NaBH4

Ar*

N

H

N

n p-Tol p-Tol

75a-d Ar* NC

PrO PrO

NC

1) 74a-d 2) MeMgBr, ZnCl 2

63a (Ar*: the corresponding binaphtyl groups)

PrO PrO

N N

N N p-Tol

n Me

76a: racemic 76c: P-Helix, 58% se 76b: P-Helix, 61% se 76d: P-Helix, 73% se

SCHEME 8.37. Screw-sense-selective synthesis of poly(quinoxaline)s 75 using chiral palladium complexes 74 as initiators.

selectivities varied from racemic to 73% se (P-helix). The highest selectivity (73% se) was achieved with the 7’-methoxy-substituted binaphthyl derivative 74d, whereas the CD spectrum indicated that the polymer promoted by the 2’-methoxy-substituted binaphthyl initiator 74a resulted in a racemic polymer. A living pentamer, which was prepared from 74a and possessed a pure right-handed helical structure, has been isolated and used in the polymerization of 65. The polymerization afforded a righthanded helical polymer of which screw-sense purity is almost comparable with that obtained in the polymerization with 74d. This result suggests that the poly(quinoxaline) obtained from 65 possesses a kinetically stable helical structure in contrast with the poly (quinoxaline)s prepared from monomer 63a. Note that the originally reported values for the screw-sense selectivity were corrected in the later report [70]. The values in this review are recalculated based on the corrected standard. A series of chiral palladium initiators 77–79 have been reported for the asymmetric polymerization of 1,2-diisocyanobenzenes (Scheme 8.38).[71] These palladium complexes were easily accessible by modification of o-iodobenzoic acid with commercially available chiral compounds. The amide- and oxazoline-based initiators, 77 and 78, resulted in low-to-moderate screw sense selectivities. The highest selectivities (>80%) were achieved by imidazoline-based initiators 79 bearing an acetyl or formyl group. These values are also recalculated based on the later report [70]. An organonickel initiator bearing the chiral oxazoline group was also developed [72]. The structure of the nickel complex 80 was designed according to the chiral palladium initiators shown previously (Scheme 8.39). The ligand on the metal center and the counter anion were optimized to trimethylphosphine and chloride, respectively. The addition of one equivalent of trimethylphosphine to the polymerization system was important for high selectivity. Using nickel initiator significantly reduced the reaction time in comparison with the corresponding chiral palladium initiator while retaining the screw-sense selectivity as high as the palladium system (84% se). The polymerization was successfully accomplished by an in situ generated organonickel initiator 80 (Scheme 8.40) [72]. The initiator was prepared in situ by

251

ASYMMETRIC SYNTHESIS OF POLY(QUINOXALINE)S

1) R*

p-Tol

NC 63a

N

PrO PrO

2) MeMgBr, ZnCl 2

N

p-Tol N

N (PPhMe2)xIPd (x = 1 or 2)

R*

NC

PrO PrO

N p-Tol

N

p-Tol 77a-f, 78a, 78b or 79a-e

n Me

Structures of chiral initiators 77a-f, 78a, 78b or 79a-e (screw-sense selectivities of the obtained polymers are also presented) R1 R2

R NH

Ph

R

N

N O

O

Ph

N

77a: (R1 = Ph, R2 = Me) 19% se, P-Helix 78a: (R = Ph) 39% se, P-Helix b: (R1 = 2-Nap, R2 = Me) 4% se, P-Helix b: (R = t-Bu) 56% se, P-Helix c: (R1 = t-Bu, R2 = Me) 22% se, P-Helix d: (R1 = i-Pr, R 2 = Me) 8% se, P-Helix e: (R1 = c-Hex, R2 = Me) 59% se, P-Helix f: (R1 = CO2Me, R2 = i-Pr) 8% se, M-Helix

79a: (R = PhCO) 42% se, P-Helix b: (R = i-PrCO) 67% se, P-Helix c: (R = MeCO) 82% se, P-Helix d: (R = HCO) 84% se, P-Helix e: (R = MeOCO) 77% se, P-Helix

SCHEME 8.38. Structures of chiral palladium initiators 77–79 and their screw-sense selectivities in the polymerization of 63a.

Ac N

Ph N p-Tol N (PMe3)ClNi

N

NC

PrO PrO

Ph N p-Tol N

NC 63a

1 equiv PMe3 2) NaBH4

N

Ph

Ac

1)

Ph

PrO PrO

p-Tol

N N

N p-Tol nH

81: 84% se, P-Helix

80

SCHEME 8.39. Screw-sense-selective polymerization of 63a using chiral nickel initiator 80.

Ph

Ac N 3) PrO PrO

Ph

Ac N N Cl

Ph 1) Ni(cod) , PMe 2 3 2) Addition of 1 equiv CN

82

Ph N p-Tol N

NC NC 63a

4) NaBH4

PrO PrO

N N

x

N p-Tol nH

NC

p-Tol

p-Tol

83a: (x = 1) 84% se, P-Helix 83b: (x = 0) 77% se, P-Helix

65

SCHEME 8.40. Screw-sense-selective polymerization of 63a in the presence of a chiral nickel initiator generated in situ from Ni(cod)2, 82, and 65.

252

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

reacting an enantiopure aryl chloride 82, Ni(cod)2 and trimethylphosphine in THF at room temperature. Diisocyanobenzene 65 was then added to generate an organonickel initiator 80, to which monomer 63a in THF was added at room temperature or lower. The obtained polymer exhibited a screw-sense selectivity, molecular weight, and polydispersity identical to those obtained with the isolated initiators. The living polymerization technique is most suitable for the preparation of welldefined block copolymers [69]. The polymerization of 1,2-diisocyanobenzene derivatives with organopalladium complexes was applied to the synthesis of block copolymers. A block copolymer 85, bearing a block of tert-butyldimethylsilyl (TBDMS) ether side chains, was successfully synthesized by block copolymerization of 63a and 84 (Scheme 8.41). The isolated polymer 85 showed good solubility in benzene, chloroform, and THF, whereas it did not dissolve in methanol and ethanol. After deprotection of the TBDMS groups, the solubility of the polymer 86 was dramatically changed, allowing for dissolution in ethanol. The living oligomers of 1,2-diisocyanobenzene with an active palladium end group was exceptionally stable and isolable, allowing for their chemical modification without loss of polymerization activity [73]. A living polymer that has silyl-protected hydroxy groups prepared by the polymerization of a 1,2-diisocyanobenzene derivative was treated with a boron trifluoride-ether complex in dichloromethane at 0  C (Scheme 8.42). The desilylated polymer was reacted with a large excess of propyl isocyanate in the presence of 4-(dimethylamino)pyridine (DMAP), yielding NC

PrO PrO

NC 63a

(PPhMe2)2IPdR* 74d t

t

BuMe2SiO BuMe2SiO

NC

O O

NC

N

PrO PrO

N

N

84

N

n

85: soluble in PhH, CHCl3 andTHF insoluble in EtOH and MeOH MeO

p-Tol N Ar* =

n H

N N

N p-Tol

OSiMe2tBu OSiMe2tBu m

TBAF, THF

Ar*

N N

O O

N

H

then MeMgBr, ZnCl2

PrO PrO

n PdI(PPhMe2)2

Ar*

N

PrO PrO

Ar*

O O

OH OH m

86: soluble in CHCl3, THF and EtOH partly soluble in PhH and MeOH

SCHEME 8.41. Block copolymerization of 1,2-diisocyanobenzenes 63a and 84 using a chiral palladium complex 74d as an initiator.

ASYMMETRIC SYNTHESIS OF POLY(QUINOXALINE)S 1) BuMe2 SiO

t t

BuMe2 SiO

74d 1) BuMe2 SiO

t t

BuMe2 SiO

NC

O O

NC 84

PrNHOCO

2) BF3 •Et2 O, CH2 Cl2 3) PrNHCO, DMAP

PrNHCOO

(PPhMe2 )2 IPdAr*

NC

PrNHOCO PrNHOCO

2) BF3 •Et2 O, CH2 Cl2 3) PrNHCO, DMAP 1) BuMe2 SiO

t

BuMe2 SiO

N

O O

Ar*

N n PdI(PPhMe2 )2

87

NC

O O 84

t

253

O O

Ar*

N

O O

N

N n

N

(PPhMe2 )2 IPd

OCONHPh

O O

OCONHPh m

88 NC

PrNHOCO

NC

PrNHOCO

O O

N

Ar*

N n

N

N

N

84 2) BF3 •Et2 O, CH2 Cl2 3) EtO2 CCH2 NHCO, DMAP

EtO2 CCH2 NHOCO EtO2 CCH2 NHOCO

O O

N

O O

OCOCNHPh OCOCNHPh m

l PdI(PPhMe2 )2

89

SCHEME 8.42. Synthesis of triblock poly(quinoxaline) 89 bearing three different urethane groups in the side chains.

N-propylcarbamate-functionalized polymer 87 in high yield. Isolated polymer 87 retained the activity toward continued polymerization of monomer 84, resulting in a diblock copolymer bearing the propylaminocarbonyl and TBDMS groups that could be converted to polymer 88 with the desilylation-aminocarbonylation sequence. This sequence was repeated one more time to yield the triblock copolymer 89 bearing three different urethane groups (PrNHCO-, PhNHCO-, and EtO2CCH2NHCO-) on their side chains. Using a nickel complex as an initiator, the copolymerization of 1,2-diisocyanobenzene derivatives and monoisocyanides was achieved [74]. Using the chiral organonickel initiator 80, 1,2-isocyanobenzene 63a was polymerized to obtain living poly(quinoxaline) (Scheme 8.43). Then monoisocyanide 90 was added to the reaction mixture. The copolymerization yielded a quinoxaline-iminomethylene diblock copolymer that still possessed a living nickel terminus. This living diblock copolymer was subjected to additional polymerization with alternating use of diisocyanide 63a and monoisocyanide 90. Pentablock copolymer 91 consisting of poly(quinoxaline-2,3-diyl) and poly(N-aryliminomethylene) was obtained in good yield. It has been confirmed that almost no chiral helicity was transmitted from the poly(iminomethylene) block to the poly(quinoxaline) block. A series of poly(quinoxaline-2,3-diyl)s bearing chiral side chains was prepared, exhibiting singular dependence of the CD spectrum on solvent [70]. Polymer 93, which has (R)-2-butoxymethyl groups as side chains, possesses an almost perfect P-helix in CHCl3. When 68 is dissolved in 1,1,2-trichloroethane (1,1,2-TCE), its screw sense is completely switched to M. The CD spectra continuously changed with

254

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

N

PrO PrO 1) 63a 2) 90 3) 63a 4) 90 5) 63a

Ar* CO2nPr

j

N

N N

PrO PrO

l

N

Ar*NiCl(PMe3)

CO2nPr CO2nPr N

6) NaBH4

80

N

PrO PrO

Ph

Ac

k

CO2nPr

m

91

nH

N

N CO2nPr

Ph N p-Tol N

NC

PrO PrO

Ar* =

CN NC

CO2nPr

N p-Tol

63a

90

SCHEME 8.43. Synthesis of pentablock copolymer 91 consisting of poly(quinoxaline-2,3diyl) and poly(N-aryliminomethylene) blocks by block copolymerization of diisocyanide 63a and aryl isocyanide 90.

the 1,1,2-TCE/CHCl3 ratio. No CD signal was observed in a 6:4 mixture of 1,1,2TCE and CHCl3, indicating that the P-and M-helical poly(quinoxaline)s coexist in a 1 : 1 ratio in the mixed solvent. The helix inversion was completely reversible, and it could be repeated several times. CD measurements for polymer 93 in various solvents revealed that the P-helical conformation was strongly preferred in CHCl3,

NC 1) o-TolNiCl(PMe 3)2, PMe3

O O

NC

2) o-TolMgBr

o-Tol

N

O O

N

92

n

o-Tol

93 P-Helix in CHCl3, CH2Cl2, THF, BuOH, BuCl and 1,1,1-TCE M-Helix in 1,1,2-TCE, 1,2-DCE, 1,3-DCP and BuCN P-Helix

Cl Cl Cl

H

Cl Cl H OH Cl

M-Helix

Cl O H Cl Cl Cl 1,1,1-TCE

Cl Cl 1,1,2-TCE Cl

Cl

Cl

Cl 1,3-DCP CN

1,2-DCE

SCHEME 8.44. Solvent-dependent helix inversion of poly(quinoxaline) 93 bearing chiral side chains.

ENANTIOSELECTIVE CATALYSIS USING HELICAL POLYMERS

255

CH2Cl2, THF, and 1-butanol, whereas a moderate P-helix induction was observed in 1,1,1-TCE. In valeronitrile (BuCN), 1,2-dichloroethane (1,2-DCE), and 1,3-dichloropropane (1,3-DCP), a moderate M-helix induction was observed. The reversible switch of helical chirality has been applied to a chirality-switchable chiral polymer ligand shown subsequently [75]. Note that a similar but incomplete switch of helical sense induced by two non-polar solvents was reported in polyacetylene bearing chiral side chains [76].

8.4 ENANTIOSELECTIVE CATALYSIS USING HELICAL POLYMERS With increasing demands for the development of practical, efficient chiral catalysts for asymmetric organic synthesis, the application of helical synthetic polymers to chiral polymer catalysts has attracted much attention. Compared with the low molecular weight chiral catalysts, a polymer-based chiral catalyst may have advantages in creating a chiral reaction environment unique for polymer scaffolds, efficient recovery and reuse of the catalyst through easy separation from the reaction mixture, and use of macromolecular conformational change to the enantiodiscrimination. Inspired by the high efficiency and enantioselectivity of the biocatalyses, synthetic peptides and DNA have been used as chiral catalysts or as chiral ligands in asymmetric synthesis. Note that, recently, a DNA-based transition metal catalyst, in which coordinating groups are introduced into the DNA backbone by intercalation, has shown remarkably high enantioselectivities in a Cu-catalyzed asymmetric Diels–Alder reaction and conjugate addition [77]. The use of synthetic helical polymers as scaffolds may be advantageous to the use of naturally occurring polymer scaffolds in that both enantiomeric forms (i.e., right- and left-handed helical structures) are accessible and that the helical structures are potentially robust under the reaction and isolation conditions. In this section, polymer-based chiral catalysts that have helical main chains such as poly(isocyanide), poly(quinoxaline)s, poly (acetylene)s, and poly(methacrylate)s are described. Polymer-based chiral catalysts with no definitive helical main-chain structures are not dealt with in this section. Two categories are provided later on for the helical polymer-based chiral catalysts. One is the chiral polymer catalyst that has chiral groups in close proximity of the reaction site. In this molecular design, the chiral group serves not only as the determinant of helical sense of the polymer but also has a critical effect on the enantiodiscrimination in the catalyses. The other category is the chiral polymer catalyst in which there is no chiral center or axis around the reaction site. In this category, the enantiodiscrimination at the catalytically active sites solely relies on the single-handed helical backbone of the polymer. 8.4.1 Chiral Polymer Catalysts with Chiral Groups in the Close Proximity of the Reaction Sites A peptide-based helical poly(isocyanide) 8a, containing imidazole and carboxylic acid functionalities, has been prepared and tested as imitations of hydrolase such as

256

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

H N

C N

O

O O2N

O

O2N

OH

NH N 8a: L-Ala, L-His, M-Helix

H * N

O HO

N-cetylpyridinium chloride Buffer solution, pH 5.63

O L- or D-94

OH

n

O

+ H * N

O kL/kD = 2.94

SCHEME 8.45. Enantioselective hydrolysis of nitrophenyl ester derivatives in the presence of peptide-based helical poly(isocyanide) 94.

chymotrypsin (Scheme 8.45) [78]. This polymer exhibited significantly higher activity than the corresponding amino acid or oligopeptides in the hydrolysis of nitrophenyl ester derivatives. This increase in activity can be ascribed to carboxylate anions, which enhanced the nucleophilicity of their neighboring imidazolyl groups. In the presence of positively charged surfactants such as N-cetylpyridinium chloride, improved activities were observed. In kinetic measurements on the hydrolysis of Dand L-4-nitrophenyl N-acetyl-2-aminopropionate with 94, a kL/kD value of 2.94 was observed in the presence of the surfactant. An ephedrine-based helical poly(acetylene) 95 was prepared and used as an optically active catalyst for the enantioselective addition of dialkylzinc to benzaldehyde (Scheme 8.46) [79]. An Enantiomeric excess of 1-phenylethanol obtained by the reaction of benzaldehyde with diethylzinc in the presence of a catalytic amount of polymer 95 was 45%, whereas 96 exhibited better enantioselectivity (80% ee). Helically chiral poly(acetylene) 97 bearing Ru complex was synthesized for use as a catalyst for the hydrogen transfer reaction of ketones (Scheme 8.47). [80] The transfer hydrogenation of 2-acetonaphthone proceeded with 36% ee in the presence of 97. Interestingly, a corresponding monomeric ruthenium complex 98 exhibited no enantioselectivity in this reaction. It was suggested that the helical

O

OH 10 mol% 95 or 96 H

Et

Et2Zn, Hexane 25 °C, 24 h

88% yield, 45% ee for 95 100% yield, 80% ee for 96 n H OH N 95

OH N 96

SCHEME 8.46. Enantioselective addition of dialkylzinc to benzaldehyde using ephedrinebased helical poly(acetylene) 95.

ENANTIOSELECTIVE CATALYSIS USING HELICAL POLYMERS

O

NH O

OH

97 or 98 t-BuOK

i-PrOH/MeOH = 95/5 50 °C, 24 h 48% yield, 36% ee for 97 1.8% ee for 98

n H

257

C18H37 H2 N Ru O

NH

H2 N Ru O

O

97

98

SCHEME 8.47. Enantioselective hydrogen transfer reaction of ketones in the presence of helically chiral poly(acetylene) 97 bearing ruthenium-containing side-chains.

structure of polymer 97 may significantly enhance the enantioface discrimination of the prochiral substrate. A series of optically active helical poly(phenylacetylene)s [81] with oligopeptide pendants were synthesized, and their use as asymmetric polymeric catalysts for the epoxidation of chalcone (1,3-diphenyl-2-propen-1-one) derivatives with basic hydrogen peroxide was examined (Scheme 8.48). These polymers exhibited characteristic Cotton effects in their CD spectra in the conjugated polyene chromophore regions, indicating that the polymers possess a predominantly single-handed helical conformations induced by chiral oligopeptide side chains. The catalytic activities of these polymers varied depending on the structures of the pendant moieties. Polymer 99 bearing a triad of L-alanine resulted in the highest enantioselectivity (38% ee) for nonsubstituted chalcone. The monomer 100 did not show enantioselectivity, indicating that the one-handed helical array of the polymer main chain is essential for enantiodiscrimination. Helical poly(phenylacetylene)s prepared from L-valine derivatives was tested as an asymmetric catalyst to reduce the aromatic ketimines to afford optically active O

O

99 or 100 H2O2 / NaOH

O

Toluene, rt, 3-6 d 68% yield, 38% ee for 99 55% yield, <2% ee for 100 n

O

H R= R 99 (X = Na)

R 100 (X = H)

N H

H N

O

H N

N H O O L-Ala-L-Ala-L-Ala-OX

O OX

SCHEME 8.48. Enantioselective epoxidation with optically active helical poly(phenylacetylene) 99 that has oligopeptide pendants.

258

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

1) 101 or 102, HSiCl3 CHCl3, rt, 3.5-18 h

N

HN *

2) NaHCO3 aq

98% yield, 26% ee (S) for 101 quant., 78% ee (R) for 102 n R= 101

R

O

H N

H

N

H

O

102 R

SCHEME 8.49. Enantioselective reduction of aromatic ketimines with poly(acetylene) 101 bearing N-methyl-L-valine side chains.

amines (Scheme 8.49) [82]. The CD and UV spectra of these polymers suggested that the polymers took helical conformations with a predominantly single-handed screw sense in solution. Among these polymers, the poly(acetylene) bearing N-methyl-Lvaline side chain resulted in the highest enentioselectivity (26% ee). Although the enantioselectivity with a polymeric catalyst 101 was rather poor, it produced products with opposite configurations to those obtained in the reaction with 102. This result suggested that the helical chirality of the backbone has a significant effect on enantiodiscrimination. 8.4.2 Chiral Polymer Catalysts with No Chiral Groups in the Proximity of the Reaction Sites The poly(trityl methacrylate) system established by Okamoto has been used as a chiral catalyst. The copolymerization of trityl methacrylate and its pyridyl derivatives in the presence of chiral initiation resulted in one-handed helical polymers with coordinating groups (Scheme 8.50) [83, 84]. The resulting polymers were complexed

OAc Ph

Ph

H n O

R N Pd Cl

CH2(CO2Me)2 105-108

O

105

H m O

R

MeO2C

CO2Me

Ph

* Ph

R

m O

O

O

N N Pd

N N Pd

106

(+)-105: quant., 33% ee (R) (–)-105: quant., 33% ee (S) rac-105: quant., racemic (+)-106: 91% yield, 6.4% ee (R) (+)-107: 99% yield, 60% ee (R) (+)-108: 99% yield, 4.5% ee (R) H n O O

H m O

R O

Cl 107

PPh 2 Pd

108

SCHEME 8.50. Asymmetric allylic alkylation using one-handed helical poly(trityl methacrylate) ligands 105–108.

259

ENANTIOSELECTIVE CATALYSIS USING HELICAL POLYMERS

with palladium to obtain the corresponding polymers 105–107 without losing the helical chirality of the main chain. Polymer 108 that has a phosphine-pendant was also similarly prepared. Catalyst 105 [83] promoted the asymmetric allylic alkylation reaction, producing the substitution product with 33% ee. Although catalyst 106, whose palladium center may have bidentate coordination, did not show a high enantioselectivity (6.4% ee), copolymer 107 showed better enantioselectivity (60% ee). The helical structure of polymer 106 was not stable, and the specific rotation in solution decreased quickly. Copolymerization with trityl methacrylate made the helix more stable, which enabled exhibiting an improved enantioselectivity. Although the catalytic activity of the palladium phosphine complex 108 was higher than the polymers bearing pyridyl derivatives 105–107, the enantioselectivity was low (4.5% ee), probably because of the low helix sense excess of the polymer, based on its optical rotation. A helically chiral polymethacrylate substituted with pyridine N-oxide (þ)-111 was synthesized from 109 to use as an organocatalyst for the asymmetric allylation of benzaldehyde (Scheme 8.51) [84]. The polymerization of a methacrylate derivative containing pyridine N-oxide moiety was not successful because of the strong coordination ability of the pyridine N-oxide, which can replace the chiral ligand of the lithium initiator. The polymer (þ)-111 was obtained by oxidizing the precursor polymer 110. Asymmetric allylation of benzaldehyde was carried out in the presence of polymer (þ)-111, yielding the corresponding allylated products up to 19% ee. Helically chiral poly(quinoxaline-2,3-diyl)s bearing metal-coordinating phosphino pendant groups [85] have been synthesized by the helix–sense-selective living block copolymerization of 1,2-diisocyanobenzene derivatives using the chiral palladium initiator 79c and its enantiomer (Scheme 8.52). The helix–senses of polymers (S)-112 and (R)-112 were induced by the optically active end groups to right- and left-handed helices, respectively. Using copolymers with an achiral spacer monomer 63a as chiral ligands, the asymmetric hydrosilylation of styrene was examined. The catalyst was prepared by mixing (S)-112 or (R)-112 with H n O

R O N

BuLi Chiral amine

O

N

O

m-CPBA O

O H +

SiCl3

N

O

(+)-111: [ α]25D = +242

110

109

H n O

R

OH

(+)-111, (i-Pr) 2NEt n-Bu4N+I-, CH2Cl2

*

56% yield, 19% ee (R)

SCHEME 8.51. Asymmetric allylation of benzaldehyde using a helically chiral polymethacrylate 111 substituted with pyridine N-oxide.

260

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

SiCl3

0.05 mol % [{Pd(μ-Cl)(η3-C3H5)}2] 0.2 mol % (S)-112 or (R)-112 + HSiCl3

*

0 ºC 97% yield, 85% ee (S) for (S)-112 98% yield, 85% ee (R) for (R)-112

PrO PrO

PrO PrO

N

H PPh2

N

~10

(S)-112: P-Helix

N N

N N

PrO PrO

p-Tol ~10

N

PrO PrO

N

H PPh2

N

~10

N

N N

N

p-Tol ~10

N

N

N

N p-Tol Ph

N p-Tol Ph

AcN Ph

(R)-112: M-Helix

AcN Ph

SCHEME 8.52. Asymmetric hydrosilylation of styrene using one-handed helical poly (quinoxaline-2,3-diyl)s 112 bearing metal-coordinating phosphino pendant groups.

[{Pd(m-Cl)(h3-C3H5)}2] in toluene at room temperature. These catalysts exhibited a remarkable catalytic activity, and the reaction was completed within 24 h with only 0.1 mol% palladium loading. Notably, the enantiomeric excess of the product was 85% ee for both helical polymers. Enantioselectivity was improved by using copolymers 113 and 114 using a chiral optically pure spacer monomer 92 (Scheme 8.53) [75]. The 20mer-based copolymer 113 adopted an almost pure single-handed helical structure, resulting in 96% ee in the asymmetric hydrosilylation. A 40mer-based block copolymer 114, in which chiral groups are not located around the reaction site showed a similarly high enantioselectivity, cleanly showing that the chiral groups at the side chain have no direct effect on the enantiodiscrimination. High molecular weight (ca. 1000mer) variants of poly(quinoxaline-2,3-diyl)s bearing phosphine pendants and chiral side chains were synthesized and exhibited remarkable profiles for use as chiral polymer ligands in asymmetric synthesis. A high molecular weight polyquinoxaline random copolymer (R)-115 and [{Pd(m-Cl)(h3-C3H5)}2] formed insoluble polymer complexes during the hydrosilylation reaction. The product was extracted with an organic solvent, leaving the insoluble polymer complex in the reaction vessel. The insoluble polymer complex could be reused up to eight times without adding the palladium source. The polymer (R)-115 obtained from its CHCl3 or toluene solution showed an excellent enantioinduction (97% ee) for the (S)-product in the asymmetric hydrosilylation of styrene (Scheme 8.54). When the same polymer was dissolved in a mixture of 1,1,2-trichloroethane/toluene (2/1), clean inversion of the helical sense

ENANTIOSELECTIVE CATALYSIS USING HELICAL POLYMERS

SiCl3

0.05 mol % [{Pd(μ-Cl)(η3-C3H5)}2] 0.2 mol % 113 or 114 + HSiCl3

261

*

0 °C 91% yield, 96% ee (S) for 113 93% yield, 95% ee (S) for 114

N

O O

H

N

H

O O

PPh2 N

~10

N

N

N

p-Tol ~10

N N

N

PrO PrO

N p-Tol Ph

N

AcN

113: P-Helix

PPh2

~10

N N

~10

N

PrO PrO

N

N

O O

N

p-Tol

114: P-Helix

N

~10

Ph N N p-Tol Ph AcN Ph

SCHEME 8.53. Asymmetric hydrosilylation of styrene using one-handed helical poly(quinoxaline-2,3-diyl)s 113 bearing phosphino pendant groups and chiral side chains.

1,1,2-trichloroethane / toluene (2 / 1), 60 °C, 6 h CHCl3 60 °C, 1 h HSiCl3 +

HSiCl3 +

SiCl3

SiCl3

(R)-87: P-helical form

(R)-87: M-helical form

[{Pd(μ-Cl)(η3-C3H5)}2] 0 °C 97% ee (S)

[{Pd(μ-Cl)(η3-C3H5)}2] 1,1,2-trichloroethane / Toluene (3 / 1), 0 °C

93% ee (R)

Ph2P H

O O

N

N

Tol

N

N 950

50

n

(R)-115

SCHEME 8.54. Asymmetric hydrosilylation of styrene using a high-molecular-weight poly (quinoxaline-diyl) derivative (R)-115 with a P-(left) and M-helical (right) structure.

262

POLY(ISOCYANIDE)S, POLY(QUINOXALINE-2,3-DIYL)S AND RELATED HELICAL POLYMERS

OH O

O Cyclohexanone, 116 H DMSO, 0 ºC, 8 d O2N

O2N NH2

Ph

20% yield, 12 % ee

NH2 OH

Ph

OH Piperazine C DMT-MM N n

C N n Helicity Induction & Memory

O

OH 53

O

OH

h-53

C N n-x

O

OH O

C N x

N

116: x < 0.1n

NH

SCHEME 8.55. Asymmetric direct aldol reaction using poly(isocyanide) 116 bearing piperazine units.

was observed with a CD measurement. The inversion of the helical sense proceeded smoothly at 60  C, reaching completion after 6 h to produce an almost pure M-helical polymer. Using the M-helical polymer, catalytic hydrosilylation of styrene in 1,1,2trichloroethane/toluene afforded 93% ee for the (R)-enantiomer. A series of helical poly(phenyl isocyanide)s with functional pendant groups were prepared by functionalizing the side groups of the optically active helical poly(4carboxyphenyl isocyanide) with a macromolecular helicity memory (Scheme 8.55) [86]. The helical poly(isocyanide) 116 partially modified with piperazine maintained their chiral memory and catalyzed a direct aldol reaction enantioselectively. Although the catalytic activity and the enantioselectivity were low (20% yield, 12% ee), it is remarkable that the enantioselectivity is sorely derived from the helically biased backbone, the chirality of which was successfully memorized after removing the chiral amines.

8.5 CONCLUSIONS Recent progress in the chemistries of poly(isocyanide)s, poly(quinoxaline-2,3-diyl)s, and helical polymers used as chiral polymer catalysts have been covered in this chapter. Screw-sense-enriched (nonracemic) poly(isocyanide)s can be prepared kinetically using bulky isocyanides as a monomer, although only limited examples are known. Most synthesis needs chiral isocyanides to induce one-handed screw sense thermodynamically. In such synthesis, isocyanides derived from optically pure peptides or oligopeptides are employed as monomers. They form an effective network of hydrogen bonds, allowing for the stabilization of the singlehanded helical conformation. In the other series of helical poly(isocyanide)s, phenyl isocyanides bearing chiral substituents on the phenyl ring are used.

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Poly(p-carboxyphenyl isocyanide) and its sodium salt retains its helical chirality even after removal of the chiral guests, which are used for helical sense induction. Poly(quinoxaline-2,3-diyl)s are prepared by living aromatizing polymerization of 1,2-diisocyanobenzenes. Their single-handed helical structure is induced either by a chiral end group or by chiral side chains. An interesting solvent-dependent switch of helical chirality has been observed recently; they show an almost perfect inversion of the helical sense in chloroform and 1,1,2-trichloroethane. Applying the helical polymers to the catalyst of asymmetric organic synthesis has been gaining interest. The polymer-based chiral catalysts can be classified into two classes. One is the chiral polymer catalyst with chiral groups in close proximity to the catalytically active site. The other is the chiral polymer catalyst with no chiral groups around the catalytically active site. Highly enantioselective systems, in which the helical chirality of the polymer backbone plays a critical role in enantiodiscrimination, have been established recently. An interesting switch of the enantioselection in the asymmetric catalysis has been achieved, which takes advantage of the solventdependent inversion of the helical chirality of poly(quinoxaline-2,3-diyl)s. With the rapid progress and improvement of the asymmetric polymer synthesis, exploration of more efficient and more applicable helical polymer systems is highly desirable. Because the chiral environment created by the polymer backbone must be different from that created by chiral small molecules, the development of such new chiral polymer catalysts may provide new opportunities in asymmetric organic synthesis. REFERENCES [1] Ugi, I. (Ed.). Isocyanide chemistry, Academic Press, London, U.K. (1971). [2] (a) Ugi, I.; Meyr, R.; Fetzer, U. Angew. Chem. 1959, 71, 386. (b) Ugi, I. Angew. Chem. Int. Ed. Engl. 1962, 1, 8–21. (c) Ugi, I. Angew. Chem. 1962, 74, 9–22. [3] (a) Millich, F.; Sinclair, R. G., II J. Polym. Sci., Part C: Polym. Symp. 1968, 22, 33–43.(b) Millich, F.; Sinclair, R. G., II J. Polym. Sci., Part A-1: Polym. Chem. 1968, 6, 1417–1430. [4] Yamamoto, Y.; Takizawa, T.; Hagihara, N. Nippon Kagaku Zasshi 1966, 87, 1355. [5] (a) Stephany, R. W.; Nolte, R. J. M.; Drenth, W. Recl. Trav. Chim. Pays-Bas 1973, 92, 275–280. (b) Nolte, R. J. M.; Stephany, R. W.; Drenth, W. Recl. Trav. Chim. Pays-Bas 1973, 92, 83–91. [6] Millich, F.; Baker, G. K. Macromolecules 1969, 2, 122–128. [7] Van Beijnen, A.; Nolte, R.; Naaktgeboren, A.; Zwikker, J.; Drenth, W.; Hezemans, A. Macromolecules 1983, 16, 1679–1689. [8] Van Beijnen, A.; Nolte, R.; Drenth, W.; Hezemans, A.; Van De Coolwijk, P. Macromolecules 1980, 13, 1386–1391. [9] Van Beijnen, A.; Nolte, R.; Zwikker, J.; Drenth, W. J. Mol. Catal. 1978, 4, 427–432. [10] Deming, T. J.; Novak, B. M. Macromolecules 1991, 24, 326–328. [11] Deming, T. J.; Novak, B. M. J. Am. Chem. Soc. 1992, 114, 4400–4402. [12] Green, M. M.; Andreola, C.; Munoz, B.; Reidy, M. P.; Zero, K. J. Am. Chem. Soc. 1988, 110, 4063–4065.

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[57] Hase, Y.; Nagai, K.; Iida, H.; Maeda, K.; Ochi, N.; Sawabe, K.; Sakajiri, K.; Okoshi, K.; Yashima, E. A. J. Am. Chem. Soc. 2009, 131, 10719–10732. [58] Ito, Y.; Ihara, E.; Hirai, M.; Ohsaki, H.; Ohnishi, A.; Murakami, M. J. Chem. Soc., Chem. Commun. 1990, 403–405. [59] Ito, Y.; Ihara, E.; Murakami, M.; Shiro, M. J. Am. Chem. Soc. 1990, 112, 6446–6447. [60] Ito, Y.; Ihara, E.; Murakami, M. Polym. J. 1992, 24, 297–299. [61] Ito, Y.; Ihara, E.; Uesaka, T.; Murakami, M. Macromolecules 1992, 25, 6711–6713. [62] Ito, Y.; Ihara, E.; Murakami, M. Angew. Chem. Int. Ed. Engl. 1992, 31, 1509–1510. [63] Ito, Y.; Ihara, E.; Murakami, M.; Sisido, M. Macromolecules 1992, 25, 6810–6813. [64] Ito, Y.; Kojima, Y.; Murakami, M. Tetrahedron Lett. 1993, 34, 8279–8282. [65] Ito, Y.; Kojima, Y.; Murakami, M.; Suginome, M. Bull. Chem. Soc. Jpn. 1997, 70, 2801–2806. [66] Ito, Y.; Kojima, Y.; Suginome, M.; Murakami, M. Heterocycles 1996, 42, 597–615. [67] Ito, Y.; Ohara, T.; Shima, R.; Suginome, M. J. Am. Chem. Soc. 1996, 118, 9188–9189. [68] Ito, Y.; Miyake, T.; Hatano, S.; Shima, R.; Ohara, T.; Suginome, M. J. Am. Chem. Soc. 1998, 120, 11880–11893. [69] Ito, Y.; Miyake, T.; Ohara, T.; Suginome, M. Macromolecules 1998, 31, 1697–1699. [70] Yamada, T.; Nagata, Y.; Suginome, M. Chem. Commun. 2010, 46, 4914–4916. [71] Suginome, M.; Collet, S.; Ito, Y. Org. Lett. 2002, 4, 351–354. [72] Yamada, T.; Noguchi, H.; Nagata, Y.; Suginome, M. J. Polymer Sci. A Polymer Chem. 2010, 48, 898–904. [73] Ito, Y.; Miyake, T.; Suginome, M. Macromolecules 2000, 33, 4034–4038. [74] Yamada, T.; Suginome, M. Macromolecules 2010, 43, 3999–4002. [75] Yamamoto, T.; Yamada, T.; Nagata, Y.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 7899–7901. [76] (a) Nakako, H.; Nomura, R.; Masuda T. Macromolecules 2001, 34, 1496–1502. (b) Okoshi, K.; Sakurai, S.-i.; Ohkawa, S.; Kumaki, J.; Yahima, E. Angew. Chem. Int. Ed. 2006, 45, 8173–8176. [77] Boersma, A. J.; Megens, R. P.; Feringa, B. L.; Roelfes, G. Chem. Soc. Rev. 2010, 39, 2083–2092. [78] Visser, H. G. J.; Nolte, R. J. M.; Drenth, W. Macromolecules 1985, 18, 1818–1825. [79] Yashima, E.; Maeda, Y.; Okamoto, Y. Polym. J. 1999, 31, 1033–1036. [80] Sanda, F.; Araki, H.; Masuda, T. Chem. Lett. 2005, 34, 1642–1643. [81] Maeda, K.; Tanaka, K.; Morino, K.; Yashima, E. Macromolecules 2007, 40, 6783–6785. [82] Terada, K.; Masuda, T.; Sanda, F. J. Polym. Sci. A Polym. Chem. 2009, 47, 4971–4981. [83] Reggelin, M.; Doerr, S.; Klussmann, M.; Schultz, M.; Holbach, M. Proc. Natl. Acad. Sci. U S A 2004, 101, 5461–5466. [84] M€uller, C. A.; Hoffart, T.; Holbach, M.; Reggelin, M. Macromolecules 2005, 38, 5375–5380. [85] Yamamoto, T.; Suginome, M. Angew. Chem. Int. Ed. 2009, 48, 539–542. [86] Miyabe, T.; Hase, Y.; Iida, H.; Maeda, K.; Yashima, E. Chirality 2009, 21, 44–50.

CHAPTER 9

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION TO ASYMMETRIC CATALYSIS TAKESHI MAEDA and TOSHIKAZU TAKATA

9.1 INTRODUCTION Accurate control of helical conformation is one of the current subjects in polymer science. Optically active helical polymers can be classified into two classes, dynamic helices and static helices, according to the stability of the helical conformations in solution [1–4]. In dynamic helices, helix inversion can occur in solution so that the excess of a screw sense can be controlled by external stimuli, e.g., temperature, solvent, and chiral additive [4–7]. Static helices undergoing no helix inversion can be synthesized by helix-sense-selective polymerization of achiral monomers with chiral initiators or catalysts [8–12] and by polymerization of chiral monomers. It is generally difficult to obtain concrete evidences for helical conformations of polymers because of the uncertainty of the directionality of the junction between their monomer units, although a limited number of helical conformations of polymers in solution are determined by X-ray crystallography of oligomers of helix and by direct observation of helical structures by atomic force microscopy [13, 14]. However, it is of importance to understand detailed helical structures for the applications of helical polymers to asymmetric catalysts, chiral recognition materials, and so on. Therefore, the structure-definite helical polymers with rigid fixed conformations are strongly desired for such applications. Rational designs of rigid helical polymers by means of the fixation of random conformation of a polymer main chain into desired helical conformation results in a solution for synthesis of helical polymers possessing well-defined helical structures. C2 chiral biaryl moiety seems a very suitable candidate as a repeating unit of optically active polymers with

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.

267

268

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

FIGURE 9.1. A concept for rational design of an artificial helix derived from disintegration of the helix into two key structural motifs, “chiral twist” and “planar unit,” by disintegration of a wooden-plate–integrated helix.

predictable helical conformations because the C2 chiral biaryl unit with atropisomerism has an inherently helical nature as a helically twisted unit. Takata et al. have demonstrated a rational design of an artificial helix using C2 chiral moiety [15, 16]. This strategy is based on the consideration of significant components constituting a helix, as illustrated in Figure 9.1. Namely, the helical structure can be broken down or disintegrated into two key structural motifs: “chiral twist” and “planar junction.” These motifs can be embodied as the C2 chiral moiety like the C2 chiral binaphthyl motif and the planar metal complex like the planar metallosalen compolex motif. The resulting polymeric architectures built from the motifs inevitably adopt helical structures because they have no freedom of movement that randomizes their conformations. Once the synthetic strategy for helical polymer is constructed according to the above concept, a variety of helical polymers possessing unique functionalities can be obtained. Because a helical polymer mainly has three possible asymmetric fields for reaction and recognition as shown in Figure 9.2, functional groups can be arranged at a desired position such as outside, inside, or groove by rational design of the helix. Several important reactions using these asymmetric fields of the helix have been reported so far, which will be introduced at the latter part of this chapter. In this chapter the authors discuss the helical polymer syntheses by using C2 chiral moiety as a twisted unit in the main chain and by rigidly binding these C2 chiral moieties for the fixation of the helix conformation, according to the as mentioned construction protocols of the helix. Furthermore, the asymmetric catalysis using the unique asymmetric fields of such helical polymers is also described.

SYNTHESIS OF C2 CHIRAL UNIT-BASED HELICAL POLYMERS

269

FIGURE 9.2. Asymmetric fields of the helix for reaction and recognition.

9.2 SYNTHESIS OF C2 CHIRAL UNIT-BASED HELICAL POLYMERS 9.2.1 Use of C2 Chiral Biaryl Moieties as Chirally Twisted Units in the Polymer Main Chain There are a large number of studies on the optically active polymers formed by polymerizations of optically active C2 chiral monomers with inherent atropisomerism such as biphenyl and binaphthyl monomers [17] (Figure 9.3). The twists originating from the atropisomeric monomers in the main chains promise to make the polymers conformationally chiral as long as the racemization is prevented during the polymerization process. In these polymers synthesized by the connection of C2 chiral biaryl units through bifunctional and conjugated linkers, the freedom in mainchain conformation was partially regulated by the rotational constraint at the chiral axis of the biaryl units. In most cases, a presence of helical structures in main chains is suggested by significant changes in circular dichroism (CD) spectra and/or specific optical rotation. In 1968, Schultz and Jung first reported on the optically active polyamide with enantiopure binaphthyl units (Scheme 9.1) [18]. The polyamide (R)-poly-1 was prepared by the polycondensation of (þ)-2,20 -diamino-bi-2,20 -naphthol and terephthaloyl chloride.

4

Chiral Twisted Unit 3 2

1

C2 - Chiral Binaphthyl

FIGURE 9.3. C2 chiral biaryls as a chiral twisted unit of Figure 9.1.

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

270

NH2 NH2

Cl

O

O

Cl

O N H

H N

n

O poly-(R) -1 Mw 7000 (anaylzed by VPO) [α]578 25= -15.0 (c = 0.1, THF)

(R) -1 [α]57825= +160.6 (c = 0.1, THF)

SCHEME 9.1.

Jaycox et al. and Takeishi et al. have demonstrated stimuli-responsive polyamides (poly-2–4, poly-10) containing C2-chiral biaryls and azobenzene units in the main chains (Schemes 9.2 and 9.3) [19–24]. Ultraviolet (UV) photoirradiation of the polymer samples to drive the trans-cis isomerization resulted in an immediate chiroptical response, with CD band intensities and specific rotation significantly diminished. These effects were fully reversible and were attributed to the presence of putative one-handed helical conformations in the trans-azobenzene–modified polymers that were disrupted by the trans-cis isomerization. This indicates that the spacers in the main chain significantly influenced their helical conformation.

NH2 + NH2

6

H H O N Ar N C

7 + 5

O C

N N

n

8 poly-2; Ar = x [(S) -1] + (100 -x) 6 (R) or (S) -1

poly-3; Ar = x [(R) -1] + y 6 +(100 -x -y) 7 poly-4; Ar = x [(S) -1] + (100 -x) 8

ClOC

NN

NH2

COCl H2N

5

7 NH2

O O H 2N

H2N

NH2

O O 6 8

SCHEME 9.2.

SYNTHESIS OF C2 CHIRAL UNIT-BASED HELICAL POLYMERS

271

Br OR RO

+ H2N-Ar -NH2

CO Pd(PPh3)4, PPh3, DBU

OR RO

DMF, 115º C

H N

Br O

(R) or (S) - 9

Ar

H N O

poly-10a -e

R = Me. Et Ar = a:

NN

b:

c:

CH2

d:

O

e: N

SCHEME 9.3.

Optically active conjugated polymers (poly-12–21) with chiral conformation along the main chains were prepared by the palladium-catalyzed cross-coupling of the corresponding aryls and enantiopure binaphthyl monomers. (Figure 9.4) [25–33]. The UV spectrum of these polymers showed only a small red shift (10 nm) of the absorption maxima when compared with their repeating unit models, indicating almost no extended conjugation between the repeating units of the polymers. The present cross-coupling synthesis has a great advantage in design of optically active polymers. The facility in the design of the resulting conformation of polymer chains has made a wide range of applications possible [34–39]. However, polybinaphthyls have single bonds in the junction of the binaphthyl units, which could induce the free rotation to partly disrupt helical conformation of the main chain. In fact, the CD spectra of the polybinaphthyls having bulky dendrons (poly-(R)-22), which was expected to restrict free rotation about the single bonds in the junctions by steric repulsions, exhibited similar Cotton effects in comparison with those of the monomeric model dendrimers (Figure 9.5) [40]. These results suggest that helical conformation was not wholly generated on their main chains, despite the steric repulsion between the bulky dendrons. Takata et al. described optically active polycarbonates (poly-(R)-23) prepared by the anionic ring-opening polymerization of a cyclic carbonate monomer prepared starting from binaphthol (Figure 9.6) [41]. The rotational freedom around the main chain of poly-(R)-23 was not zero but low because of the direct connection of C2 chiral binaphthyl moieties through the carbonate bond. Poly-(R)-23a having no alkyl groups was insoluble in common organic solvents, although racemic poly-(rac)-23a was soluble in some solvents. The introduction of octyl group in the naphthalene ring improved the solubility of

n

272

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

(a) Sonogashira coupling polymerization

O O

RO OR

O O RO OR

3

m

O O

RO

RO

OR

OR

m 3

n

n

n

R = C18 H37 RO OR

RO OR

poly-(R) -13 (Ref. 25)

poly-(R) -12a (m = 1) poly-(R) -12b (m = 2) (Ref. 24)

O

O

O

O

O

O

poly-(R) -14 (Ref. 26)

R' R1

NO2 NO2

R2

R3

O2N

R3

n

n

R = (CH2)17CH3

R = (CH2)17 CH3

R = (CH2)17 CH3

n

RO OR

R R

poly-(R) -15a (R = OC6H13, R1 = H, R2 = NO2, R3 = H) poly-(R) -15b (R = OC6H13, R1, R2 = NO2, R3 = H) poly-(R) -16 (R = N(CH3)C6H13, R1, R2, R3 = F) (Ref. 27)

poly-(R) -17a (R' = H) poly-(R) -17b (R' = NO2) (Ref. 27)

RO OR

(c) Heck coupling polymerization

(b) Suzuki-Miyaura coupling polymerization RO

poly-(R) -18 (Ref. 27)

OR

O2N

NO2

Ar =

Ar

a

Ar

n

n

S m b (m = 1, 2)

m

RMeN

NMeR

c (m = 1, 2, 4)

poly-(R) -20 (Ref. 31)

RO OR

poly-(R) -19a (Ref. 28) poly-(R) -19b (Ref. 29) poly-(R) -19c (Ref. 30)

(d) Stille coupling polymerization S

hexO Ohex

O

N O

m

N N

em (m = 1, 3) S

x

S y n

O

poly-(R) -21a; R = e1, R' = e1 poly-(R) -21b; R = e3, R' = e 3 poly-(R) -21c; R = e1, R' = hex poly-(R) -21d; R = e3, R' = hex

RO OR'

(Ref. 32)

FIGURE 9.4. Optically active conjugated polymers containing binaphthyl groups in main chains.

poly-(R)-23 to make the structural analysis possible. The specific optical rotation and CD spectra of poly-(R)-23b were significantly different from those of the unit model compound 24. The opposite signs of Cotton effect and specific rotation of poly-(R)23b and 24 suggested the emergence of some special conformation of poly-(R)-23b.

SYNTHESIS OF C2 CHIRAL UNIT-BASED HELICAL POLYMERS

RO

273

OR

Br OR OR

Ni(II)/ Zn

n

Br (R) -22a; R = D0 (R) -22b; R = D1 (R) -22c; R = D2

RO OR poly-(R) -22a; R = D0 poly-(R) -22b; R = D1 poly-(R) -22c; R = D2

D0 = -CH2Ph O D1

Ph

=

Ph O

O Ph

O D2

Ph O

=

O O

[α]D

Yield % 62

3600 (1.8) -174

poly-(R) -22b

71

5200 (1.6) -89.7

poly-(R) -22c

86

poly-(R) -22c Ph

Mn (PDI)

Polymer poly-(R) -22a

a Determined

7200 (1.6) -30.5 19300 (1.4)a

by MALLS technique.

Ph O

FIGURE 9.5. Optically active polybinaphthyls having bulky dendrons.

The CD spectrum calculated for the MM2-simulated structure of a model decamer of poly-(R)-23 coincided with the measured one and supported the occurrence of the stable 41-helical structure. Furthermore, the CD spectra of several oligomers (R)-25 (1, 2, 4, 8-mer), synthesized independently, exhibited a drastic change of Cotton effect between 3-mer and 4-mer (Figure 9.7). Because the Cotton effects of 4-mer and 8-mer resembled that of poly-(R)-23, they seemed to hold similar secondary structures, i.e., 41-helical conformation like the calculated structure of its decamer model. The prediction that poly-(R)-23 takes a helix structure was finally evidenced by the X-ray crystal structure of a 1:1 mixture of (R) and (S) model 4-mers (Figure 9.8) [42]. A similar polycarbonate to poly-(R)-23 could be synthesized simply by polycondensation of binaphthol and bis(4-nitrophenyl)carbonate [43]. Optically active poly(biphenyl carbonate)s poly-(R)-26 synthesized by the anionic ring-opening polymerization of optically active cyclic carbonate (R)-26 was also expected to adopt a stable helical conformation (Scheme 9.4) [44, 45]. The intensity of the CD Cotton effect of poly-(R)-26 was much larger than that of the unit model compound 27. Similarly, the Cotton effect of model 8-mer was much stronger than those of 1–4-mers, suggesting the generation of the stable helical structure of poly-(R)-26.

274

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

(a)

O

O HO OH

4-nitrophenyl chiroformate

O

O O

O

n

t-BuOK

R

R a; R = H b ; R = n-C8 H 17

R

R

(R)- 23a; R = H [α] D24 = +440 (c = 1.0, THF) (R)-23b; R = n-C 8H 17 [α] D24 = –280 (c = 0.15, THF)

(b)

R

R

poly-(R)-23a; R = H poly-(R)- 23b ; R = n-C 8H 17 [α]D24 = +530 (c = 0.15, THF)

(c)

O

20 mer

HO O

R

R

24; R = n-C 8H 17 [α] D24 = –21 (c = 0.15, THF)

Top View

Side View

FIGURE 9.6. Synthesis of optically active polycarbonates by anionic ring-opening polymerization of a cyclic carbonate prepared from a binaphthol derivative (a). Simulated structure (MM2) of a model decamer of poly-(R)-23 (b). Structure of monomeric model 24 (c).

Polycondensation of optically active (R)-2,20 -dihydroxy-9,90 -spirobifluorene (R)28 and bis(4-nitrophenyl)carbonate yielded the corresponding optically active polycarbonate poly-(R)-28) (Figure 9.9) [46]. The helical structure, originated from the rigid spiro structure and consisting of a C2 chiral spirobifluorene (SBF) moiety, was suggested by the CD spectral analysis. In addition, the structural feature of optically active polyesters poly-(R)-29 obtained from the same C2 chiral monomer (R)-28 and a few homoditopic acid chlorides (Figure 9.10) was studied by UV-vis and CD spectroscopies [47]. Poly-(R)29 exhibited Cotton effects around the absorption regions of terephthaloyl, naphthaloyl, and azodibenzoyl linkers, suggesting the generation of some ordered polymer structure. However, their decrease in CD intensity with an increase in temperature indicated that poly-(R)-29 takes an unstable helical structure, in comparison with polycarbonate poly-(R)-28 that exhibited no temperature dependency on CD intensity. Thus, the introduction of C2 chiral biaryl units, in addition to the reduction in rotational freedom by the rigid linkers between the C2 chiral units, effectively contributes the induction of helical conformation to the corresponding polymer.

SYNTHESIS OF C2 CHIRAL UNIT-BASED HELICAL POLYMERS

275

2000 1 mer 2 mer 3 mer 4 mer 8 mer

1500

O

R

8 mer

O

O

R R

OR'

n

1000

R

(R)-25; R' =H or SiMe2But n = 0, 1, 2, 3, 4

Δε / dm3mol–1

OR'

4 mer 2 mer

500

1 mer 0 3 mer

–500

–1000

–1500 solvent : THF –2000 200

250

300

Wavelength / nm

FIGURE 9.7. CD spectra of model oligomers (R)-25.

FIGURE 9.8. X-ray crystal structure of a 1 : 1 mixture of (R) and (S) model tetramers of (R)-25.

276

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

O HO OH

O

O

triphosgene

bis ch (4-n lor itr ofo op rm hen ate yl )

(R)-26 t-BuOK

O HO O

O OCH3

O

27 [α]D24 = +4 (c = 0.1, THF)

O

poly-(R)-26 [α]D26 = +27.4 (c = 0.1, THF)

SCHEME 9.4.

O

(a) OH HO

O

O

Bis(4-nitrophenyl) carbonate DMAP (2eq) (R )toluene, reflux n

(R )-28 [α] D20 = +27.6

poly-(R )-28 [α]D 20 = +116 (c = 0.1, THF)

(b)

FIGURE 9.9. Synthesis of poly-(R)-28 (a) and MM2-optimized structure of poly-(R)-28 (b).

SYNTHESIS OF C2 CHIRAL UNIT-BASED HELICAL POLYMERS O

277

O

Ar = a: O

O

Ar b:

c:

N N

n

poly-(R)-29a-c

FIGURE 9.10. Optically active polyesters containing a spirobifluorene moiety.

9.2.2 Synthesis of Stable Helical Polymers by the Fixation of Main-Chain Conformation 9.2.2.1 Helical Polymers Generated via Intramolecular Cyclization. In the helical polymers prepared by linking C2 chiral biaryl units through single bond formation, the helix usually tends to become unstable because of the free rotation around the linker units to randomize the conformation. For example, poly-(R)-22 having single bonds combining C2 chiral binaphthyl units was not considered as a helical polymer stable in solution, even if it had a bulkier side chain. In fact, the CD spectrum of poly-(R)-22 was close to that of its unit model compound. The single bonds in the junctions of the binaphthyl units allow for several main-chain conformations with almost the same stability. Elimination or a large decrease of degree of rotational freedom in the main chains results in the formation of highly stable helical polymers in solution. The fixation of atropisomeric units by intramolecular cyclization produces a successful entry into the construction of helical molecules. Grimme, V€ogtle, and coworkers reported on the extended atropisomeric compound 30 that was prepared by the intramolecular reactions of a triaryl (Figure 9.11) [48]. Because the rotation around the aryl-linking single bonds was inhibited by the cyclizative linking of the aryl moieties, the resulting three possible conformers 30 of the helical terarylophane

CO2Et Br

Na2S benezene/ or ethanol

Br

CO2Et

X

X

NaH +

Br X

+ P,M helix

X

Br P, P helix

M,M helix 30a: X = S 30b: X = C(CO 2Et)2

FIGURE 9.11. Synthesis of helical molecules having an elongated screw shape.

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

278

MOMO O O B

R

R OMOM + OMOM

O B O

OMOM

R

Br

Ph(PPh3)4 Br

K2CO3 H2O/THF

R

R

R

R = Ph-p-OC12H25 MOMO OMOM

poly-(R)-31 [α]D = -115.7 (c = 0.1, CH2Cl2) OH OH

R

R

CF3CO2H CH2Cl2, r.t. 97% yield R

R

OHOH

poly-(R)-32 [α]D = -708 (c = 0.1, CH2Cl2)

FIGURE 9.12. Helical polybinaphthyls obtained by acid-catalyzed cyclization.

were separated with a chiral high-performance liquid chromatography (HPLC) column. In 2004, Pu and Zhang prepared optically active helical polybinaphthyls (poly-(R)-32) having no single bond, allowing for unrestricted rotation in the main chain (Figure 9.12) [49]. These helical polymers were obtained according to two-step synthesis consisting of initial polymerization of two monomers to poly-(R)-31 followed by cyclization on the main chain to poly-(R)-32 that eliminate the freely rotatable single bonds between the monomer units. Effective conversion of poly-(R)-31 into poly-(R)-32 using Swager’s acid-catalyzed cyclization of arylalkynes to polyaromatics resulted in the formation of a helical polymer. UV, fluorescence, and CD spectra of poly-(R)-31 and poly-(R)-32 were measured for the evaluation of the structural change. Specific rotation of poly-(R)-32 was fluctuated at 708, which was compared with that of poly-(R)-31 (115.7). Some molecular weight-dependency of poly-(R)-32 in CD Cotton effect was confirmed. 9.2.2.2 Helical Polymers Generated via the Metal Complexation of Linker Moiety. Fixation of main-chain conformation using a rigid framework

SYNTHESIS OF C2 CHIRAL UNIT-BASED HELICAL POLYMERS

MeO

CHO OHC

OMe

MeO H 2N

OH

HO

N

Ni(OAc)2 OR

RO

OMe

N

NH2 RO

Ni O

279

O OR

MeO R= -(CH2)2O(CH2)3CH3 OR

33

SCHEME 9.5.

of the metal complex is actually used in both biological and chemical processes. Protein-folding reactions in either natural and synthetic proteins often occur via metal complexation, causing activity enhancement [50–52]. Use of complexation between transition metal and ligands for stabilizing and/or regulating conformation of molecule has recently been recognized as an effective synthetic protocol in rapidly growing supramolecular chemistry. Many regulated architectures, foldamers, stepladders, chains, rings, cages, and dendric macromolecules have been given so far by the coordination of polytopic ligands to metal ion [53–55]. These complexes with specific conformation and geometry are well designed by considering binding sites, metal ions, and ligands involving linkers between the binding sites. Utilization of metal complex formation should be also advantageous to construct helical polymers. A successful example can be observed in construction of helicates via reaction of polytopic ligands and metal ions [56]. A lot of single, double, and triple helices were obtained through the appropriate designs of ligands including metal binding sites and spacers between the binding sites and the choice of metal ions [57, 58]. Katz et al. reported the most straightforward helix synthesis, i.e., the polymerization of a formyl group-functionalized helicene monomer 33 having a intrinsic helical geometry followed by the complexation with nickel acetate to nickel salen complex capable of serving as a rigid planar connection between the helicenes to eventually afford a helical ladder polymer (Scheme 9.5) [59, 60]. This approach using the fixation of main-chain conformation through the rigid planar complex formation seems a very efficient protocol that exclusively provides a desired stable helical polymer. Takata et al. used a similar metallosalen complex formation for the helicate synthesis. Namely, according to the discussion in Figure 9.1, a metallosalen complex was chosen as the planar rigid junction in addition to the choice of (R)-binaphthl group as the chiral twist (Figure 9.13). The synthesis of helical poly(binaphtyl-salen complex)es poly-(R)-34 was carried out by the two-step procedure via the initial polymerization of the monomer components through a [2, 3; a,b] fusion mode followed by the metal complexation for the rigid junction (Figures 9.14 and 9.15) [15, 16]. The precursor polymer, poly (binaphthyl-Schiff base) poly-(R)-34, was prepared by the polycondensation of binaphtyl dialdehyde 34 and a diamine. Treatment of poly-(R)-34 with metal acetate

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

280

Chiral Twisted Unit

4

Planar Joint

3 A

2

N

1

N M

+

O

O

Planar MetalComplex

C2 - Chiral Binaphthyl [2,3; α–β] fusion

FIGURE 9.13. Molecular design of a helicate constructed by the fusion of C2 chiral binaphthyl as the chiral twist and metallosalen complex as the planar junction.

Fix by Coordination to Metal Ions Polymerized

Conformation Change

Unit Structure

FIGURE 9.14. Schematic representation of synthetic strategy of helical polymers constructed a priori.

R2

N

CHO

diamine a-e

OH OH R2

N

N

OH HO R

CHO

R

R

(R)-34

N M

M(OAc)2

O R

M= Zn(II), Cu(II), Mn(III)-OAc,

R poly-(R)-34a-e

diamine

O R

R

R poly-(R)-34a-e(M)

N

N M

NH2 NH2 a

NH2 NH2 b

H2N

NH2 c

(R,R) H2N

NH2 d

(S,S) H2N

NH2

O OR

O RO

e (R)-35(M)

R = -(CH)2CH3

FIGURE 9.15. Synthesis of helical poly(binaphthyl salen complex)es.

SYNTHESIS OF C2 CHIRAL UNIT-BASED HELICAL POLYMERS

281

quantitatively yielded poly(binaphthyl-metallosalen complex) poly-(R)-34M. Random coil poly-(R)-34 changed its form to a very stable helical poly-(R)-34M having a 31-helical conformation by the metal insertion so as to form a rigid planar metallosalen complex structure in the main chain. Therefore, the constrained helical structure of poly-(R)-34M can be predictable as illustrated in Figure 9.13. The salen ligand features two covalent and two coordinate sites situated in a planar array, whereas the two axial sites are open for ancillary ligand and substrate. Studies on an energy-minimized molecular model (built with MM2) of poly-(R)34(Cu) calculated using the crystalline data of (R)-35(Cu) as the initial structure, in addition to the careful investigation with the Corey–Pauling–Kolturn (CPK) spacefilling model, showed a helical conformation as only possible main chain structure (pseudo 31-helix, ca.1.6 nm in diameter, an interval of ca. 0.8 nm, a helical cavity of ca. 0.3 nm in diameter) (Figure 9.16). Moreover, the molecular dynamics (MD) simulations of a model decamer of poly-(R)-34(Cu) indicated that no break of the helix occurred at least in tens of picoseconds at 400 K. A clear evidence for the helical conformation was obtained in CD spectra revealing the gradual conversion of poly(Schiff base) poly-(R)-34 to poly-(R)-34(Cu) depending on the amount of Cu(II) added, around 401 nm assignable to the p-p* type transitions of C¼N chromophore and at 400–600 nm assignable to LMCT transitions of the metal complex (Figure 9.16 (C)). In CD spectral change, it was also confirmed that the addition of Cu(II) caused a drastic change of the Cotton effect at the range from 220 to 380 nm. These clear (c)

(a) Top view

210 0 eq

(L mol-1 cm-1)

140

ca. 6 Å

1.33 eq

70

0

0 eq 0.13 0.27 0.67 1.00 1.33

-70

ca. 13 Å

-140

-210 200

(b) Side view

1.33 1.00 0.67 0.27 0.13 0 eq

300

400 500 600 Wavelength (nm)

700

ca. 6 Å

FIGURE 9.16. MM2-optimized structures of poly-(R)-34e(Cu) (a, b, 10-mer model) and CD spectral change of poly-(R)-34e to poly-(R)-34e(Cu) upon mixing with Cu(II) in THF (c).

282

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

N

N

OH HO

O

N

CHO NH2

OH

ZnEt2

o-chlorophenol r.t. 48 h

HO

N Zn

H2N

O

CH2Cl2 r. t. 1 h

OHC

(R)-36

poly(R)-36

poly(R)-37

FIGURE 9.17. Synthetic scheme and MM2 calculated structure of 21-helical poly(spirobifluorene-salen complex) (poly(R)-36(Zn)).

changes could indicate that naphthalene rings were rearranged along the helical main chain from the random one. Successive binding of a C2 chiral SBF moiety (R)-36) with two sets of two functional groups like (R)-34 and a planar metallosalen moiety, which is similar to the case of poly-(R)-34(M) (Figure 9.15), resulted in the formation of a zigzag 21helix (poly-(R)-36(M), Figure 9.17). Takata et al. found that the C2 chiral SBF moiety with a completely fixed dihedral angle at 90 absolutely affords the structuredefinite 21-helix by the two-point junction using the metallosalen complex [61]. Initial synthesis of poly(Shiff base) (poly-(R)-36) using a diamine was followed by the metal-introduction to fix the main chain by the formation of a planar metallosalen complex to the 21-helix. The rigid helical conformation of poly-(R)-36(M) was suggested by the good thermal stability of the CD Cotton effect, which is similar to poly-(R)-34(M).

9.3 ASYMMETRIC REACTIONS CATALYZED BY HELICAL POLYMER CATALYSTS Optically active helical polymers having metal complex moieties can provide their helical backbones and metal complex moieties as chiral recognition and asymmetric catalytic sites. In the early 1970s, Hatano et al. reported that the poly-L-lysine– copper(II) complex catalyzed enantiomer-selectively the oxygen oxidation of 3,4dihydroxyphenylalanine (Scheme 9.6) [62]. Copper(II) ion at the catalysis center was fixed by amino groups of lysine residues of the poly(S)-lysine helix.

COOH

poly-(S)-lysine Cu2+, O2,

NH2

HO OH

COOH NH2

O (R)-isomer selective

SCHEME 9.6.

O

ASYMMETRIC REACTIONS CATALYZED BY HELICAL POLYMER CATALYSTS

O

O N +

283

N

DNA-based catalyst water

X

> 99 %ee X

Cu2+

N N

DNA-based catalyst

FIGURE 9.18. DNA-bound catalysts used in the catalytic asymmetric Diels–Alder reaction of cyclopentadiene with aza-chalcone.

Roelfes and Feringa et al. used a DNA-bound copper catalyst for the asymmetric Diels–Alder reaction of an enone and cyclopentadiene in water (Figure 9.18). The catalyst consisted of a DNA double helix and a nonchiral intercalating moiety incorporating a metal complex, which enables the noncovalent anchoring of the metal complex to DNA. The Diels–Alder adduct was obtained in more than 99%ee via the asymmetric induction from a double-strand DNA helix [63–65]. This result indicated that the chiral environment provided by the DNA double helix could be transferred to the reaction products, whereas the ligand with the intercalatable part was achiral. The role of the DNA was found to act as not only a chiral scaffold but also as a rate-accelerating field, although it depended on the sequence of the DNA [66]. Similar DNA-bound catalysts were applicable to asymmetric syntheses in water such as the Michael reaction and the Friedel–Crafts reaction, in addition to hydrolytic kinetic resolution [67–69]. As mentioned, optically active helical polymers can be regarded as attractive chiral recognition materials and asymmetric catalysts because of their specific asymmetric fields originating from both the main chain helix and the helical arrays of the side chains. The chiral environment provided by an artificial stable helical polymer is also effective for enantioselective reaction. Takata et al. demonstrated the asymmetric reactions catalyzed by helical polymer complexes consisting of C2 chiral binaphthyl units and metallosalen complexes, poly-(R)-34M. The metallosalen complex moiety is placed in the groove of the helix constructed by the regular arrangement of both the naphthalene moieties and the diamine units, according to the helix-forming concept shown in Figures 9.13–19.16. The asymmetric addition of diethylzinc to benzaldehyde was catalyzed by poly-(R)-34(Zn) (5 unit mol%) to afford 1-phenyl-1-propanol with 13–95%ee in 19–99% yield by 24 h reaction (Figure 9.19) [16]. Among several solvents, tetrahydrofuran (THF) was the most effective solvent for achieving favorable yield and enantioselectivity. The enantiomeric excess of the product increased up to 95% in the reaction at 60 C in which no by-product was

284

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

PhCHO + Et2Zn

poly-(R)-34(Zn) (5 mol%)

OH Ph *

THF, r.t., 24 h

N

N Zn

O

O

R

R

R

R poly-(R)-34(Zn)

Catalyst

Conv. (%)

ee (Config.) (%)

poly-(R)-34a(Zn)

> 99a

29 (R)

poly-(R)-34a(Zn)

> 99

77 (R)

poly-(R)-34a(Zn)

> 19b

95 (R)

poly-(R)-34b(Zn)

> 99

59 (R)

poly-(R)-34d(Zn)

> 99

81(R)

poly-(R)-34e(Zn)

96

13(R)

(R)-35a(Zn)

85

5(R)

aSovent:

Toluene. bReaction temperature: –40 ºC.

FIGURE 9.19. Asymmetric addition of diethylzinc to aromatic aldehydes catalyzed by poly(R)-34(Zn).

observed. The enatioselectivity of poly-(R)-34b(Zn) was slightly lower than that of poly-(R)-34a(Zn), indicating the unfavorable effect of the vic-dimethyl group placed on the diamine unit. Although enantiomeric excess of products obtained by poly-(R)34e(Zn) having a (S,S)-cyclohexanediamine unit was low (13%ee), the reaction catalyzed by poly-(R)-34d(Zn) having a (R,R)-1,2-cyclohexanediamine unit afforded to the products with high enantioselectivity (81%ee). These results revealed that the chiral environment around the metallosalen active site of the catalyst can be effectively modified by the structure of the diamine unit, suggesting a potential finetuning of the chiral space in the groove of the helical poly(binaphthyl salen zinc complex)es. In contrast, a polymer unit model (R)-35a(Zn) resulted in a very low enantioselectivity, indicating that asymmetric catalysis was attributed to the helical structure of polymers rather than to the chiral repeating unit. Catalysis of helical poly [N-(4-ethynylbenzyl)ephedrine], a optically active polyacetylene, which predominantly took a one-handed helical conformation induced by the chiral pendant groups, in the asymmetric addition of dialkylzinc to benzaldehyde was also reported by Yashima et al. [70]. The ee of the product obtained with the helical polymer was lower than that with the monomer unit model catalyst, indicating that the one-handed helical structure negatively affected the enantioselectivity. The present catalytic reaction using poly-(R)-34(Zn) was the first report that directly used the secondary structure of the polymer as the asymmetric field. It is important for asymmetric synthesis to increase efficiency of the reaction and the degree of enantiomeric excess with as little amount of chiral auxiliary as possible. Helical polymer catalysts have a great advantage to reduce the chiral sources with retaining high enantioselectivity because dominant single-handed helical structures are generated by the propagation of chirality from optically active comonomers to achiral comonomer or helix-sence-selective polymerization using optically active additives and initiators. The propagation of chirality through the polymer backbones in the polymer complex consisting of binaphthyl units to achiral bisphenyl and biphenyl units (copoly-37(Zn), copoly-38(Zn)) were studied together with their

285

ASYMMETRIC REACTIONS CATALYZED BY HELICAL POLYMER CATALYSTS

(a) R1

R2O

CHO

CHO

OH + (1-n) OH

n R1

OH OH

R2O

CHO

CHO

N

R1 1. NH2 NH2 2. Zn

N

OR2

Zn

2+

O

R1

R1 = n-C8H17 R2 = n-C12H25

O

n

OR2

copoly-37(Zn)

(b)

(1-n)

(c)

N

R1

N Zn

O

R1

O

(1-n)

n

copoly-38(Zn) Ratio of chiral and achiral units (n)

FIGURE 9.20. Synthesis of polymer complexes consisting of optically active binaphthyl units and achiral biphenyl units (copoly-40, 41(Zn)) (a, b). Plots of enantiomeric excess of the product in the diethylzinc addition to benzaldehyde catalyzed by copoly-40(Zn) versus content of chiral units (n) (c).

application to asymmetric addition of diethylzinc to benzaldehyde (Figure 9.20) [71]. Weak nonlinear correlations between the content of chiral unit and the enantiomeric excess were observed in the catalytic reactions probably because of the chirality induction in achiral comonomer units. Reggelin and coworkers have reported the asymmetric catalysis of single-handed helical poly(methacrylate)s with sterically congested methacrylates (poly-39, poly40) prepared by helix-sense-selective polymerization [72, 73]. These optically active helical polymers having no optically active moiety were designed to offer the coordination sites for organopalladium compounds and the catalytically active site of pyridine N-oxide (Figure 9.21). Catalytic sites located in the helically oriented side chain provide efficient reaction fields for an asymmetric C-C bond forming reaction such as allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate and allylation of benzaldehyde with allyltrichlorosilane. In addition to a static helical polymer, dynamic poly(isocyanate)s (poly-41) with a dominant one-handed helical structure dictated by a smaller amount of optically active monomer units compared with achiral phosphorus monomer units can complex with rhodium and catalyze an asymmetric hydrogenation of Nacetamidocinnamic acid to produce the corresponding saturated product in moderate enantioselectivity (Scheme 9.7) [74]. Poly(binaphthyl salen manganese complex) catalyzed the epoxidation of alkene with m-chloroperbenzoic acid (mCPBA) (Figure 9.22) [75]. Although poly-(R)-34a (Mn) showed no enantioselectivity, poly-(R)-34b(Mn) having a 2,2-dimethyl-1,3propanediyl unit as the diamine unit exhibited enentioselectivity in the epoxidation

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

286 (a)

CO 2 Me x

y

O

CO 2 Me cat. poly-39 ( 25 mol%)

O

O

O

OAc

N

Ph

N Pd

MeO 2C

Ph

CO 2 Me

*

Ph

Ph

99 % yield, 60 %ee

poly-39

(b) x

y

O

O

O

O

O N

N

H O

+

SiCl3

OH

cat. poly-40 i Pr2 NEt

*

n-Bu 4 NI CH 2Cl 2

56 % yield, 19 %ee

poly-40

FIGURE 9.21. Asymmetric catalysis of helically chiral palladium complexes in the allylic substitution reaction (a). Helically chiral organocatalysts for allylation of benzaldehyde with allyltrichlorosilane (b).

O NC

O N

N

x

H

H2, cat. [Rh(COD) 2]OTf / poly-41

COOH

y

Ph

COOH

NHAc

Ph

Ph2P

*

NHAc

quant. 14.5% ee

poly-41

SCHEME 9.7.

N

N

O

Mn+3 O

m -CPBA poly-(R)-34(Mn) (8 mol%)

OAc

R

O

R Yield/%

ee /%

poly-(R)-34a(Mn)

92

1

poly-(R)-34b(Mn)

40

17

(R)-35b(Mn)

43

1

Catalyst

R

R poly-(R)-34(Mn)

FIGURE 9.22. Asymmetric epoxidation of 1,2-dihydronaphthalene catalyzed by poly-(R)-34 (Mn).

ASYMMETRIC REACTIONS CATALYZED BY HELICAL POLYMER CATALYSTS poly-(R)-34(Cu) (1.5 mol%) Ph

Ph

Ph

+ N2CHCOOEt

+ CO2Et

CO2Et Catalyst (Mn)a poly-(R)-34e(Cu)b

a

Yield/% (trans/cis)

ee /% (trans/cis)

(87000)

14 (64/ 36)

28 / 46

poly-(R)-34e(Cu) (87000)

45 (65/ 35)

11 / 35

poly-(R)-34e(Cu) (18000)

42 (60/ 40)

6 / 19

poly-(R)-34d(Cu) (10000)

42 (68/ 32)

2/0

36 (62/ 38)

2 / 16

(R)-35e(Cu)

287

Mns of the precursor poly(Schiff base)s. bReaction temperature 0ºC.

N

N Cu

O

O

R

R

R

R

poly-(R)-34(Cu)

FIGURE 9.23. Poly-(R)-34(Cu)-catalyzed asymmetric cyclopropanation of styrene with ethyl diazoacetate.

of 1,2-dihydronaphthalene. The polymer unit model (R)-35b(Mn) showed almost no enantioselectivity. Therefore, the chiral space originating from the helical poly-(R)34b(Mn) was effective for this reaction, although enantioselectivity was not high. Helical poly(phenylacetylene)s having oligopeptide groups also catalyzed the asymmetric expoxidation of the chalcone derivative [76]. The helical array of oligopeptide pendants was crucial for the enantioselective synthesis of epoxides. Takata et al. elucidated the potential utility of poly-(R)-34(Cu) as the asymmetric catalyst for the cyclopropanation of styrene with diazoacetate (Figure 9.23) [77]. Some asymmetric induction was observed in the asymmetric cyclopropanation catalyzed by poly-(R)-34e(Cu), although the yield was small because of their low catalytic activity. The reaction catalyzed by the corresponding polymer model (R)35e(Cu) afforded cyclopropanes with a low enantiomeric excess. Thus, it is apparent that the higher enantioselectivity of poly-(R)-34e(Cu) than that of its model catalyst is attributed to the helical environment. The effect of molecular weight of the polymer catalyst on enantioselectivity was observed [35%ee (Mn ¼ 87000), 19%ee (Mn ¼ 18000)]. This might be attributed to the concentration of polymer terminal forming incomplete helical fields. Thus, the helical structure of poly(binaphthyl salen complex) played a significant role in the catalytic asymmetric reactions. The synergistic effect between the helical array of the salen complexes and the diamine units was confirmed in all catalytic reactions. All these catalytic reactions with the helical polymers mentioned previously were also the epoch-making reports that directly used the secondary structure of a polymer as the asymmetric field. Complementary double-helical molecules based on an amidinium-carboxylate salt-bridge with a predominant single-handed helical conformation have been demonstrated by Yashima et al. as the first double-helix catalysts 42 that have no chiral auxiliaries except for dissymmetrical helicity of the strands (Figure 9.24) [78–80]. They were prepared by the substitution of chiral ligands for platinum linkages with achiral bridged phosphine ligands. The predominantly double-helical

288

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

Ph

cat. 42 (1.5 mol%)

+ N2CHCOOEt

Ph

Ph

+

95% yield 62/38 (trans/cis)

CO2Et 85% ee

PPh2

Ph2P TMS TMS

N

H N

H

H

O

O

Pt

CO2Et 5% ee

Pt

Ph2P

O

O

H N

H N

TMS TMS

PPh2

42

FIGURE 9.24. Complementary double-helical catalysts for asymmetric cyclopropanation.

conformation formed in the complex formation of an amidine strand with chiral ligands with carboxyl strands was memorized and provided suitable reaction fields for the asymmetric cyclopropanation. Sanda et al. also reported the catalytic asymmetric reduction of ketone with optically active polyacetylene, i.e., poly(N-propargylamides) with ruthenium complex moiety as the catalyst site (poly-43) (Scheme 9.8) [81]. Some synergistic effect of the helical main chain and the optically active pendants played a crucial role in the asymmetric reduction. Suginome and Yamamoto have reported on the asymmetric catalysis of optically active helical poly(quinoxaline-2,3-diyl)s (poly-44) having coordination sites of phosphines (Scheme 9.9) [82]. The polymers were prepared by the asymmetric living block copolymerization of an achiral comonomer having no metal-binding sites and a comonomer with phosphorus donor atoms using the chiral initiator, and they exhibited high catalytic activity in palladium-catalyzed asymmetric hydrosilylation. Thus, one-handed static helical structures generated by the helix-sense-selective

O

n

O H 2N Ru O Cl

OH cat. poly-43

NH

H

*

CH3 48% yield 36% ee

poly-43

SCHEME 9.8.

CH3

289

CONCLUSIONS

Me H

N

R R

N

n

N

Me Me R

N

R

N Me

[Pd(μ-Cl)(η3−C2H5)]2 ( 0.05 mol%) (S)-poly-44 (0.2 mol%)

PPh3

N

SiCl3

*

+ HSiCl3

m

Me l

97% yield 85% ee

Ar*

R = CH2OCH2CH2CH3 Ar* = chiral initiator poly-44

SCHEME 9.9. NH2

C N

Ph

n

addition

OH

removal

C N

n

HN

helix induction OH and memory

OH

O

C N

NH

condensation agent

y

OH

O

O

h-poly-45

poly-45

C N

x

N

NH

O h-poly-46

O

O

OH O H

O 2N

* *

h-poly-46 DMSO, 24 h

O2N 11% yield 12% ee

SCHEME 9.10.

polymerization using a small amount of chiral sources offered effective chiral environments for asymmetric synthesis. Recently, dynamic helical polymers that have no chiral center in repeating units were applied to asymmetric polymeric catalysts. Yashima et al. have reported on the catalytic activity of poly(phenyl isocyanide)s with achiral amino pendants (h-poly46) that have no chiral functionalities except for macromolecular helicity induced by the agency of chiral amines followed by complete removal of the chiral amines and modification of the side-chain groups with achiral amines (Scheme 9.10) [83]. The dynamic helical polymers promoted the direct aldol condensation to produce nonracemic aldol derivatives, although the enentiomeric excess was low.

9.4 CONCLUSIONS This chapter has focused on the syntheses of optically active helical polymers based on C2 chiral biaryl units as the inherently helically twisted units introduced into the main chain and helical polymers possessing more rigidly fixed conformations by the rigid

290

C2 CHIRAL BIARYL UNIT-BASED HELICAL POLYMERS AND THEIR APPLICATION

binding of the C2 chiral biaryl units. In addition, there have been discussed on the asymmetric reactions catalyzed by helical polymers, some of which use the asymmetric field of helix, a secondary structure of polymer. As shown in Figure 9.1, the helix can be disintegrated into two motifs: chiral twisted part and planar part binding the two chiral twisted parts. According to this protocol, many helical polymers have been prepared to date, although polymers prepared using only C2 chiral biaryls can take the one-handed helix stable in solution in some cases. Further fixation of helical conformation by using planar metal complex formation is effective to obtain stable helical conformations constructed a priori. Meanwhile, it has been demonstrated that the asymmetric fields providedbyhelicalpolymerseffectivelyworkinvariousasymmetricreactions.Polymer catalysts having no chiral unit except for its main-chain helicity have also caused the asymmetric reactions. Thus, the syntheses of helical polymers with predictable conformations are of importance from the viewpoint of not only new helical polymer synthesis but also development of efficient polymer asymmetric catalysts.

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CHAPTER 10

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs) HIROAKI SASAI and SHINOBU TAKIZAWA

10.1 INTRODUCTION Immobilization, as a method to recover and reuse catalysts effectively, has attracted the interest of many research groups, resulting in a large number of catalysts being subjected to the procedure [1]. Multicomponent asymmetric catalysts (MACs: Figure 10.1) [2], composed of plural ligands, metals, and functional moieties, have proven to be challenging systems in this regard. Some MACs activate a substrate synergistically to afford unique optically active products that are difficult to obtain by a single component catalyst even in racemic form [2g–j]. Al-Li-bis(binaphthoxide) (ALB) [2b] and Ga-Na-bis(binaphthoxide) (GaSB) [2c] complexes are representative examples of MACs (Figure 10.2) and function like enzymes to facilitate a wide range of regio- and stereoselective reactions. ALB is prepared by the addition of LiAlH4 (or AlMe3 and n-BuLi) to two molar equivalents of 1,10 -bi-2-naphthol (BINOL) in tetrahydrofuran (THF) and is revealed to have high enantioselectivity in the asymmetric Michael reaction [e.g., 2-cyclohexenone (1) with dibenzyl malonate (2)]. If ligands are attached to a polymer backbone and the position of each ligand in a catalyst is controlled appropriately to produce MACs, the polymer support would enhance MAC formation and stabilize the resulting catalysts. This would offer the advantages of easy product separation, recovery, and reuse of the catalysts. To that end, a study of polymer-supported catalysts would provide a general method for the construction of further useful MACs. The conventional method for the preparation of polymer-supported catalysts relies on the random introduction of ligands into a sterically irregular solid polymer backbone (e.g., polystyrene resin). This method produces undesirable results for MACs because of the highly disordered orientation of ligands along the polymer chain. For example, the polymer-supported ALB 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.

293

294

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs)

re f [2 a] N N

ref [2b,2c] O O

P P

re f [2 d] O O

O O

O O

ref [2f ] ref [2e] O O

O O

O O

X : Ligand X

O O O O O O

ref [2g] O O O O O O

: Metal and/or functional moiety

FIGURE 10.1. Schematic representation of typical multicomponent asymmetric catalysts (MAC).

Li O O Al O O

Na O O Ga O O

Al-Li-bis(binaphthoxide) (ALB)

Ga-Na-bis(binaphthoxide) (GaSB) O

O

O

Catalyst (10 mol %)

O

O

+ BnO 1

OBn

OBn

THF, rt

2

OBn 3

O

72h, 88%, 99% ee (using ALB) 143h, 45%, 98% ee (using GaSB)

FIGURE 10.2. Al-Li-bis(binaphthoxide) and Ga-Na-bis(binaphthoxide) mediated asymmetric Michael reaction of 2-cyclohexen-1-one (1) with dibenzyl malonate (2).

catalyst 5 derived from randomly introduced BINOL derivatives 4 [3] on commercially available polystyrene resin gave 3 in racemic form (Figure 10.3). Herein we describe various strategies developed by us for the immobilization of MACs. 10.2 DENDRIMER-SUPPORTED AND DENDRONIZED POLYMERSUPPORTED MACs 10.2.1 Dendrimer-supported MACs [4] Dendrimers are a class of spherical polymers with hyperbranched chains, possessing a central core with a specific number of dendron units attached. The structure, size,

295

Cl

m

n

Ph

HO

4

Cl

Cl

Cl

Cl

Cl

OTBS OTBS

Cl

Cl

HO OTBS

OTBS

3

Cl

HO

Al O O

Me

27%, 0% ee

1. 4, NaH 2. TBAF 3. AlMe3, nBuLi

THF, rt, 72h

Catalyst 5 (10 mol %)

Cl

HO

Cl

Catalyst 5

OLi

Cl

FIGURE 10.3. A primitive attempt at preparing polystyrene-supported ALB.

Cl

Cl

1+2

Cl

OLi

Me

Al

O O

296

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs)

shape, and solubility of dendrimers are readily tunable and hence have attracted considerable attention as a new class of well-defined nanometer-scale materials [5]. The positive effects of dendrimers have already been realized in some cases [6]. For instance, Jacobsen and Breinbauer reported an example in which two catalytic sites at the terminal positions of a dendrimer assisted the ring opening of epoxides [7]. We envisaged that dendrimers containing BINOL ligands at the periphery might be suitable for the construction of an efficient multicomponent asymmetric catalytic site [2f]. Molecular dynamics simulations [polymer-specific consistent forcefield (PCFF) [8], T ¼ 600 K on Cerius 2] of the dendrimer-supported ALB catalysts with varying spacer lengths indicated that a C4 to C6 alkyl chain would be optimal. Accordingly, the synthesis of the dendrimer was initiated with 4 (Scheme 10.1). Two molecules of 4 were reacted with methyl 3,5-dihydroxybenzoate (8) under Mitsunobu conditions to obtain the terminal unit 9 in 66% yield, which was reduced with LiAlH4 to afford compound 10 in 98% yield. The resulting alcohol was subsequently coupled with 1,3,5-tris(4-hydroxyphenyl)benzene (13) [9] as the core to obtain the first-generation (G1) dendrimer 14, which contains six BINOL units at the terminal positions, in 63% yield. Deprotection of 14 using TBAF afforded the corresponding G1 dendrimer-supported BINOL (G1 DSB) 6 in 92% yield. A second-generation, dendrimer-supported BINOL 7 (G2 DSB) containing 12 BINOL units at the terminal positions was prepared using the improved Mitsunobu reagent [10]. Insoluble ALBtype catalysts were readily obtained by the treatment of 6 or 7 with AlMe3 and n-BuLi (Figure 10.4). The G1 dendritic ALB catalyst afforded the Michael adduct 3 in 63% yield with 91%ee (Table 10.1, Entry 2). Under similar conditions, the G2 dendritic ALB catalyst afforded the product 3 in 59% yield with 91%ee (Entry 5). The recovery of G1 dendritic ALB was carried out simply by removing the clear supernatant via syringe under a stream of argon. THF and the substrates 1 and 2 were successively added to the residue to carry out the next reaction. The catalyst was found to maintain its activity even during the third use affording the product in 57% yield with 94%ee (Entry 4). The activity of the G1 dendritic ALB was improved by the addition of 0.3 equivalents of a basic reagent to the parent ALB catalyst (Entry 6) [2c]. G1 dendritic GaSB as another type of MAC, consisting of gallium, sodium, and two BINOL moieties, was also heterogenized using 6. Although the G1 dendritic GaSB provided the adduct in 40% yield with 92%ee (Entry 7), the addition of 0.5 equivalents of the basic reagent resulted in enhanced activity, affording the product in 83% yield with 97%ee (Entry 8). 10.2.2 Dendronized Polymer-supported MACs [11] Although the use of dendrimers to immobilize MACs resulted in catalysts that were effectively reusable, the yields obtained were still modest. Furthermore, the synthesis of dendrimers by either the convergent or the divergent route involves multiple steps. However, dendronized polymers combine the advantages of both dendrimers and linear polymers [5b, 12]. They are readily obtained by the polymerization of a dendron with a co-monomer. The bisBINOL unit 10 for the dendrimer synthesis was

DENDRIMER-SUPPORTED AND DENDRONIZED POLYMER-SUPPORTED MACs

297

TBSO OTBS

HO

OTBS OTBS

OH

O H3CO

8

PPh3,DEAD

OTBS OTBS

O O

O

PPh3,DEAD

O

CH2Cl2 -THF, -5 oC

X CH2Cl2-THF, -10 oC

X

66%

4

OTBS OTBS

O OH

8

O O

71%

OTBS OTBS

O OTBS OTBS

9 , X = COOCH3 10, X = CH2OH

11, X = COOCH3 LiAlH 4, THF, rt, 98%

LiAlH4,THF, rt, 83%

12, X = CH2OH

TBSO OTBS

13 PBu3, ADDP, CH2 Cl2, -5 oC 45%

OH

HO

OH

13

o

PPh3, DEAD, CH2Cl2-THF, -5 C 63% RO RO

RO RO

OR OR

RO RO

OR OR

O O

O

O

OR OR

O

O

O

O RO RO

OR OR

TBAF, THF, rt, 92%

O

O

O

G1 dendrimer-supported BINOL (G1 DSB) 6, R = H

OR OR

O

OR RO

14, R = TBS

O

O O

RO RO O

O

RO RO

O

O

OR OR

O

OR

OR

O O

O

O

O

RO RO

O

O

O

O

OR OR

O

OR OR

RO RO

G2 dendrimer-supported BINOL (G2 DSB) 15, R = TBS

TBAF, THF, rt, 94%

7, R = H

SCHEME 10.1. Synthesis of dendrimer-supported BINOL (DSB) 6 and 7.

used to prepare dendronized polymers. Accordingly, 10 was converted to the monomer 16 by coupling with acryloyl chloride followed by cleavage of the protecting groups (Scheme 10.2). Copolymerization of 16 with one equivalent of methyl methacrylate (MMA) in the presence of AIBN afforded the polymersupported bisBINOL ligand 17a [Mw ¼ 84,000, polydispersity index (PDI) ¼ 10 by size exclusion chromatography (SEC)]. The polymer-supported ALB catalyst was obtained as a white precipitate by the addition of AlMe3 and t-BuLi to the polymer 17a in THF. The catalyst 18a promoted the asymmetric Michael reaction, affording the product 3 in 36% yield and 96%ee (Table 10.2, Entry 1). A possible reason for the low yield could be the overcrowding of catalytic sites resulting in diminished

298

HO HO

O

O

O

O

O

O

O

O

OH OH

O

OH OH

OH OH HO HO

HO HO

O

O

OH HO HO

O

O O

O

O

O

O

O

O

O

O

OH OH

O

O

O

HO HO

O

O

O

OH OH

G2 dendrimer-supported BINOL (G2 DSB) 7

OH

O

O

HO HO

OH OH

OH OH

OH OH

THF

1) AlMe3 2) nBuLi

FIGURE 10.4. Efficient construction of ALB on the periphery of dendrimers.

G1 dendrimer-supported BINOL (G1 DSB) 6

HO HO

HO HO

HO HO

O

O

terminal part

O

Li O O O Al O

DENDRIMER-SUPPORTED AND DENDRONIZED POLYMER-SUPPORTED MACs

299

TABLE 10.1. Asymmetric Michael reaction promoted by dendritic catalysts 1+2

Entry

Catalyst

1 2 3 4 5 6 7 8

ALB G1 dendritic G1 dendritic G1 dendritic G2 dendritic G1 dendritic G1 dendritic G1 dendritic

Catalyst (10 mol % a) THF, rt

ALB (1st use) ALB (2nd use) ALB (3rd use) ALB ALB þ NaOtBuc GaSB GaSB þ NaOtBud

3

Time (h)

Yield (%)b

ee (%)

48 48 48 48 72 48 22 72

68 63 63 57 59 79 40 83

98 91 93 94 91 89 92 97

a

Based on a single catalytic site on the dendrimer. Isolated yield. c 0.3 equiv. of NaOtBu to Al was added. d 0.5 equiv. of NaOtBu to Ga was added. b

reaction rates. To facilitate site separation, the monomer 16 was polymerized with three equivalents of MMA to obtain the polymer 17b (Mw ¼ 16,000, PDI ¼ 2.1 by SEC). As expected, the catalyst 18b derived from 17b afforded 3 in 91% yield with 93%ee (Entry 2). Thus, the polymers enable easy site separation, thereby resulting in enhanced reactivity. Although a similar effect could account for lower yields in the case of dendrimer-supported catalysts (Entry 3), site separation on the periphery with higher generation dendrimers is difficult. Thus, by virtue of a simpler synthetic route, these polymer-supported catalysts promise better advantages. To demonstrate the generality of the use of such polymers, 17b was used to generate a m–oxodititanium complex [2e]. The catalyst 19 was obtained as a reddish brown solid by the reaction of polymer 17b with one equivalent of Ti(O-i-Pr)4 followed by treatment with water (Scheme 10.3). The heterogeneous catalyst 19 promoted the carbonyl-ene reaction of 20 with 21 in Et2O to give the adduct 22 in 53% yield and 95%ee after 72 h (Table 10.3, Entry 1). The addition of MS 4A dramatically improved the catalytic activity (Entry 2). The enantioselectivities obtained with this system are higher than those reported with soluble linear polymers [2q] and highlight the advantages of the polymer 17b. The catalyst 19 was recovered by removing the clear supernatant with a syringe under argon atmosphere and reused (Entries 3 and 4). The catalyst maintained high enantioselectivity even during the third use (Entry 4). Although the ICP-AES analysis revealed that less than 2% of the immobilized titanium was lost after the first use, a 17% decrease in chemical yield was observed between the first and second use of the catalyst. The decrease in yield was unavoidable despite the addition of MS 4A to the reaction during the second use of the catalyst. The decrease in yield could likely be a result of the conversion of the polymer bound complex to a less active form over time.

300

10

Cl ,TEA

2) tBuLi

1) AlMe3

O

O

O

OH OH

16

m

MeO2 C

O

HO HO

O

O

n

O

18a m/n = 1/1 18b m/n = 3/1

O

Li O O Al O O

THF, 70 o C

MMA, AIBN

m

MeO 2C

O

O

n

O

OH OH

17a m/n = 1/1 17b m/n = 3/1

O

HO HO

SCHEME 10.2. Synthesis of polymer-supported bisBINOL ligand and preparation of supported ALB.

THF, 79%

2) TBAF

1)

O

301

DENDRIMER-SUPPORTED AND DENDRONIZED POLYMER-SUPPORTED MACs

TABLE 10.2. Asymmetric Michael reaction catalyzed by polymer-supported ALB 1+2

Catalyst (10 mol %a) THF, rt, 72 h

3

Yield (%)b

Entry

Catalyst

1 2 3

18a 18b G1 dendritic ALB

ee (%)

36 91 77

96 93 90

a

As a monomeric catalyst. Isolated yield.

b

O O O Ti Ti O O O 1) Ti(O-i-Pr) 4

17b

2) H2 O 3) Azeotropic dist. O

MeO2 C

O

O

m

O

19 m/n = 3/1

n

SCHEME 10.3. Preparation of polymer-supported m-oxodititanium complex.

TABLE 10.3. Application and reuse of polymer-supported Ti catalyst in asymmetric carbonyl-ene reaction O EtO2 C H 20

Entry

Mol% of catalyst

1 2 3 4

10 10 (1st use) 20 (2nd use) 20 (3rd use)

a

Isolated yield.

OH

Catalyst 19

+ Ph 21

Et 2O, rt, 72 h

EtO2 C

Ph 22

MS 4A

Yield (%)a

Ee (%)

 þ þ þ

53 Quant 83 74

95 96 98 92

302

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs)

10.3 NANOPARTICLES AS SUPPORTS FOR CHIRAL CATALYSTS [13] 10.3.1 Micelle-derived Polymer Supports [14] These dendrimer-supported chiral catalysts exhibit levels of selectivity comparable with those of their homogenous counterparts, especially when the chiral ligands are placed at the periphery [4]. However, the synthesis of dendrimers involves multiple steps and often results in low yields. To realize advantages of dendrimer-supported catalysts, there must be developed new, innovative methods to prepare dendrimerlike architectures via short and simple routes. The process of micelle formation is well known and has been studied extensively [15]. Surfactants possessing hydrophilic (polar) “heads” and hydrophobic (nonpolar) “tails” form micelles upon addition to polar solvents such as water. A micelle in aqueous solution forms an aggregate with the hydrophilic head groups in contact with the surrounding solvent, sequestering the hydrophobic tail regions in the micelle center. Micelles possess unique characteristics and spherical shapes. Surfactants bearing a functionalized chiral or achiral head group and an olefin unit at the terminus of the hydrophobic nonpolar tail would produce spherical nanoparticles upon polymerization, with a functionalized hydrophilic region at the periphery [15d]. We explored two different synthetic strategies toward developing a new immobilization method for chiral catalysts. As shown in Figure 10.5, Method A involves direct polymerization of surfactant monomers bearing chiral hydrophilic regions, whereas Method B relies on stepwise synthesis of the micelle-derived polymer (MDP) and immobilization of chiral catalysts (Scheme 10.5). The chiral surfactant 23 was designed as a monomer for conversion to a chiral catalyst after polymerization and removal of the phosphate functionality. The hydrophobic region includes an olefin unit for polymerization and is attached to the chiral hydrophilic region through a C8 alkyl chain, which also serves as a spacer for the catalyst after polymerization. The synthesis of chiral surfactant monomer 23

ONa O P O O

Hydrophilic region (ligand)

1) Formation of Micelle 2) Polymerization

Polymer

O

Hydrophobic region

O

23

Chiral surfactant monomer

Micelle-derived polymer (MDP-I)

FIGURE 10.5. Polymerization of chiral surfactant monomer under micellar system (Method A).

NANOPARTICLES AS SUPPORTS FOR CHIRAL CATALYSTS

303

O ()

H MOMO

BrPPh 3(CH 2) 6CO2 Et, NaH

MOMO

MOMO

80%

MOMO

93% (3 steps)

24

25

OH 5 CO2 Et

5

LAH

TBSO TBSO

93 %

, TEA

98 %

27 O

O

6 O

6 O

TBAF 9 0%

28

O Cl

TBSO TBSO

26

TBSO TBSO

1) Pd-C/H 2 2) TsOH 3) TBDMSCl

5CO2 Et

HO HO

1) POCl3 , TEA 2) 15% NaOH-THF 91 % (2 step s)

23

29

SCHEME 10.4. Preparation of surfactant monomer 23.

was achieved in 56% overall yield in eight simple steps starting from (R)-6-formyl-220 -bis(methoxymethyloxy)-1-10 -binaphthyl (24) (Scheme 10.4) [16]. Effective polymerization of the chiral surfactant monomer 23 was achieved by means of 10 mol% of Et3B as a radical initiator and maintaining the concentration higher (100 mM) than the cmc (9.0 mM at 25  C) of monomer 23 at 0  C under Ar for 8 h. The apparent molecular weight (Mw ¼ 188,000, PDI ¼ 1.81) and diameter (6.7 nm) of micellederived polymer MDP-I were determined at 25  C by a size-exclusion chromatograph connected to a ultraviolet (UV) detector and multi-angle light scattering instrument (SEC-MALS). The spherical shape of polymer MDP-I was confirmed by scanning tunneling microscopy (STM), which revealed spherical nanoparticles 5 nm in diameter along with aggregates 9–20 nm in diameter (Figure 10.6). Although Method A afforded chiral spherical nanoparticles, a more general method is desirable to introduce a variety of chiral catalysts onto the surface of micelle-derived, dendrimer-like nanoparticles. Method B was developed, in which an achiral surfactant monomer, upon polymerization under a micellar system, provides spherical nanoparticles bearing immobilization sites at the periphery. The monomer 30 [17] possesses polyethyleneglycol as the hydrophilic region, and upon polymerization provides free hydroxyl groups at the periphery for the immobilization of chiral ligands (Scheme 10.5). Polymerization of the monomer 30 was carried out by use of styrene (1 equiv) in the presence of photopolymerization initiator 2,20 dimethoxy-2-phenylacetophenone. This method produced the spherical polymer MDP-II (Mw ¼ 28,400, PDI ¼ 2.85, diameter ¼ 3.2 nm as determined by SECMALS and STM analysis) consisting of 30 and styrene in a 1:1 ratio, as confirmed

304

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs)

FIGURE 10.6. STM image of MDP-Ia: (a) 200  200 nm and (b) 30  30 nm.

by 1 H nuclear magnetic resonance (NMR) spectroscopy. Immobilization of BINOL moieties was achieved by the coupling reaction of MDP-II and the BINOL derivative 31 in the presence of NaH and NaI to afford soluble polymer MDP-III. 1 H-NMR studies revealed 90% of 31 was immobilized onto the surface of MDP-II. The remaining free hydroxyl groups were capped with methyl groups by treatment with methyl iodide, to avoid hydroxyl group interference in further asymmetric reactions. The removal of the MOM group produced the corresponding polymers MDP-IVb having free BINOL moieties at the periphery. The polymer MDP-IVa was also synthesized by deprotection of MDP-III in order to compare the catalytic efficiency with that of the capped polymer MDP-IVb. Additionally, to evaluate the catalytic efficiency of the micelle-derived, polymer-supported catalysts, a linear polymer LP was synthesized by copolymerization of the monomer 30 and styrene (1 equiv) in THF (Mw ¼ 11000, PDI ¼ 2.56 by SEC). The treatment of LP with 31 in the presence of NaH and NaI followed by removal of the MOM group produced the linear polymer-supported BINOL (LP-SB) (Scheme 10.6). The catalyst loading of linear polymer-supported BINOL (LP-SB) was low (0.025 mmol/g) compared with the high catalyst loadings observed for the spherical micelle-derived polymer-supported BINOL MDP-IVa (1.32 mmol/g) and MDPIVb (1.31 mmol/g), as confirmed by 1 H NMR analysis. The high catalyst loading obtained using micelle-derived polymer MDP-II compared with the linear polymer LP is considered to reflect the exposed nature of the hydroxyl groups located at the periphery in MDP-II. To demonstrate the catalytic activity of spherical polymers MDP-IVa and MDP-IVb, the catalytic asymmetric alkylation of benzaldehyde (32) with Et2Zn (33) was performed (Table 10.4) [18]. The heterogeneous Ti-BINOLate complexes [19] were formed by addition of Ti(O-i-Pr)4 to the capped polymer MDPIVb and the uncapped polymer MDP-IVa. The alkylation of 32 with 2 equiv of 33 and 1 equiv of Ti(O-i-Pr)4 using polymer MDP-IVa (9 mol%) proceeded smoothly to produce the product (S)-34 in moderate

305

THF, 90%

NaH, NaI

31

OMOM OMOM

HO

HO

O

O

O

O

+

O

O

OH

O

O OMOM OMOM

MDP-III

O

OMOM OMOM

O

OH

1. MeI, NaH, THF, 84% 2. TsOH, CH2Cl2, quant.

MOMO OMOM

O

O

Polymer

O

HO

1 eq

O

O

HO HO

O

MeO

MeO

O

CH2Cl2,quant.

TsOH

H2O, 20 C, hυ o

(10 mol%)

O

O

HO

O

O

O

OH

O

Polymer

O

HO

O

O

OH

O

OH

O

O

O

O

OH OH

HO

O

O

OMe

O

O

HO

O

HO OH

O

O

Polymer

O

MeO

HO HO O

HO

O

MDP-IVb

OH OH

HO OH

O

O

O

OH

Polymer

MDP-II

Micelle-derived polymer

HO

HO

OH

O

O OH OH

MDP-IVa

O

OH OH

SCHEME 10.5. Copolymerization of 30 with styrene in water and introduction of 31 onto the surface of MDP-II (Method B).

Cl

MOMO MOMO

30

O

MeO OMe Ph Ph O

306

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs)

AIBN (10 mol %), styrene (1 eq.) 30

Linear polymer (LP)

o

THF, 60 C 1) NaH, NaI, THF, rt LP + 31

2) TsOH-H2 O, CH 2Cl2 , rt

Linear polymer supported-BINOL (LP-SB )

SCHEME 10.6. Linear polymer-supported BINOL.

yield and enantioselectivity (Table 10.4, Entry 1). As expected, the capped polymer MDP-IVb showed slight enhancement in the catalytic activity as compared with the uncapped polymer MDP-IVa (Entry 2). Increasing the amount of polymer MDPIVb (18 mol%) afforded product (S)-34 in quantitative yield and 79%ee (Entry 3). Moreover, the use of 2 equiv of Ti(O-i-Pr)4 further improved the level of enantioselectivity up to 84% (Entry 4) [20]. Linear polymer-supported BINOL (LP-SB) under the present conditions produced product (S)-34 with low yield and enantioselectivity (50% yield, 25%ee, Entry 5). The catalytic efficiency of micelle-derived polymer MDP-IVb is comparable with that of homogeneous catalysis using BINOL (Entries 4 and 6). As an investigation for the reuse of MDP-IVb, the reaction was quenched by using 1 N HCl and MDP-IVb was recovered easily by precipitation using a hexane/EtOAc mixture. The reuse of recovered MDP-IVb with Ti(O–i-Pr)4 resulted in the adduct 34 with 89% yield and 57%ee. Next we focused our attention toward immobilization of ALB and GaSB, although the polymer-supported MACs generated from the MDP-Ia, IVa, and IVb produced the Michael adduct 3 in racemic form. TABLE 10.4. Catalytic asymmetric alkylation using micelle-derived, spherical polymer-supported Ti-BINOLate complex O

Ligand, Ti(O-i-Pr) 4 H

+

1 2 3 4 5 6 a

33 (2 eq)

Ligand (mol%) a

MDP-IVa (9) MDP-IVb (9)a MDP-IVb (18)a MDP-IVb (18)a LP-SB (18) BINOL (9)a

As a monomeric ligand. Determined by 1 H NMR.

b

OH

Et2Zn

32

Entry

H

CH 2 Cl2 , -10o C, 10 h 34

Ti(O-i-Pr)4 (eq.)

Yield (%)b

ee (%)

1.0 1.0 1.0 2.0 1.0 1.0

51 60 >95 >95 50 >95

76 81 79 84 25 89

307

NANOPARTICLES AS SUPPORTS FOR CHIRAL CATALYSTS

10.3.2 Monolayer-protected Au Cluster (Au-MPC)-supported Enantioselective Catalysts [21] A monolayer-protected metal cluster (MPC) of nanometer size provides another efficient method for the immobilization of catalysts [22]. The design and synthesis of structurally well-defined Au clusters is relatively simple and provides most of the advantages offered by spherical dendrimer-like nanoparticles. For example, AuMPC prepared with thiols/disulfides containing a chiral ligand moiety positioned chiral ligands on the surface of a metal cluster. To prepare MPCs bearing chiral BINOL moieties on the Au surface for applications to asymmetric reactions, disulfides 35 with varying lengths of alkyl chain possessing BINOL units at the terminal end were synthesized (Scheme 10.7). Preparation of 35 with various lengths of alkyl chain as spacers (n ¼ 4, 5, and 6) was achieved in overall yields of 31–34% in seven steps. The obtained disulfides 35a-c with various spacer lengths were used to synthesize BINOL-functionalized MPCs (Figure 10.7). The disulfide 35 consisting of two BINOL moieties was added to a toluene solution of AuCl4(n-C8H17)4N generated

O

O () MeO

MeO 2CC6 H 12 COCl, AlCl3

MeO

MeO

n=4, 75% n=5, 62% n=6, 69%

MeO

36

n-2 OEt

37 ()

1) Et3 SiH, TFA 2) LAH 3) PPh3 , CBr 4

n Br

MeO MeO

n=4, 62% n=5, 72% n=6, 72% (3 steps)

n=4, 71% n=5, 75% n=6, 69% (2 steps)

38

()

1) (NH2 )2 =C=S 2) I2 , aq. NaOH

()

nS

nS

BBr 3

MeO MeO

quant.

HO HO

2 39

2 35 (n = 4, 5, 6)

SCHEME 10.7. Preparation of disulfide 35.

308

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs) HO HO ( )n S

1) HAuCl4 .4H2 O, (n-C8 H17) 4N +Br35a-c

()

nS

HO HO

Au

2) aq. NaBH 4 35a : n = 4 35b : n = 5 35c : n = 6

() S n

HO HO 40a : n = 4 40b : n = 5 40c : n = 6

FIGURE 10.7. MPC-supported BINOL (MPC-40) and TEM image of MPC-40b.

in situ by treatment of an aqueous solution of HAuCl4 with tetraoctylammonium bromide [23]. Subsequently, the reaction mixture was treated with NaBH4 to obtain BINOL-functionalized MPCs 40a-c quantitatively. The amounts of disulfide immobilized onto MPCs and loading of BINOL (40a: 1.30 mmol/g; 40b: 1.28 mmol/g; 40c: 1.26 mmol/g) were determined by elemental analysis. The size of representative MPC-40b was analyzed by transmission electron microscopy (TEM), and the TEM image revealed formation of MPC with a diameter less than 5 nm for the Au core (Figure 10.7). The catalytic efficiency of BINOLfunctionalized MPCs 40a-c was screened in the asymmetric alkylation of 32 with 33 [18]. Similar to the case of micelle-derived polymers [14], the addition of Ti(O-i-Pr)4 to MPCs 40a-c resulted in heterogeneous Ti-BINOLate complexes [19]. The reaction of 32 with 2 equiv of 33 and 1 equiv of Ti(O-i-Pr)4 was promoted by 10 mol% of MPC-40a to produced adduct (R)-34 in 92% yield with 80%ee (Table 10.5, Entry 1). The use of MPC-40b, having spacer length (n ¼ 5), improved enantioselectivity up to 86% (Entry 2). However, a further increase in spacer length (n ¼ 6) employing MPC-40c lowered the enantioselectivity (Entry 3). The catalyst amount could be decreased to 5 mol% with a slight decrease in enantioselectivity (Entry 4). The use of three equivalents of 33 improved the reaction rate (Entry 6). Notably, the activity of heterogeneous MPC catalyst was comparable with those of the homogeneous parent Ti-BINOLate complexes (Entry 7). The high loading of BINOL on the Au surface, the TEM image, and the excellent catalytic activity of MPC suggest the naked character of BINOL moieties on the surface of MPC. In an attempt to reuse MPC-40b, after the first cycle, the reaction was terminated using 1 N HCl, and 40b was easily recovered by simple precipitation from EtOH. The recovered 40b was reused for asymmetric alkylation of 33 with Ti(O-i-Pr)4 to afford product (R)-34 in 92% yield and 68%ee.

309

NANOPARTICLES AS SUPPORTS FOR CHIRAL CATALYSTS

TABLE 10.5. Catalytic asymmetric alkylation using Au-MPC-supported Ti-BINOLate complex 32

MPC, Ti(O-i-Pr)4, Et2Zn (33)

Entry

MPC (mol%)a

nb

1 2 3 4 5 6 7

40a (10) 40b (10) 40c (10) 40b (5) 40b (10) 40b (10) BINOL (10)

4 5 6 5 5 5 —

34

CH 2Cl2, -10o C

Et2Zn (33) (eq.)

Time (h)

Yield (%)c

ee (%)

2 2 2 2 1 3 2

7 7 7 7 16 3 7

92 98d >95 >95 31 >95 >95

80 86 72 80 73 84 90

a

As a monomeric ligand. Lengths of alkyl chains as spacers. c Determined by 1 H NMR. d Isolated yield. b

The ALB complex prepared from MPC-40b promoted the Michael reaction but afforded the adduct 3 in only 7% yield and 7%ee. In MPC-40b, because of the shorter spacer, the BINOL moieties are arranged on the Au surface in close proximity and with limited flexibility, and thus synergistic cooperation between two BINOL ligands required to generate catalytically active ALB complex is hampered. To obtain efficient synergistic cooperation between two BINOL ligands, orientation of BINOL units on the Au surface is crucial (Figure 10.8). We envisaged use of long alkyl spacers, which would provide enough flexibility to BINOL moieties to adopt

HO HO

OHOH

OH OH

OH OH

HO HO

S

S

Au

S

O

O

O

O

O

OH OH

S

O

O

O

O

S S

S

S

S

O O

O

S

Au

S

S

M2 HO HO

HO HO

Au-MPC-Supported BINOL

O

O

O

O

O M1 O O O M1=Al, Ga M2=Li, Na Au-MPC-Supported Multicomponent Asymmetric Catalyst

FIGURE 10.8. Au MPC-supported multicomponent asymmetric catalysts.

310

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs) O CO Me 13 2 Pd(OH)2 , H 2, AcOH

H IPh3P(CH 2) 14 CO2Me, MeONa

MOMO MOMO

97%

MOMO MOMO

96% 42

24

15 CO2 Me HO HO

MOMCl, NaH quant

CO2 Me 15 LiAlH4

MOMO MOMO

65% 44

43

16 OH MOMO

1) PPh 3, CBr 4 2) (NH2 )2 CS

MOMO

78% (2steps)

S 16 MOMO MOMO

45

2

41

SCHEME 10.8. Synthesis of disulfide 41.

favorable orientations. After screening several BINOL-terminated disulfides with spacers of varying alkyl chain lengths, disulfide 41 (Scheme 10.8), having spacer length (n ¼ 16), was chosen to prepare BINOL-immobilized MPC. The disulfide 41 was then used to prepare MPC-46, which upon deprotection of the MOM group produced MPC-47 (Figure 10.9). HO HO 16

S

41

1) HAuCl4 .4H2 O (n-C8 H17) 4N +Br 2) aq. NaBH4

S

MPC-46

TsOH

16

HO HO

Au

S

16

HO HO

MPC-47

FIGURE 10.9. Preparation of Au-MPC-supported BINOL 46 and 47.

THE CATALYST ANALOG APPROACH

311

TABLE 10.6. Asymmetric Michael reaction using Au-MPC-supported GaSB 1+2

Entry 1 2 3 4 5 6 a b

MPC-47 (20 mol%a), GaCl3, NaOtBu THF, rt, 72h

3

GaCl3 (mol%)

NaOtBu (mol%)

Yield (%)b

ee (%)

15 15 15 20 20 25

65 75 85 85 95 95

44 58 67 67 89 87

85 97 88 98 69 70

As a monomeric ligand. Isolated yield.

The loading of BINOL units on MPC-47 was determined by elemental analysis (1.09 mmol/g), and the size of MPC-47 was 5 nm as analyzed by TEM. To demonstrate the catalytic activity of MPC-47 in the asymmetric Michael reaction, GaSB catalyst, which is less sensitive to moisture compared with ALB catalyst, was prepared from MPC-47 (Table 10.6). The GaSB catalyst prepared from MPC-47 (20 mol%), GaCl3 (15 mol%), and NaO-t-Bu (65 mol%) afforded Michael adduct 3 in 44% yield and 85%ee (Table 10.6, Entry 1). Increasing the amount of NaO-t-Bu improved enantioselectivity up to 97% with a slight increase in yield (Entry 2) [2b, 2c, 2l]. After screening several reaction parameters, we were pleased to find optimum conditions using NaO-t-Bu (85 mol%) and GaCl3 (20 mol%) to produce 3 in 67% yield with 98%ee (Entry 4). Although the yield of 3 using MPC-47-supported GaSB catalyst was slightly lower than that using the parent homogeneous catalyst prepared from BINOL, a comparable level of enantioselectivity was observed. To the best of our knowledge, this is the first example on Au-MPC-supported MAC.

10.4 THE CATALYST ANALOG APPROACH [24] A strategy based on the use of a “catalyst analog” was developed to fix the position of BINOL ligands on the polymer backbone. After copolymerization of a catalyst analog with a monomer in the presence of a cross-linker, the resulting polymer is used to prepare an active catalyst by exchanging the connecting group or element with the catalytically active metal or functional group. In this way, the position and orientation of each ligand in the resulting polymers can be controlled (Figure 10.10). The catalyst analog is a silicon-tethered BINOL derivative that closely resembles the parent catalyst in structure and is stable under the polymerization conditions (Scheme 10.9). Its role is to fix the ligands suitably on the polymer backbone, and it can be easily replaced with the catalytically active metal species after polymerization. The synthetic route for the catalyst analog is described in Scheme 10.10.

312

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs)

Copolymerization MAC(ALB)

R'

R, Catalyst analog

: Metal or functional group : Connecting group or element

-

+

FIGURE 10.10. Construction of MAC(ALB) by using a polymer support.

The monomer 48b was stable under neutral anhydrous conditions. The diastereoselectivity of 48 was about 1:1 determined by 1 H-NMR analysis. The copolymerization of 48b with methyl methacrylate (MMA) at a ratio of 1:2 was initiated by 5 mol% of AIBN with 3 mol% of ethyleneglycol dimethacrylate (EGDMA) as a cross-linker. After polymerization, the Si-O bond was cleaved with H2O to obtain the polymer-supported BINOL 51a (Mw ¼ 8,850, PDI ¼ 2.94 by SEC). For reference, polymer 53 (48b:MMA:EGDMA ¼ 100:1000:11, Mw ¼ 52,700, PDI ¼ 2.14 by SEC) was prepared without using the Si tether. The heterogeneous polymer-supported ALB catalysts 52 and 54 were generated by the treatment of a THF solution of the polymer with AlMe3 and t-BuLi. The catalyst 52a generated from polymer 51a promoted the Michael reaction affording the product 3 in 26% yield with 48%ee (Table 10.7, Entry 1). A possible reason for the low yield and ee could be the overcrowding of ligands resulting in poor ALB complexation (Figure 10.11). To facilitate ligand separation, the copolymerization of 48b with MMA at a ratio of 1:20 was initiated by using 5 mol% of AIBN with 3 mol% of EGDMA (Mw ¼ 17,800, PDI ¼ 2.03 by SEC). As expected, the catalyst 52b generated with the polymer 51b promoted the Michael reaction affording 3 in 73% yield with 91%ee (Entry 2). The corresponding catalyst 54, which was constructed from the polymer 53, produced 3 with only 21%ee indicating

OH OH

2 eq

SiCl4 (1 eq), TEA (4 eq) THF

O O Si O O

Catalyst analogue 48a

SCHEME 10.9. Preparation of catalyst analog 48a.

313

2) TBAF

O

Cl

4

48b

OH

OH

, TEA

a)

a)

d)

O

O

O

O

( )4

O

OH OH

49

( )4

O

( )4

O

O O

( )4 O

SiCl4, TEA

b)

O

O

OH

OH

HO

53

O

( )4

c)

O

54

O

50a (48b:MMA:EGDMA=100:200:3) 50b (48b:MMA:EGDMA=100:2000:3)

O

O

HO

Si

OH OH

O

O

O Li

Al O

O

51a 51b c)

OH HO

OH HO

O

O

O

( )4

O

( )4

48b

Si

O

O

polymer supported ALB (52a, 52b)

O

( )4

O

( )4

O

O

O O

SCHEME 10.10. Preparation of polymer-supported ALB catalyst. (a) MMA, ethyleneglycol dimethacrylate (EGDMA), AIBN, THF, reflux; (b) H2O; (c) AlMe3 (0.5 eq to BINOL), t BuLi (0.5 eq to BINOL), THF, 78  C; (d) TBAF, THF.

4

1)

314

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs)

TABLE 10.7. Asymmetric Michael reaction catalyzed by polymer-supported ALB 1+2

Catalyst (10 mol %a)

Entry

Catalyst

1 2 3 4 5

52a 52b (1st use) 54 52b (2nd use) 52b (3rd use)

THF, rt

3

Yield (%)b

ee (%)

26 73 77 74 76

48 91 21 89 88

a

As a monomeric ligand. Isolated yield.

b

Si

Si

Si Si

H2 O

Too close

Catalyst formation : Lignad : Metal

FIGURE 10.11. Polymer-supported catalyst derived from 50a.

that the use of a catalyst analog is advantageous for the construction of polymersupported MACs (Entry 3). Next, the reusability of polymer 52b was investigated. After the second and third use, the product 3 was obtained in 74% yield with 89%ee and 76% yield with 88%ee, respectively (Entries 4 and 5). The polymer 52b was recovered in 97% yield after the third use. As an alternative approach toward the construction of polymer-supported MACs, application of the method of molecularly imprinted polymers (MIPs) might be fascinating [25]. In contrast to MIPs, our method using a “catalyst analog” allowed chiral ligands to be arranged at suitable positions along the polymer chains even in the case of a flexible polymer. 10.5 METAL-BRIDGED POLYMERS AS HETEROGENEOUS CATALYSTS: AN IMMOBILIZATION METHOD FOR MACs WITHOUT USING ANY SUPPORT [26] Immobilization of MACs can be accomplished by employing a wide range of macromolecules. However, from a practical point of view, it is also important to

METAL-BRIDGED POLYMERS AS HETEROGENEOUS CATALYSTS

X

Y

X

rigid spacer

Y

X

chiral region

Y

M1 : metal

X

315

X X X

X X

X

X XX

Y

Y

X

Y

coordination unit

X

Y X

Y

building block

chiral ligand M2 : metal

homochiral metal-organic porous materials

FIGURE 10.12. Schematic drawing of homochiral metal-organic porous materials (MOPMs).

develop strategies that do not involve the tedious preparation of polymer-supported ligands. In this regard, homochiral metal-organic porous materials (MOPMs) seem to be promising alternatives (Figure 10.12) [27]. Despite considerable efforts, attempts to synthesize MOPMs capable of enantioselective separation and/or catalysis have met with only limited success [28]. Kim et al. reported that L-proline-based, chiralligand–derived MOPMs provide enantioselectivities superior to their homogeneous counterparts [29] in asymmetric aldol reactions. Although chromium is responsible for the immobilization, L-proline functions as the asymmetric organocatalyst. Alternatively, chiral multidentate ligands with attached sites for metals at the exact opposite sides in the molecular skeleton readily form insoluble metal-bridged linear polymers in the presence of a suitable metal source (Figure 10.13). If the chiral

X

X

n X X chir al multidentate ligands

M : metal

X

X

X

X

M n metal-br idged polymer s as enantioselective catalysts

FIGURE 10.13. Concept of metal-bridged polymers as enantioselective catalysts.

TABLE 10.8. Asymmetric Michael reaction catalyzed by Al-bridged polymer

1+2

LiAlH4 (0.2 eq), nBuLi (0.1 eq) Bi(BINOL) 55 or Bis(BINOL) 56 (0.2 eq) THF, MS 4A, rt

3

HO HO HO HO

HO HO HO

HO

56 a

56 b

OH OH

HO HO 56c

O Al O OH OH

Li LiAlH 4

O

THF

O

O Al O

HO Li

HO

O

Al-bridged Polymer

O

55

n

Entry

Ligand

1 2 3 4 5 6 7 8 9

55 56a 56b 56c 55 (1st use) 55 (2nd use) 55 (3rd use) 55 (4th use) 55 (5th use)

a

Isolated yield.

Time (h)

Yield (%)a

ee (%)

48 48 48 48 72 98 98 98 98

86 94 69 89 88 86 74 60 59

96 6 17 88 96 87 85 77 77

317

O

H

+

Isolated yield.

a

1 2 3 4 5

Entry

20

EtO2C

21

Ph

1 use 2nd use 3rd use 4th use 5th use

st

Cycle

Et2O, MS 4A, rt

Ti-bridged polymer (20 mol%) EtO2C 22

OH Ph

Ti O

O

98 98 98 147 147

Time (h)

O

O

O

O Ti O

O Ti

O

O Ti

Ti-bridged polymer

88 72 71 88 66

Yield (%)a

O

O

TABLE 10.9. Application and reuse of Ti-bridged polymer in asymmetric carbonyl-ene reaction

n

88 92 89 88 88

ee (%)

318

IMMOBILIZATION OF MULTICOMPONENT ASYMMETRIC CATALYSTS (MACs)

metal-bridged regions can function as asymmetric catalysts, a simple and efficient approach for the immobilization of MACs without the need for a polymer support would be realized. Rigid (R,R)-6,60 -bi(BINOL) (55) and (R,R)-6,60 -bis(BINOL) (56a-c) were synthesized by linking the BINOL units at the 6-position. All the ligands readily formed the expected metal-bridged polymers as heterogeneous solids upon reaction with LiAlH4 in THF at 0  C. n-BuLi was subsequently added to obtain the second-generation catalysts [2c]. The catalysts were then used in the enantioselective Michael reaction, and the results are summarized in Table 10.8. Catalysts derived from 56a and 56b were inferior in activity. Although the yields were moderate to good, the enantioselectivities were poor (Table 10.8, Entries 2 and 3). It is presumed that the bent shape of these ligands facilitates the formation of unsuitable aggregates [2l]. However, catalysts obtained with ligands 55 and 56c were found to be highly effective, affording the product with 96%ee and 88%ee, respectively (Entries 1 and 4). The reuse of the catalyst in the asymmetric Michael reaction was then explored by removal of the clear supernatant solution containing the product with a syringe under argon followed by the addition of substrates (Entries 5–9). The Al-bridged polymer maintained its activity even after being reused five times, albeit a slight decrease in enantioselectivity (77%ee) was observed. The generality of the concept of metal-bridged polymer catalysis has also been demonstrated through the asymmetric carbonyl-ene reaction catalyzed by the polymeric m–oxodititanium catalyst (Table 10.9). The titanium-bridged polymer catalyzed the reaction of aldehyde 20 and olefin 21 to produce product 22 in 88% yield with 88%ee. In contrast to the Al-bridged polymer, the Ti-bridged polymer could be recovered in air. After being reused five times, the Ti-bridged polymer exhibited consistent catalytic activity affording 22 with 88%ee. Immobilization of various MACs using metal-bridged polymers has been used recently by other groups [30].

10.6 CONCLUSION Several methodologies for the immobilization of MACs, which consist of two molecules of BINOL and two metals, have been developed. First, Al-Li-bis(binaphthoxide) (ALB) and/or Ga-Na-bis(binaphthoxide) (GaSB) catalysts were introduced to dendrimers and soluble polymers containing dendron units. Because these dendritic molecules required multistep syntheses, efficient syntheses of the spherical particles that function like dendrimer-supported catalysts were realized by use of an MDP and an MPC. Second, a novel approach based on the use of a “catalyst analog” was found to be effective to position the ligands suitably on the polymer backbone. Third, by using metal-bridged polymers, a simple and efficient method for immobilization without the need for a polymer support was realized. Heterogeneous ALB, GaSB, and m–oxodititanium complexes thus obtained were used as catalysts for the asymmetric Michael addition and the asymmetric carbonyl-ene reaction, respectively. The catalysts displayed high activity, affording the corresponding products with

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CHAPTER 11

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS AND THEIR USE IN ASYMMETRIC CATALYSIS QIAO-SHENG HU and LIN PU

11.1 INTRODUCTION Asymmetric catalysis constitutes one of the most efficient ways to access optically active compounds that are starting materials and/or building blocks for organic synthesis. Optically active chiral catalysts involved in asymmetric catalysis are often expensive and/or difficult to obtain. It is thus of great interest to recover and reuse such optically active chiral catalysts. During the past decades, great efforts have been devoted to this area [1, 2]. One approach to recover/reuse chiral catalyst systems is to immobilize chiral catalysts on insoluble polymer supports such as the cross-linked polystyrenes. These polymer-supported chiral catalysts can be easily recovered by simple filtration and washing. However, because of the insolubility of the polymersupported catalysts in the reaction media and, more severely, the altered environment of the catalytically active sites in the polymer-supported catalysts, significant decreases in catalytic activity and/or enantioselectivity are often observed. An alternative way to generate the polymeric catalysts is by polymerization of the ligand-containing monomers. By using this strategy, the catalytic sites and the solubility of the polymers could be systematically tuned. A large number of such polymeric chiral catalysts have been developed, and some of them have exhibited enantioselectivities parallel to that of the monomeric chiral catalysts [3, 4]. Dendritic catalysts represent another type of macromolecular catalysts with tunable structures. The catalytically active sites in a dendritic catalyst could be placed at the core, branch or periphery of the dendrimers. These materials can generally achieve high solubility in various solvents [5].

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.

323

324

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

In this chapter, the chiral 1,10 -bi-2-naphthyl-based polymeric catalysts, prepared through the polymerization of the ligand-containing monomers, and their applications in asymmetric catalysis are described. The 1,10 -bi-2-naphthyl-based dendrimers and the ephedrine-based dendronized polymers are also discussed.

11.2 SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS 11.2.1 Synthesis of BINOL-Based Optically Active Polymers 1,10 -Bi-2-naphthol (BINOL, 11.1) (Chart 11.1) and its derivatives have been established as one of the most extensively studied and used chiral ligands/auxillaries in asymmetric synthesis/catalysis [6]. Incorporating this chiral unit into a polymer backbone creates a new family of polymers with stable main chain chirality [7–13]. Depending on how BINOL units are linked in the polymer systems, the BINOLbased polymers can be generalized as the 6,60 -linked (major groove) or 3,30 -linked (minor-groove) polymers. The 6,60 -linked BINOL-containing polymer (R)-11.2 was prepared by the Ni(0)promoted polymerization of monomer (R)-11.3a followed by basic hydrolysis (Scheme 11.1) [7a]. Polymerization of (R)-11.3b followed by acidic hydrolysis also produced (R)-11.2. Polymer (R)-11.2 was insoluble in common organic solvent such as CH2Cl2, tetrahydrofuran (THF), or toluene but soluble in aqueous KOH solution.

4 6

3

2 1 OH 1' OH 2' 3' 4'

6'

OH OH

(R)-11.1

BINOL (11.1)

OH OH

(S)-11.1

CHART 11.1. BINOL.

OH OH Br OR OR

OH OH

1). Ni(1, 5-COD)2 1, 5-COD, Bipyridine, DMF 2). KOH, THF, H2O or HCl

Br (R)-11.3a: R = OAc (R)-11.3b: R = MOM

OH OH

(R)-11.2 OH OH

SCHEME 11.1. Synthesis of BINOL polymer (R)-11.2.

325

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

HO

Br

OC6H13 B(OH)2

OMOM OMOM

+ (HO)2B

1. Pd(PPh3)4 1M K2CO3, THF

RO

2. HCl

OR

OR

OC6H13

Br

11.4a

(R)-11.3b

OH

RO

R = nC6H13

HO

OH

(R)-11.5

0

SCHEME 11.2. Synthesis of the 6,6 -linked BINOL-containing polymer (R)-11.5.

The 6,60 -linked optically active BINOL-based polymer with a phenylene linker, (R)-11.5, was prepared by using the Pd-catalyzed Suzuki cross-coupling polymerization followed by hydrolysis (Scheme 11.2) [7b]. Because of the introduction of the flexible hexyl groups, (R)-11.5 was soluble in common organic solvents such as THF, toluene, and CH2Cl2. Scheme 11.3 shows the synthesis of another 6,60 -linked polyBINOL (S)-11.7 [8]. Monomer (S)-11.6 containing two different protecting groups was polymerized with the diboronic acid 11.4a. After removal of the acetyl group under basic condition, the monomethylated polyBINOL (S)-11.7 was obtained. The gel permeation chromatography (GPC) analysis showed that the molecular weight of this polymer was Mw ¼ 36,000 and Mn ¼ 12,800 (Polydispersity index [PDI] ¼ 2.8). Its specific optical rotation [a]D was 301.1 (c ¼ 0.5, CH2Cl2). This polymer showed better solubility than (R)-11.5 in organic solvents. The 3,30 -linked BINOL-based polymers were also prepared. The Pd-catalyzed Suzuki cross-coupling of the optically active monomer (R)-11.8 with the diboronic acids 11.4 followed by hydrolysis generated the 3,30 -linked BINOL-based polymers (R)-11.9 (Scheme 11.4) [9]. Polymers 11.9 were soluble in common organic solvents such as toluene, THF, and CH2Cl2 and could be easily precipitated from poorer solvents such as MeOH. By using two different reaction conditions, polymers (R)-11.9a/a0 were obtained with two different molecular weights. With Pd(PPh3)4 as MeO

Br OAc OMe

OC6H13 B(OH)2

1. Pd(PPh3)4 2M K2CO3, THF

RO

(S)-11.6

OR

+ 2. KOH

(HO)2B

OR

OC6H13

Br

OH

11.4a

RO R = nC6H13

MeO

OH

(S)-11.7

SCHEME 11.3. Synthesis of monomethylated 6,60 -linked polyBINOL (S)-11.7.

326

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

I

OR B(OH)2

OMOM + OMOM (HO)2B

1. Pd catalyst Base, THF or DMF

OR HO

2. HCl

OH HO

OR

11.4a : R = n-C6H13 11.4b : R = i-Pr

(R)-11.8

OH

OH

RO

OR

I

RO

OH

(R)-11.9a/a': R = n-C6H13 (R)-11.9b: R = i-Pr

SCHEME 11.4. Synthesis of BINOL-containing polymers 11.9.

the catalyst, K2CO3 as the base, and THF/H2O as the solvents, (R)-11.9a was obtained in 97% yield with a molecular weight of Mw ¼ 20,200 and Mn ¼ 7,300 (PDI ¼ 2.8). Its specific optical rotation [a]D was 90.1 (c ¼ 0.51, THF). With Pd (OAc)2/tris-o-tolylphosphine as the catalyst, Ba(OH)2 as the base, and DMF/H2O as the solvents, (R)-11.9a0 was obtained with a molecular weight of Mw ¼ 5,900 and Mn ¼ 3,900 (PDI ¼ 1.5). Its specific optical rotation [a]D was 63.4 (c ¼ 0.50, THF). GPC showed the molecular weight of the polyBINOL (R)-11.9b as Mw ¼ 15,100 and Mn ¼ 8600 (PDI ¼ 1.8). The specific optical rotation [a]D was 25.3 (c ¼ 0.78, CH2Cl2). On the basis of the polymer (R)-11.9- and the monoBINOL compound (R)-11.10catalyzed asymmetric additions of ZnEt2 to aldehydes [10] (see Section 11.2.2a), another 3,30 -linked BINOL-based polymer (R)-11.11 was designed and synthesized [11, 12]. As shown in Scheme 11.5, the Pd-catalyzed Suzuki coupling

I OC6H13

OC6H13 OMOM OMOM + (HO)2B

B(OH)2

2. HCl C6H13O

C6H13O

I

1. Pd(PPh3)4, 2M K2CO3, THF

11.12

(R)-11.8

C6H13O

C6H13O HO OH C6H13O

HO

OC6H13

OC6H13

OH

OC6H13

C6H13O

C6H13O C6H13O OC6H13

OC6H13 HO OH

(R)-11.11 OC6H13

SCHEME 11.5. Synthesis of the polyBINOL (R)-11.11.

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

327

polymerization of the diiodide (R)-11.8 with the terphenylene diboronic acid 11.12 followed by hydrolysis generated polymer (R)-11.11 in 90% yield during the two steps. The well-resolved 1 H and 13 C NMR spectra of this polymer were consistent with the expected sterically regular structure. GPC analysis showed its molecular weight as Mw ¼ 25,800 and Mn ¼ 14,300 (PDI ¼ 1.8). This polymer had very good solubility in common organic solvents such as chloroform, THF, toluene, and methylene chloride. Its specific optical rotation [a]D was 92.9 (c ¼ 1.01, CH2Cl2). OC6H13

OC6H13 OH OH OC6H13

OC6H13 (R)-11.10

11.2.2 Application of BINOL-based Optically Active Polymers 11.2.2.1 Asymmetric Organozincs Addition to Aldehydes. The poly BINOL (S)-11.5/Ti(OiPr)4-catalyzed ZnEt2 addition to benzaldehyde and 1-naphthaldehyde was studied (Scheme 11.6) [11]. As shown in Table 11.1, this polymer showed high enantioselectivity for the ZnEt2 additions in toluene at 0  C. The catalytic properties of (S)-11.5 are similar to those of BINOL for these reactions. This suggests that when BINOL was used, the catalytically active species for the ZnEt2 addition to aldehydes might be the monomeric BINOL-Ti(IV) complex rather than its intermolecular aggregates such as dimer or oligomers. Both the polyBINOL (R)-11.2 and the polyBINOL (S)-11.5 were used to catalyze the ZnEt2 addition to benzaldehyde without Ti(OiPr)4, but only low yields and low enantioselectivity were observed. Polymer (R)-11.9 was also employed to catalyze the reaction of ZnEt2 with aldehydes in the absence of Ti(OiPr)4 [9]. As the results summarized in Table 11.2 show, polymer (R)-11.9a was a promising catalyst. Particularly, excellent enantioselecitivity was observed for the reaction of the para-substituted benzaldehydes. The enantiomeric polyBINOL (S)-11.9a was also used to catalyze the reaction of OH

(S)-11.5 ArCHO

+

ZnEt2 Ti(O iPr)4

Ar

SCHEME 11.6. Asymmetric diethylzinc addition to aldehydes.

328

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

TABLE 11.1. The asymmetric ZnEt2 addition to aldehydes catalyzed by (S)-11.5 and Ti(OiPr)4 Aldehyde H

O

Solvent

Conversion (%)a

ee (%)b

Configurationd

CH2Cl2

84

86

S

Toluene

100

86

S

19

82

S

94

c

S

THF H

O

Toluene

92

a

Determined by GC. Determined by chiral GC (b-Dex capillary column). c Determined by HPLC-Chiralcel OD column. d Determined by comparing the GC and HPLC data with the known compounds. b

benzaldehyde with ZnEt2. In the presence of (S)-11.9a, the product was obtained with 93%ee, similar to that obtained from (R)-11.9a. As expected, the configuration of the resulting chiral alcohol was opposite to that obtained with (R)-11.9a [9a–b]. Thus, the R polyBINOL produced the R chiral alcohol and the S polyBINOL produced the S chiral alcohol. The polyBINOL (R)-11.9b, with increased steric hindrance at the BINOL unit, was also employed to catalyze the ZnEt2 additions to benzaldehyde and cyclohexanecarboxaldehyde, producing 89%ee and 79%ee respectively [9c]. These ee’s were slightly lower than those obtained by using the polyBINOL (R)-11.9a. To understand better the catalytic properties of polymer (R)-11.9, the monomeric compound (R)-11.10 was prepared and studied for the asymmetric ZnEt2 addition to aldehydes [10]. It showed that the monomeric compound (R)-11.10 was a much more generally enantioselective catalyst than polymer 11.9 [10]. This suggested that the environment of the catalytically active sites in (R)-11.10 should not be completely preserved in polymer (R)-11.9. In the reaction catalyzed by (R)-11.10, the catalytically active species is probably monomeric. It was speculated that the catalytic property difference between the monoBINOL ligand (R)-11.10 and the polyBINOL (R)-11.9 might be because of the structural difference of their zinc complexes. When the polyBINOL (R)-11.9 was treated with ZnEt2, the polyBINOL-Zn complex (R)-11.13 could be formed, in which each of the two alkoxy groups in one of the phenylene linkers coordinated to a zinc center separately on the adjacent BINOL units. One phenylene linker in (R)-11.13 could generate two new chiral biaryl conformations as shown because it connects two naphthalene rings. These two chiral biaryl conformations are interdependent. Thus, the adjacent binaphthyl units in (R)-11.13 interfered with each other both electronically and sterically. This could make the catalytic sites in polymer (R)-11.13 structurally different from those in the monoBINOL ligand (R)-11.10, leading to their differences in the catalytic ZnEt2 addition to aldehydes.

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

329

TABLE 11.2. Polymer 11.9-catalyzed addition reaction of diethylzinc with aldehydes

ZnEt2

+ H

R

Polymer

Aldehyde

H3 C

CHO

Cl

CHO

H3CO

CHO

But

R

Isolated yield (%)

CHO

CHO

F

(R)-11.9a

OH

(R)-11.9

O

ee (%)a

89

92

91

92b

90

93b

94

93b

84

88b,c

63

74b

86

35b

90

59b

86

90b,d

67

83b,d,e

89

74d

70

83b,d

65

74b,d

90

93

95

94

94

93

CHO OCH3 CHO CHO

CHO

CHO

CHO CHO

(R)-11.9a0

CHO

Cl

(S)-11.9a

CHO

CHO

(continued)

330

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

TABLE 11.2

(Continued)

ZnEt2

+ R

Polymer

OH

(R)-11.9

O

R

H

Aldehyde

(R)-11.9b

CHO

(R)-11.9b

CHO

ee (%)a

Isolated yield (%) 85f

89

90f

79

a All the ees were determined by GC with a chiral column (b-Dex capillary column, Supelco Company) except those specifically indicated. b The recycled polymer was used. c The ee was measured by the HPLC-Chiralcel OD column. d The ee was measured by GC analysis (b-Dex capillary column) of the corresponding acetate derivative. e The absolute configuration of the product was not determined. [a]D ¼ 13.25 (c ¼ 1.95, THF). f Conversion.

a chiral biaryl

O Zn Et

O Zn

O Et R

O R Et Et R O O Zn Zn O

a chiral biaryl

O

Zn Zn O O R Et Et R

O

R Et Et R O O Zn Zn O

OR

O

(R)-11.13

It was thus hypothesized that if the interference between the catalytic sites in (R)-11.13 could be removed, it could produce a polyBINOL catalyst as highly enantioselective as the monoBINOL ligand (R)-11.10. On the basis of this hypothesis, the polyBINOL (R)-11.11, in which the adjacent units of the monomeric ligand (R)-11.10 are separated by a rigid phenylene linker, was designed and synthesized (Scheme 11.5) [11, 12]. Compared with the polyBINOL (R)-11.9, there should be minimum interference between the BINOL sites in (R)-11.11. Study showed that the polyBINOL (R)-11.11 was an excellent catalyst for the dialkylzinc addition to aldehydes (Table 11.3), with the catalytic activity and enantioselectivity comparable with those of the monomeric compound (R)-11.10. The polymer showed the advantage of easy recovery and reuse. The observed similar enantioselectivity of the polyBINOL (R)-11.11 and the monoBINOL ligand (R)-11.10 demonstrated that the rigid and sterically regular

331

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

TABLE 11.3. PolyBINOL (R)-11.11-catalyzed addition reaction of dialkylzincs with aldehydes O R

Aldehyde

R

Time (h)

Isolated yield (%)

ee (%)

Configuration

a

R

ZnEt2

5

92

98

ZnEt2

5

90

98b

R

ZnEt2

5

94

98b

R

ZnEt2

3.5

89

97a

R

CHO

ZnEt2

4

88

91b

R

CHO

ZnEt2

4

90

93b

R

ZnEt2

4

93

98a

R

ZnEt2

12

95

96a

R

ZnEt2

5

93

98a

R

ZnEt2 ZnEt2 ZnEt2 ZnEt2

20 20 24 24

71 85 88 81

98c 97c 97c 98d

R – R R

ZnEt2

24

65

98e

R

CHO

Cl

ZnEt2

H

Dialkylzinc CHO

H3C

OH

(R)-11.11 +

CHO

H3CO

CHO

F

OCH3

CHO

H3CO

CHO

CHO

nC5 H11 CHO nC7 H15 CHO nC8 H17 CHO CHO CHO

(continued)

332

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

TABLE 11.3

(Continued) O R

Aldehyde

ZnEt2

R

H

Dialkylzinc CHO

OH

(R)-11.11 +

Time (h)

Isolated yield (%)

ee (%) a,f

Configuration

ZnEt2

5

93

92

R

ZnEt2

6

92

97a

–

CHO

ZnMe2

48

92

93a

R

nC7 H15 CHO

ZnMe2

72

78

89c

R

CHO

a

Determined by HPLC-Chiralcel OD column. Determined by chiral GC (b-Dex capillary column). c Determined by analyzing the acetate derivative of the product on the GC-b-Dex capillary column. d Determined by analyzing the propionate derivative of the product on the GC-b-Dex capillary column. e Determined by analyzing the Mosher’s ester of the product on the GC-b-Dex capillary column. f The solvent was a 1:1 mixture of toluene:diethyl ether. g 3 equiv. ZnMe2 and 0.2 equiv polymer were used. b

polymer structure can be used to preserve the catalytic properties of a monomer catalyst as long as the catalytically active species of the monomer catalyst are not its intermolecular aggregates. This work provided a new strategy to convert a monomeric catalyst to a polymer-supported catalyst. Polymer (R)-11.11 was also employed to catalyze the ZnPh2 addition to propionaldehyde and p-anisaldehyde (Table 11.4). High enantioselectivity was achieved with the use of 0.2 to 0.4 equiv (based on the BINOL unit) of the polymer. For the reaction with p-methoxybenzaldehyde, a slow mixing of the reactant with the catalyst was required (Table 11.4, entries 3 and 4), likely due to the uncatalyzed background reaction of ZnPh2 with p-methoxybenzaldehyde. The slow mixing was achieved by adding two solutions, one containing (R)-11.11, ZnEt2 and ZnPh2 in toluene and the other containing the aldehyde in toluene, simultaneously into a flask containing toluene at -30  C over 20 h via a syringe pump. Up to 92% ee was observed when the double slow addition technique was applied. In these reactions, the polymer was pretreated with excess ZnEt2. Since the ZnPh2 addition was much faster than the ZnEt2 addition, no product from the reaction of ZnEt2 with the aldehyde was observed even though the amount of ZnEt2 was 2 - 3 times more than ZnPh2 during the reaction. The excess ZnEt2 was added in order to dissolve the gel formed from the reaction of (R)-11.11 with 2 equiv [versus the BINOL unit of (R)-11.11] of ZnEt2.

333

H3CO

CHO

CHO

Aldehyde

b

ZnPh2

20 þ 200 ZnEt2 40 þ 320 ZnEt2 5 5

50

20 þ 40 ZnEt2

1

1 1

75

20

Aldehyde (mM)

+

2

(R)-11:11 or (R)-11:11þ Et2Zn (mol%)

H

Determined by HPLC-Chiralcel-OD column. Determined by comparing the optical rotation with the literature data. c Slow mixing of the catalyst, reagent, and substrate via a syringe pump.

a

3 4

2

1

entry

Ph2Zn (equiv.)

R

O

Tol Tol

Tol

Tol

Solv

cat* Ph

30 30

30

0

Temp ( C)

R

OH

TABLE 11.4. PolyBINOL (R)-11.11-catalyzed asymmetric ZnPh2 addition to aldehydes

40 56

20

66

Time (h)

59c 72c

65

82

Isolated yield (%)

ee

(%)

82 92

76

85

a

R R

R

S

Configb

334

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

Compound (R)-11.10 was also found to be a highly enantioselective catalyst for the ZnPh2 addition to aldehydes [12]. It showed higher catalytic activity than the polyBINOL (R)-11.11 as evidenced by the fact that a greater amount of (R)-11.11 (20 or 40 mol%) than the monoBINOL (R)-11.10 (10 or 20 mol%) was required in order to achieve the high enantioselectivity. The catalytic property differences between the polyBINOL (R)-11.11 and (R)-11.10 in the asymmetric ZnPh2 addition might be accounted for by the following explanation. Because the catalytic sites in (R)-11.11 are almost identical to the structure of the monomeric ligand (R)-11.10, in principle, the polymer should have the same stereoselectivity as the monomer. This would be true if there were no competition from the uncatalyzed background reaction as demonstrated for the dialkylzinc addition catalyzed by polymer (R)-11.11 and monomer (R)-11.10. However, in the ZnPh2 addition, the rate difference between the catalyzed and the uncatalyzed reactions is small. Because of the mobility differences between the polymer and the monomer, there may be less collision between the substrate and the catalytic sites of the polymer, which will make the uncatalyzed reaction more competitive. Therefore, higher concentration of the polymer and lower concentration of the substrate are needed to suppress the competing uncatalyzed ZnPh2 addition in order to maintain the high enantioselectivity of the monomeric catalyst. 11.2.2.2 Asymmetric Reduction of Prochiral Ketones Catalyzed by the Chiral BINOL Monomer and Polymer Catalysts [12]. The poly BINOL/ZnEt2-catalyzed asymmetric reduction of prochiral ketones with catecholborane to generate optically active secondary alcohols was studied (Scheme 11.7). As shown in Table 11.5, in the presence of 5 mol% of the poly BINOL (S)-11.9a or (R)-11.11 and 10 mol% ZnEt2, prochiral methyl aryl or methyl vinyl ketones were reduced with moderate-to-good enantioseletivities. For nonmethyl ketones, the enantioselectivities were low. The polyBINOL (R)-11.11 exhibited enantioselectivity similar to that of the monomeric compound (R)-11.10. This demonstrated that the catalytic properties of the monomeric ligand (R)-11.10 were preserved in the rigid and sterically regular polymer (R)-11.11. The lower enantioselectivity of the polyBINOL (S)-11.9a indicated a negative interference between the adjacent BINOL units in this polymer similar to that observed in the asymmetric ZnEt2 addition to aldehydes. Polymer (R)-11.11 was easily recovered from the reaction mixture, and the threetime recovered polymer still produced 78%ee and 86% yield for the acetophenone reduction. The 1 H nuclear magnetic resonance (NMR) spectrum and optical rotation of the recovered polymer were also very close to those of the original one. Thus, there was little structural or functional change for the recycled polymer.

O R

CH3

+ H B

O

polyBINOL ZnEt2

R

O

SCHEME 11.7. PolyBINOL-zinc catecholborane.

HO H

complex-catalyzed

reduction

CH3

of

ketones

with

335

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

TABLE 11.5. PolyBINOL-zinc complex-catalyzed reduction of ketones with catecholboranea Entry

Ketone

Ligand

Solvent

Yield (%)

ee (%)b

Product configuration

1

O

(S)-11.9a

Toluene

77d

54

R55

2

O

(S)-11.9a

Toluene

85

67

R

3

O

(S)-11.9a

CH2Cl2

90

62

R

4

O

(S)-11.9a

Et2O

88

59

R

5

O

(S)-11.9a

THF

51

56

R

6

O

(R)-11.10

Toluene

87

81

S

7

O

(R)-11.10

Toluene

88e

77

S

8

O

(R)-11.10

Toluene

86f

14

S

9

O

(R)-11.10

Toluene

90g

10

O

(R)-11.11

Toluene

89

80

S

(R)-11.11

Toluene

78

70c

S

(R)-11.11

Toluene

86

79c

S

(R)-11.11

Toluene

88

74c

S

(R)-11.11

Toluene

92

76c

S

11

O

8.5

S

MeO

12

O Br

13

Br O

14

O

(continued)

336

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

TABLE 11.5

Entry

(Continued)

Ketone

15

16

O

O

ee (%)b

Product configuration

Ligand

Solvent

Yield (%)

(R)-11.11

Toluene

89

78c

S

(R)-11.11

Toluene

90

14c

R

(R)-11.11

Toluene

91

(R)-11.11

Toluene

79

Cl

17

18

O

O

4.3c

36c

R

S

The reactions were carried out at 30  C in the presence of 5 mol% chiral ligand and 10 mol% ZnEt2 using catecholborane as the reducing agent unless otherwise specified. b Determined by GC (b-Dex capillary column). c Determined by HPLC-Chiralcel OD column. d The reaction was performed at rt. e 5 mol% ZnMe2 was used in place of ZnEt2. f BH3.SMe2 was the reducing agent. g 0.2 equiv ZnEt2 was used. a

The isopropyl substituted polyBINOL (R)-11.9b was also used in combination with Ti(OiPr)4 to catalyze the reduction of acetophenone with catecholborane [9c]. In the presence of 11 mol% of (R)-11.9b and 10 mol% of Ti(OiPr)4 in CH2Cl2 at 30  C, acetophenone was reduced with 94% conversion and 48%ee over 18 h. The reduction of other ketones such as 10 -acetonaphthone, 40 -chloroacetophenone, and 2-chloroacetophenone produced lower than 15%ee. Using other reducing agent such as BH3.THF, 9-BBN, and BH3.SMe2 also produced lower ee. No enantioselectivity was observed when TiCl2(OiPr)2 was used in place of Ti(OiPr)4. 11.2.2.3 Asymmetric Hetero-Diels–Alder Reaction of 2,3-Dimethyl-1,3butadiene with Ethyl Glyoxylate. The BINOL-based polymer (R)-11.2/ Me2AlR (R ¼ Cl, Me)- and (S)-11.5/Me2AlR (R ¼ Cl, Me)-catalyzed heteroDiels–Alder (HDA) reactions of 2,3-dimethyl-1,3-butadiene with ethyl glyoxylate were studied (Scheme 11.8) [13]. As shown by the results summarized in Table 11.6, besides the expected HDA reaction product, an ene reaction product was also observed. It was found that the soluble polyBINOL (S)-11.5 exhibited better enantioselectivity than the insoluble polyBINOL (R)-11.2, and the use of AlMe3 was better than Me2AlCl. An 89%ee of the HDA product with an overall yield of 69% was achieved with the use of 10 mol% (S)-11.5 in combination with AlMe3 in diethyl ether at room temperature. A study also showed that increasing the amount of

337

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

chiral Lewis acid catalyst

O +

H

OH

CO2Et

CO2Et

CO2Et HDA product

ene product

SCHEME 11.8. Hetero-Diels–Alder reaction of 2,3-dimethyl-1,3-butadiene with ethyl glyoxylate.

(S)-11.5 to 20 mol% improved the yield but not the selectivity (entry 5). Although lowering the reaction temperature led to higher ee, it slowed down the reaction significantly (entry 6). It was found that the chiral polymer ligand (S)-11.5 was easily recovered and the recovered polymer exhibited similar catalytic properties as the original polymer (entry 9). It was reported that BINOL/AlMe3-catalyzed the same HDA reaction shown in Scheme 11.8 at 78  C to afford the HDA product with 97% ee and a 7:1 ratio of HDA/ene product (entry 10) [14]. In comparison with the monomeric BINOL catalyst, the polymer provided the added advantage of easy recovery and reuse. 11.2.2.4 Asymmetric 1,3-Dipolar Cycloaddition of Nitrones and Vinyl Ethers. The polyBINOL/AlMe3-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones with vinyl ethers was investigated (Scheme 11.9) [15]. In the reaction, the polymeric Al(III) complex (R)-11.14, generated when the polyBINOL (R)-11.9a was treated with AlMe3, was likely the catalytically active species (Scheme 11.9). In the presence of 20 mol% of (R)-11.14, the reaction of a nitrone with a vinyl ether TABLE 11.6. The HDA reaction in the presence of 10 mol% of the polyBINOL-Al (III) complexes

Entry

Polymer

X (Me2 AlX)

1 2 3 4 5 6 7 8 9 10

(R)-11.2 (R)-11.2 (S)-11.5 (S)-11.5 (S)-11.5 (S)-11.5 (S)-11.5 (S)-11.5 (S)-11.5f (S)-11.1

Me Me Me Me Me Me Cl Cl Cl Me

a

Solvent CH2Cl2 CH2Cl2 CH2Cl2 Et2O Et2O Et2O Et2O Et2O Et2O Et2O Et2O

Temp ( C)

Total Yield (%)

HDA Product (ee%)a

Ene Product (ee%)

Product Ratiob

rt 40 40 rt rt 40 to 10 rt 78 to rt rt 78

49 45 10c 69 80e 10 10 <10 63 82

27 (S) 46 (S) 84 (R) 89 (R) 88 (R) 95 (R) 42 (R) 76 (R) 85 (R) 97 (R)

7 7 ndd 46 38 42 4 18 39 88

2:1 3:1 Ndd 5:1 5:1 Ndd 2:1 3:1 5:1 7:1

Absolute configuration in brackets determined by comparison of optical rotation to reported values. Ratio of HDA/ene product. c Isolated yield of HDA adduct. d Not determined. e 20 mol% catalyst. f Recovered polymer (2nd run). b

338

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

O-

Ph

OR2

N+

polyBINOL catalyst

Ph

O

OR2

N

+ R1 nitrone

R1 vinyl ether

exo

isoxazolidine

SCHEME 11.9. Asymmetric 1,3-dipolar cycloaddition.

proceeded at room temperature to produce an isoxazolidine product in high yield with very high diastereoselectivity. The exo isomer was favored with high enantioselectivity (Table 11.7). After the reaction, the polymer was precipitated out with methanol, which allowed the isolation of the product with high purity even without further purification. This significantly simplified the purification of the product. The recovered polymer ligand was reused for the catalysis. After four consecutive uses, this polymer still produced the exo product (R1 ¼ Ph and R2 ¼ Et) with 88% yield and 92%ee. Treatment of the monoBINOL (R)-11.10 with AlMe3 probably formed the Al(III) complex (R)-11.15. This complex was also examined for the reaction of nitrones with vinyl ethers. As shown in Table 11.7, this monomeric Al(III) complex exhibited very TABLE 11.7. (BINOL)AlMe-catalyzed 1,3-dipolar cycloadditions of nitrones and vinyl ethers Entry

Catalyst

Nitrone R1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

(R)-11.14 (R)-11.14 (R)-11.14 (R)-11.14 (R)-11.14 (R)-11.15 (R)-11.15 (R)-11.15 (R)-11.15 (R)-11.15 (R)-11.15 (R)-11.15 (R)-11.15 (R)-11.16 (R)-BINOL/AlMe3

Ph Ph Ph Ph p-Tolyl Ph Ph Ph p-tolyl p-ClPh Ph p-Tolyl p-ClPh Ph Ph

a

Isolated yield. Determined by 1 H NMR. c Determined by HPLC using a Chiralcel OD column. d 10 mol. e  0 C. f solvent ¼ toluene. g Conversion determined by 1 H NMR spectroscopy. b

Vinyl Ether R2

Yield (%)a

Exo:endob

Exo ee %c

Et Et t Bu Bn t Bu Et Et Et Et Et t Bu t Bu t Bu Et Et

97 80d 86 72 77 93 83e 76 c,f 76 85 89 85 82 >90g

>98:<2 >98:<2 >98:<2 >98:<2 >98:<2 >98:<2 >98:<2 >98:<2 >98:<2 >98:<2 >98:<2 98:2 >98:<2 75:25 73:27

99 94 95 93 94 99 99 99 94 95 95 93 93 23 <5

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

OH OH OR

RO

RO

OH OH

OR

R Me O Al O O

OR

RO

OH OH AlMe3

n

R = C6H13

O O

O Al Me O

R

R

R O

339

R

Me O Al O O

O R

R = nC6H13

(R)-11.9a

(R)-11.14

SCHEME 11.10. Formation of the polyBINOL-Al(III) complex (R)-11.14.

high stereoselectivities that were similar to those of the polyBINOL-Al(III) complex (R)-11.14 (Scheme 11.10). It demonstrated that the catalytically active species of (R)-11.15 was probably monomeric and that its intermolecular aggregates did not play a role in the catalysis. The adjacent catalytic sites in the polyBINOL-Al(III) complex (R)-11.14 also did not interfere with each other, allowing the catalytic properties of (R)-11.15 to be mostly preserved in the polymer. This behavior was quite different from the Zn(II) complex (R)-11.13 derived from (R)-11.9a in which there was significant interference between the adjacent catalytic sites. The 6,60 -linked polyBINOL (R)-11.5 was also treated with AlMe3 to form the polymeric Al(III) complex (R)-11.16. Polymer (R)-11.16 was used to catalyze the reaction of a nitrone (R1 ¼ Ph) with a vinyl ether (R2 ¼ Et). It produced greatly reduced diastereoselectivity (exo:endo ¼ 75:25) and enantioselectivity (23%ee). That is, the 3,30 -aryl substituents in the BINOL units of polymer (R)-11.9 are important for the observed high stereoselectivity. Despite the low stereoselectivity of the polyBINOL (R)-11.16, it was still significantly better than the use of BINOLþAlMe3, which gave only 5%ee. This indicates that in the BINOL-AlMe3 catalyzed reaction, the catalytically active species may not be monomeric but its intermolecular aggregates. In polymer (R)-11.16, its catalytic sites should be the isolated BINOL-AlMe units that cannot form significant intermolecular aggregate. Me

Me Al O O

Al O

O

OR

O

OR

AlMe O OR

RO

OR RO

R = nC6H13 OR (R)-11.15

O

O

OR RO

R = nC6H13

Al Me

(R)-11.16

OR RO

O

O Al Me

OR

340

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

11.2.2.5 PolyBINOL-Catalyzed Asymmetric Michael Addition. The heterobimetallic Al-Li-BINOL complex 11.17 was shown to catalyze the Michael addition of malonates to enones with high enantioselectivity [16]. The Al-Li complexes of the polyBINOLs were also studied for the asymmetric Michael reaction of 2-cyclohexenone with dibenzyl malonate (Scheme 11.11) [17]. The insoluble 6,60 -linked polyBINOL 11.2 was treated with LiAlH4 (LAH), which generated an insoluble polyBINOL-Al-Li complex. When the soluble 6,60 -linked polyBINOL (R)-11.5 was treated with LAH, its resulting polyBINOL-Al-Li complex also became insoluble. When the 3,30 -linked polyBINOL (R)-11.9a was treated with LAH, the resulting Al-Li complex was soluble. These polyBINOL-Al-Li complexes were used to catalyze the reaction shown in Scheme 11.11 and the results are summarized in Table 11.8. Among the three polymers, (R)-11.5 showed the highest enantioselectivity (85% ee, entry 3). When the Al-Li complex of the polyBINOL (R)-11.5 was treated with one equivalent n BuLi, the resulting insoluble polymeric complex exhibited further enhanced catalytic activity and enantioselectivity (93%ee, entry 4). Li O

Li O

Al

O

O

O

O

11.17

Al

O O

11.18

Because the polyBINOL (R)-11.2 was insoluble, when it was treated with LAH, the BINOL units in the polymer could not associate with each other to form the dimeric complex like 11.18. In the case of polymer (R)-11.9, the steric hindrance around the BINOL units also prevented their association to generate the dimeric units like 11.18 when this polymer was treated with LAH. Thus, the polymeric Al-Li complexes of (R)-11.9a remained soluble. However, when the soluble polyBINOL (R)-11.5 was treated with LAH, it could generate the dimeric complex like 11.18 through interpolymer interaction, leading to the formation of a cross-linked insoluble polymer network. That is, the structure of the highly enantioselective catalyst 11.18 could be generated from polyBINOL (R)-11.5 but not from (R)-11.2 and (R)-11.9a. This could explain the high enantioselectivity of the complex (R)-11.5þLAH and that of (R)-11.5þLAHþn BuLi. The polymer ligand (R)-11.5 was recovered after treatment with 1N HCl and precipitation with methanol. In addition, the cross-linked polymeric Al-Li complex O + CH2(CO2Bn)2

polyBINOLAl-Li complex

O

CH(CO2Bn)2

SCHEME 11.11. The Michael addition catalyzed by the polyBINOL complexes.

341

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

TABLE 11.8. Asymmetric Michael reaction catalyzed by polyBINOL complexes Entry

Catalys

1 2 3 4 5 6

(R)-11.2þLAH (R)-11.2þLAHþn BuLi a (R)-11.5þLAH (R)-11.5þLAHþn BuLi a (R)-11.9aþLAH (R)-11.9aþLAHþn BuLi a

Time (h)

Yield (%)

ee (%)

73 26 49 48 49 52

32 85 69 78 26 66

55 58 85 93 56 11

a The second-generation catalysts: 0.9 molar equiv of n BuLi is added to ca 10 mol% of the polyBINOLLAH complex.

TABLE 11.9. Reuse of the Al-Li complex from polyBINOL (R)11.5 þ LAH þ n BuLi (10 mol%) Run

Yield (%)

ee (%)

78 66 68 56 51 83

93 89 88 76 73 85

1 2 3 4 5 6a

Recovery of catalyst Quant. 98% 97% 95% 95% 93%

5 mol% of n BuLi is added to the (R)-11:5 þ LAH þ n BuLi complex recovered from run 5.

a

of (R)-11.5þLAHþn BuLi was also recovered by simple filtration after reaction. The recovered ligand-Li complex was directly reused as the catalyst. This is different from the use of most of the polymer-supported Al(III) catalysts where it is the polymeric ligand being recovered not the metal complex because of the moisture sensitivity of the Lewis acidic Al(III) complexes. Thus, the cross-linked polymer network not only allows easy recovery but also provides stabilization of the catalysts. Table 11.9 shows the catalytic properties of the recovered catalyst after multiple runs for the reaction shown in Scheme 11.11. The catalytic activity of the polymeric catalyst was mostly restored with the addition of n BuLi after five runs. 11.2.2.6 Asymmetric Epoxidation of a,b-Unsaturated Ketones Catalyzed by the BINOL-Based Polymers. The 3,30 - and 6,60 -linked BINOL-based polymers were used for the asymmetric epoxidation of a,b-unsaturated ketones to generate chiral a,b-epoxy ketones (Scheme 11.12) [18]. With oxygen as the oxidant, the polyBINOL (R)-11.5 in combination with ZnEt2 was used to carry out the epoxidation of chalcone, an a,b-unsaturated ketone with PolyBINOLs ZnEt2

O R1

R2

[O]

O R1

O R2

SCHEME 11.12. Asymmetric epoxidation of a,b-unsaturated ketones.

342

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

TABLE 11.10. The epoxidation of a,b-unsaturated ketones in the presence of the major-groove polyBINOL (R)-11.5, diethylzinc and oxygen

Entry

Ketone

1

O Ph

2

O

Ph

Ph

Ph

1:0.95:0.90

99

50

CH2Cl2

0

1:1.9:0.90

64

49

CH2Cl2

30

1:1.9:0.90

11

58

CH2Cl2

r.t.

1:1.9:0.90

34

37

Toluene

0

1:0.95:0.90

0

0

THF

0

1:1.9:0.90

34

54

CH2Cl2

15

1:1.9:0.90

75

54

CH2Cl2

0

1:1.9:0.90

91

47

CH2Cl2

0

1:1.9:0.90

18

25

Toluene

0

1:0.95:0.90

Ph O

Ph

7

0

Ph O

6

CH2Cl2

Ph O

5

71

41

Ph O

4

Mole ratio [(R)-11:5/Et2Zn/ ketone]

ee [%]

Ph

Ph

3

Solvent

Temp ( C)

Yield [%]

Ph

O Ph Me

8

O Ph

9

O Ph

10

O

R1 ¼ R2 ¼ Ph [18]. As shown in entry 1 of Table 11.10, up to 71%ee was observed for the epoxidation of chalcone using one equivalent of the polymer and 0.95 equivalent of ZnEt2 in methylene chloride at 0  C. Even though a stoichiometric amount of the polyBINOL ligand was used, the yield was only 41%. The absolute configuration of the product was 2S and 3R. Although the yield was improved with the use of 1.9

343

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS O OH OR'

Ph

O

ZnEt2

O

O2

ZnEt O

(R)-11.5: R' = H

O

O

R'

R'

Ph chalcone

Zn O

Et

11.20

11.19 Ph O

H

O

O

O

+

O

Ph

Ph

O

R'

Et

Zn O R'

H O

O

O

Zn

Ph Et

SCHEME 11.13. A proposed mechanism for the polyBINOL-mediated epoxidation of chalcone.

equivalent of ZnEt2, the ee was significantly reduced (50% ee, entry 2). The use of 0.95 equivalent of ZnEt2 in combination with one equivalent of the polyBINOL probably generated a catalyst that was different from the use of 1.9 equivalent of ZnEt2. Other reaction conditions and other substrates produced poorer results. For example, THF inhibited the epoxidation probably by coordination to the zinc centers in the polyBINOL-zinc complex (entry 6). Scheme 11.13 shows a possible mechanism for the asymmetric epoxidation promoted by the polyBINOL (R)-11.5 in combination with ZnEt2 and oxygen. Reaction of (R)-11.5 with one equivalent of ZnEt2 can generate the intermediate 11.19. In the presence of oxygen, the Zn-Et bond can be oxidized to the zinc peroxide 11.20, which can conduct the epoxidation of chalcone via a Michael addition mechanism to produce the epoxy ketone product. The resulting zinc alkoxide cannot be oxidized by oxygen to regenerate the zinc peroxide complex 11.20. Thus, this reaction is not catalytic. Polymer (S)-11.7 was also used in combination with ZnEt2 and oxygen for the asymmetric epoxidation of a,b-unsaturated ketones. As shown in Table 11.11, TABLE 11.11. (S)-11.7/ZnEt2-catalyzed asymmetric epoxidation of a,b–unsaturated ketones Entry

Ketone

1

O Ph

2

3

O Ph

ee (%)

Solvent

Temp ( C)

Mole ratio [(S)-11.7/ ZnEt2 =ketone

>90

35

CH2Cl2

0

1:0.95:0.9

>90

38

CH2Cl2

0

1:0.95:0.9

95

33

CH2Cl2

0

1:0.95:0.9

Ph O

Ph

Yield (%)

Ph

344

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

polymer (S)-11.7 produced greatly improved yields over the use of (R)-11.5 without using excess ZnEt2. The diastereoselectivity for these reactions remained to be high (>99% de), but the enantioselectivity was low. The use of oxygen as the oxidant in the above epoxidation required a stoichiometric amount of the chiral ligand-Zn(II) complex. When t BuOOH was added as the oxidant, it was found that only a catalytic amount of the chiral ligand-Zn(II) complex was needed for the asymmetric epoxidation of a,b-unsaturated ketones. For example, chalcone was oxidized to the corresponding epoxy ketone when 5 mol% of polymer (R)-11.5 and 10 mol% of ZnEt2 were used. The reaction was conducted in methylene chloride at 0  C, which produced the product with 95% isolated yield, >99% de, and 28%ee. Scheme 11.14 shows a proposed mechanism for the reaction catalyzed by (R)-11.5. The zinc complex 11.19 generated from the reaction of (R)-11.5 with ZnEt2 can react with t BuOOH to form the zinc peroxide intermediate 11.21. Reaction of 11.21 with chalcone via a Michael addition mechanism will produce the epoxy ketone product and the zinc t-butoxide complex 11.22. Complex 11.22 can react with t BuOOH to regenerate the zinc peroxide 11.21 and allows the epoxidation to be conducted catalytically. The monomeric BINOL ligands such as (R)-11.10 were tested for the catalytic asymmetric epoxidation of a,b-unsaturtaed ketones. For the epoxidation of a b-propyl substituted enone, 1-phenyl-hex-2-en-1-one, (R)-11.10 produced 75% yield and 30%ee. Despite the low enantioselectivity of the monomeric ligands, when the short linker minor-groove polyBINOL (R)-11.9a was used to catalyze the epoxidation of the b-propyl substituted enone, it showed greatly improved enantioselectivity. This polymer produced the epoxy ketone product with 91% yield and 76%ee. The results for the epoxidation of various a,b-unsaturated ketones catalyzed by (R)-11.9a in combination with ZnEt2 are summarized in Table 11.12. In the presence of 20 mol% of (R)-11.9a, up to 81%ee was achieved for the asymmetric epoxidation of the a,b-unsaturated ketones.

O O

O Ph

Ph

t

OH OR'

ZnEt2

(R)-11.5: R' = H

O O R'

11.19

tBuOOH

ZnEt

O

Ph

Ph

Bu

O O Zn

O

tBu

Zn O O R'

O R'

11.22

11.21 t

BuOH

tBuOOH

SCHEME 11.14. A proposed mechanism for the polyBINOL-catalyzed asymmetric epoxidation of chalcone.

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

345

TABLE 11.12. (R)-11.9a-catalyzed asymmetric epoxidation of a,b-unsaturated ketonesa Temp

Time (h)

Isolated yield (%)

eeb (%)

[a]D (c, CH2Cl2) 1.7 (1.0)

Entry

Ketone

Solvent

1

O

Et2O

r.t.

5

92

76

O

t

r.t.

4.5

89

71

O

n

r.t.

3.5

87

62

O

Anisole

r.t.

6

98

48

O

THF

r.t.

6

97

0

O

Et2O

r.t.

4.5

81

73

O

Et2O

r.t.

3.5

93

78

26.6 (0.9)

O

Et2O

r.t.

3.5

94

81

27.1 (0.9)

O

Et2O

r.t.

8

67

64

14.0 (0.36)e

O

Toluene

0 C

3

89

39

Et2O

0 C

5

95

74

Et2O

r.t.

3

92

73

151.1 (1.0)

Et2O

r.t.

5.5

81

79

176.8 (0.7)

Ph

2

BuOMe

Ph

3

BuOMe

Ph

4 Ph

5 Ph

6c Ph

7 Ph

8d Ph

9 Ph

10 Ph

11

Ph O

Ph

12

Ph O

Ph

13

Ph

O Ph Cl

(continued)

346

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

TABLE 11.12 (Continued)

Entry

Ketone

14

Solvent Et2O

O

Temp r.t.

Time (h) 8

Isolated yield (%)

eeb (%)

[a]D (c, CH2Cl2)

93

70

171.0 (1.1)

Ph Me a

All reactions used 20 mol% of (R)-11:9a (based on the repeating unit), 36 mol% of ZnEt2, 1.2 equiv of t-BuOOH unless indicated otherwise. b Determined by HPLC with a Daicel-OD column. c 1.2 equiv of (R)-11:9a, 1.8 equiv of ZnEt2 and 1.0 equiv of t BuOOH were used. d 40 mol% of the polymer and 72 mol% of ZnEt2 were used. e Measured in CHCl3.

When the long linker polyBINOL (R)-11.11 was used for the asymmetric epoxidation, under the same conditions as the use of the short linker polyBINOL (R)-11.9 in entry 1 of Table 11.12, it produced 37%ee and 99% yield for the epoxidation of the b-propyl substituted enone, trans-1-phenyl-hex-2-en-1-one, and 55%ee and 88% yield for the b-isopropyl substituted enone, 4-methyl-1-phenylpent-2-en-1-one. That is, the catalytic properties of the long linker polymer (R)-11.11 were very similar to those of the monomeric ligand (R)-11.10, and the structure and function of (R)-11.10 were mostly preserved in (R)-11.15. The significantly enhanced enantioselectivity of polymer (R)-11.9a over polymer (R)-11.15 and monomer (R)-11.10 was attributed to a collaborative effect between the adjacent catalytic sites in the zinc complex of (R)-11.9a. The interaction between the adjacent catalytic sites in the zinc complex (R)-11.13 generated from the reaction of (R)-11.9a with ZnEt2 decreased the enantioselectivity of (R)-11.9a in the asymmetric ZnEt2 addition to aldehydes as described in Section 11.2.2.1 and in the asymmetric reduction of ketones as described in Section 11.2.2.2. However, this interaction apparently greatly increased the enantioselectivity of (R)-11.9a in the epoxidation of a,b-unsaturated ketones. In the zinc complex of the long linker polymer (R)-11.15, there should be minimum collaborative effect between the catalytic sites because of its long and rigid linkers. The Yb(III) and La(III) complexes of the polyBINOLs were also employed to catalyze the asymmetric epoxidation of a,b-unsaturated ketones (Scheme 11.15) [19]. The results for the epoxidation of trans-4-phenyl-but-3-en-2-one [trans-PhCH¼CHC (CO)CH3] in the presence of polyBINOLs (R)-11.2, (R)-11.5, (R)-11.9a and (R)-11.11 in combination with Yb(OiPr)3 are summarized in Table 11.13. Among these chiral polymers, it was found that the 6,60 -linked polyBINOL (R)-11.5 was the most enantioselective one for this reaction. As shown in entry 6, in the presence of 2.5 mol% of polymer (R)-11.5, the epoxide product was obtained in 86% yield and 71%ee. In this reaction, a 2:3 ratio of the ligand to Yb(OiPr)3 was heated at 40  C first. The resulting complex (2.5 mol%) was used in combination with t BuOOH, Ph3P¼O  and 4 A molecular sieves to catalyze the epoxidation at room temperature. Increasing the amount of Ph3P¼O to 75 mol% only slightly increased the ee (entry 9).

347

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

O

Yb-ligand (2:3) (2.5 mol%) Ph3P=O (15 mol%)

Ph

Ph

La-ligand (1:1) (5 mol%) Ph3P=O (15 mol%) Ph

O

O

O

Ph

TBHP (1.5 eq) THF, rt, 4 Å MS O

O

Ph

CMHP (1.5 eq) THF, rt, 4 Å MS

Ph

SCHEME 11.15. PolyBINOL-Yb(III) and –La(III) complexes-catalyzed asymmetric epoxidation of a,b-unsaturated ketones.

TABLE 11.13. Asymmetric epoxidation of 4-phenyl-but-3-en-2-one with t BuOOH catalyzed by Yb-Ligand complexa Additive (mol%) Entry

Ligand

1 2 3 4 5 6 7 8

(R)-11.2 (R)-11.5 (R)-11.9a (R)-11.11 (R)-11.5 (R)-11.5 (R)-11.5 (R)-11.5

H2O

Ph3P¼O

Time (h)

Yield (%)b

ee (%)c

— — — 5 — — 5 —

— — — — — 15 15 15

18 22 20 18 24 24 18 18

84 91 47 51 73 86 59 76

34 49 39 41 50 71 63 72

The metal-to-ligand ratio is 2:3, and the catalyst is generated at 40  C. Isolated yields after column chromatography. c By HPLC analysis. a b

Table 11.14 provides the results for the use of the major-groove polyBINOL (R)11.5 in combination with La(OiPr)3 to catalyze the asymmetric epoxidation of chalcone in the presence of CMHP. As shown in entry 6, up to 73%ee and 99% yield  were achieved in 1.5 h. This reaction also used 30% Ph3P¼O additive and 4 A molecular sieves. 11.2.3 Synthesis and Application of a BINAP-containing Polymer Bisphosphines such as 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl (BINAP) (11.23) represent a large family of bidentate ligands for transition metals [2, 20], and have been demonstrated as useful ligands in several reactions, including catalytic hydrogenations and cross-coupling reactions [1, 20]. Since the 1970s, bisphosphines have been immobilized in polymer networks [1]. Most of the early work focused on

348

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

TABLE 11.14. (R)-11.5-La(III) complex-catalyzed asymmetric epoxidation of chalcone with CMHP Entry 1 2 3 4 5 6

La:(R)-11.5

Tempa ( C)

Time (h)

Ph3P¼O (mol%)

Time (h)

Yield (%)b

ee (%)c

2:3 2:3 1:1 1:1 1:1 1:1

rt 40 40 40 40 40

12 12 1 1 1 1

— — 15 30 50 15þ15d

4 4 15 14 14 1.5

95 97 98 97 97 99

35 37 62 52 53 73

a

Temperature at which the catalyst is generated. Time required to generate the active catalyst. c Reaction time. d 15 mol% of the additive was added before the catalyst generation step, and an additional 15 mol% was added before the addition of substrate. b

the polymer-linked bisphosphines, which have afforded easy recovery and reuse, and sometimes also showed higher catalytic activities compared with their monomeric counterparts. Incorporation of the bisphosphine units into the polymer backbones has also been the subject of research in more recent years. PPh2 PPh2

BINAP 11.23

BINAP (11.23) is one of the most versatile and effective ligands used for asymmetric catalysis, and it has also been developed into recoverable and soluble polymeric catalysts [2]. Poly-BINAP 11.25, in which BINAP was incorporated into the polymer backbone, was prepared by the Suzuki cross-coupling reaction of the diborate 11.24 followed by reduction (Scheme 11.16) [21]. This polymer was soluble in common organic solvents, such as methylene chloride, THF, chloroform, and toluene, but insoluble in methanol.

PPh2 PPh2 O O B

O PPh2 PPh2 + Br O

O B O

n-C6H13

n-C6H13 1. Pd(dppf)Cl2. CH. 2Cl2 2 M K2CO3, THF Br 2. HSiCl3, Et3N, Xylene

nC6H13n-C6H13

n-C6H13

n-C6H13

(R)-11.24 (R)- 11.25

PPh2 PPh2

SCHEME 11.16. Synthesis of the BINAP-containing polymer (R)-11.25.

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

349

The polyBINAP (R)-11.25 was used as a ligand for the Rh(I)-catalyzed asymmetric hydrogenation of dehydroamino esters or acids. In this process, the polymeric Rh complex (R)-11.26 was probably generated from the treatment of the polymeric ligand with Rh(COD)2BF4 (COD ¼ cyclooctadiene) (Scheme 11.17). As shown in Table 11.15, in the presence of 2 mol% of (R)-11.26 under 30 psi H2, the hydrogenation proceeded with quantitative conversion and up to 75%ee (entry 1). The catalytic properties of (R)-11.26 were almost the same as the catalyst derived from BINAP (entry 2). This demonstrates that the structure and function of BINAP are retained in the rigid and sterically regular polymer. The polymeric catalyst was easily recovered by simple filtration after reaction, and the recovered catalyst showed the same catalytic properties as the original one (entry 3). The polyBINAP (R)-11.25 was also employed as the ligand for the Ru(II)catalyzed asymmetric hydrogenation of ketones. It was treated with [RuCl2(C6H6)]2 in DMF followed by the addition of (R,R)-1,2-diphenylethylenediamine to form an air stable polymeric Ru complex (R)-11.27 (Scheme 11.18). The 31 P NMR spectrum of (R)-11.27 showed a predominate signal at 46.3 ppm, which is very close to the corresponding monomeric BINAP complex (47.4 ppm). The polymeric Ru complex (R)-11.27 was used to catalyze the asymmetric TABLE 11.15. The polyBINAP (R)-11.25/Rh(I)-catalyzed hydrogenation of dehydroamino acid derivativesa R1

CO2R3 +

2

R

NHCOR

4

H2 (30 psi)

(R)-11.26 THF

R1 R2

CO2R3 *

NHCOR4

R1 = Ph, H; R2 = H, Ph R3 = Me, H; R3 = Me, Ph

Entry Substrate 1 2 3 4 5 6 7

(Z)-methyl a-(benzamido) cinnamate (Z)-methyl a-(benzamido) cinnamate (Z)-methyl a-(benzamido) cinnamatee methyl a-(acetamido)acrylate (Z)-a–benzamido-cinnamic acid (Z)-a-benzamido-cinnamic acidg (E)-methyl a-(benzamido) cinnamate

Chiral ligand Conv (%)b ee (%)c Conf.d (R)-11.25 (R)-BINAP (R)-11.25 (R)-11.25 (R)-11.25 (R)-11.25 (R)-11.25

>99 >99 >99 >99 >99 >99 >99

75 76 75 32 59f 57f 40

S S S ND S S ND

a All the reactions were carried out at room temperature under 30 psi of H2 in the presence of 2 mol% of Rh (COD)2BF4 and 2.2 mol% of (R)-11:25 in THF. b Determined by 1 H NMR. c Determined by HPLC chiral OD column. d The absolute configuration was determined by comparing the sign of the optical rotations with the literature data.12 e Recovered catalyst (2 mol%) was used. f Determined by HPLC after converted to the methyl ester. g 0.5 equiv of Et3N was added.

350

Ph2P

RO

PPh2

Ph2P

PPh2

R = nC6H13

OR RO

Ph2P

OR

PPh2

Rh(COD)2BF4

Ph2P PPh2 +Rh

OR RO

(R)-11.26

RO

Rh + Ph2P PPh2

R = nC6H13

OR RO

+ Rh Ph2P PPh2

SCHEME 11.17. Formation of the polymeric Rh(I) complex (R)-11.26.

(R)-11.25

PPh2

OR RO

Ph2P

Ph2P PPh2 +Rh

OR

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

351

hydrogenation of ketones. As shown in Table 11.16, high enantioselectivity was observed for the hydrogenation of several aryl methyl ketones. The enantioselectivity was found to be independent of the hydrogen pressure (60–200 psi) but higher pressure led to a faster reaction. The reaction was worked up in air, and the catalyst (R)-11.27 was recovered by precipitation with methanol. The catalytic properties of the recovered (R)-11.27 were similar to those of the original catalyst (entry 8). The catalytic properties of this polyBINAP catalyst were also similar to those of the complex prepared from the monomeric BINAP. That is, the rigid and sterically regular polyBINAP has preserved the structure and function of the monomeric Ru catalyst, and it provides the advantage of easy recovery and reuse. 11.2.4 Synthesis of an Optically Active BINOL–BINAP-based Bifunctional Polymer and Application in Asymmetric Alkylation and Hydrogenation Polymers containing more than one type of ligand in their backbones could be very useful for asymmetric catalysis because they could function as ligands for sequential reactions to enhance the efficiency of the polymeric catalyst systems. A BINOL–BINAP-based bifunctional polymeric ligand (R,R)-11.28 [22] that contained two distinctively different catalytic sites, BINOL and BINAP, was prepared by the co-polymerization of two binaphthyl monomers followed by hydrolysis and reduction (Scheme 11.19). Upon treatment of (R,R)-11.28 with 0.5 equivalent of [RuCl2(C6H6)]2 and (R,R)1,2-diphenylethylenediamine, complex (R,R)-11.29 was obtained (Scheme 11.20). Its 31 P NMR spectrum showed a predominate singlet at d 46.33, which was identical to that of the corresponding monomeric BINAP-Ru complex. The remaining BINOL units in (R)-11.29 allowed the in situ introduction of Lewis acidic metal centers upon treatment within metal complexes such as ZnEt2. Polymer (R,R)-11.29 (4 mol% based on the repeating unit) was used to catalyze the sequential catalytic asymmetric ZnEt2 addition followed by asymmetric hydrogenation of p-acetylbenzaldehyde (Scheme 11.21). In this sequential reaction, ZnEt2 first added to the aldehyde to form a R alcoholic center followed by the hydrogenation to generate another S alcoholic center. As shown in Table 11.17, the ee for the ZnEt2 addition was excellent and the de for the hydrogenation step was also high (75–87%). The stereoselectivities of the corresponding monomeric BINOL and BINAP catalysts were mostly preserved in this copolymer. The polymeric catalyst was easily recovered by precipitation with methanol, and the recovered catalyst showed similar catalytic properties as the original polymer (entry 3). The tandem asymmetric ZnEt2 addition and hydrogenation of m-acetylbenzaldehyde was also catalyzed by polymer (R,R)-11.29. It produced 94%ee for the ZnEt2 addition and 75% de for the hydrogenation (entry 4). The BINOL–BINAP copolymer (R,R)-11.28 was also used to catalyze the individual asymmetric reactions. At a BINAP-unit-to-substrate ratio of 1:4900, polymer (R,R)-11.28 catalyzed the asymmetric hydrogenation of acetophenone to

352

Ph2P

RO

PPh2

Ph2P

(R)-11.25

R = nC6H13

OR RO

PPh2

Ph2P

OR

PPh2

H2N

NH2

1). [RuCl2(C6H6)]2 Ph Ph 2).

(R)-11.27

RO

Ph

Ph

Ph2P PPh2 Cl Ru Cl H2N NH2

OR RO

SCHEME 11.18. Synthesis of BINAP-containing polymer (R)-11.27.

PPh2

OR RO

Ph2P

Ph

H2N NH2 Cl Ru Cl Ph2P PPh2

Ph

Ph

Ph

Ph2P PPh2 Cl Ru Cl H2N NH2

OR

R = nC6H13 Ph

OR RO

H2N NH2 Cl Ru Cl Ph2P PPh2

Ph

SYNTHESIS AND APPLICATION OF BINOL/BINAP-BASED OPTICALLY ACTIVE POLYMERS

353

TABLE 11.16. (R)-11.27-catalyzed asymmetric hydrogenation of ketonesa O Ar

Entry 1

2

3

4

Substrates O

O

O

O

5

OH

(R)-11.27 + Me

H2

t

BuOK, iPrOH

Ar

Me

H2 (psi)

Time (h)

Conversion (%)b

ee (%)b

60

72

100

80

60

100

78

91

200

24

86

c

90

200

44

>99c

90

60

96

13

nd.

>99

92

O

6

200

66.5

200

22

200

66

O

7

33.5c

87

O

8

>99c

89

O

a

The reactions were carried out in 2-propanol at room temperature by using a suspension of 0.5 mol% of (R)-11:27 and 20 mol% of potassium t-butoxide. b Determined by GC with a chiral b-Dexc 120 column. c Recovered (R)-11:27 catalyst was used.

(S)-1-phenylethanol with >99% conversion and 84%ee. The reaction was conducted in toluene/i PrOH (1:1) under H2 (175 psi) in the presence of t BuOK at room temperature. At a BINOL-unit-to-substrate ratio of 1:50, polymer (R,R)-11.28 catalyzed the ZnEt2 addition to p-acetylbenzaldehyde to (R)-1-p-acetylphenyl propanol with 95%ee and complete conversion at 0  C in 5.5 h [22].

354

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

O OB

O PPh2 PPh2

+ OR

OR

OH OH OR RO

RO

O

OB O Br

OR

. 1. Pd(dppf)Cl2, CH2Cl2 K2CO3 (aq.), THF

Br

RO

2. H+ 3. HSiCl3, NEt3

RO +

RO

OR

O BO

RO

OR

R = nC6H13

OMOM OMOM

Ph2P

PPh2

(R, R)-11.28

BO O

SCHEME 11.19. Synthesis of the BINOL–BINAP-containing polymer (R,R)-11.28.

RO

OR

OR

RO

OR

H2N

Ph RO

NH2

PPh2

OR

RO

OR

R = nC6H13

R = nC6H13

Ph2P

OR

(RuCl2C6H6)2 Ph

RO

OH OH OR RO

RO

OH OH OR RO

PPh2 Ph2P Ru Cl Cl NH2 H2N

(R, R)-11.28

Ph

(R, R)-11.29

Ph

SCHEME 11.20. Preparation of BINOL–BINAP-containing polymer (R,R)- 11.29.

1. Polymer (R)-11.29 , ZnEt2 toluene, 0 ºC, 5 h

O

HO

OH

CHO Me

2. H2, iPrOH, tBuOK rt, 2 d

Me

S

R

Et

SCHEME 11.21. A sequential asymmetric ZnEt2 addition and hydrogenation.

SYNTHESIS AND APPLICATION OF OPTICALLY ACTIVE DENDRIMERS

355

TABLE 11.17. The Sequential Asymmetric Reactions of Acetyl Benzaldehydes Catalyzed by Multifunctional Chiral Polymer Catalyst (R,R)-11.29 Solvent

Entry 1

ZnEt2 addition

Substrate O CHO

H2 addition

Conversion (%)a

ee (%)b,c

de (%)b,d

Toluene

i

PrOH

>99%

92

86

Toluene

Tolueneþi PrOH e

>99%

94

87

Toluene

i

PrOH

>99%f

93

78

Toluene

i

PrOH

>99%

94

75

Me

2

O CHO Me

3

O CHO Me

4

O Me CHO

a

Determined by 1 H NMR. Determined by GC-chiral b-Dex 120 column after converted to the diacetate. c For the diethylzinc addition. d For the hydrogenation. e Toluene:i PrOH ¼ 1:1. f The recovered catalyst was used. b

11.3 SYNTHESIS AND APPLICATION OF OPTICALLY ACTIVE DENDRIMERS Dendrimers are tree-like molecules with unique structure and solubility [5]. The catalytic sites of a dendritic catalyst could be at the core, branch or periphery. Extensive research on the synthesis and preparation of dendrimer catalysts has been carried out [5]. Although dendritic catalysts are generally more soluble than their linear polymeric counterparts, the enantioselectivity of many dendritic catalysts were observed to be lower than their parent chiral catalysts, which was most likely due to the dense packing of the catalytically active sites at the periphery. Two types of dendritic chiral catalysts are described in the subsequent discussion, and their catalytic properties are compared with those of their corresponding parent catalysts. 11.3.1 Synthesis of BINOL-based Dendrimers and Application in Asymmetric Alkylation Dendrimers (S)-11.32, (S)-11.33, and (S)-11.34 were prepared from the Sonogashira coupling of alkynes 11.30a-c with the binaphthyl tetrabromide (S)-11.31 followed by hydrolysis (Scheme 11.22) [23]. These molecules were characterized by NMR and FAB/MALDI mass spectroscopies.

356

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

t-Bu t-Bu

t

Br Br

Bu

H t-Bu

OAc OAc

t-Bu

11.30a Br Br

t-Bu

t-Bu

(S)-11.31 H

t-Bu t-Bu

Pd(PPh3)4/CuI Et3N, THF 70 oC

11.30c

KOH THF, MeOH H2O, r.t.

H t-Bu t-Bu

t-Bu t-Bu 11.30b

t-Bu

t-Bu

t-Bu

t-Bu t-Bu t-Bu t-Bu OH OH

t-Bu

t-Bu t-Bu

t-Bu t-Bu

t-Bu

t-Bu

t-Bu

(S)-11.32 (G0)

t-Bu

t-Bu

t-Bu t-Bu

t-Bu t-Bu

t-Bu t-Bu

t-Bu

t-Bu t-Bu

t-Bu t-Bu

t-Bu OH

t-Bu

t-Bu

OH

t-Bu

(S)-1134 (G2)

t-Bu t-Bu t-Bu t-Bu

OH OH

t-Bu

t-Bu t-Bu

(S)-11.33 (G1)

t-Bu

t-Bu t-Bu

t-Bu

t-Bu t-Bu

t-Bu t-Bu

t-Bu t-Bu t-Bu t-Bu

t-Bu

t-Bu

t-Bu t-Bu t-Bu

t-Bu

SCHEME 11.22. Synthesis of the optically active aryleneethynylene-BINOL dendrimers.

357

SYNTHESIS AND APPLICATION OF OPTICALLY ACTIVE DENDRIMERS

Br Br OnC6H13 OnC6H13

Ph

B(OH)2

Br

Ph

11.35a

3%Pd(PPh3)4

1. BBr3

K2CO3 (2 M aq.) THF, reflux

2. H2O

B(OH)2 Ph 11.35c

Ph

B(OH)2 Ph

(S)-11.36

Br

Ph

11.35b

Ph

Ph

Ph

Ph

Ph Ph

Ph Ph

Ph Ph

Ph Ph

Ph

Ph OH Ph

OH OH

OH OH

OH

Ph

Ph Ph

(R)-11.37 (G0)

Ph

Ph Ph

Ph

(R)-11.38 (G1)

Ph Ph Ph

Ph

Ph

Ph

(R)-11.39 (G2)

SCHEME 11.23. Synthesis of optically active arylene-BINOL dendrimers.

The phenylene-based dendrimers (S)-11.37, (S)-11.38, and (S)-11.39 were prepared from the Suzuki coupling of the boronic acids 11.35a-c with the tetrabromide (S)-11.36 followed by hydrolysis (Scheme 11.23) [24]. Dendrimers (S)-11.32–34 and (S)-11.37-39 were used as enantioselective sensors to differentiate optically active compounds such as amino alcohols [23–25]. (S)-11.34 was also used to catalyze the asymmetric reaction of benzaldehyde with diethylzinc (Scheme 11.24) [23]. The catalytic properties of this dendrimer OH

(S)-11.34 PhCHO +

ZnEt2

With or without Ti(O iPr)4

Ph

SCHEME 11.24. (S)-11.34-catalyzed asymmetric ZnEt2 addition to benzaldehyde.

358

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

have been compared with that of the parent BINOL molecule. It was found that the nanoscale dendritic material behaved very differently from the small BINOL molecule. Although both the enantioselectivities of (S)-11.34 [19] and BINOL were very low, (S)-11.34 showed much higher catalytic activity than (S)-BINOL and also generated the opposite enantiomeric product. The increased catalytic activity of (S)-11.34 over BINOL suggested that the zinc complex generated from the reaction of (S)-11.34 with ZnEt2 might have much higher Lewis acidity than the zinc complex generated from BINOL. The zinc complex formed from the reaction of BINOL with ZnEt2 likely existed as aggregates in solution through intermolecular Zn-O-Zn bonds, which should greatly reduce the Lewis acidity of the zinc center [9]. Such aggregates could not form in the case of (S)-11.34 because of the large dendritic arms. These bulky and rigid dendritic arms prevent (S)-11.34 from forming oligomers through Zn-O-Zn bonds, and yet still allowed small molecules such as benzaldehyde and ZnEt2 to approach the chiral core for the catalytic reaction. The opposite enantioselectivity of (S)-11.34 versus (S)-BINOL also indicated that the in situ generated catalytically active species when these ligands were used were very different. It might be monomeric for (S)-11.34 but oligomeric for BINOL. In the presence of Ti(OiPr)4, (S)-11.34 became highly enantioselective for the reaction of aldehydes with ZnEt2 [20]. In toluene, (S)-11.34 (20 mol %) and Ti(OiPr)4 (1.4 equiv) catalyzed the reaction of 1-naphthaldehyde with ZnEt2 with 100% conversion and 90%ee in 5 h. No side product was observed. Under similar condition, (S)-11.34 showed 100% conversion and 89%ee for the reaction of benzaldehyde with ZnEt2 in the presence of Ti(OiPr)4. These catalytic properties of (S)-11.34 were very similar to those of BINOL in the presence of the titanium complex as reported by Chan and co-workers [26]. The same enantiomeric product was produced by using either (S)-11.34 or (S)-BINOL in the presence of Ti(OiPr)4. This study indicates that unlike the reaction in the absence of Ti(OiPr)4, the asymmetric reaction of aldehydes with ZnEt2 in the presence of the titanium complex might involve structurally similar catalytically active species when either the chiral dendrimer (S)-11.34 or the small molecule BINOL was used. Because the titanium complex of (S)-11.34 was not expected to generate any dimeric or oligomeric structure through the binaphthyl core, the catalytically active species formed from the interaction of BINOL with Ti(OiPr)4 may also be monomeric. In these catalytic reactions, (S)-11.34 was easily recovered from the reaction mixture by precipitation with methanol because of the large size differences between this dendritic molecule and the products and reagents. 11.3.2 Synthesis of Optically Active, Ephedrine-based Dendronized Polymers Dendronized polymers are macromolecules with dendritic side chains attached to polymeric cores [27–30]. In dendronized polymers with rigid polymeric cores that can easily attain rod-like shapes, dendritic wedges are attached to the polymer backbone in a rotating fashion along the polymer axis. This unique structural feature renders them having great potential to compete with linear polymers and dendrimers for asymmetric catalysis. Optically active dendronized polymers containing lower generation dendritic wedges with monomeric chiral units in their peripheries could overcome the

359

SYNTHESIS AND APPLICATION OF OPTICALLY ACTIVE DENDRIMERS

condensed packing problem existing in the dendrimer-based chiral catalysts without sacrificing the advantage of easy recovery by either filtration or precipitation. They also possess multiple catalytic sites per repeat unit with higher solubility. The combined features of more catalytic sites, higher solubility, and nanoscopic dimensions of the optically active dendronized polymers render them potentially more efficient than the linear polymeric and dendritic chiral catalysts. These optically active dendronized polymers represent a new type of polymeric chiral catalysts. The optically active ephedrine-based dendronized polymers 11.43 and 11.44 were prepared by the Suzuki coupling polymerization of the dibromides 11.40/11.41 with the diboronic acids 11.42 (Scheme 11.25) [31]. These ephedrine-containing polymers were soluble in common organic solvents such as THF, toluene, and dichloromethane but insoluble in methanol. Ph

HO

Ph

OH

N N

N

OH Ph

OR

n

OR

n

OR

n R = C6H13

OR

n n

OR

n

OR

OR

n

R = n-C6H13

11.43a: n = 0 11.43b: n = 1 Ph

OR

n

11.44a: n = 0 11.44b: n = 1 N

N

OH

HO

N Ph

Ph

OH

Polymers 11.43 and 11.44 were employed as catalysts for the asymmetric addition of ZnEt2 to benzaldehyde and good enantioselectivity was observed (Table 11.18). The catalytic properties of these dendronized polymers were compared with their HO OH N

Ph

Ph

OH N

N

Ph

RO (HO)2B

or

n

OR

n B(OH)2

11.42 (n = 0, 1) Pd(PPh3)4, 2M K2CO3/ THF reflux, 24 h Br

Polymer 11.43 Polymer 11.44

Br Br

11.40

Br

11.41

SCHEME 11.25. Synthesis of the optically active dendronized polymers 11.43 and 11.44.

360

OPTICALLY ACTIVE POLYMER AND DENDRIMER SYNTHESIS

TABLE 11.18. Asymmetric Addition of ZnEt2 to Benzaldehyde Catalyzed by the Ephedrine-based Ligandsa

CHO

Entry

OH

Ephedrine-based Ligands toluene, 0 ºC, 5 h

ZnEt2

+

Et

Chiral Ligand

Catalyst (mol%)

Time (h)

Conversion (%)b

ee (%)c

11.43a 11.43b 11.43b 11.44a 11.44b 11.45 11.46 11.47

5 5 5 5 5 5 5 3.3

24 24 24 12 12 24 24 22

99 99 99d 99 99 99 99 61

76 74 76 73 75 83 76 78

1 2 3 4 5 6 7 8

a The reactions are carried out in toluene at 0  C by using 5 mol% of catalyst (based on the repeat units of the polymer). b Determined by 1H NMR analysis. c Determined by HPLC (Chiralcel OD column). d Recovered 11:43b was used.

corresponding monomeric catalyst 11.45, linear polymeric catalyst 11.46 [32], and dendritic chiral catalyst 11.47 [33]. It was found that the enantioselectivities were slightly lower than those using the corresponding monomer (1R,2S)-N-benzylephedrine 11.45 but were similar to those using the corresponding linear polymeric catalyst 11.46 and the dendritic catalyst 11.47. Polymers 11.43 and 11.44 were easily recovered by filtration and reused without loss of enantioselectivity. OH N

Ph

OH OH N

N

Ph Ph

Ph Ph

OH

HO Br 11.45

11.46

n

N

N 11.47

11.4 CONCLUSIONS The development of recoverable and reusable polymeric/dendritic chiral catalysts has been the research of intense study during the past decades. The soluble polymeric/dendritic chiral catalysts are expected to have the advantages of homo-

REFERENCES

361

geneous catalysts during reactions and be easily recovered by precipitation. In this chapter, the synthesis and application of the soluble main-chain chiral binaphthylbased polymeric catalysts are summarized. Studies showed that it is possible to systematically fine-tune the structure, size, shape, and solubility of these polymeric chiral catalysts. Highly enantioselective and easily reusable catalysts have been obtained. In addition, distinctively different catalytic sites are incorporated into the chiral polymer chains to construct catalysts that are capable of catalyzing multiple asymmetric reactions. The BINOL-based dendrimers and the ephedrine-containing dendronized polymers are also discussed. The dendronized polymers are considered as a unique type of soluble polymeric catalysts, and they might also have a promising future to fill the gap between the homogeneous and heterogeneous catalysis.

ACKNOWLEDGMENT Q.S.H. thanks the U.S. National Institutes of Health, the donors of the Petroleum Research Fund, administered by the American Chemical Society, the U.S. National Science Foundation, and the PSC-CUNY Research Award Programs for their generous support. L.P. thanks the supports of the following U.S. funding agents: NSF, NIH, AFOSR, NASA, ONR and ACS-PRF. We are also grateful for the contributions of the dedicated students and postdoctoral associates in our laboratories, whose names are in the references cited. REFERENCES [1] (a) Itsuno, S. In Polymeric Materials Encyclopedia; Synthesis, Properties and Applications, Vol. 10 ( Salamone, J. C. Ed.), CRC Press, Boca Raton, FL (1996). For recent comprehensive reviews: (b) Gladysz, J.(Guest Editor). Chem. Rev. 2002, 102, 3215– 3810. Also see: (c) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 2000, I, 3815–4195. [2] (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, Y. Comprehensive Asymmetric Catalysis, Springer, New York (1999). (b) Ojima,I. Catalytic Asymmetric Synthesis, VCH, Weinheim, Germany (1993). [3] (a) For example: Bolm, C.; Dinter, C. L.; Seger, A.; H€ ocker, H.; Brozio, J. J. Org. Chem. 1999, 64, 5730. (b) Dumont, W.; Poulin, J. C.; Dang, T. P.; Kagan, H. B. J. Am. Chem. Soc. 1973, 95, 8295. [4] (a) Pu, L. Chem. Eur. J. 1999, 5, 2227. (b) Yu, H.-B.; Hu, Q.-S.; Pu, L. J. Am. Chem. Soc. 2001, 122, 6500. (c) Fan, Q.-H.; Ren, C.-Y.; Yeung, C.-H.; Hu, W.-H.; Chan, A. S. C. J. Am. Chem. Soc. 1999, 121, 7407. [5] Recent reviews: (a) Oosterrom,G. E.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Angew. Chem. Int. Ed. Engl. 2001, 40, 1827. (b) Seebach,D.; Rheiner, P. B.; Greiveldinger, G.; Butz, T.; Sellner, H. Top. Curr. Chem. 1998, 197, 125.(c) Newkome, G. R.; Moorfield, C. N.; Vogtle, F. Dendritic Molecules: Concepts, Synthesis, Perspectives, VCH, Weinheim, Germany (1996).

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[31] [32] [33]

363

Am. Chem. Soc. 1998, 120, 1278. (c) Jahromi, S.; Coussens, B.; Meijerink, N.; Braam, A. W. M. J. Am. Chem. Soc. 1998, 120, 9753. (d) Percec, V.; Ahn, C.-H.; Ungar, G.; Reardley, D. J. P.; M€oller, M.; Sheiko, S. S. Nature 1998, 391, 161. (a) For examples of dendronized polymers with rigid polymeric cores: (a) Wyatt, S. R.; Hu, Q.-S.; Yan, X.-L.; Bare, W. D.; Pu, L. Macromolecules 2001, 34, 7983. (a) Marsitzky, D.; Vestberg, R.; Blainey, P.; Tang, B. T.; Hawker, C. J.; Carter, K. R. J. Am. Chem. Soc. 2001, 123, 6965. (b) Bo, Z.; Schl€uter, A. D. Chem. Eur. J. 2000, 6, 3235. (c) Sato, T.; Jiang, D.-L.; Aida, T. J. Am. Chem. Soc. 1999, 121, 10658. (d) Bao, Z.; Amundson, K. R.; Lovinger, A. L. Macromolecules 1998, 31, 8647. (e) Kaneko, T.; Horie, T.; Asano, M.; Aoki, T.; Oikawa, E. Macromolecules, 1997, 30, 3118. (a) Hu, Q.-S.; Sun, C.; Monaghan, C. E. Tetrahedron Lett. 2002, 43, 927. (b) Hu, Q.-S.; Sun, C.; Monaghan, E. M. Tetrahedron Lett. 2001, 42, 7725. Ituno, S.; Frechet, J. M. J. J. Org. Chem. 1987, 52, 4142. Sato, I; Shibata, T.; Ohtake, K.; Kodaka, R.; Hirokawa, Y.; Shirai N.; Soai, K. Tetrahedron Lett. 2000, 41, 3123.

CHAPTER 12

ASYMMETRIC POLYMERIZATIONS OF N-SUBSTITUTED MALEIMIDES KENJIRO ONIMURA and TSUTOMU OISHI

12.1 INTRODUCTION Polymerization in which chirality is introduced to a polymer main chain through polymerization is defined as asymmetric polymerization. Concerning the polymerization process and the structure of the obtained polymer, asymmetric polymerization is classified into the following three categories: (1) asymmetric synthesis polymerization, (2) helix-sense-selective polymerization, and (3) enantiomer-selective polymerization [1]. In this chapter, the following topics will be addressed. After a short overview of chirality of the polymer obtained from 1-subustituted and 1,1-disubstituted olefins, we will discuss the asymmetric polymerization of N-substituted maleimide (RMI), followed by the applications using optically active RMI. 12.2 CHIRALITY OF 1-MONO- OR 1,1-DISUBSTITUTED AND 1,2-DISUBSTITUTED OLEFINS There have been many reports on the relationship between optical activity of a polymer and its main-chain configuration. [2–5]. Concerning chirality of vinyl polymers, we should consider that a chiral center in the main chain is pseudoasymmetric. A growing polymer chain end attacks a vinyl monomer to generate a new asymmetric center every time. But long polymer chains contain a large number of configurations. It has been well known that the three typical arrangements of homopolymer chain; isotactic, syndiotactic, and atactic, cannot show optical activity although atactic polymers are chiral. The reason for optical inactivity of isotactic and syndiotactic polymers can be attributed to possession of a mirror plane in the whole

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.

365

366

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FIGURE 12.1. Possible microstructural variations in polymer formed by additional polymerization of a cyclic olefin monomer without a C2 axis of symmetry.

polymer chain, neglecting asymmetric centers in the vicinity of the main-chain ends. Because an atactic polymer is a mixture of many racemic compounds, the polymer cannot show optical activity. To obtain an optically active vinyl polymer with main-chain configurational chirality, several higher order tacticities (stereoregularities) should be recognized when asymmetric induction to the main-chain occurs. Vinyl homopolymers containing a hexad sequence with triad tacticity (mm:mr:rr ¼ 0:67:33) are chiral because of no mirror plane, and the homopolymers having stereotactic sequences of diad, triad, tetrad, and pentad are not chiral because of the presence of mirror planes. A cyclic olefin monomer without a C2 axis of symmetry such as benzofuran (X ¼ O) can afford a chain of 2,3-dihydrobenzofuran repeating units that rise to three independent types of isomerism (Figure 12.1). The first, difference comes from the direction of monomer units (regioselectivity). The oxygen atom in successive units of the polymer backbone may be oriented head-to-tail (H-T), tail-to-head (T-H), tailto-tail (T-T), or head-to-head (H-H). The second, stereochemical variation originates from the fact that two asymmetric carbons in 2,3-dihydrobenzofuran are chiral and possess opposite configurations. In the polymer chain, these pairs of methine carbon atoms can therefore adopt two regular arrangements: [-(R,S)-(R,S)-]n comprises meso dyads and corresponds to an isotactic sequence, whereas [-(R,S)-(S,R)-]n comprises racemic dyads and a syndiotactic segment. A cyclic olefin monomer without a C2 axis of symmetry is polymerized to produce a polymer, in which having all the asymmetric centers in the main chain are true chiral ones. Natta, Farina, and coworkers presented the first successful examples of asymmetric homopolymerization of a cyclic olefin without a C2 axis of symmetry. Benzofuran was polymerized with AlEtCl2 or AlCl3 in the presence of optically active co-catalysts such as (S)-phenylalanine, 10-camphorsulfonic acid, and brucine to obtain optically active polymers with specific rotation [a]D of þ 13.1 to 33.1 in AlEtCl2 systems and þ56.7 as the highest value in AlCl3 systems [6–10]. Fueno, Furukawa, and coworkers reported on polymerizations of benzofuran with various chiral initiator systems at 75  C. Asymmetric polymerizations were carried out to obtain optically active polymers ([a]D ¼ þ 10.4  þ 79.4 ). Several catalyst systems consisting of aluminum chloride and the (-)-menthoxy group or binary catalyst systems consisting of aluminum chloride and (-)-menthoxytriethylmetals (Metal ¼ Si, Ge, and Sn) were used as an initiator [11, 12]. However, a cyclic olefin monomer with a C2 axis of symmetry such as RMI is polymerized to produce a polymer, in which all resulting asymmetric centers in the main chain are not always true chiral ones. Polymerizations of RMI can belong to the category of asymmetric synthesis polymerization. Previously, Cubbon reported on

CHIRALITY OF 1-MONO- OR 1,1-DISUBSTITUTED AND 1,2-DISUBSTITUTED OLEFINS

367

SCHEME 12.1. Asymmetric polymerization of benzofuran.

the anionic and radical polymerizations of RMI and structures of poly(RMI) [13]. RMI has a 1,2-disubstituted cyclic olefinic structure, so that the polymer can produce four types of structures, such as threo-diisotactic, threo-disyndiotactic, erythrodiisotactic, and erythro-disyndiotactic, as shown in Figure 12.2. However, erythrodiisotactic and erythro-disyndiotactic structures, which are originated from cis additional polymerization, cannot be formed because of steric hindrance of carbonyl groups in the imide ring. Even if the erythro structures are produced in the main

FIGURE 12.2. Structures of maleimide polymer.

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chain, they cannot show optical activity because two stereogenic centers in the monomeric unit exhibit an opposite absolute configuration; that is, the monomeric unit always has a mirror image plane. It is considered that one poly(RMI) chain possesses threo-diisotactic and threo-disyndiotactic structures, which are given by trans opening reactions of a carbon–carbon double bond of RMI. Each succinimide unit of these threo type structures possesses no mirror image plane, so that two stereogenic centers become chiral. However, because the threo-disyndiotactic main chains consist of a succession of an alternating (S,S)- and (R,R)-configurational pair, whole polymer chains cannot exhibit optical activity. The threo-diisotactic main chain consists of a succession of an (S,S)- or (R,R)-configurational pair. If one of two configurational pairs predominantly is formed in the main chain, the poly(RMI) can be optically active. In addition, if the threo-diisotactic sequence with the same configurational pair successively connects, the main chain can form a helical conformation, which can exhibit a large optical activity. Cubbon reported that the threo-diisotactic structure of the poly(RMI) (R ¼ ethyl, isopropyl, n-butyl, isobutyl,  t-butyl, n-octyl, benzyl) can form a 31 helix in which the repeat distance is 4.7 A [13]. It was expected that the poly(RMI) with a threo-diisotactic structure would be able to maintain a thermodynamically stable helical conformation by sterical repulsion of bulky substituents. However, there have been few systematic studies on the effects of the substituent on the chiroptical property of the polymer. 12.3 ASYMMETRIC POLYMERIZATIONS OF ACHIRAL N-SUBSTITUTED MALEIMIDES Polymerizations of chiral or achiral RMI have been systematically studied by the authors. In the 1991, the first research on asymmetric anionic polymerizations of 11 types of achiral RMIs [N-substituent (R) ¼ n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl (TBMI), cyclohexyl (CHMI), benzyl, phenyl (PhMI), 1-naphthyl (1-NMI), and 2-fluorenyl] with a n-butyllithium (n-BuLi)–sparteine (Sp) complex was reported by Oishi et al. [14], and the specific rotation of the poly(CHMI) (the maximum [a]D ¼ ca. 40 ) was the largest in the poly(RMI)s (Scheme 12.2). They concluded that the optical activity of the poly(RMI) could be attributed to

SCHEME 12.2. Asymmetric anionic polymerizations of achiral N-substituted maleimides.

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369

enantiomeric threo-diisotactic structures in the main chain. In the same year, Okamoto and co-workers presented asymmetric polymerization of PhMI with various chiral anionic initiators, and the poly(PhMI) with the highest specific rotation ([a]D ¼ 23.7 ) was obtained using a n-BuLi–Sp–CuI complex [15]. In the 1997, Xi et al. published the asymmetric polymerization of RMI bearing a huge substituent [N-substituent (R) ¼ diphenylmethyl [16] (DPhMI) and triphenylmethyl [17, 18] (TrMI)] with chiral ligand–organolithium complexes and chiral lithium alkoxides. TrMI exhibited a poor polymerizability because of poor solubility, and specific rotations of the poly(TrMI) ([a]D ¼ 10 to þ 9.4 ) were much smaller than those of poly(DPhMI) ([a]D ¼ 37.2 to þ 64.0 ), indicating that the triphenylmethyl group as a N-substituent is too bulky to form a maleimide polymer with a high molecular weight and a large optical activity. Oishi and Fujimoto also reported optically active poly(N-a-methylbenzylmaleimide) obtained with AIBN or n-BuLi [19]. Optically active poly(RMI)s were summarized in Figure 12.3 [20–26]. The poly(RMI) exhibiting high specific rotation cannot be synthesized by Sp as a chiral ligand. The authors have attempted to examine a new chiral ligand. They took note of a chiral bisoxazoline derivative as a chiral ligand. The chiral bisoxazoline derivatives were employed as ligands in a wide variety of metal-catalyzed asymmetric reactions with high ee, such as enantioselective alkylations, reduction, and Michael addition reactions [27]. In the 1997, the authors reported on the anionic polymerizations of three types of RMI (CHMI, PhMI, and TBMI) using organolithium–directly-coupled-chiral-bisoxazoline-derivative complexes (Scheme 12.3) [28]. However, the obtained polymers exhibited only a little optical activity ([a]435 ¼ 7.4 to 2.9 ), indicating that the directly coupled bisoxazolines cannot build a

FIGURE 12.3. Synthesis of optically active N-substituted maleimide polymers.

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SCHEME 12.3. Asymmetric polymerization of RMI using organolithium–directly-coupledchiral-bisoxazoline-derivative complexes.

better asymmetric field at the growing polymer end. After that, they carried out the polymerization using methylene bridged chiral bisoxazoline derivatives as chiral ligand and reported very interesting results in 1998 [29]. In that report, CHMI, PhMI, and TBMI were polymerized using n-BuLi–four-types-methylene-bridged-bisoxazoline-derivative complexes (Figure 12.4), and the poly(CHMI) initiated with nBuLi–()-2,2’-(1-ethylpropylidene)bis(4-benzyl-2-oxazoline) (Bnbox) showed a high specific rotation ([a]435 ¼ þ 111.4 ). Poly(TBMI) also exhibited large specific rotations (the maximum [a]435 ¼ 49.4 ). However, specific rotations of poly(PhMI), which possesses an aromatic group as the N-substituent, were much smaller ([a]435 ¼ 18.3 to þ 8.7 ) than those of poly (CHMI) and poly(TBMI), and they employed diethyl zinc (Et2Zn) instead of n-BuLi as an organometal. The Et2Zn–Bnbox complex produced a highly optically active poly(PhMI) ([a]435 ¼ þ 94.6 ), and the complex was also suitable for the polymerization of CHMI ([a]435 ¼ þ 117.5 ) [30]. The use of the Et2Zn–Bnbox complex may make it possible to improve widely the enantiomeric synthesis of the anionic polymerization of RMI. Therefore, the further experiments of the asymmetric polymerization of RMI using organometal–chiral bisoxazoline derivatives are desired at present. Similar phenomena were observed in the polymerizations of other RMI having Naromatic substituents. The Et2Zn–Bnbox complex has been found very useful for the asymmetric polymerization of RMI having N-aromatic substituents. Table 12.1

FIGURE 12.4. Four types methylene-bridged bisoxazoline derivatives for asymmetric anionic polymerizations.

ANIONIC POLYMERIZATION MECHANISM OF RMI

371

TABLE 12.1. Specific rotationsof poly(PhMI), poly(1-NMI), and poly(1-AMI) obtained with chiral ligand/organometal Specific rotations [a]435a Chiral Ligand/Organometal Run

Poly(RMI)

1 2 3

Poly(PhMI) Poly(1-NMI) Poly(1-AMI)

Sp/n-BuLi

Bnbox/n-BuLi

Sp/En2Zn

Bnbox/En2Zn

15.4b þ1.6 —

þ0.9 18.7 —

5.3 23.0 þ1.1

þ94.6 þ392.4 þ92.5

a

In THF. [a]D in THF.

b

shows the results of polymerization of RMI (R ¼ phenyl (PhMI), 1-naphthyl (1-NMI), and 1-anthryl (1-AMI)). The absolute values of specific rotations of the poly(RMI) obtained with Et2Zn-Bnbox were higher than those of polymers obtained with Et2ZnSp [31–34]. 12.4 ANIONIC POLYMERIZATION MECHANISM OF RMI Anionic polymerization of RMI proceeds through a common additional reaction as a result of nucleophilic attack of carbanion, as shown in Scheme 12.4(a), which demonstrates the polymerization path in the case of using n-BuLi as an anionic initiator. In the propagation steps, an RMI monomer reacts non-stereoselectively and non-enantioselectively with the carbanion, resulting in formation of poly(RMI) with atactic and optically inactive main chains. However, when a chiral ligand is present, the additional reaction of the RMI monomer can be controlled, as shown in Scheme 12.4(a). The chiral ligand makes a complex with Liþ, which exists closely to the carbanion as an ion pair. In the propagation steps, the growing carbanion attacks the RMI monomer selectively on one side of the enantio-face. If the nucleophilic attack produces a threo-diisotactic structure, part of the main chain of the poly(RMI) can show optical activity. That is, it is necessary for the formation of optically active poly(RMI) to control continually both the stereoregularity and the enantiomeric selectivity of the nucleophilic reaction. However, Bnbox efficiently promoted asymmetric anionic polymerizations of RMI initiated by Et2Zn. The increase of the polymerizability can be explained by the following reason. The first, Et2Zn exists as a dimer (Scheme 12.4(b)). Et2Zn with sp hybridized linear geometry is inert to monomers such as RMI because the ethyl groups-metal bonds are nonpolar. When Et2Zn complexes with electronegative substituents such as bisoxazolines, the polarity between the carbon and zinc bond is enhanced by creating a bent geometry in which the zinc atom used molecular orbitals of a higher p character. Therefore, the Et2Zn–ligand complexes have both a high electron–donor ability at the ethyl groups and an acceptor character at the zinc atom [35, 36].

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SCHEME 12.4. Mechanism of asymmetric anionic polymerization of RMI.

12.5 ASYMMETRIC POLYMERIZATIONS OF CHIRAL N-SUBSTITUTED MALEIMIDES Asymmetric anionic polymerizations of achiral 1-NMI and its derivatives were described, and the obtained polymers exhibited high optical activities [31–34]. In particular, poly(1-NMI) separated by gel permeation chromatography (GPC), which has a high molecular weight, showed the highest specific rotation of þ762.3 in all the poly(N-substituted maleimide)s (poly(RMI)s) prepared so far. Oishi and coworkers synthesized and copolymerized optically active RMI bearing N-substituents (R): amino acid residues, (R)-a-methylbenzyl, l-menthyl, and cholesteryl groups [37–41]. The results suggested that the chiroptical properties of the polymers and copolymers were ascribed to asymmetric induction, that is, formation of new asymmetric centers in the polymer main chain and asymmetric perturbation by the side-chain chromophores. Polymerizations of chiral RMIs such as N-a-methylbenzylmaleimide (MBZMI) [42, 43], N-1-(cyclohexyl)ethylmaleimide (CEMI) [44], N-1-(1-naphthyl)ethylmaleimide (NEMI) [45], and RMI-bearing amino acid derivatives have been investigated (Figure 12.5). [46–48]. These chiral RMIs possess a chiral center at the adjoining position of the imide ring. In the polymerization of (RS)-MBZMI with Et2Zn–()-2,2’-(1-ethylpropylidene)bis(4-benzyl-2-oxazoline) (Bnbox) as an initiator, enantiomer-selective reaction took place, and the maximum

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373

FIGURE 12.5. Asymmetric anionic polymerizations of chiral N-substituted maleimides.

enantiomer excess was (S)-9.7 % [49]. Specific rotations of the poly((RS)-MBZMI) obtained were relatively high, and the maximum [a]435 was þ188.2 . In the polymerizations of (S)-MBZMI and (S)-CEMI, which are chiral and optically active monomers, the formed polymers exhibited high specific rotations. In particular, poly((S)-MBZMI) prepared with Et2Zn–Sp in toluene showed a very high specific rotation of þ551.7 . Thus, polymerizations of chiral RMI are interesting and continuing investigations on the asymmetric polymerization of the RMI are desired now. Recently, Oishi and coworkers briefly reported on the polymerization of chiral (S)-N-maleoyl-L-leucine propargyl ester (S)-PLMI) and (S)-N-maleoyl-L-leucine allyl ester ((S)-ALMI) [50–52]. Because (S)-PLMI has one olefinic group in the maleimide ring and one ethynyl group in the N-substituent simultaneously, it can be polymerized under anionic, radical, and transition-metal–catalyzed conditions. Asymmetric anionic, radical, and transition-metal–catalyzed polymerizations were carried out using organometal/chiral ligands, 2,2’-azobisisobutyronitrile (AIBN), and (bicyclo[1, 2]hepta-2,5-diene) chloro rhodium (I) dimer ([Rh(nbd)Cl]2), respectively. Poly((S)-PLMI) obtained by [Rh(nbd)Cl]2 in DMF showed the highest specific rotation [a]435 of 280.6 . Chiroptical properties and structures of the polymers obtained were investigated by GPC, circular dichroism (CD), infrared (IR), and nuclear magnetic resonance (NMR) measurements. The chemoselective polymerization behavior of the monomer (S)-PLMI was found (Scheme 12.5). 12.6 STRUCTURE AND ABSOLUTE STEREOCHEMISTRY OF POLY(RMI) In our previous work, detail of the structure of poly(RMI) at the main chain was made clear by the investigation of 13 C NMR spectra. According to 13 C NMR studies on poly(CHMI) and model compounds of poly(CHMI), i.e., trans- and cis-3,4-dimethylN-cyclohexylsuccinimide (CHDMSI), methine carbons from the main chain of poly(CHMI) showed peaks at about 40 and 43 ppm assigned to trans configurations, namely, threo-diisotactic and threo-disyndiotactic structures, respectively [28, 29, 53]. Threo-diisotacticdiisotactic and threo-disyndiotactic structures of poly(CHMI) obtained with anionic initiators were assigned by comparing with the polymer

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SCHEME 12.5. Chemoselective polymerizations of chiral RMI-bearing polymerizable groups.

initiated by AIBN. The structure of poly(CHMI) obtained with radical initiators could be a threo-disyndiotactic configuration because of the smallest steric repulsion. The signal based on the poly(CHMI) main chain appeared only at 43.5 ppm in the 13 C NMR spectrum. The peak at the lower magnetic field of about 43 ppm for the poly(CHMI) initiated by the n-BuLi-(S,S)-Bnbox complex was assigned to threo-disyndiotactic structures. Another peak at the higher magnetic field of about 40 ppm was assigned to the threo-diisotactic structure. We found interesting polymerization results of poly(MBZMI) [43]. Specific rotations ([a]435) of the poly((S)-MBZMI) prepared by Et2Zn-Sp were þ20.5 to þ 466.2 . The poly((S)-MBZMI)s were partly insoluble in toluene or tetrahydrofuran (THF). Yields and specific rotations of the polymers obtained by Sp increased by long reaction periods. The poly((S)-MBZMI) growth-end very slowly and selectively attacks a monomer at low temperatures. Polymerization time exceeded 120 h, and specific rotations of the polymer’s THF-insoluble remarkably increased. Poly((S)-MBZMI) obtained 35  C for 144 h exhibited the highest positive specific rotation of þ466.2 . THF-insoluble parts of the polymer showed specific rotation ([a]435 ¼ þ 551.7 in CHCl3). Figure 12.6 shows X-ray diffraction (XRD) diagrams for poly((S)-MBZMI)s obtained with Et2Zn-Sp and AIBN. The width of XRD peaks is related to crystallinity degree [43]. A small crystallinity degree results in a broaden peak. A larger crystallinity degree leads to a narrow peak. XRD curves of poly((S)-MBZMI) obtained from AIBN showed no characteristic crystalline peaks, as shown in Figure 12.6(a), indicating that the polymers are not crystalline but completely amorphous. In these polymerizations, syndiotactic additions possibly took place, resulting in lower stereoregularity and specific rotations.

STRUCTURE AND ABSOLUTE STEREOCHEMISTRY OF POLY(RMI)

375

FIGURE 12.6. X-ray diffraction (XRD) diagrams for poly((S)-MBZMI).

However, with poly((S)-MBZMI)s having higher specific rotations, the THFinsoluble and THF-soluble parts exhibited crystalline peaks, as shown in Figure 12.6 (c and d). The peak of THF-soluble part (c) of the polymer showed a more disordered crystalline pattern than that of the THF-insoluble one (d). The crystallinity of the THF soluble part was relatively small. THF-insoluble parts had larger crystallinity,   and XRD exhibited two stronger peaks at 4.5 A and 8.0 A (11 and 18 deg). These results are consistent with those reported by Cubbon [13]. The poly(RMI) model made by Cubbon indicated threo-diisotactic polymers to form the 31 helix with a  repeat distance of 4.7 A regardless of the substituent on nitrogen. But the diameter of the helix varies with the substituent on the nitrogen. Our result suggests that part of the crystallinity in the polymer originated from the helix produced by the threodiisotactic configuration, as shown in Figure 12.7.

FIGURE 12.7. Highly ordered structures of poly((S)-MBZMI) such as helical conformations.

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The chiroptical properties of poly(RMI) could be attributed to threo-diisotactic structures, which originates from the excess of the chiral stereogenic centers (S,S) or (R,R). However, the absolute stereochemistry of the main chain has not been assigned yet. If the absolute stereochemistry of the main chain of the polymer is clarified, it will be possible to investigate the mechanism of asymmetric polymerization or to design the chiral ligands. Oishi and coworkers introduced a 1-naphthyl group into a maleimide ring as a chromophore to extend the applicability of the exciton-coupled circular dichroic method to configurational studies of optically active poly(1NMI) [54, 55]. Poly(1-NMI) prepared with n-BuLi-Bnbox, fluorenyl lithium (FlLi)-Bnbox, and Et2Zn-Bnbox showed [a]435 ¼ 18.7 , 36.8 , and þ190.5 , respectively. Figure 12.8 shows the CD and ultraviolet (UV) spectra attributing to 1 La [short axis; see Figure 12.8(a)] and 1 Bb [long axis; see Figure 12.8(b)] electron transition of naphthalene chromophore of poly(1-NMI) in THF. In the UV spectra, 1 La and 1 Bb transitions appeared as a maximum peak at 282 nm (emax ¼ ca. 7400) and 223 nm (emax ¼ ca. 53,000), respectively. Split CD spectra were observed around UV absorption bands on the basis of both transitions, and the magnitude of molar ellipticity depended on that of specific optical rotation. In Figure 12.8(a) (1 La ), (þ)-poly(1-NMI) ([a]435 ¼ þ 190.5 ) showed a positive first ([]284 ¼ ca. þ 4500 deg cm2 dmol1) and a negative second ([]260 ¼ ca. 4400 deg cm2 dmol1) Cotton effect. To the contrary, ()-poly(1-NMI) ([a]435 ¼ 18.7 ) showed a negative first ([]284 ¼ ca. 330 deg cm2 dmol1) and a positive second ([]260 ¼ ca. þ 330 deg cm2 dmol1) Cotton effect. These results indicate that (þ)- and ()-poly(1-NMI)

FIGURE 12.8. CD and UV spectra of poly(1-NMI): (1) [a]435 þ190.5 , (2) [a]435  18.7 , and (3) [a]435  36.8 in THF.

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377

possess a positive and a negative exciton chirality, respectively. In other words, the transition dipole moment of each naphthyl group exists clockwise for the (þ)polymer, and counterclockwise for the ()-polymer against the back from the front. However, a split CD pattern caused by the 1 La transition also reflects –(S, S)–(S, S)– or –(R, R)–(R, R)– sequences in threo-diisotactic structures because two chiral centers in the succinimide unit contain not an (S,R) or (R,S) pair but an (S, S) or (R, R) one, and the 1 La transition dipole moment is parallel to the C2 axis of the succinimide unit. Therefore, the CD pattern shows predominant absolute configurations of chiral centers in the threo-diisotactic main chains; namely, according to the exciton chirality method, it was clarified that (þ)-poly(1-NMI) main chains had more of the (S,S)- than the (R,R)-configuration, and ()-poly(1-NMI) main chains had more of the (R,R)- than the (S,S)-ones in threo-diisotactic structures. In Figure 12.8(b) (1 Bb ), the CD pattern was similar to the case of Figure 12.8(a) (1 La ). (þ)-Poly(1NMI) ([a]435 ¼ þ 190.5 ) exhibited a positive first ([]230 ¼ ca. þ 45,000 deg cm2 dmol1) and a negative second ([]220 ¼ ca. 34,000 deg cm2 dmol1) Cotton effect. ()-Poly(1-NMI) ([a]435 ¼ 36.8 ) exhibited a negative first ([]230 ¼ ca. 18,000 deg cm2 dmol1) and a positive second ([]220 ¼ ca. þ14,000 deg cm2 dmol1) one. The CD pattern of the 1 Bb transition represents no configurations of the polymer main chain but conformation of naphthyl groups; that is, the long axis of each naphthyl group of (þ)-polymer can form a clockwise conformation, and that of the ()-polymer can form a counterclockwise conformation. Furthermore, the similar relationship between the sign of specific rotation and the absolute stereochemistry of the main chain was observed in the case of optically active poly(1-NMI), poly(4benzoyloxyphenylmaleimide) (poly(4BzPhMI)) [56], poly(9-fluorenylmaleimide) (poly(9-FlMI)) [57] and poly(1-AMI) [33] (Figure 12.9). Judging from these results, the optical activities of poly(RMI) were attributed to differences between the (S,S)and the (R,R)-configuration in the threo-diisotactic structure. When poly(RMI) contains the (S,S)-configuration more than the (R,R)-configuration, specific rotations of polymers could show a positive sign (dextro). However, when poly(RMI) contains the (R,R)-configuration more than the (S,S)-configuration, specific rotations of polymers could show a negative sign (levo).

FIGURE 12.9. Relationships between absolute configuration of the main chain and specific rotation of poly(RMI) derivatives.

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ASYMMETRIC POLYMERIZATIONS OF N-SUBSTITUTED MALEIMIDES

12.7 ASYMMETRIC RADICAL POLYMERIZATIONS OF N-SUBSTITUTED MALEIMIDES Control of stereochemistry in free radical polymerization is an important goal in macromolecular science for polymer synthesis using radical catalysis in industry. Radical polymerizations of chiral RMI have been systematically studied by the authors. But the stereocontrolled polymerizations are very difficult. Nakano et al. recently reported on the asymmetric polymerization of CHMI and PhMI with chiral cobalt (II) complexes such as (R,R)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminatocobalt (II) (DBCCo) and induction of configurational chirality to the polymer [58–60]. Also, detailed mechanisms of the polymerization of CHMI with DBCCo were examined. However, the specific optical rotations of polymers were very low: 4 to 7 ([a]D, THF); accordingly, there is little possibility of asymmetric induction onto the polymer main chain. Asymmetric polymerizations of 1-NMI with AIBN and DBCCo were performed under several conditions to obtain chiral poly(1-NMI) with the maximum [a]D of þ36.5 in Scheme 12.6. The degree of asymmetric induction to the main chain decreased with enhancement of the molecular weight of the polymer. The conformation of poly(1-NMI) ([a]D þ36.5 ) obtained in toluene may be different from that in THF–pyridine ([a]D þ35.1 ) [61].

SCHEME 12.6. Asymmetric radical polymerizations of 1-NMI using chiral cobalt (II) complexes.

12.8 CHIRAL DISCRIMINATION USING POLY(RMI) Chiral recognition is one of the interesting functions exerted by an optically active polymer. Optically active polymers are used as a chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC). For example, the CSP prepared from optically active polymethacrylate derivatives bearing bulky substituents (Figure 12.10) developed by Okamoto et al. can optically resolve many racemates [1, 62–66]. These polymers can exert an optical resolution ability by a chiral, onehanded helical conformation. Polysaccharide derivatives (Figure 12.11) [67–74], which are prepared from natural polymers, can also provide excellent CSPs. Many CSPs derived from them are commercialized. Typical synthetic polymers with an

CHIRAL DISCRIMINATION USING POLY(RMI)

379

FIGURE 12.10. CSPs prepared from optically active polymethacrylate derivatives bearing bulky substituents.

excellent optical resolution ability were also developed by Okamoto et al. These polymers possess highly ordered structures such as helical conformations, which are effective in chiral recognition. However, there are only a few reports about chiral recognition or optical resolution using optically active poly(N-substituted maleimide) (poly(RMI)). In previous chapters, various optically active poly(RMI)s with aryl derivatives were prepared and characterized, and optical activities of the polymers were attributed to configurational chirality in addition to conformational one. These properties are useful for chiral discrimination. Chiral recognition abilities of optically active poly(RMI)s with several aryl derivatives and chiral substituents were characterized by 1 H NMR spectroscopy, which is very suitable for monitoring interaction mechanisms [75, 76]. The CSP was prepared from optically active poly(RMI) and macroporous silica gel. Optical resolution ability using the CSP was estimated by HPLC.

FIGURE 12.11. CSPs using polysaccharide derivatives for HPLC.

380

12.8.1

ASYMMETRIC POLYMERIZATIONS OF N-SUBSTITUTED MALEIMIDES 1

H NMR Titration

1

H NMR spectra were measured to obtain the information on chiral discrimination of optically active poly(RMI). 1 H NMR spectra of BINOL in the presence of optically active poly(1-NMI) ([a]435 ¼ þ 190.5 ) are displayed in Figure 12.12. Figure 12.12(a) shows the spectrum of only (RS)-BINOL. When optically active (þ)-poly(1-NMI) was added in the solution of (RS)-BINOL, signals due to the hydroxyl groups split into two peaks and sifted in the lower magnetic field, as shown in Figure 12.12(b and c). This indicates that optically active (þ)-poly(1-NMI) interacts with (R)- or (S)-BINOL by hydrogen bond, and the strength of interaction differs between two enantiomers of (RS)-BINOL. To clarify the enantiomer that strongly interacts with optically active (þ)-poly(1-NMI), (S)-BINOL was added in the solution of (RS)-BINOL and (þ)-poly (1-NMI) in CDCl3. The change of peak intensity of two hydroxyl groups revealed that optically active (þ)-poly(1-NMI) selectively and strongly interacts with (S)-BINOL by hydrogen bond. The hydrogen bond can be formed between carbonyl groups in the imide ring of poly(1-NMI) and hydroxyl groups in BINOL. Similar results were obtained in 1 H NMR spectra of the mixture of optically active (þ)-poly(PhMI), (þ)-poly(1-AMI), and (þ)-poly((5,6,7,8-tetrahydro)-1-naphthylmaleimide) ((þ)-poly (THNMI)) and BINOL; that is, both (þ)-poly(RMI) showed a selective interaction with (S)-BINOL. We explained that (þ)-poly(1-NMI) possesses more (S, S)-configurational main chains than (R, R)-configurational ones. On the basis of these concepts, a chiral

FIGURE 12.12. 1 H NMR spectra of BINOL in the presence of poly(1-NMI) in CDCl3.

CHIRAL DISCRIMINATION USING POLY(RMI)

381

FIGURE 12.13. The p–p stacking interaction of (S)-BINOL and poly(1-NMI).

discrimination mechanism is presumed as shown in Figure 12.13. Stereochemistry formed between succinimide units of (þ)-poly(1-NMI) is more suitable for (S)()-BINOL interposed by hydrogen bonds and p–p stacking interactions than for (R)-BINOL. Therefore, (þ)-poly(1-NMI) interacts more strongly with (S)()-BINOL than with (R)-BINOL. The p–p stacking interaction was scarcely observed in 1 H NMR spectra of the poly(PhMI)–BINOL, poly(1-AMI)–BINOL, and poly(THNMI)–BINOL systems because of low p–electron cloud in the N-substituents. 12.8.2 Optical Resolution Using Poly(RMI) To evaluate the optical resolution ability of optically active poly(RMI), poly(RMI) was coated on macroporous silica gel, as shown in Figure 12.14 Racemates using the HPLC estimation are listed in Figure 12.15. Those columns could resolve racemate 1, (RS)-BINOL. Typical chromatograms of HPLC are displayed in Figure 12.16. The top and the bottom chromatograms were

FIGURE 12.14. HPLC using optically active poly(RMI) as a chiral stationary phase (CSP).

382

ASYMMETRIC POLYMERIZATIONS OF N-SUBSTITUTED MALEIMIDES

FIGURE 12.15. Racemates using the HPLC estimation.

monitored by polarimetric and UV detectors, respectively. From the sign of the aHg chromatogram, the first-eluted enantiomer was (R)-(þ)-BINOL and the secondeluted enantiomer was (S)-()-BINOL. In Figure 12.16, (RS)-BINOL was optically resolved with a large separation factor and resolution. The column obtained by optically active poly(1-NMI) ([a]435 ¼

FIGURE 12.16. HPLC chromatograms of BINOL (1) on poly(RMI)–coated–silica gel column.

CHIRAL DISCRIMINATION USING POLY(RMI)

383

FIGURE 12.17. Optical resolutions using poly(RMI).

þ 195.2 ) could resolve only racemate 1 as well as the case of poly(PhMI). The firsteluted enantiomer was (R)-(þ)-BINOL, and the second-eluted enantiomer was (S)()-BINOL. This elution order reflected the selectivity confirmed in Figure 12.13; that is, the interaction force between (þ)-poly(1-NMI) and (S)-BINOL is stronger than that between (þ)-poly(NMI) and (R)-BINOL. The column prepared from highly optically active poly(1-NMI) ([a]435 ¼ þ718.6 ) could resolve many racemates, 3, 4, 11, 16, 27, 30–32, suggesting that the optical activity of the poly(1-NMI) is very important for the extension of optical resolution ability. This column optically resolved racemates 27, 30–32 containing an epoxy structure, but trans-stilbene oxide 26, which also has an epoxy ring, was not separated. This indicates that the carbonyl group adjacently connecting with the epoxy ring in racemates 27, 30–32 is very important for optical resolution using the CSP prepared from poly(1-NMI). We explored the relationship between optically active poly(RMI) bearing a chiral N-substituent group and chiral recognition abilities as CSPs for HPLC as shown in Figure 12.17. Among these two kinds of polymers, poly(R)-N-maleoyl-D-phenylglycine methyl ester) (poly(R)-MPGMI)) showed excellent optical resolution ability to many racemates. Optical resolution results using a poly(1-NMI)–coated–silica gel column are summarized in Table 12.2 [33, 34, 47, 48, 51, 52, 77–80]. The good optical resolution ability of (poly(RMI)) to varieties of racemates has mainly resulted from the stereoregular threo-diisotactic structure of the main chain of the polymer, and the asymmetric atmosphere of the side chain probably makes a contribution to the optical resolution. The coated-type CSPs are limited by the kinds of mobile phase solvent resulting from a dissolving chiral selector. Poly((S)-ALMI)s and poly((S)-PLMI)s bearing unsaturated functional groups such as an alkene or an alkyne group could react with alkoxysilane to produce the reactive intermediate via hydrosilylation reaction, as shown in Scheme 12.7. The obtained reactive intermediate could sequentially react with silica gel to afford “chemical-bonded-type” CSPs for HPLC. The chemicalbonded-type CSPs of the poly((S)-ALMI) or poly(S)-(PLMI) showed relatively high chiral resolution and had little limitation on the mobile phase [48, 51, 52].

384

ASYMMETRIC POLYMERIZATIONS OF N-SUBSTITUTED MALEIMIDES

TABLE 12.2. Optical resolution using a poly(RMI)-silica gel columna Run

Poly(RMI)

1 2 3 4 5 6 7 8 9 10 11 12

Poly(1-NMI) Poly(1-NMI) Poly((S)-MBZMI) Poly((S)-MBZMI) Poly((R)-CEMI) Poly((S)-CEMI) Poly((R)-MPGMI) Poly((S)-MPAMI) Poly((S)-MLMI) Poly((S)-PLMI) f Poly((S)-ALMI) f Poly((S)-ALMI) f

[a]435 (deg)

Mobile phase (v/v)

Racematesb No.

k1’c

ad

Rse

þ195.5 þ718.6 þ311.5 30.1 103.1 þ190.2 þ396.3 499.6 454.7 198.5 376.6 376.6

Hex/IPA (9/1) Hex/IPA (9/1) Hex/IPA (9/1) Hex/IPA (9/1) Hex/IPA (9/1) Hex/IPA (9/1) Hex/IPA (9/1) Hex/IPA (9/1) Hex/CHCl3 (9/1) Hex/CHCl3 (9/1) Hex/IPA (9/1) Hex/CHCl3 (9/1)

1 12 8 8 31 32 31 9 27 27 27 28

2.22 0.49 5.21 4.90 0.58 0.62 0.24 0.56 0.32 2.40 0.24 0.26

2.03 2.10 1.27

2.34 1.61 2.39

4.4 14.1 4.02 2.45 5.93 1.19 3.99 5.57

4.80 3.90 2.68 1.57 3.89 1.25 1.90 2.47

a

Hex: n-hexane, IPA: 2-propanol. Racemates: Figure 12.15. c Capacity factor for the first-eluted enantiomer: k1’ ¼ (t1  t0)/t0, dead time (t0) was determined with 1, 3, 5-tri-tert-butylbenzene. d Separation factor: a ¼ k2’/k1’. e Resolution: Rs ¼ 2 (t2  t1)/(w1 þ w2). f Chemical bonded type. b

SCHEME 12.7. Synthesis of chemical-bonded-type CSPs for HPLC.

12.9 CONCLUSIONS In this chapter, achiral and chiral RMIs were polymerized with different initiators to obtain optically active polymers. The optical activities of formed poly(RMI)s were strongly affected by initiators, N-substituents, solvents, and other polymerization conditions. Structures of poly(RMI) were investigated with 13 C NMR spectroscopy.

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The polymerization of RMI proceeded only with trans additional reactions. It was clear that optically active poly(RMI)s possess more threo-diisotactic structures. The absolute stereochemistry of the main-chain carbons of poly(1-NMI) was investigated from the CD exciton chirality method. According to this method, the (þ)- and ()-poly(1-NMI) main chain possessed more excessive (S, S)- and (R, R)-configurations in the threo-diisotactic structures, respectively. The chiroptical properties of the polymers could be attributed not only to configurational chirality of optically active N-substituent groups and main chain but also to a higher order structure such as helical conformation. Racemates could be resolved by the CSP synthesized by poly(RMI). On the basis of these results, the magnitude of optical activity of poly(RMI) was very important for the extension of optical resolution ability.

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CHAPTER 13

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS VIA OXIDATIVE CROSS-COUPLING POLYMERIZATION SHIGEKI HABAUE

13.1 INTRODUCTION The hyperbranched polymers and dendrimers are highly branched macromolecules having unique three-dimensional structures with a large number of terminal groups; therefore, have attracted considerable attention because of their interesting chemical and physical properties and potential applications [1–10]. In particular, the hyperbranched polymers are a polydispersed macromolecule with a randomly branched structure, and they can be easily produced on a large scale and by a one-step polymerization process using the ABx-type monomers (x
2), where the reaction between the A and B groups takes place. Compared with their linear analogs, the hyperbranched polymers possess a good solubility in organic solvents, lower viscosity, etc. [1, 2, 10]. Axially dissymmetric 1,1’-bi-2-naphthol derivatives are very important and versatile chiral auxiliaries, and they have been extensively used in asymmetric synthesis, catalyses, and resolutions. Polymers with binaphthol units are also interesting as functional chiral materials, and numerous reports can be found on their syntheses and applications [11–16]. For example, optically active 1,1’-binaphthyl-based polymers, as well as racemic ones, have been studied as electroluminescent materials because the conjugation length of a polymer could be controlled without inserting a nonconjugated spacer group into the polymer main chain [11, 15, 16]. From these points of view, there has been an intense interest in the preparation of the optically active binaphthols. The oxidative coupling reaction of the 2-naphthol derivatives is a facile and effective method for their synthesis, and many studies on

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.

389

390

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS

the homo- or self-coupling reaction with chiral metal catalysts, such as V(IV), Ru(II), and Cu(I), producing a symmetrical binaphthol skeleton have been reported [11–13, 17–24]. In contrast, there have been few reports on the synthesis of the binaphthol derivatives having an unsymmetrical framework through the catalytic cross-coupling reaction [25–29]. The oxidative coupling reaction of a 1:1 mixture of naphthol 1 and hydroxynaphthoate 2 can afford a mixture of the three coupling products, two of which are obtained by the homo-coupling of 1 and 2 (X and Z), respectively, and one by cross-coupling (Y) (Scheme 13.1). For example, Kozlowski et al. reported that the oxidative coupling reaction of 2-naphthol 1a and methyl 3-hydroxy-2-naphthoate 2a with the CuBF4-(S,S)-1,5-diaza-cis-decalin catalyst resulted in a poor yield (8%) of the cross-coupling product with an enantioselectivity of 72%ee (R) [30, 31]. We found that the oxidative coupling reaction between two differently substituted 2-naphthol derivatives, 1 and 2, with the CuCl-(S)-2,2’-isopropylidenebis(4-phenyl2-oxazoline) [(S)Phbox] (Scheme 13.2) catalyst at room temperature under an O2 atmosphere proceeded in a highly cross-coupling selective manner [32–34]. This method was further used for the polymerization of the 6,6’-dihydroxy-2,2’-binaphthalene-7-carboxylic acid derivatives as a monomer leading to a polymer with unsymmetrical binaphthol units [34–37]. The hyperbranched polymers have been mainly produced by polycondensation reactions [1, 2, 38–40]. However, there is no report on their synthesis via the oxidative coupling reaction of 2-naphthol derivatives, to the best of our knowledge. The aforementioned cross-coupling reaction could be successfully applied to the hyperbranched polymer synthesis. That is, the monomer has an AB2-type structure, where the naphthol and hydroxynaphthoate moieties correspond to the A and B

SCHEME 13.1. Oxidative coupling reaction between 1 and 2.

OXIDATIVE CROSS-COUPLING REACTION

391

SCHEME 13.2. Various ligands for copper catalyst.

groups, respectively, and cross-coupling–specific polymerization of this monomer can produce the hyperbranched structure with unsymmetrical binaphthol units [41]. 13.2 OXIDATIVE CROSS-COUPLING REACTION BETWEEN 2-NAPHTHOL AND 3-HYDROXY-2-NAPHTHOATE The results of the oxidative coupling reaction of 1 and 2 (1:1) using various Cu(I) catalysts in tetrahydrofuran (THF) under an O2 atmosphere are summarized in Table 13.1 [32, 33]. During the reaction between 1a and 2a with (þ)-1-(2-pyrrolidinylmethyl)pyrrolidine [(þ)PMP] (Scheme 13.2), which is known as the conventional TABLE 13.1. Oxidative coupling reaction between 1 and 2 with Cu catalysta Cross-coupling product (Y)

Run

1

2

Catalyst (equiv.)

Time (h)

Coupling ratiob X:Y:Z

3

yield (%)c

ee (%)d

1 2 3 4 5 6 7 8 9e 10f

1a 1a 1a 1a 1a 1a 1b 1b 1b 1b

2a 2a 2a 2a 2a 2b 2b 2b 2b 2b

CuCl-(þ)PMP (0.2) CuCl-()Sp (0.2) CuCl-(S)Phbox (0.2) CuCl-(S)Phbox (0.1) CuCl-(S)Phbox (0.01) CuCl-(S)Phbox (0.2) CuCl-(S)Phbox (0.2) CuCl-(S)Phbox (0.01) CuCl-(S)Phbox (0.05) CuCl-(S)Phbox (0.1)

48 5 3 6 24 3 3 24 48 72

2:38:60 6:94:<1 <1:96:4 0:97:3 0:>99:<1 5:86:9 13:85:2 12:86:2 11:87:2 13:85:2

3a 3a 3a 3a 3a 3b 3c 3c 3c 3c

9 14 87 82 79 72 73 71 70 44

2 (S) 74 (S) 10 (S) 8 (S) 8 (S) 55 (R) 65 (R) 67 (R) 70 (R) 74 (R)

Conditions: [1]/[2] ¼ 1/1, solvent ¼ THF, temp. ¼ rt, O2 atmosphere. Determined by 1H NMR analysis and isolated yields. c Isolated yield. d Determined by HPLC analysis (Chiralpak AD). e Temp. ¼ 0 C. f Temp. ¼ 40 C. a b

392

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS

SCHEME 13.3. Oxidative cross-coupling between 1 and 2 in the presence of Yb(OTf)3.

ligand for the copper catalyst of the asymmetric oxidative homo-coupling of the 2-naphthol derivatives [22], the homo-coupling product of 2a (Z) was predominantly afforded (run 1). The CuCl-()-sparteine [()Sp] complex preferentially produced a cross-coupling compound 3a with a selectivity of 94% but in a poor yield (run 2). These complexes did not work as the catalyst. In contrast, 3a was obtained in a good yield with a higher cross-coupling selectivity of 96%, when CuCl-(S)Phbox was used as the catalyst (run 3). However, the product showed a low enantioselectivity. With a decreasing molar ratio of the Phbox catalyst, the cross-coupling selectivity increased with almost no decrease in the yield and the enantioselectivity (runs 4 and 5). The oxidative coupling with 1.0 mol% of CuCl-(S)Phbox proceeded in a crosscoupling–specific manner with a 79% yield, demonstrating that the Phbox ligand is significantly effective for the cross-coupling of the 2-naphthol derivatives. The enantioselectivity during the cross-coupling reaction improved when the phenyl ester 2b was used as a substrate. The reaction between 1b and 2b produced a cross-coupling product 3c in a 65%ee (R) (run 7). By lowering the reaction temperature to 40 C, the enantioselectivity was further improved to 74%ee (R) (run 10). The structure of the ester on the substrate 2 and the substituent at the 3-position of 1 significantly affects both the cross-coupling and the stereoselectivities [32, 33]. The catalytic oxidative cross-coupling reaction of 2-naphthol derivatives was attained by using the CuCl-Phbox catalyst. However, we recently found that the a catalytic amount of a Lewis acid, such as ytterbium trifluoromethansulfonate [Yb(OTf)3], can further control the oxidative cross-coupling reaction between 1 and 2 with the copper catalyst (Scheme 13.3) [42–44]. For example, the oxidative coupling reaction of 1a and 2a (1:1) with the CuCl(OH)-N,N,N’,N’-tetramethylethylenediamine (TMEDA) [45, 46] (Scheme 13.2) in the presence of Yb(OTf)3 at room temperature under an O2 atmosphere proceeded in a cross-coupling–specific manner with a good yield, whereas the reaction in the absence of Lewis acid resulted in a low yield with the cross-coupling selectivity of 88%. In this novel binary catalyst system, the yields of the cross-coupling products, and stereoselectivities were significantly affected by the structures of both the copper and the Lewis acid catalysts [42–44]. 13.3 OXIDATIVE CROSS-COUPLING POLYMERIZATION AFFORDING LINEAR POLY(BINAPHTHOL) The catalytic oxidative cross-coupling reaction with CuCl-Phbox was used for the controlled synthesis of poly(binaphthol)s [35, 37]. The monomers, 6,6’-dihydroxy-

OXIDATIVE CROSS-COUPLING POLYMERIZATION AFFORDING

393

SCHEME 13.4. Oxidative coupling polymerization of 4.

2,2’-binaphthalene-7-carboxylate 4, which has both naphthol and hydroxynaphthoate moieties, were employed. The oxidative coupling polymerization of 4 produce a polymer, in which three different 1,1’-bi-2-naphthol units can exist, that is, two homo-coupling units (X and Z) and a cross-coupling one (Y) (Scheme 13.4). The completely random polymerization leads to a polymer with the unit ratio, X:Y:Z ¼ 25:50:25, whereas the polymer having a head-to-tail sequence structure is constructed via the cross-coupling–specific polymerization (X:Y:Z ¼ 0:100:0). The results of the oxidative coupling polymerization of 4 using the various copper catalysts, at room temperature for 24 h, are listed in Table 13.2. The polymerization with the TMEDA, (þ)PMP, and ()Sp catalysts afforded a methanol-ethyl acetate1 N HCl (2/1/0.3 v/v/v)-insoluble part with a relatively lower number average molecular weight (Mn) in low-to-moderate yields (runs 1–3, 5, 8, and 10) or resulted in no yield (run 6). The CuCl-(S)Phbox catalyst produced a polymer with a good

394

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS

TABLE 13.2. Oxidative coupling polymerization of 4 with Cu catalysta

Run

4

Catalyst

Yieldb (%)

1 2 3 4 5 6 7 8 9 10 11

4a 4a 4a 4a 4b 4b 4b 4c 4c 4d 4d

CuCl(OH)-TMEDA CuCl-(þ)PMP CuCl2-()Spg CuCl-(S)Phbox CuCl(OH)-TMEDA CuCl-(þ)PMP CuCl-(S)Phbox CuCl(OH)-TMEDA CuCl-(S)Phbox CuCl(OH)-TMEDA CuCl-(S)Phbox

55 81 22 71 (47) 62 0 91 (33) 27i 78i 81 95

Mn ( 103) (Mw/Mn)c 2.0 1.9 1.7 4.5 3.4 — 5.0 3.5 7.7 4.1 9.1

(1.3) (2.3) (1.3) (2.8)h (1.3) (1.8) (1.2) (1.3) (1.2) (2.3)

[a]Dd

Unit ratioe X:Y:Z

ee of Y-unitf (%)

— 16 19 þ20 — — 15 — þ40 — þ55

18:79:3 19:63:18 14:85:1 3:96:1 11:71:18 — 3:95:2 7:87:6 0:99:1 12:87:1 0:97:3

— 16 (R) 5 (R) 31 (S) — — 10 (R) 28 (S) — 30 (S)

Conditions: [4]/[catalyst] ¼ 1/0.2, solvent ¼ THF, temp. ¼ rt, time ¼ 24 h, O2 atmosphere. Methanol-ethyl acetate-1N HCl (2/1/0.3 v/v/v)-insoluble part. In parentheses, the values for the THFsoluble and methanol-insoluble part are given. c Determined by SEC in THF (polystyrene standard). d In THF at 25 C. e Estimated by 1H NMR analysis (DMSO-d6, 50 C). f Evaluated from the model coupling reaction. g [4]/[CuCl2]/[()Sp] ¼ 1/0.5/1, solvent ¼ methanol, N2 atmosphere. h Mn ¼ 1.2  104, determined by 1H NMR analysis. i Methanol-ethyl acetate-1N HCl (1/3/0.4 v/v/v)-insoluble part. a b

yield and an Mn value of
4.5  103 (runs 4, 7, 9, and 11). In particular, poly-4d, which showed an Mn of 9.1  103, is totally soluble in THF. The circular dichroism (CD) analysis of the obtained polymers showed that poly4a, poly-4c, and poly-4d obtained with the (S)Phbox catalyst were determined to be rich in the S-configuration, whereas the R-structure is preferentially constructed during the polymerization of 4b [6, 35, 37]. These results are in good agreement with those of the oxidative cross-coupling reaction of the corresponding 2-naphthol derivatives as shown in Table 13.1. The coupling ratio, X:Y:Z, was determined by the 1H NMR analysis of the hydroxyl absorption intensities, and the details will be described later for the hyperbranched polymers. The estimated coupling ratios are also shown in Table 13.2. For the polymerization with the (S)Phbox catalyst, the cross-coupling reaction predominantly proceeded with a coupling selectivity Y of
95%, which is much higher than that observed for the polymerizations with the TMEDA, (þ)PMP, and ()Sp catalysts. In particular, the polymer obtained from 4c showed the highest Y-selectivity of 99%. Accordingly, the poly(binaphthol) having an almost complete head-to-tail sequence structure was successfully constructed by the oxidative cross-coupling polymerization. The coupling stereoselectivity was evaluated by the oxidative coupling reaction of the model compounds, in which one hydroxyl group of the monomer is protected by

OXIDATIVE CROSS-COUPLING POLYMERIZATION AFFORDING

395

SCHEME 13.5. Model compounds 5-7 for poly-4.

the methoxymethyl group. The reaction can again afford two homo-coupling products, 5 (X) and 7 (Z), and one cross-coupling product, 6 (Y) (Scheme 13.5). The observed stereoselectivities for 6 obtained by the model reaction with the copper catalysts are also listed in Table 13.2. In every reaction with the Phbox catalyst, the corresponding cross-coupling compound 6 was produced in good yield (
67%) with a high selectivity (
89%). The obtained cross-coupling product having a phenyl ester group is rich in the R-configration (10%ee), whereas the others preferentially have the S-structure (28–31%ee). These results for the cross-coupling selectivity and the absolute configuration are similar to those observed for the polymerization, supporting the belief that the stereochemistry constructed during the polymerization should be controlled to a degree similar to that of the model reaction. However, the coupling reaction with (þ)PMP and ()Sp for 48 h resulted in a much lower cross-coupling selectivity [X:Y:Z ¼ 46:36:18 for (þ)PMP, 42:46:12 for ()Sp] than that observed for the polymerization. In these coupling reactions, the homo-coupling product 7 is the most unfavorable, based on the observed coupling selectivity. Therefore, during the first stage of the polymerization, both the homo-coupling unit X and the cross-coupling unit Y should be mainly produced, and then the cross-coupling reaction predominantly proceeds to afford polymers because the homo-coupling reaction leading to the unit Z hardly occurs. The observed stereoselectivities were lower than that observed for the reaction with the Phbox catalyst.

396

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS

13.4 OXIDATIVE CROSS-COUPLING POLYMERIZATION LEADING TO A HYPERBRANCHED POLYMER The triphenylamine derivatives 8–10 were synthesized, and the compounds 9 and 10 have both the naphthol and hydroxynaphthoate moieties (Scheme 13.6) [41]. Therefore, the cross-coupling–specific polymerization of these two monomers can construct a hyperbranched polymer structure, whereas the homo-coupling reaction can form a cross-linkage during the polymerization. The results of the oxidative coupling polymerization using the CuCl-Phbox catalyst at room temperature in THF under an O2 atmosphere are summarized in Table 13.3. During the polymerization of 8, the homo-coupling reaction between the 2naphthol units took place to afford a cross-linked polymer. The product yield increased with the increasing polymerization time, whereas the THF-soluble part of the obtained product significantly decreased (runs 1–3). For example, the 24 h polymerization resulted in a 94% yield, in which the product is almost insoluble in THF, and the THF-soluble fraction (2%) showed a low Mn value of 0.6  103 (run 3). During the polymerization of the monomer 9, the yield of the THF-soluble part and the Mn value of the obtained polymer were much higher than those observed for the polymerization of 8 (runs 4–6). For example, the 1 h-polymerization afforded a polymer in a good yield, whose THF-soluble fraction (46%) showed an Mn of 8.3  103 (run 5). However, the polymerization for 24 h produced a polymer including a large amount of the THF-insoluble fraction (run 6). Therefore, some cross-linking reaction, that is, the homo-coupling reaction in addition to the crosscoupling one, should occur during the polymerization of 9. In contrast, the polymerization of 10 having one naphthol and two hydroxynaphthoate moieties resulted in a high yield, in which the product is fully soluble in common organic solvents, such as THF and chloroform (runs 7 and 8). The polymer obtained by the 1 h polymerization showed an Mn of 1.02  104. These results

SCHEME 13.6. Monomers 8-9 for hyperbranched polymer synthesis.

OXIDATIVE CROSS-COUPLING POLYMERIZATION LEADING

397

TABLE 13.3. Oxidative coupling polymerization of 8–10 with CuCl-(S)Phboxa Run 1 2 3g 4 5 6g 7 8i

Monomer

Time (h)

Yieldb (%)

8 8 8 9 9 9 10 10

0.5 1 24 0.5 1 24 0.5 1

70 83 (27) 94 (2) 78 87 (46) 91 (15) 92 95

Mn ( 103) (Mw/Mn)c

[a]Dd

Unit ratioe X:Y:Z

3.1 (1.4)f 1.1 (—) 0.6 (—) 5.4 (1.9)h 8.3 (1.8) 1.2 (—) 4.8 (2.0) 10.2 (2.6)

29 — — þ65 þ74 — þ52 54

— — — 8:91:1 6:92:2 — 0:>99:0 0:99:1

Conditions: [monomer]/[catalyst] ¼ 1/0.1, solvent ¼ THF, temp. ¼ rt, time ¼ 24 h, O2 atmosphere. Methanol-1N HCl (9/1 v/v)-insoluble part. In parentheses, the values for the THF-soluble and methanolinsoluble part are given. c Determined by SEC in THF (polystyrene standard). d In THF at 25 C. e Estimated by 1H NMR analysis (DMSO-d6, 50 C). f Mn ¼ 1.0  104 (Mw/Mn ¼ 3.2), determined by MALLS in THF. g [Monomer]/[catalyst] ¼ 1/0.2. h Mn ¼ 6.7  104 (Mw/Mn ¼ 2.6), determined by MALLS in THF. i Catalyst: CuCl-(R)Phbox. a b

suggest that the polymerization of 10 should proceed in a highly cross-coupling selective manner. In poly-9 and poly-10, three different units, two homo-coupling units (X and Z) and a cross-coupling one (Y), can again exist (Scheme 13.7). The coupling ratio

SCHEME 13.7. Structure of hyperbranched polymer.

398

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS

FIGURE 13.1. 1H NMR spectra of hydroxyl protons of (a) poly-4d (Table 2, run 11), (a) poly-8 (Table 3, run 2), (b) poly-9 (Table 3, run 4), and (c) poly-10 (Table 3, run 7) (in DMSO-d6, 50 C).

X:Y:Z can be calculated from the 1H NMR analysis. Figure 13.1 demonstrates the 1 H NMR spectra of the hydroxyl protons region of the obtained polymers, together with that of poly-4d prepared with the Phbox catalyst. The internal and terminal hydroxyl protons with different chemical shifts appeared as shown in the figure. For example, the coupling selectivity of poly-4d was determined to be X:Y:Z ¼ 0:97:3 (Table 13.2, run 11). The estimated coupling ratios for the obtained polymers are also listed in Table 13.3. Poly-10 showed a Y-selectivity of 99% and higher (runs 7 and 8). Therefore, these polymers must consist of a hyperbranched structure. During the polymerization of 9, the cross-coupling reaction preferentially proceeded to produce

OXIDATIVE CROSS-COUPLING POLYMERIZATION LEADING

399

a polymer with a cross-coupling selectivity of 91–92% (runs 5 and 6), supporting the fact that the homo-coupling also took place to form a cross-linkage. A part of the poly-9 was then insoluble in common organic solvents. Because poly-10 has a nearly ideal hyperbranched polymer structure, the number average molecular weight can be calculated from the 1H NMR analysis. It was determined to be 6.2  103 (run 7) and 2.0  104 (run 8). These values were much higher than that estimated from the size exclusion chromatography (SEC) analysis. This result again indicates that the polymers obtained by the oxidative coupling polymerization of the monomer 10 have a spherical and hyperbranched structure. Figure 13.2 shows the CD spectra of the obtained polymers. The spectral pattern indicates that poly-8 is rich in the R-structure, whereas the S-configuration is predominantly constructed during the polymerization of the monomers 9 and 10. This result is similar to that observed for the oxidative coupling polymerization of the corresponding monomer 4d. Accordingly, the stereoselectivity during the oxidative cross-coupling polymerization with the CuCl-(S)Phbox catalyst may be controlled to a degree similar to that for the polymerization of 4d, which was estimated to be 30%ee (S) by the model coupling reaction.

FIGURE 13.2. CD spectra of (a) poly-8 (Table 3, run1), (b) poly-9 (run 4), and (c) poly-10 (run 7) (monomer unit, in THF).

400

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS

13.5 PHOTOLUMINESCENCE PROPERTIES OF HYPERBRANCHED POLYMERS To examine the UV-vis (UV) and fluorescence (FL) properties of the obtained hyperbranched-type polymers (Table 13.3, runs 1, 4, and 7), the acetylation of the hydroxyl groups was carried out to produce the acetylated polymers (Scheme 13.8): poly-8(Ac) (Mn ¼ 4.6  103, Mw/Mn ¼ 2.8), poly-9(Ac) (Mn ¼ 5.7  103, Mw/Mn ¼ 2.2), and poly-10(Ac) (Mn ¼ 5.7  103, Mw/Mn ¼ 1.8). Poly-4d (Table 13.2, run 11) was also acetylated to afford poly-4d(Ac) (Mn ¼ 1.5  104, Mw/Mn ¼ 4.3) (Scheme 13.9). The model compounds, 8(MOM), 9(MOM), 10(MOM), and 4d(Ac), for these polymers were also prepared (Scheme 13.10). The UV absorption and FL spectra of poly-4d(Ac) and its model 4d(Ac) in chloroform are shown in Figure 13.3 and Figure 13.4. The UV spectral patterns of these compounds were similar with a strong absorption around lmax ¼ 270 nm, whereas the FL spectral pattern of poly-4d(Ac) was different from that of 4d(Ac). Poly-4d(Ac) exhibited red-shifted and broadened emission bands. The FL spectrum of the poly-4d(Ac) film was also obtained, and the observed spectral pattern was similar to that of the dilute solution. These results suggest that the polymer forms an intermolecular excimer. The UVabsorption spectra of poly-10(Ac) and its model 10(MOM) in chloroform are depicted in Figure 13.5. The other polymers and models, such as poly-8(Ac), poly-9(Ac), 8(MOM), and 9(MOM), also showed similar spectral patterns, and these spectra showed two strong bands around 250 and 360 nm. Figure 13.6

SCHEME 13.8. Acetylated hyperbranched polymers.

PHOTOLUMINESCENCE PROPERTIES OF HYPERBRANCHED POLYMERS

401

SCHEME 13.9. Acetylated 4d and poly-4d.

demonstrates the FL spectra of the polymers and the model compounds measured at an excitation wavelength of 360–370 nm. In contrast to the FL behavior of poly-4d (Ac) and its model of 4d(Ac), the spectral patterns of the polymers, such as poly-8 (Ac), poly-9(Ac), and poly-10(Ac), were similar to that observed for each model

SCHEME 13.10. Methoxymethylated 8–10.

402

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS

FIGURE 13.3. UV absorption spectra of (a) poly-4d(Ac) and (b) 4d(Ac) (C ¼ 1.0  105 M, chloroform).

compound. Poly-8(Ac) and 8(MOM) showed an emission of blue light, whereas poly-9(Ac), poly-10(Ac), 9(MOM), and 10(MOM) exhibited an emission in the green region around 470 nm. The FL spectral pattern of the poly-9(Ac) film was also similar to that observed for the dilute solution. Accordingly, these results suggest that the intermolecular excimer formation hardly takes place because of the characteristic hyperbranched-type structure.

FIGURE 13.4. FL spectra of (a) poly-4d(Ac) (lexc ¼ 313 nm) and (b) 4d(Ac) (lexc ¼ 312 nm) (C ¼ 1.0  105 M, chloroform), and (c) poly-4d(Ac) (lexc ¼ 313 nm) (thin film)

.

CONCLUSIONS

403

FIGURE 13.5. UV spectra of (a) poly-10(Ac) and (b) 10(MOM) (C ¼ 1.0  105 M, chloroform).

FIGURE 13.6. FL spectra of (a) poly-8(Ac) (lexc ¼ 365 nm), (b) poly-9(Ac) (lexc ¼ 365 nm), (c) poly-10(Ac) (lexc ¼ 370 nm), (d) 8(MOM) (lexc ¼ 365 nm), (e) 9(MOM) (lexc ¼ 365 nm), (f) 10(MOM) (lexc ¼ 360 nm) (C ¼ 1.0  105 M, chloroform), and (g) poly-9(Ac) (lexc ¼ 363 nm) (thin film).

13.6 CONCLUSIONS A highly cross-coupling selective oxidative coupling reaction between 2-naphthol and 3-hydroxy-2-naphthoate derivatives using the CuCl-Phbox catalyst was developed. This reaction system was successfully used for the synthesis of poly(binaphthol) and the hyperbranched polymer with binaphthol units. The polymerization of the triphenylamine monomer having a naphthol and two hydroxynaphthoate

404

SYNTHESIS OF HYPERBRANCHED POLYMER HAVING BINAPHTHOL UNITS

moieties, with the CuCl-Phbox catalyst, proceeded in an almost cross-coupling– specific manner to afford a polymer with a hyperbranched structure, which is fully soluble in common organic solvents. The obtained polymer showed a characteristic FL property based on the hyperbranched structure, which was different from that observed for the corresponding linear polymer with binaphthol units.

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Gao, C.; Yan, D. Progr. Polymer Sci. 2004, 29, 183–275. Yates, C. R.; Haye, S.W. Eur. Polymer J. 2004, 40, 1257–1281. Zimmerman, S. C.; Lawless, L. Top. Curr. Chem. 2001, 217, 95–120. V€ogtle, F.; Gestermann, S.; Hesse, R.; Schwierz, H.; Windisch, B. Progr. Polymer Sci. 2000, 25, 987–1041. Gong, L.-Z.; Hu, Q.-S.; Pu, L. J. Org. Chem. 2001, 66, 2358–2367. Wyatt, S.R.; Hu, Q.-S.; Yan, X.-L.; Bare, W.D.; Pu, L. Macromolecules, 2001, 34, 7983–7988. Ma, L.; Lee, S.J.; Lin, W. Macromolecules, 2002, 35, 6178–6184. Satoh, N.; Nakashima, T.; Yamamoto, K. J. Ame. Chem. Soc. 2005, 127, 13030–13038. Imaoka, T.; Tanaka, R.; Arimoto, S.; Sakai, M.; Fujii, M.; Yamamoto, K. J. Ame. Chem. Soc. 2005, 127, 13896–13905. Yamanaka, K.; Jikei, M.; Kakimoto, M. Macromolecules, 2000, 33, 6937–6944. Pu, L. Chem. Rev. 1998, 98, 2405–2494. Putala, M. Enantiomer, 1999, 4, 243–262. Brunel, J.M. Chem. Rev. 2005, 105, 857–898. Pu, L. Macromol. Rapid Comm. 2000, 21, 795–809. Ma, L.; White, P.S.; Lin, W. J. Org. Chem. 2002, 67, 7577–7586. Jen, A.K.-Y.; Liu, Y.; Hu, Q.-S.; Pu, L. Appl. Phys. Lett. 1999, 75, 3745–3747. Irie, R.; Masutani, K.; Katsuki, T. Synlett, 2000, 1433–1436. Luo, Z; Liu, Q.; Gong, L.; Cui, X.; Mi, A.; Jiang, Y. Angew. Chem. Int. Ed. 2002, 41, 4532–4535. Somei, H.; Asano, Y.; Yoshida, T.; Takizawa, S.; Yamataka, H.; Sasai, H. Tetrahedron Lett. 2004, 45, 1841–1844. Habaue, S.; Murakami, S.; Higashimura, H. J. Polymer Sci.: Part A Polymer Chem. 2005, 43, 5872–5878. Murakami, S.; Habaue, S.; Higashimura, H. Polymer, 2007, 48, 6565–6570. Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.; Noji, M.; Koga, K. J. Org. Chem. 1999, 64, 2264–2271. Gao, J.; Reibenspies, J.H.; Martell, A.E. Angew. Chem. Int. Ed. 2003, 42, 6008–6012. Habaue, S.; Seko, T.; Okamoto, Y. Macromolecules, 2003, 369, 2604–2608. Hovorka, M.; G€unterova, J.; Zavada, J. Tetrahedron Lett. 1990, 31, 413–416.  cigel, R.; G€unterova, J.; Tichy, M.; Zavada, J. Tetrahedron, 1992, 48, Hovorka, M.; S 9503–9516.

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[27] Smrcina, M.; Lorenc, M.; Hanusˇ, V.; Sedmera, P.; Kocovsk y, P. J. Org. Chem. 1992, 57, 1917–1920.  Kocovsk [28] Smrcina, M.; Polakova, J.; Vyskocil, S.; y, P. J. Org. Chem. 1993, 58, 4534–4538.  Maca, B.; Polasˇek, M.; Claxton, T.A.; Abbott, A.P.; [29] Smrcina, M.; Vyskocil, S.; Kocovsky, P. J. Org. Chem. 1994, 59, 2156–2163. [30] Li, X.; Yang, J.; Kozlowski, M.C. Org. Lett. 2001, 3, 1137–1140. [31] Li, X.; Hewgley, J.B.; Mulrooney, C.A.; Yang, J.; Kozlowski, M.C. J. Org. Chem. 2003, 68, 5500–5511. [32] Temma, T.; Habaue, S. Tetrahedron Lett. 2005, 46, 5655–5657. [33] Temma, T.; Hatano, B.; Habaue, S. Tetrahedron, 2006, 62, 8559–8563. [34] Habaue, S.; Takahashi, Y.; Temma, T. Tetrahedron Lett. 2007, 48, 7301–7304. [35] Temma, T.; Habaue, S. J. Polymer Sci.: Part A Polymer Chem. 2005, 43, 6287–6294. [36] Temma, T.; Hatano, B.; Habaue, S. Polymer, 2006, 47, 1845–1851. [37] Temma, T.; Takahashi, Y.; Yoshii, Y.; Habaue, S. Polymer J. 2007, 39, 524–530. [38] Fukuzaki, E.; Nishide, H. J. Ame. Chem. Soc. 2006, 128, 996–1001. [39] Wu, C.-W.; Lin, H.-C. Macromolecules, 2006, 39, 7232–7240. [40] Li, Z.; Di, C.; Zhu, Z.; Yu, G.; Li, Z.; Zeng, Q.; Li, Q.; Liu, Y.; Qin, J. Polymer, 2006, 47, 7889–7899. [41] Temma, T.; Habaue, S. J. Polymer Sci.: Part A Polymer Chem. 2008, 46, 1034–1041. [42] Habaue, S.; Temma, T.; Sugiyama, Y.; Yan, P. Tetrahedron Lett. 2007, 48, 8595–8598. [43] Yan, P.; Sugiyama, Y.; Takahashi, Y.; Kinemuchi, H.; Temma, T.; Habaue, S. Tetrahedron, 2008, 64, 4325–4331. [44] Yan, P.; Temma, T.; Habaue, S. Polymer J. 2008, 40, 710–715. [45] Noji, M.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1994, 35, 7983–7984. [46] Nakajima, M.; Hashimoto, S.; Noji, M.; Koga, K. Chem. Pharm. Bull. 1998, 46, 1814–1815.

CHAPTER 14

OPTICALLY ACTIVE POLYKETONES KYOKO NOZAKI

14.1 INTRODUCTION Synthesis of polyketone by copolymerization of ethylene and CO was first reported in the 1950s via a radical process, providing copolymers with an ethylene/CO ratio of higher than one [1]. A completely alternating copolymer is produced when catalyzed by transition metal complexes [2]. For practical usage, ethylene/propylene/CO terpolymer, which is suitable for the melt process, is widely used rather than the ethylene/CO alternating copolymer whose melting point is almost as high as its decomposition temperature. Most widely used catalysts for this purpose are palladium complexes of the type [Pd(L^L’)(S)2][X]2, where L^L’ (L ¼ or 6¼ L’) is a cis-chelating bisphosphine ligand such as 1,3-propanediyl-bis(diphenylphosphine) (dppp), S is a solvent molecule, and X is an anion with low coordination capability. Additionally, an oxidant is often added to the dicationic palladium complexes in order to minimize the formation of inactive reduced palladium species [3, 4]. However, for styrene/CO copolymerization or for ethylene/styrene/CO terpolymerization, bis-sp2-nitrogen ligands, such as bipyridine or diimines, are suitable as the L^L’ in [Pd(L^L’)(S)2][X]2. Recently, several excellent review articles on the catalytic synthesis of olefin/CO copolymers have been published and include information on catalysts, substrates, and polymer performance [3–11]. Propylene/CO and styrene/CO copolymers possess side chains (methyl and phenyl groups, respectively); thus, multiple possibilities for regioisomers and stereoisomers exist. Several mechanistic studies have proposed that the key step that determines the regio- and stereochemistry of olefin/CO copolymers is olefin insertion into the acylpalladium species [5, 6]. Polymers with high regio-regularity are produced if the olefin-insertion reaction is regioselective to either 1,2- or 2,1addition. As shown in Scheme 14.1, propylene insertion is mostly 1,2-, whereas styrene insertion is usually 2,1-. For styrene/CO copolymerization, syndiotactic

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.

407

408

L2Pd

O

polymer

Me

2

Ph

L2Pd

L2Pd

2 Ph

O

1

O

1

polymer

2 Me

polymer

CO

CO

Ph 2,1-insertion chiral-catalyst control

chain-end control

Me 1,2-insertion chiral-catalyst control

L2Pd

L2Pd

L2Pd

O

Ph

O

O

Ph

O

O

O

Ph

polymer

Ph

polymer

Me

polymer Me

Ph

Ph

Ph

O O syndiotactic

Ph

Ph

O

Ph

O O O O isotactic, single enantiomer

Ph

O

Ph

O O O O isotactic, single enantiomer

SCHEME 14.1. Stereocontrols in the alternating copolymerization of propylene/CO and styrene/CO.

2,1-insertion

1

1,2-insertion

1

2

(c)

(b)

(a)

ASYMMETRIC SYNTHESIS OF ISOTACTIC POLY(PROPYLENE-ALT-CO)

409

copolymers are obtained if efficient chain-end control to the unlike (relevant to racemo) diad controls chain propagation (Scheme 14.1b). This is the case when achiral bis-nitrogen ligands, such as bipyridine or 1,10-phenanthroline, are employed. However, like (relevant to meso) diad predominates, originating from enantiofacial selection by the catalyst (enantiomorphic-site control). Using chiral catalysts that differentiate between the two olefin enantiofaces, isotactic copolymers are produced for both propylene/CO and styrene/CO (Scheme 14.1a and 14.1c)). Isotactic copolymers can also be produced using an achiral catalyst if efficient chain-end control prefers the like diad to the unlike diad. In fact, propylene/CO copolymerization catalyzed by Pd complexes containing 1,3-bis(diethylphosphino) propane [12] or bis(diarylphosphinomethyl)-1,2-phenylene ligands produces stereoregular, isotactic polyketones [13]. It should be noted, however, that this like selectivity might be attributed to the enantiomorphic-site control if the achiral ligands create chiral complexes upon their coordination [14]. The stereoregular olefin/CO copolymers reported to date are isotactic poly(propylene-alt-CO), isotactic poly(styrene-alt-CO), and syndiotactic poly(styrene-alt-CO) (Scheme 14.1a, Scheme 14.1b, and Scheme 14.1c, respectively). It should be noted that, differing from polypropylene or polystyrene, asymmetric centers exist in the main chain of the propylene/CO and styrene/CO copolymers. Thus, one enantiomer of a chiral catalyst should produce the corresponding enantiomer of the isotactic polyketone as long as stereoregularity originates from catalyst control (enantiomorphic-site control). In other words, optically active catalysts potentially produce optically active polyketones. Asymmetric synthesis polymerization is a reaction that produces polymers with configurational chirality in the main chain starting from achiral monomers [15, 16]. The alternating copolymers of a-olefin monomers with carbon monoxide possess true chiral centers in the polymer main chain, because of the absence of a plane of symmetry in a polymer chain. Accordingly, two enantiomers exist, namely RRRR--and SSSS---, for isotactic polyketones. Here in this chapter, examples of asymmetric synthesis polymerization to produce optically active polyketone will be discussed first in relation to the chiral catalysts. Then the properties of the chiral copolymers will be described. 14.2 ASYMMETRIC SYNTHESIS OF ISOTACTIC POLY(PROPYLENE-ALT-CO) The regioregularity and stereoregularity of poly(propylene-alt-CO) could be estimated by 13 C nuclear magnetic resonance (NMR) spectroscopy in the region of the carbonyl resonances [17]. The head-to-head (h-h) and the tail-to-tail (t-t) propylene enchainments exhibit peaks at 223 and 214 ppm, respectively, whereas the peaks around 218–219 ppm are attributed to the head-to-tail (h-t) structure. The sharpness of the d 219 peak, which corresponds to the like-like triad, provides an indication of the degree of isotacticity present in the polymer. It should be noted that high isotacticity does not necessarily mean high polymer enantiopurity, because both

410

OPTICALLY ACTIVE POLYKETONES

RRRR--- and SSSS--- chain segments can exist in the same polymer in amounts determined by the nature of its stereoerrors. Chiral ligands so far employed for asymmetric copolymerization of propylene with CO are summarized in Figure 14.1. The first attempted synthesis of isotactic poly (propylene-alt-CO) using an optically active ligand involved DIOP (1); however, the product was both regioirregular and stereoirregular [18]. In 1992, Consiglio succeeded in synthesizing of isotactic poly(propylene-alt-CO) using 6,6’-disubstituted-2,2’-bis (dialkylphosphino)-1,1’-biphenyl ligands such as 2. With this ligand, a completely alternating copolymer was obtained in 100% head-to-tail selectivity with 91% for the major peak at d 219) [19]. Ths use of chiral bisphosphine 2,4-bis(diphenylphosphino) pentane (3), provided isotactic copolymer [20]. Highly isotactic poly(propylene-altCO) was also produced using Pd complexes of chiral ligands 4 [21], 5 [22, 23], and 6 [24, 25]. Notably, not only the C2-symmetric ligands 1-4, but also C1-symmetric 5 and 6, efficiently produced the corresponding isotactic polyketone. The highest productivity for propylene/CO alternating copolymerization, 1797 g polyketone/g Pd h, has been reported using the catalyst system Pd(OAc)2/ligand 6/BF3OEt2 (OAc ¼ acetate) in CH2Cl2-MeOH at 50 C under 7.5 MPa of CO pressure (polymer Mn ¼ 14,000; >99% h-t; >97.5% for the major peak at d 219). For the asymmetric centers in the main chain of poly(propylene-alt-CO) prepared using a catalyst system containing ligand 2, almost complete enantioselectivity (preferential existence of one chain stereoisomer) was confirmed by 13 C NMR analysis using a chiral shift reagent [21]. Shorter units of the copolymer, which contains one propylene unit or two propylene units, were prepared by 2 [26] and by 5 [22, 23], respectively, with the results also supporting the exclusive formation of a single poly(propylene-alt-CO) enantiomer. (Figure 14.2). More practically, the molar absorption for the carbonyl group by circular dichroism (CD) can be used as an indicator for the enantioselectivity of the poly .

O

PPh2 PPh2

O

1

MeO

PCy2

MeO

PCy2

Cy = cyclo-C6H11 2

PPh2 PPh2

3 PCy2

P

PPh2

Me O

Fe PAr 2

O

Cy = cyclo-C6H11 Ar = 3,5- (CF3)2C6H3

O P P

4

5

6

FIGURE 14.1. Ligands used for the asymmetric alternating propylene/CO copolymerization.

ASYMMETRIC SYNTHESIS OF ISOTACTIC SYNDIOTACTIC POLY(STYRENE-ALT-CO)

2 1,4-benzoquinone (excess) + CO

411

O MeO

OMe O

(a)

O

85% selectivity >98%ee

P

NCCH3

+

P

CO

–

BAr4

Pd

OP

Me

OP

NCCH3 Pd Me

+ –

BAr4

O (b)

P

O Pd

OP P =5

+ –

BAr4

CO MeOH

O S

OMe

O 68% overall yield 95%ee (S)

OP

FIGURE 14.2. Determination of enantioselectivity for the asymmetric alternating copolymerization of propylene with CO: (a) the preparation of a dimer by chain transfer and (b) the preparation of a monomer by carbomethoxylation of alkyl palladium species.

(propylene-alt-CO) chain. High values, such as De þ1.73 with a catalyst system containing 4 [21] and De 1.66 with a catalyst system containing 5 [22, 23], were reported using (CF3)2CHOH as a solvent. Although the presence of higher order polymer structures, e.g., helical structures, would affect CD absorption, the absence of such structures was confirmed by comparing the CD spectrum of the polyketone with that of (S)-3-methyl-2,5-hexanedione, a single configurational unit analogue [27]. Accordingly, the molar absorption of poly(propylene-alt-CO) by CD can be taken as proportional to the enantiomeric excess of the asymmetric center in the main chain. 14.3 ASYMMETRIC SYNTHESIS OF ISOTACTIC SYNDIOTACTIC POLY(STYRENE-ALT-CO) The first styrene/CO alternating copolymers were obtained using [Pd(2,2’-bipyridine)(S)2][X]2 or [Pd(1,10-phenanthroline)(S)2][X]2 complexes as catalysts where S is a solvent, mainly methanol, and X is a noncoordinating anion [28–30]. Remarkably, using these planar symmetrical ligands, the product poly(styrene-alt-CO) was regioregular and prevailingly syndiotactic with a triad selectivity of uu:ul:lu:ll ¼ 0.80:0.10:0.10:0. The triad stereochemical composition can be estimated by 13 C NMR peak using the enchained styrene ipso-carbon peak at 136.1 [19]. For copolymers of para-substituted styrenes with CO, the peaks from the main-chain

412

OPTICALLY ACTIVE POLYKETONES

Ph O

O

O N

N

N i-Pr

i-Pr

N

N

i-Pr

i-Pr

7

N

O

Ph

8

9

O

O N

N

Ph

N

P

Ph

CH2OMe

10

11

FIGURE 14.3. Ligands used for the asymmetric alternating styrene/CO copolymerization.

carbons at d 43.2 (CH2), 54.0 (CH), 209.7 (C¼O) are used to discuss the stereoregularity because there are two ipso-carbons for the substituted styrenes. Brookhart and Wagner first reported on the asymmetric alternating copolymerization of 4-tert-butylstyrene with carbon monoxide using [Pd(Me)(MeCN)(7)] [BAr4] (Ar ¼ 3,5-(CF3)2C6H3), a methylpalladium catalyst containing a chiral bisoxazoline ligand [31]. The ligands employed for the isotactic copolymerization of styrenes with CO are summarized in Figure 14.3. In this copolymerization, the enantioface of the olefin was selected by the chiral ligand instead of the chain-end; as a result, the polymer was completely isotactic. Because one enantioface was discriminated against the other by the chiral catalyst, it is probable that the copolymer is also of high enantiopurity. Bidentate sp2-nitrogen ligands, such as 8, 9, and 10, are most commonly used [20, 32–34], along with the phosphine-nitrogen bidentate ligand 11 [35, 36] and phosphinephosphite 5 (Figure 14.1) [22, 23]. The enantioselectivities for styrene/CO copolymerizations were mostly estimated by molar optical rotation [F]D or CD De. By now, [F]D ¼ 536 for 4-tertbutylstyrene/CO using a catalyst system [Pd(Me)(MeCN)(7)][BAr4] [31] and De ¼ 11.75 for styrene/CO using a catalyst Pd(Me)(MeCN)(11)[BAr4] [37] are the highest reported values. A few studies involving the synthesis and characterization of oligomeric species have also been reported. Based on NMR analysis, Consiglio et al. revealed that styrene insertion into the acylpalladium complex [(11)Pd(C(¼O)Me) (MeCN)]þ(OTf) (OTf ¼ OSO2CF3) is both completely regioselective for 2,1-insertion and enantioselective, producing [(11)Pd(CHPhCH2C(¼O)Me)]þ(OTf) as a single species [38, 39]. This result is consistent with the fact that dimethyl (R)-2phenylbutanedioate was obtained almost exclusively as the S enantiomer (95%ee) when styrene/CO copolymerization with [(11)Pd(Me)(MeCN)]þ(OTf)- was carried out in the presence of a high concentration of the oxidant, benzoquinone. It is noteworthy that only low-molecular-weight oligoketones can be obtained with bisphosphine ligands in alternating styrene/CO copolymerizations. Drent and Budzelaar have attributed this fact to the higher electron density on the Pd center

ASYMMETRIC TERPOLYMERS CONSISTING OF TWO KINDS OF OLEFINS

413

when phosphine ligands rather than nitrogen ligands are used because the growing styrene/CO copolymer has a higher tendency to terminate by b-hydride-elimination than growing propylene/CO chains [6]. The unusual fact that a high copolymer can be prepared with catalyst systems [(5)Pd(Me)(MeCN)]þ[B(3,5-(CF3)2-C6H3)4]- is proposed to be attributable to the steric demand of this bulky ligand, which causes styrene to undergo 1,2-insertion rather than the more typical 2,1-insertion [40]. The continuous 1,2-insertion provided the h-t polyketone with high enantiofacial selection ([F]D ¼ 451). 14.4 ASYMMETRIC TERPOLYMERS CONSISTING OF TWO KINDS OF OLEFINS AND CARBON MONOXIDE Using a mixture of two kinds of olefins, a terpolymer can be generated by alternating olefin/CO copolymerization. An olefin and carbon monoxide are incorporated in a completely alternating manner, and the order of the two olefins is mostly random. Asymmetric terpolymerization of styrene/ethylene/CO has been intensely studied by Consiglio et al. [32, 37, 41]. Using [(11)Pd(CH3)(MeCN)]þ(OTf)- as a catalyst, ethylene was preferentially and randomly enchained in the terpolymer, despite the comparably higher reactivity of styrene for the copolymerization. The enantioselectivity for styrene in the terpolymerization is as high as that observed for the styrene/ CO copolymerization. Asymmetric terpolymerization of propylene/ethylene/CO with Pd–bisphosphines such as Pd(OAc)2/2/Ni(ClO4)2/1,4-naphthoquinone, [(7)Pd(Me)(MeCN)]þ[B(3,5(CF3)2-C6H3)4]-, or [(8)Pd(Me)(MeCN)]þ[B(3,5-(CF3)2-C6H3)4]- (ligands 2, 5, and 6 are in Figure 14.1) also provide a terpolymers in which the two olefins are incorporated in a random manner [20, 42]. By changing the partial monomer pressures, the propylene/ethylene unit-ratio (CH2CHMeC(¼O))/(CH2CH2C(¼O)) in the terpolymer was varied. The molar ellipticity De per chiral unit, -CH2CHMeC (¼O)-, as measured by CD, was essentially the same as for poly(propylene-alt-CO). Two examples have been reported of asymmetric 1-alkene/styrene/CO terpolymerizations, which involve catalyst systems incorporating either phosphine-phosphite ligand 5 [43] or bisoxazoline 7 [44]. Propylene and 1-hexene were employed as the 1-alkene. Successive enantiofacial selection for both styrene and 1-alkene produced the like-rich terpolymer. The stereoregularity was estimated by optical rotation values. With phosphorus-based [(5)Pd(Me)(MeCN)]þ[B(3,5-(CF3)2-C6H3)4]-, propylene was preferably incorporated into the terpolymer over styrene, whereas styrene was preferentially incorporated when nitrogen-based [(7)Pd(Me)(MeCN)]þ[B(3,5-(CF3)2C6H3)4]- was employed. A stereoblock copolymer consisting of isotactic and syndiotactic 4-tert-butylstyrene/CO alternating copolymer was prepared by Brookhart and Wagner [45]. First, copolymerization was initiated by using a Pd catalyst containing chiral bisoxazoline 7 to produce the isotactic block. Subsequently, the addition of 2,2’bipyridine to the system resulted in ligand replacement, so that the second block (formed by further copolymerization) was syndiotactic (Scheme 14.2).

414

OPTICALLY ACTIVE POLYKETONES

isotactic +

2,2'bipyridine

Ar Ar

Ar

isotactic

syndiotactic

Ar

Ar

Ar

Ar

Me (7)Pd NCMe

O

Ar = 4-tert-Bu-C6H4

O

n-1

Pd(7) 7

O

O

n

O

O

m

SCHEME 14.2. Synthesis of a stereoblock 4-tert-butylstyrene/CO alternating copolymer by sequentially using two different ligands at the Pd center.

14.5 ASYMMETRIC POLYMERIZATION OF OTHER OLEFINS WITH CO Because palladiumcatalysts are tolerant to various functional groups, alternating olefin/CO copolymers with polar-functionalized olefin units are accessible (Figure 14.4). Sen et al. have reported that alternating Pd-catalyzed copolymerization proceeds with alkenes having hydroxyl and carboxylic groups using ligand 4 [46]. For the products, highly isotactic copolymer is suggested by 13 C NMR. Mono-epoxides of nonconjugated dienes are also employable as the olefin moiety [47]. The introduction of a fluorine atom into the olefin side chain, such as CH2¼CH-CH2-C6F5 or CH2¼CH-CH2-C4F9, affords fluorinated polyketones with 4 [48] or with 5 [49, 50]. The stereoregularity of the fluorinated copolymers thus obtained was as high as that was produced with simple 1-alkene/CO. Fluorinated isotactic polyketones show a higher tendency to form polyspiroketals (vide infra) as compared with their hydrocarbon analoges. a,w-Dienes can also be used as the alkene comonomer for olefin/CO copolymerization; in this instance, cyclocopolymerization proceeds if the two C-C double bonds are separated by an adequate distance. Thus, cyclocopolymerization has been reported for 1,5-hexadiene [51] and 1,4-pentadiene (Scheme 14.3) [52]. In both examples, complete cyclization has been achieved. When a chiral catalyst is employed for the copolymerization of CO with a cyclopolymerizable diene, the R

O R=

n

-(CH2)8COOH, -(CH2)2CHCH2O, -CH2C6F5, -(CH2)2C4F9, etc.

FIGURE 14.4. Copolymers from functionalized olefins and CO.

O m

+ CO

Pd catalyst m

O

n

m = 1 or 2

SCHEME 14.3. Cyclocopolymerization of an a,w-olefin and CO.

CHEMICAL TRANSFORMATIONS OF OPTICALLY ACTIVE POLYKETONES

415

Pd(dba)2/ PR2 SO3H

FG + CO

R = 2-MeOC6H4or cyclo-Hex

FG

O

n

FG = -OC(=O)CH3, -COOCH3

SCHEME 14.4. Completely alternating copolymerization of vinyl acetate/CO and methyl acrylate/CO.

first olefin insertion takes place via catalyst-controlled enantiofacial selection. After a CO insertion, the second olefin insertion takes place in an intramolecular manner; the cis/trans relative configuration between the two substituents on the resultant cycloalkanone is not controlled completely. More recently, completely alternating olefin/CO copolymerization has been achieved starting from vinyl acetate [53] and methyl acrylate [54] employing a phosphine-sulfonate ligand (Scheme 14.4). For this polymerization, however, chiral ligand has not been applied, yet. 14.6 CHEMICAL TRANSFORMATIONS OF OPTICALLY ACTIVE POLYKETONES Chemical transformation of optically active polyketone opens a new route to various functionalized optically active polymers. The optically active polyketone derived from propene/CO copolymerization has a chilarity center at the a-position of each carbonyl group. It is of much interest whether the configuration is maintained under the reaction conditions. In addition, another interest focuses on the diastereoselectivity when a chirogenic center is newly created in the main chain through the chemical transformations. Diastereoselective reduction of poly(propene-alt-CO), a g-polyketone, was reported using metal hydride reagents. Using tetrabutylammonium borohydride as a reductant, (S)-poly(propene-alt-CO) was reduced into the corresponding polyol with the S/R ratio of 70/30 for the absolute configuration of the newly created chirogenic center (Scheme 14.5(a)) [55]. The local structure was determined by the unambiguous synthesis of four diastereomers of 3-methyl-2,5-hexanediol. Comparison of 13 C NMR spectrum of the polyol with those of the model diols indicated that no epimerization occurred on the a-carbon atoms. The S-selectivity contradicts the conventional Cram-selectivity with which R-configuration is predicted. Considering that free rotation around the C–C bond between the carbonyl carbon and the a-carbon is a prerequisite for the Cram rule, the present S-selectivity should be attributed to the restricted free rotation around the C–C bond. Baeyer–Villiger oxidation of the (S)-polyketone with m-chloroperbenzoic acid provided poly(ketone/ester) in a ratio of ketone/ester ¼ 82/18 in 73% isolated yield

416

OPTICALLY ACTIVE POLYKETONES

S/R up to 70/30 Bu4N•BH4 S

S

n

CH2Cl2 rt, 9 d

O

*

n

OH

quantitative

O

mCPBA n

CH2Cl2 rt, 4 d

O

O

x

y

O

73% isolated yield x/y= 82/18

CH2(ZnI)2-TiCl3 n

O

THF-CH2Cl2 rt

x

y

O

78% isolated yield x/y = 96/4

SCHEME 14.5. Chemical transformation of (S)-poly(propylene-alt-CO): (a) reduction of ketones, (b) oxidation of ketones, and (c) methylenation of ketones. All transformations took place without epimerization at the a-carbon stereogenic center.

(Scheme 14.5(b)) [56]. An ester unit likely exists to distribute randomly in the product rather than to form a block copolymer of a polyketone and a polyester. This was suggested by methanolysis of the product polymer to produce oligomers rather than methyl 3-hydroxybutyrate. Because poly((R)-3-hydroxybutyrate) (PHB), the ester part of the current polymer, is a well-known biodegradable polymer [57], further improvement of this oxidation is highly desired. The carbonyl group could be transformed into a C-C double bond. The methylenation of the (S)-polyketone using an organozinc-titanium reagent, CH2(ZnI)2– TiCl3, provided the corresponding methylenated polymer (Scheme 14.5(c)) [58]. The reaction proceeded without any significant epimerization, and the product was highly isotactic. The products, a new class of hydrocarbon polymers with main-chain chirality, are attainable only by this transformation but not by any other methods, such as ring-opening polymerization of 2-alkyl-1-methylenecyclopropanes. 14.7 CONFORMATIONAL STUDIES ON THE OPTICALLY ACTIVE POLYKETONES Depending on the reaction conditions, poly(propylene-alt-CO)s can be isolated as either the true polyketone, poly(1-methyl-2-oxo-propanediyl), or as a polyspiroketal, poly[spiro-2,5-(3-methyltetrahydrofuran)] (Figure 14.5) [59]. The latter polymer can

CONFORMATIONAL STUDIES ON THE OPTICALLY ACTIVE POLYKETONES

OH- O

O

O

H+

O

O O

O

HO

O

O

417

OH

O OOOO O OO OOO O

FIGURE 14.5. Polyketone under equilibrium with polyspiroketal. This phenomenon is unique for a highly isotactic copolymer generated from propene or other higher aliphatic 1-alkenes. The helical conformation of the main chain may be responsible for the spiroketal formation.

be transformed into the thermodynamically more stable polyketone either thermally or by dissolution in (CF3)2CHOH (abbreviated as HFIP) [12, 21]. There are no solvents other than HFIP that stabilize the polyketone form, and the reason is not clarified, yet. Because of their isotactic nature, the formation of helical conformation can be anticipated for optically active polyketones. However, by optical rotation [21] or CD [27, 60], no evidence has yet been obtained indicating the presence of a stable helical conformation in solution. Meanwhile, an extended conformation has been estimated for isotactic poly(propene-alt-carbon monoxide) by static light scattering measurements, and it might correspond to a helical structure [27]. In one of the possible helical conformations, a carbonyl oxygen of a polyketone comes close to the neighboring carbonyl carbon, and this may result in the formation of spiroketal (Figure 14.5). A larger population of spiroketal structures was reported for polyketones bearing fluorine atoms in the side chain [49, 50, 61]. This might be attributed to the preferable helical conformation for fluorinated side chains because a larger space is available for the side to avoid the electrostatic repulsion between the side chains. In a solid amorphous state, a helical structure has been suggested below the glass-transition temperature for an optically active methylstyrene/1-decene/CO terpolymer [44]. At a certain temperature above the glass-transition temperature, the molar ellipticity of a film drastically decreases, whereas the molar ellipticity in solution does not. A single enantiomer of a side-chain, liquid-crystalline polyketone forms a chiral nematic phase, and this might be attributed to a helical structure of the main chain [62]. The ketal formation is unique for highly isotactic copolymers generated from propylene or other higher aliphatic 1-alkenes. A helical structure was suggested by

418

OPTICALLY ACTIVE POLYKETONES

N N

N N

O

O

(CH2)4 O

O (CH2)4

(CH2)4 n

O

3m

O

(a)

N N

m

(b) 2.0

before irradiation

0.8

Absorbance

0.4

Δε

before irradiation

after irradiation after 4 h under visible light

0

-0.4

after irradiation after 4 h under visible light

1.5

1.0

0.5

-0.8 240

290

340

390

440

Wavelength (nm)

490

530

0 240

290

340

390

440

490

530

Wavelength (nm)

FIGURE 14.6. Alternating copolymer of a-olefin having an azobenzene side chain with CO in a pure polyketone form and a 3:1 mixture of polyspiroketal and polyketone. The strong Cotton effect around 340 nm in CD spectrum is attributed to the helical orientation of the azobenzene moiety in the polyspiroketal structure.

CD spectrum for a spiroketal having azobenzene side chains. Asymmetric alternating copolymerization of CH2¼CH-(CH2)4-O-C6H4-N¼N-C6H5 with CO provided a 3:1 mixture of polyspiroketal and polyketone upon reprecipitation from methanol and CHCl3. A strong Cotton effect of the azobenzene moiety around 340 nm was indicative of the helical orientation of the azobenzene moiety in the polyspiroketal structure (Figure 14.6) [63]. In crystalline states, the conformation of the polyketone has been well investigated. The crystal structure of poly(ethene-alt-CO) in well-oriented fibers (a-structure) was determined by wide-angle X-ray scattering methods [64]. The cross-sectional area of the unit cell perpendicular to the fiber axis amounts to 0.352 nm2, which is even smaller than the polyethylene unit cell (0.362 nm2). The very dense packing is a result of the arrangement of the dipoles in the crystal lattice, giving rise to strong lateral forces between the polymer chains. In an imperfectly alternating copolymer, the b-crystal was formed [64], whereas the a-crystal was formed in a perfectly alternating copolymer [65]. Both crystalline structures have two polymer chains in an all-trans conformation along the c-axis, but the chain packing is different. The a-structure has denser packing than the b-structure. Klop et al. showed that the a-form was dominant in the perfectly alternating copolymer at room temperature and that the phase transition from a to b was observed at 110–125 C [66]. Crystallization from the melt on slow cooling to room temperature

CONCLUSIONS

419

TABLE 14.1. Melting points of isotactic polyketones and their stereocomplexes Copolymer (þ)- or ()-propene–CO ()-propene–CO complex (þ)- or ()-1-butene–CO ()-1-butene–CO complex (þ)- or ()-allylbenzene–CO ()-allylbenzene–CO complex (þ)-propene–CO/()-1-butene–CO

mp (T m)/ C 171 239 137 265 62 169 230

produces the a-phase [67], whereas rapid cooling affords the b-phase [67]. Only one example has been reported for the crystal structure of the alternating propene–CO copolymer. A high-molecular-weight propene–CO copolymer with random regioand stereoregularity exhibits elastomeric behavior [68]. A 31 helical structure was proposed by an X-ray investigation of an elastic film of the copolymer at 650% elongation [69]. For syndiotactic poly(styrene-alt-CO), a nearly trans-planar conformation with tc glide plane symmetry is suggested [70]. In contrast, a s(2/1) helical conformation was confirmed for isotactic optically pure poly(styrene-alt-CO), by powder X-ray diffraction [71, 72]. The observed chain conformation has a repeat period almost identical to that observed in syndiotactic polyketone despite the different symmetry connecting the monomeric units, s(2/1) instead of tc. It has been known that blending two polymers with the same chemical composition but a different stereochemical sequence produces a polymer–polymer stereocomplex, occasionally [73–75]. A stereocomplex was suggested to be formed from racemic mixtures of enantiomeric polyketones (Table 14.1) [76]. Optically pure (þ)- and ()-poly(1-alkene-alt-CO) were prepared from propene, 1-butene, and allylbenzene using Pd–(S)-Me-DUPHOS and its enantiomer. For all three kinds of polyketones, the higher Tm was observed for a 1:1 mixture of (þ)- and ()- poly(1-alkene-alt-CO) when compared with optically pure (þ)- or ()- poly-(1-alkene-alt-CO). Furthermore, chiral recognition and the stereocomplexation between two different polyketones, such as (þ)-propene/CO and ()-1-butene/CO, were confirmed. 14.8 CONCLUSIONS The isotactic polyketone has an asymmetric center in the main chain. Thus, asymmetric synthesis, that is, the production of one enantiomer of the isotactic polyketone by use of the corresponding enantiomer of a chiral catalyst, has been achieved. The reaction is applicable to variety of olefins, such as propylene, styrene, and various olefins with functional groups. Chemical transformation of the carbonyl groups in the optically active polyketone allowed formation of another class of

420

OPTICALLY ACTIVE POLYKETONES

optically active polymers. The isotactic polyketone tend to undergo reversible isomerization to a spiroketal structure, which may be related to the helical structure of the optically active polyketones. REFERENCES [1] Reppe, W.; Magin, A. U.S. Patent 2, 577, 208, December 4, 1951. [2] Drent, E. European Patent 0121965 B1 (Shell Internationale Research Maatschappij B. V.), December 27 1989. [3] Sen, A. Acc. Chem. Res. 1993, 26, 303. [4] Drent, E.; Van Broekhoven, J. A. M.; Doyle, M. J. J. Organomet. Chem. 1991, 417, 235. [5] Sen, A. (Ed.). Catalytic Synthesis of Alkene-Carbon Monoxide Copolymers and Cooligomers, Kluwer Academic, Dordrecht, the Netherlands (2003). [6] Drent, E.; Budzelaar, P. H. M. Chem. Rev. 1996, 96, 663. [7] Sommazzi, A.; Garbassi, F. Prog. Polymer Sci. 1997, 22, 1547. [8] Nozaki, K.; Hiyama, T. J. Organomet. Chem. 1998, 576, 248. [9] Abu-Surrah, A. S.; Rieger, B. Top. Catal. 1999, 7, 165. [10] Bianchini, C.; Meli, A. Coord. Chem. Rev. 2002, 225, 35. [11] Robertson, R. A. M.; Cole-Hamilton, D. J. Coord. Chem. Rev. 2002, 225, 67. [12] Bronco, S.; Consiglio, G.; Hutter, R.; Batistini, A.; Suster, U. W. Macromolecules 1994, 27, 4436. [13] Sesto, B.; Consiglio, G. J. Chem. Soc. Chem. Comm. 2000, 1011. [14] Camalli, M.; Caruso, F.; Chaloupka, S.; Leber, E. M. Rimml, H.; Venanzi, L. M. Helv. Chim. Acta 1990, 73, 2263. [15] Okamoto, Y.; Nakano, T. Chem. Rev. 1994, 94, 349. [16] Nakano, K.; Kosaka, N.; Hiyama, T.; Nozaki, K. Dalton Trans. 2003, 4039. [17] Batistini, A.; Consiglio, G.; Suter, U. W. Angew. Chem., Int. Ed. Engl. 1992, 31, 303. [18] Wong, P. K. European Patent 0384517 B1 (Shell Internationale Research Maatschappij B. V.), January, 18, 1995. [19] Barsacchi, M.; Batistini, A.; Consiglio, G.; Suter, U. W. Macromolecules 1992, 25, 3604. [20] Jiaing, Z.; Adams, S. E.; Sen, A. Macromolecules 1994, 27, 2694. [21] Jiang, Z.; Sen, A. J. Am. Chem. Soc. 1995, 117, 4455. [22] Nozaki, K.; Sato, N.; Takaya, H. J. Am. Chem. Soc. 1995, 117, 9911. [23] Nozaki, K.; Sato, N.; Tonomura, Y.; Yasutomi, M.; Takaya, H.; Hiyama, T.; Matsubara, T.; Koga, N. J. Am. Chem. Soc. 1997, 119, 12779. [24] Gambs, C.; Chaloupka, S.; Consiglio, G.; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 2486. [25] Gambs, C.; Consiglio, G.; Togni, A. Helv. Chim. Acta 2001, 84, 3105. [26] Sperrle, M.; Consiglio, G. J. Am. Chem. Soc. 1995, 117, 12130. [27] Kosaka, N.; Nozaki, K.; Hiyama, T.; Fujiki, M.; Tamai, N.; Matsumoto, T. Macromolecules 2003, 36, 6884.

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CHAPTER 15

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS FROM PHENYLACETYLENES TOSHIKI AOKI, TAKASHI KANEKO, and MASAHIRO TERAGUCHI

15.1 INTRODUCTION p-Conjugated polymers such as polymers from phenylacetylenes have attracted much more attention among numerous scientists and engineers than other conventional polymers like vinyl polymers because they offer many possible useful properties owing to their p-electrons such as electric conductivity, optical nonlinear susceptibility, electroluminescence, molecular magnetism, photoluminescence, and so on. A famous p-conjugated polymer is nonsubstituted polyacetylene, its wellknown electrically conductive polymer discovered by Professor Shirakawa who received the Nobel Prize for Chemistry in 2000. The chemical structure of this p-conjugated polymer, which is synthesized by addition polymerization of acetylene [1], is simple, allowing for no variation. To introduce variations such as functional groups and chiralities into the structure and to improve the properties of the nonsubstituted polyacetylene, other synthetic methods (i.e., new monomers and new initiators) have been developed by excellent researchers (e.g., Prof. Masuda and Prof. Grubbs and Prof. Schrock who received the Nobel Prize for Chemistry in 2005). Therefore, the availability of many kinds of conjugated polymers has been increasing. In particular, new initiators of addition polymerizations of substituted acetylenes, including phenylacetylenes, were intensively studied by Masuda et al. [2]. In this chapter, the synthetic methods of two types of chiral p-conjugated polymers are described from phenylacetylenes we reported on. One is the p-conjugated polymer obtained by the addition polymerization of substituted phenylacetylenes that contains alternating double bonds in the backbone and are usually called “substituted poly(phenylacetylene)s” (the systematic name is “substituted poly (1-phenylvinylene)s”) (Scheme 15.1a). The other type of p-conjugated polymer from 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.

423

424

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

(a) Addition polymerization n H

Ph H

Phenylacetylene

Ph n

Ph- = phenyl group

Poly(phenylacetylene) (b) Condensation polymerization n H

Ph

X

Ph n

Halophenylacetylene Poly(phenyleneethynylene) -Ph- = phenylene group

SCHEME 15.1. Synthesis of two types of chiral polymers from phenylacetylenes: (a) by addition polymerization of phenylacetylenes and (b) by polycondensation of halophenylacetylenes.

phenylacetylenes is obtained from halo-substituted phenylacetylenes by condensation polymerization (Scheme 15.1b). In this case, the substituted phenylacetylene monomers need to have a halogen atom present on the aromatic ring. The resulting p-conjugated polymers, which contain alternating triple and double bonds, also can be called “substituted poly(phenylacetylene)” but usually are called by their systematic name, “substituted poly(phenyleneethynylene)s” (Scheme 15.1b). The polymers are also synthesized from two monomers—dihalobenzene and diethynylbenzene [3, 4]. Poly(phenylacetylene)s prepared by addition polymerization by using a rhodium complex as an initiator have highly controlled chemical structures, such as a high ciscontent and helical main chains. In addition, if the helical sense of the p-conjugated polymers is controlled, then the polymer backbone itself becomes optically active. Such one-handed helical polymers were researched by Akagi [1] and Yashima et al. [5]. The backbone chirality of the p-conjugated polymers can be detected directly by measuring their circular dichroism (CD) behavior because the main chain itself is a chromophore. The synthetic methods of chiral poly(phenylacetylene)s by the addition polymerization that we reported will be mentioned in Section 15.2. Poly(phenyleneethynylene)s can also form precise molecular architectures, such as foldamers, macrocycles, and dendrimers, through control of the linkage position of the aromatic units. In addition, if the helical senses of the foldamers are controlled, then the polymer backbones themselves become optically active. The description of synthesis of chiral poly(phenyleneethynylene)s by condensation polymerization is included in Sections 15.3.2.2 and 15.4.2. These unique chiral p-conjugated polymers could have possibly many kinds of functions. For example, they can be used as chiral catalysts (Section 15.2.4.1) or as optical resolution membranes (Section 15.2.4.2). In addition, the polymers that have a unique regulated structure can react in a topochemical manner (Section 15.2.4.3).

HELIX-SENSE-SELECTIVE POLYMERIZATION

425

Chapter 15 describes the author’s investigation into synthesis and the properties of chiral p-conjugated polymers from phenylacetylenes (i.e., poly(phenylacetylene)s and poly(phenyleneethynylene)s).

15.2 HELIX-SENSE-SELECTIVE POLYMERIZATION (HSSP) OF SUBSTITUTED PHENYLACETYLENES AND FUNCTION OF THE RESULTING ONE-HANDED HELICAL POLY(PHENYLACETYLENE)S 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 There are two main synthetic methods to obtain chiral polymers by addition polymerization of phenylacetylenes. They are asymmetric-induced polymerization (AIP) and helix-sense-selective polymerization (HSSP), which we found first as shown in Scheme 15.2. In this chapter, AIP is mentioned concisely in Sections 15.2.1.1, 15.2.2.4, 15.3.2.1, and 15.4.2 because some other reviews are available [1–5], whereas HSSP is explained more precisely in Sections 15.2.2–15.2.4 and 15.4.3 because the method, which we reported first [12], is unique and no reviews on this subject have been published. 15.2.1.1 AIP of Chiral Phenylacetylenes. In this section, monomers suitable for AIP of chiral substituted acetylenes containing chiral phenylacetylenes that we

Asymmetric-induced polymerization(AIP) HC C

Bulky chiral group

Polymerization

Achiral catalyst

Chiral monomer

One-handed helical polymer with chiral groups Chiral polymer

T. Aoki et al., Chem. Lett., 2009(1993), Macromolecules, 29, 4192(1996), Macromolecules, 32, 79(1999), J. Polym. Sci., A40, 1689(2002).

Helix-sense-selective polymerization(HSSP) HC C

? Achiral monomer

Polymerization

One-handed helical polymer without chiral groups

Chiral catalyst

Chiral polymer

T. Aoki et al., J. Am. Chem. Soc., 125, 6346(2003), Chem.Lett., 34, 854(2005), Macromolecules, 40, 7098(2007). Macromol. Chem. Phys., 210, 717(2009). Macromolecules, 42, 17(2009). Polymer, 51, 2460(2010).

SCHEME 15.2. Concepts of AIP and HSSP of poly(phenylacetylene)s.

426

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

reported [6–11] are discussed. During the course of an investigation into the synthesis of a new enantioselective permeability membrane material, the authors accidentally discovered an AIP in which a one-handed helical chirality was induced in the main chain during polymerization of a phenylacetylene with a bulky chiral L-menthoxycarbonyl group, p-{L-(-)-menthoxycarbonyl}phenylacetylene [6]. The polymer could be fabricated into a self-supporting membrane that showed a CD spectrum similar to that of the solution. The membrane showed enantioselectivity in permeation. After this discovery, the authors synthesized and polymerized many other phenylacetylenes that had a chiral substituent to check whether any main-chain chirality was induced. As a result, many chiral monomers were suitable for the the AIP, and the resulting chiral polymers were applicable to optical resolution membranes as shown in Scheme 15.3. For example, the homopolymrs of (-)-p-(dimethyl(10-pinanyl)silyl)phenylacetylene obtained with a Rh complex showed strong CD absorptions similar to that of p-{L-(-)-menthoxycarbonyl}phenylacetylene [6], whereas p-{L-(-)-2-methylbutylcarbonyl}phenylacetylene and p-{tetramethyl-3-(10-pinanyl)disiloxanyl}phenylacetylene showed weak CD absorptions [4]. The position and size of the chiral substituents is important for asymmetric induction in AIP. Interestingly, the homopolymers of (-)-p-(dimethyl(10-pinanyl)silyl)phenylacetylene prepared using WCl6 showed much weaker CD absorptions than those prepared by a Rh complex [4]. (-)-o-(Dimethyl(10-pinanyl)silyl)phenylacetylene was synthesized and polymerized using WCl6 [4, 6]. The resulting polymer with a pinanylsilyl group at the ortho position showed weak CD absorptions similar to poly((-)-p-(dimethyl(10-pinanyl)silyl)phenylacetylene) prepared with WCl6. Poly((-)-p-(dimethyl(10-pinanyl)silyl)phenylacetylene)s made using a rhodium complex had a high cis content, whereas those made with WCl6 did not. Therefore, cis-trans regularity was an important factor for making one-handed chiral conformations.To investigate the effects of the chemical structures of the chiral groups, including the number and position of the chiral groups in the monomers, on the induction of chirality in the main chain during polymerization and on the degree of enantioselectivity in the permeation of the polymeric membranes, oligosiloxanylphenylacetylenes with one or two bulky chiral pinanyl groups at the 1-, 3-, and/or 5-position CH3

CH3 CH3 Si

n

R CH3 Si

Pi

n

CH3

CH3

*

Si CH3 n

Pi

CH3

R- = -H, -CH 3, -C 6H5 H

CH3 CH3 Si O Si CH3

n

R1

R2

*

Pi- =

*

R1- = -Pi, -CH 3, R 2- = -CH3, -Pi

SCHEME 15.3. Examples of one-handed helical poly(phenylacetylene)s with chiral pendant groups for optical resolution membranes prepared by AIP.

HELIX-SENSE-SELECTIVE POLYMERIZATION

427

of an oligosiloxane chain were polymerized with a Rh complex to produce high molecular weight polymers [8]. With the exception of polymers with bulky substituents, polymers with a chiral pinanyl group at the 1-position of an oligosiloxanyl group showed high molar ellipticity in the main-chain region in the CD spectra. The exceptional polymers with bulky substituents had ultraviolet (UV)-vis absorptions at longer wavelengths. However, the polymers from monomers with a chiral pinanyl group at the 3- or 5- position of an oligosiloxanyl group showed almost no CD absorptions. The flexible Si-O spacer did not transmit the chiral information to the main chain [8]. Although the polymers of p-{pentamethyl-1,3-bis(10-pinanyl) trisiloxanyl}phenylacetylene and p-{tetramethyl-1,3,5-tris(10-pinanyl)trisiloxanyl} phenylacetylene had a pinanyl group at the 1 position, they showed almost no CD absorptions. In this case, their UV-vis absorptions shifted to longer wavelengths than those of the corresponding polymers that had disiloxanyl groups. However, the case of polyphenylacetylenes with a branched oligopinanylsiloxane(p-[tris{dimethyl(10pinanyl)siloxy}silyl]phenylacetylene) showed CD absorptions despite not having pinanyl group at the 1-position. This may be because their bulky substituents changed the main-chain structure. Other than the phenylacetylenes described, the polymerization of other chiral disubstituted acetylenes (Scheme 15.3) by using another catalyst such as WCl6 yielded chiral p-conjugated polymers with one-handed helical main chain. The detail of modified AIP, AIP followed by polymer reaction in membrane state (RIM) we developed to obtain one-handed helical poly(phenylacetylene)s that do not have chiral pendant groups is described in Section 15.3. 15.2.1.2 HSSP of Achiral Phenylacetylenes. As described in the previous section (15.2.1.1), chiral-substituted polyphenylacetylenes have been synthesized by polymerization (AIP) of monomers with bulky chiral substituents. However, after the chiral side groups were removed by hydrolysis or reduction, the resulting polymer did not show CD absorptions in the main chain region in solution. A chiral helical nonsubstituted polyacetylene had been synthesized by polymerization of acetylene in a chiral nematic reaction field [1]. However, there were no reports of obtaining chiral helical substituted polyacetylenes that had no other chiral moieties in the side or end groups. Therefore, in Section 15.2, we describe details of HSSP that can produce onehanded helical substituted poly(phenylacetylene)s that had no other chiral moieties in the side and end groups. 15.2.2 HSSP of Three Types of Monomers (RDHPA, RDAPA, and RDIPA, Scheme 15.4a) The authors have found a simple and novel synthetic method (HSSP) for obtaining such a chiral polymer from an achiral substituted acetylene monomer using a chiral catalytic system. In addition, the helical conformation was stable in solution. This is the first example of helix-sense-selective polymerization of substituted acetylenes whose chiral helicity is stable in solution without the aid of other chiral substituents or other small molecules [12].

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

428 (a)

OH OC12H25

OH HC

C

OR

OH

: RDHPA

O

OH

HC

C

OH CH3 CH3 CH3 Si O Si O Si CH3 CH3 CH3 CH3

O

R'

OR C N

OH

:RDAPA

HC

C

C(CH3)3

O C(CH3)3

OR'

OR N

:HGPA C(CH3)3

:RDIPA OR'

C(CH3)3

OH

(b) O

OCH3 HC

C

OR

:1 HC

OCH3

N C C

N C

C12H25

C O

C12H25

:4

O

R'

OR

C O C

H O

HC

:2 HC

R'

OH

NH

C

:5

H O CH3 N HC

: S3BDHPA

R'

O H

N

: DoBDHPA

OC12H25

OH

O H C N

: DoDHPA

OH

OR

C

CH3 :3

N

OR

HC

Si

C CH3

OH OC12H25

Si

:6

OH

CH3 R-, R'- = alkyl group

SCHEME 15.4. Monomers (a) suitable and (b) unsuitable for HSSP.

HELIX-SENSE-SELECTIVE POLYMERIZATION

429

In Section 15.2.2, the method of HSSP we found first as well as the monomers suitable for HSSP are discussed [12–22]. Modification of HSSP is also discussed in Section 15.2.3 [23–25]. In Section 15.2.4, application of HSSP is described. 15.2.2.1 HSSP of Phenylacetylenes Having Two Hydroxyl Groups (RDHPA) [12, 13, 17–19]. The authors polymerized an achiral phenylacetylene that had two hydroxyl groups (RDHPA, Scheme 15.4a) and a dodecyloxy (DoDHPA, Scheme 15.4a), a dodecyloxybenzyl (DoBDHPA, Scheme 15.4a), or hexamethyltrisiloxanylbenzyloxy group (S3BDHPA, Scheme 15.4a) using a chiral catalytic system consisting of a rhodium dimeric complex, [Rh(nbd)Cl]2 (nbd¼2,5norbornadiene), as a catalyst and a chiral amine, (R)-1-phenylethylamine (R)PEA), as a cocatalyst. All polymers showed Cotton effects at wavelengths around 430 nm and 310 nm where there are no UV absorptions of RDHPA and (R)-PEA (Figures 15.1 and 15.2). The absorption band at 430 nm is assigned to the conjugated main chain, and the peak at 310 nm may result from a chiral position between adjacent pendant groups. The intensity of the band at 430 nm was similar, and the peaks at 310 nm were a little stronger compared with other one-handed helical poly(phenylacetylene)s that had chiral side groups prepared by AIP. Therefore, the authors realized the first HSSP of a substituted acetylene using a chiral catalyst. However, no helix-sense-selective polymerizations occurred in the case of achiral phenylacetylenes, a monomer with two methoxy groups instead of two hydroxyl groups (1, Scheme 15.4b), and p-trimethylsilylphenylacetylene, which does not have any hydroxy groups (Scheme 15.4b). The polyphenylacetylene without chiral substituents derived from the chiral homopolymer prepared by AIP showed no CD in solution. However, the chiral structure of polyDoDHPA was stable in chloroform at room temperature for 5 months. Moreover, even when the solution was heated to 50  C, almost no change was detected in the CD. This stability may be caused by intramolecular hydrogen bonds between hydroxy groups in different monomer units. To confirm this theory, the authors

FIGURE 15.1. CD and UV-vis spectra of one-handed helical polyphenylacetylenes prepared by HSSP of RDHPA. (A): a: poly(S3BDHPA), b: poly(DoBDHPA) prepared by using (R)-PEA in chloroform at 20  C; (B): poly(S3BDHPA) prepared by using (S)-PEA in DMSO/CHCl3 having different contents (vol.-%) of DMSO (a: 0, b: 9, c: 23, d: 33, e: 44, f: 50, g: 52); (C): poly (DoBDHPA) prepared by using (R)-PEA in DMSO/CHCl3 having a different content(vol.-%) of DMSO (a: 0, b: 5, c: 10). Riprinted from [19]. Copyright(2009), with permission from Elsevier.

430

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

35000

[θ]deg . cm2/dmol)

a b c d

20000

e

e

0

a b c d

ε (l . mol –1 . cm–1)

-20000 12000 a

5000

e b cd

0 265 300

400

500

600

Wavelength (nm)

FIGURE 15.2. Change of CD and UV-vis spectra of one-handed helical polyphenylacetylenes prepared by HSSP of DoDHPA in various solvents: (a) in CCl4, (b) in CCl4/DMSO(50/1), (c) in CCl4/DMSO(30/1), (d) in CCl4/DMSO(20/1), and (e) in CCl4/DMSO(10/1). (Reprinted with permission from [12]. Copyright 2003 American Chemical Society.)

measured CD and infared (IR) data in various two-component solvents that have different polarities. As the content of the polar dimethyl sulfoxide(DMSO) solvent component increased, the CD signal became smaller and then disappeared (Figures 15.1 and 15.2). At the same time, the OH absorption at 3300 cm1 shifted to a longer wavelength, indicating that the hydrogen bonds had weakened [12]. Therefore, the intramolecular hydrogen bonds were effective in stabilizing the chiral structure. The authors have also examined the role of the chiral amine cocatalyst in HSSP. Several chiral amines were effective for the polymerization reaction, and their effectiveness depended on their bulkiness and ability to coordinate to rhodium. To determine the structure of the true active species in the catalytic system, the authors have synthesized a new chiral rhodium complex that has two chiral amines as ligands ([Rh(nbd) ((R)-PEA)2]þBF4). The isolated chiral complex also catalyzed the helix-sense-selective polymerization. These findings suggest that a chiral rhodium complex that has two chiral amines may be the true active species when using the catalytic system consisting of [Rh(nbd)Cl]2 and a chiral amine [13]. 15.2.2.2 HSSP of Phenylacetylenes Having Two Amido Groups (RDAPA) [20, 21]. It was of interest to see whether acetylene monomers other than RDHPA, could be adapted for HSSP. To achieve such a polymerization of other

HELIX-SENSE-SELECTIVE POLYMERIZATION

431

achiral monomers by the chiral catalytic system, new achiral phenylacetylenes with two N-alkyamido groups (RDAPA, Scheme 15.4a) were designed as monomers. The N-alkylamido groups in RDAPA were thought to play an important role, causing the formation of intramolecular hydrogen bondings between the amido groups. Consequently, the polyRDAPA obtained using the chiral catalytic system showed Cotton signals in CD measurements. This result proved that the monomer with two amide groups could polymerize in a helix-sense-selective fashion. To confirm the importance of hydrogen bonding for this helix conformation, a polar solvent was added to the CD solution once again. As a result, the CD intensity of polyRDAPA decreased significantly. A homopolymer of another achiral phenylacetylene (Scheme 15.4b), that has two alkyl ester groups (4 in Scheme 15.4b) that cannot make hydrogen bonds instead of N-alkylamido groups was obtained in a similar chiral condition but showed no CD signal. From the previous experiments, it became clear that the hydrogen bonds in the helix conformation of the polyRDAPA are crucially important [20, 21] similar to that of polyRDHPA. Although some monomers have two groups that can make hydrogen bonds, such as two N-phenylamido groups (2) instead of N-alkylamido groups in RDAPA and two hydroxysilyl groups (6), they were not suitable for HSSP. This finding suggests that the position of the functional groups that can make hydrogen bonds is important to maintain a one-handed helical conformation in the resulting polymers. In addition, because a monomer with only one hydroxyl group that can make hydrogen bonds (5) was not suitable for HSSP, two groups that can make hydrogen bonds per monomer were necessary. In summary, monomers such as ethers (1 and 3) and ester (4) derivatives, which were not suitable for HSSP, do not have functional groups that can make hydrogen bonds. However, because we found that some monomers with no functional groups making hydrogen bonds were suitable for HSSP, they are described in Section 15.2.2.3. 15.2.2.3 HSSP of Phenylacetylenes Having Two Imino Groups (RDIPA). All aforementioned monomers suitable for HSSP need functional groups that can make hydrogen bonds. However, some HSSP active monomers do not have such functional groups like RDIPA [22] and HGPA [14] as shown in Scheme 15.4a. These monomers cannot make hydrogen bonds but do have a bulky substituent that may keep an one-handed helical conformation. In these RDIPAs, long alkyl chains were necessary to yield soluble one-handed helical polymers and to avoid exchange reactions during polymerization described in Section 15.2.3.2. The requirement of bulky groups for HSSP active monomers is not clear at present, and only a few examples are available so far [14–16]. The details of other examples are described in Section 15.4.3. 15.2.2.4 AIP of Chiral Phenylacetylenes Followed by Removing the Chiral Groups by RIM. Other than HSSP, which can produce one-handed helical poly(acetylene)s without the coexistence of any other chiral groups, we found another method referred to as modified AIP. After obtaining one-handed helical

432

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

poly(substituted acetylene)s with many chiral pendant groups by AIP, the chiral groups were removed completely by RIM (polymer reaction in membrane state). The detail is described in Section 15.3. As another example of RIM, selective cycloarmatization (SCAT) is described in 15.2.4.3. 15.2.3 Modified HSSP 15.2.3.1 Self HSSP (SHSSP). In Section 15.2.2 on HSSP, we described only achiral monmers such as RDHPA. Now we will describe new chiral RDHPA-type monomers that have two hydroxyl groups and a chiral group(R). Three novel chiral RDHPA-type monomers, phenylacetylenes that have a chiral octyloxyethylaminomethyl or hydroxyethylaminomethyl group derived from an L-aminoalcohol and two hydroxymethyl groups, were synthesized and polymerized by two achiral catalysts (nbd)Rhþ[h6-(C6H5)B(C6H5)3] and [Rh (nbd)Cl]2/triethylamine (TEA) as well as a chiral catalytic system ([Rh(nbd)Cl]2/ (S)- or (R)-phenylethylamine ((S)- or (R)-PEA)). All the resulting polymers showed Cotton effects at wavelengths around 430 nm. This observation indicated that they had an excess of one-handed helical backbones. Positive and negative Cotton effects were observed for the polymers (poly(RVDHPA)) with an L-valinol residue produced by using (S)- and (R)-PEA as a cocatalyst, respectively, although the monomers had the same chirality (Scheme 15.5a). However, the two polymers (poly(RPDHPA) and poly(RADHPA), which have L-phenylalaninol residue or an (a) OH

*

HSSP

NH

O

OR

Chiral catalytic system

OH AIP Achiral catalyst RVDHPA

(b)

OH

* NH

O OH

OR

No HSSP

AIP Achiral catalyst

RPDHPA R- = -H or alkyl group

SCHEME 15.5. Monomers (a) suitable and (b) unsuitable for both HSSP and AIP.

HELIX-SENSE-SELECTIVE POLYMERIZATION

(a)

433

(b)

OH

CH3

*

NH

O OH

N

OH

N

OH

OR

RADHPA R- = -H or alkyl group

SCHEME 15.6. Monomers suitable for modified HSSP: (a) SHSSP and (b) PHSSP.

L-alaninol residue obtained by using (S)- and (R)-PEA as a cocatalyst, showed CD absorptions with identical signs (Scheme 15.5b)). Therefore, we found that the chiral monomer with an L-valinol residue(RVDHPA) was suitable for both modes of asymmetric polymerization (i.e., HSSP with the chiral catalytic system and AIP with the achiral catalysts (Scheme 15.5a)) [23]. However, the other monomers that have an L-phenylalaninol residue (RPDHPA) or an L-alaninol residue (RADHPA) were not suitable for HSSP because the helix sense could not be controlled by the chirality of PEA (Scheme 15.5b)). During the aforementioned experiments, we observed some unexpected behavior in the asymmetric polymerizations of RPDHPA and RADHPA. Despite the bulkier chiral group in RPDHPA, the CD peaks of the resulting polymers were lower than those of RADHPA. To explain the unexpected behaviors in the asymmetric polymerizations of the two chiral monomers with a chiral bidentate ligand, a novel third mechanism of asymmetric polymerization (i.e., self helix-sense-selective polymerization (SHSSP)) was proposed. A chiral ligand group in the monomers worked as a chiral substituent for chiral induction in AIP as well as a chiral cocatalyst in HSSP. If the effect of the chiral group on the chiral induction in AIP is low, then it functions only as a chiral cocatalyst for HSSP. Therefore, the monomer works as a chiral cocatalyst of HSSP of the monomer itself. We call it SHSSP. For example, RADHPA was the best in the three monomers for SHSSP (Scheme 15.6a). 15.2.3.2 Pseudo HSSP (PHSSP). RDIPA that has imino groups was HSSP suitable as described in Section 15.2.2.3. However, some of them showed an exchange reaction of the imino group with amines added as a cocatalyst. In that case, because the imino groups were substituted by chiral amines, which were added as a chiral cocatalyst, they were not suitable for the HSSP. However, if the formed chiral imine can be resubstituted by the corresponding achiral amine, which was the same as that in the monomer, then the corresponding polymer of the monomer can be obtained. Therefore, this polymerization consisting of polymerization and a

434

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

simultaneous exchange reaction followed by a reexchange reaction seems to be similar to HSSP because the corresponding polymer of the starting achiral monomer is obtained. Therefore, we call it “pseudo helix-sense-selective polymerization” (PHSSP) [24]. To promote PHSSP, monomers should be selected that have a substituent that can be exchanged easily. For example, when monomers that have no substituents at 4-position as shown in Scheme 15.6b) were used, PHSSP could occur smoothly. We found that the monomer shown in Scheme 15.6b) was suitable to PHSSP [24]. 15.2.4 Functions of One-Handed Helical Polyphenylacetylenes Prepared by HSSP Because the resulting chiral polymers from HSSP of RDHPA have unique structures, such as cis-cisoidal conformation, double-strand helical structure, one-handed helicity maintained by hydrogen bonds Figure 15.3, extremely high molecular weights, good self-membrane-forming ability, and so on, it showed many unusual properties (Scheme 15.7). In this section, some of these properties are described concisely. 15.2.4.1 Chiral Cocatalysts of HSSP. Several kinds of chiral compounds such as chiral amines, L-aminoalcoholes, and a polymer that has chiral amino groups were suitable for HSSP. We found that the chiral polymers prepared by HSSP of RDIPA were also effective as a cocatalyst of HSSP of RDIPA and RDHPA. For example, one kind of RDIPA was suitable for HSSP of the other kind of RDIPA (Scheme 15.8) [25].

FIGURE 15.3. Possible conformation of one-handed helical poly(RDHPA) prepared by HSSP.

435

SCHEME 15.7. Unique properties of one-handed helical poly(phenylacetylene)s prepared by HSSP of RDHPA.

436

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

N OH OC12H25 N OH

N

OR

OC12H25 N

N OH OC12H25 N OH

OR

Cocatalyst Cl Rh

Rh Cl

OR N OC12H25 OR N

OR N OC12H25 OR N

Catalyst

R- = alkyl group

SCHEME 15.8. HSSP by using one-handed helical polyphenylacetylenes prepared by HSSP as a chiral cocatalyst.

15.2.4.2 Optical Resolution Membranes. In this section, enantioselective permeations through the resulting polymeric membranes prepared by AIP and HSSP are presented [5, 11]. To realize good optical-resolution membrane materials, the authors thought that the polymers should possess the following properties: (1) The polymers should have a self-membrane–forming ability, thereby eliminating domains and defects that have no recognition ability. (2) The polymers should have a high content of chiral structures to enhance the amount of chiral recognition sites. The authors reported that poly[(-)-1-{dimethyl(10-pinanyl)silyl}-1-propyne] prepared by AIP yielded a self-supporting membrane that showed enantioselective permeation for many kinds of racemates. Notably, the enantioselectivity was almost 100% in the initial period. Because the polymer powder had no enantioselectivity in adsorption, the enantioselectivity appeared only in permeation (diffusion) through the pure membrane. Subsequently, the authors selected other poly(substituted aromatic acetylene)s, especially poly(substituted phenylacetylene)s, many of which were newly synthesized by homopolymerization of the corresponding new chiral monomers (¼AIP), for use as enantioselective membranes (Scheme 15.3). The reasons for the selection of chiral-substituted poly(phenylacetylene)s were as follows: (1) Many kinds of substituted aromatic acetylenes can polymerize to yield soluble high-molecular-weight polymers, even if the monomers bear bulky groups. Poly(phenylacetylene)s tend to have good self–supporting-membraneforming abilities because of their high molecular weights. Even if it has an extremely large and bulky group such as macromonomers shown in Scheme 15.9, it will result in good self-supporting membranes. Therefore, the polymerizable group, phanylacetylene, is thought to be suitable to yield polymers that can be fabricated to membrane materials. For example, polymers from some macromonomers (Scheme 15.9) were soluble and had high molecular weights. Therefore, they have a self-membrane-forming ability. (2) When substituted phenylacetylenes have chiral substituents, the monomers can polymerize to yield one-handed helical polymers. Therefore, the membranes can have a high chiral content.

H3C

n

CH3

CH3

CH3

n

Si

CH3 CH3

H3C

Si

CH3 Si

CH3 CH3

H3C

Dendoron macromonomer

CH3

Si

CH3

SCHEME 15.9. Examples of macromonomers that have a phenylacetylene as a polymerizable group.

Siloxane macromonomer

CH3

CH3 Si

O

Si

O

CH3 Si

Si

CH3

n

437

Si H3C

CH3

438

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

140 120

–6

QTrp (x10 g)

100 80 60 40 20 0 0

200

400 600 Permeation time (h)

800

1000

FIGURE 15.4. Enantioselective permeation thorough membranes from one-handed helical polyphenylacetylenes prepared by HSSP of poly(DoDHPA). Plots of quantity (QTrp) of permeated R-(þ)-(.)- and S-(-)-(*)-tryptophan(Trp) from 0.50wt% racemic aq. solution v. s. permeation time.

15.2.4.2.1 Optical Resolution Membrane from Chiral Polymers by the HSSP. In our laboratory, many kinds of chiral poly(substituted acetylene)s have been synthesized by AIP (Scheme 15.3) and applied for optical resolution membranes [5–11]. However, because the chiral poly(substituted acetylene)s prepared from chiral monomers had two kinds of chiral recognition sites, (i.e., a chiral main chain and chiral pendant groups), we could not confirm the optical resolution abilities of the chiral helical main chain. Recently, as described previously, we succeeded in obtaining a chiral helical poly(substituted phenylacetylene) that has an asymmetric structure onlyinthemainchain byHSSP [12]. Thispolymerwassynthesized by HSSP of achiral 4-dodecyloxy-3,5-bis(hydroxymethyl)phenylacetylene (DoDHPA) using a chiral catalytic system consisting of [Rh(2,5-nornornadiene(¼NBD))Cl]2 and chiral phenylethylamine ((R)- or (S)-PEA). In addition, the polymer showed a good membrane-forming ability, and its membrane exhibited enantioselective permeatbility. The fact directly indicated the effectiveness of the main chain’s chirality on enantioselectivities. To our knowledge, this was the first example to confirm the effectiveness (Figure 15.4). However, because enantioselectivity of the chiral membrane from poly(DoDHPA) was not so high, achiral ligands were introduced to its pendants that can interact more effectively with permeants to improve enantioselectivity [26]. 15.2.4.3 Selective cyclic aromatization(SCAT). The resulting polymers from HSSP of RDHPA had a highly ordered structure such as cis-cisoidal conformation, double-strand helical structure, one-handed helicity, and so on (Figure 15.3). As a result, the polymer membrane showed an unexpected reaction when it was exposed in light. The SCAT produced the corresponding cyclic trimer,

CHIRAL DESUBSTITUTION OF SIDE GROUPS IN MEMBRANE STATE

439

1,3,5-trisubstituted benzene almost quantitatively. In addition, the resulting membrane maintained self-membrane–forming ability despite the low molecular weight. The SCAT so far was observed only for the polymers obtained by HSSP of RDHPA. This may be because the reaction largely depends on the configuration and conformation of the starting polymers. 15.3 CHIRAL DESUBSTITUTION OF SIDE GROUPS IN MEMBRANE STATE 15.3.1 Polymer Reaction in Membrane State(RIM) In general, two methods exist to synthesize chiral polymers whose chiral structures are present alone in the main chain as asymmetric carbons and/or as a one-handed helical conformation. One is HSSP, using a chiral catalytic system as a chiral source, of achiral monomers that have no chiral groups and the other is AIP, using achiral catalysts, of monomers that have a chiral group as a chiral source. One-handed helical poly(substituted aromatic acetylene)s obtained by HSSP or AIP are useful for enantioselectively permeable membranes and chiral polymer catalysts because the polymers can have a high chiral content [4, 5, 11]. Recently, we proposed a new method for the synthesis of one-handed helical polymers without the coexistence of any other chiral moieties [9, 27]. In this method (AIP-RIM) a chiral compound is used as a starting monomer in AIP followed by the desubstitution of the chiral groups from a one-handed helical polymer membrane (RIM) (Scheme 15.10). The most important feature of this method is that the desubstitution (a polymer reaction) of the chiral groups was carried out with the polymer as a solid membrane. In the membrane, quantitative desubstitution was realized with maintenance of the onehanded helical conformation. It is interesting that the “membrane state” acted almost like a protecting group. We call the method RIM (polymer reactions in a solid membrane), and in Sections 15.3.2.1 and 15.3.2.2, the desubstitution of chiral groups of one-handed helical polymers from phenylacetylenes is described as examples of RIM. In addition, an application of RIM to the synthesis of chiral porous materials from polystyrene that has chiral groups is described in Section 15.3.2.3. 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 15.3.2.1 Poly(phenylacetylene) Membranes. Poly[(–)-1-p-[dimethyl(10pinanyl)silyl]phenyl-2-phenylacetylene](poly(p-PSDPA)) obtained with a TaCl5– n-Bu4Sn catalyst is soluble in common solvents such as toluene and chloroform and possesses high molecular weight (>1  106) and displays strong CD signals because of the one-handed helical main chain structure [7]. It is known that aryltrimethylsilanes undergo scission of the aryl–Si bond in the presence of proton acids. The membrane (thickness 0.89 mm) of poly(p-PSDPA) was prepared by casting a toluene solution of the polymer onto a quartz plate, and

440

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

RIM

: polymer matrix Y X Z

Y X Z

removal of chiral groups

membrane

membrane

chiral pore

removal of polymer addition of functional groups side groups

functional membrane

AIP-RIM

chiral monomer

AIP

*

*

*

*

*

achiral catalyst

*

1) membrane formation 2) removal of chiral groups

one-handed helix (two chiral sources: main chain and side groups)

HSSP

RIM

* chiral catalyst

achiral monomer one-handed helix (only one chiral source: main chain)

SCHEME 15.10. Concepts of RIM, AIP-RIM, and HSSP.

desilylation was carried out by immersing the membrane in a mixture of hexane/ CF3COOH (1:1 v/v) for 1 day (Scheme 15.11). The completion of the reaction was confirmed by the IR spectrum [27]. The resultant polymer (thickness 0.65 mm), poly(diphenylacetylene(DPA)), showed a specific rotation ([a]D þ 5590 ) even larger than the value ([a]D þ 2380 ) of poly(p-PSDPA) as well as intense CD signals comparable with those of poly(p-PSDPA) in the 350–450 nm region. The large [a]D value and CD signals of poly(DPA) compared with those of poly(p-PSDPA) partly should be caused by the shrinkage of the membrane upon desilylation. These results indicate that poly(DPA) retains practically the same one-handed helical conformation in the main chain as in

441

CHIRAL DESUBSTITUTION OF SIDE GROUPS IN MEMBRANE STATE

CH3 Si CH3

AIP TaCl 5-n-Bu4Sn

C C

C

C

CH3

Si

RIM n

C

CF3COOH

n

in hexane, r.t., 1day CH3

Poly(DPA)

poly(p-PSDPA)

p-PSDPA

C

Ph Ph Ph

Ph Ph Ph

CF3COOH in membrane

Si R R=

Si Si R R CH2

SCHEME 15.11. AIP-RIM of p-PSDPA and molecular-scale voids produced by RIM.

poly(p-PSDPA). In other words, the main chain of poly(DPA) can exist in a sufficiently stable helical conformation with a large excess helix sense in the solid state irrespective of the absence of any chiral pendant groups. Diphenylacetylenes that have one or two pinaylsilyl groups (p-PSDPA, BPSDPA) polymerized by AIP yield chiral helical polymers with various chiral pinanyl contents (Scheme 15.12) [9]. Then, fabrication of the chiral poly(diphenylacetylene) membranes was achieved via Si–C scission catalyzed by trifluoroacetic acid. As a result, chiral desubstitution in the membrane state proceeded quantitatively despite the reaction being heterogeneous. Completion of the reactions was confirmed by IR spectra of the membranes before and after the reaction. Thus, the characteristic absorptions at 3060 (ds,aliphatic C–H), 1250 (ds, SiC–H), 1119 (nas, Si–CH3), 855 (nas, Si– 1 completely disappeared in the IR spectrum of a CH3), and 812 (n s, Si–CH3) cm polymer membrane, which agreed well with that of poly(diphenylacetylene) synthesized directly by polymerization of DPA. CD spectra of the desubstituted polymer

CH3 Si CH3

C C

AIP

RIM

TaCl 5-n-Bu4Sn

CF3COOH

C

p-PSDPA

C C

C

Cn

in hexane, r.t. CH3

+ CH3 Si CH3

Cm

CH3 Si CH3

C

C m+n

Si CH3 Si CH3 Si CH3 CH3 CH3

Copoly (BPSDPA/p-PSDPA)

BPSDPA

SCHEME 15.12. AIP-RIM of p-PSDPA and BPSDPA.

Poly(DPA)

442

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

membranes showed Cotton effects in the UV-vis region despite the absence of chiral pendant groups. This fact indicates that the desubstituted polymer membranes retain the same chiral helical conformation as in the original polymer. We can conclude that we had obtained polymer membranes that have a chiral structure that have only a chiral main chain as the chiral source. Also, enantioselective permeations of the polymeric membranes were investigated. In the permeation of ()-tryptophan (0.5wt% aqueous solution) through the depinanylsilylated poly(p-PSDPA), an enantioselectivity (aR) of 2.89 (48.5%ee) was observed. In addition, the enantioselective pervaporation of ()-2-butanol was achieved (aR ¼ 3.83 [58.6%ee]). Similarly, the Si–C bonds of the chiral pinanylsily groups of a chiral helical poly (phenylacetylene)(p-PSPA) were cleaved quantitatively in the membrane state. The desubstituted polymer had a CD signal in the UV-vis region despite the lack of any chiral pendant groups, so that a chiral structure resulting from only a main chain was confirmed. At the next level of investigation, the scission of a Si–O bond was examined as a second approach for in situ chiral desubstitution in a membrane. Thus, poly (phenylacetylene)s membranes that have chiral pinanylsilyl groups tethered through Si–O bonds (PSOMPA, PSOPA) as well as an induced chiral helical structure were treated with trifluoroacetic acid to examine the effects in situ desubstitution (Scheme 15.13) [10]. The results indicated that chiral desubstitution in the membrane state proceeded quantitatively despite the heterogeneous reaction. The IR spectra of the desubstituted polymers showed absorptions at 3300 cm1 (ns, O-H), indicating the formation of the hydroxyl groups, and the absorptions at 3010 (ns, aliphatic C-H), 1210 (ds, SiC-H), 1150 (nas, Si-CH3), 925 (nas, Si-CH3), and 900 (ns, Si-CH3) cm1 present in the IR spectra of the original polymer membranes, which indicated the presence of pinanylsilyl groups, completely disappeared. The desubstituted polymer membranes showed CD signals in the UV-vis region similar to those of the original polymer despite the absence of the chiral substituents—a fact indicating that the main chains of the polymers retained their chiral helicity. AIP HC C

CH3 CH2 O Si m CH3

C H

[Rh(nbd)Cl]2-Et3N

AIP HC C

p-PSPA

RIM n

C H

CF3COOH

CH2 CH3 m O Si CH3

m = 0 : PSOPA = 1 : PSOMPA

CH3 Si CH3

C

[Rh(nbd)Cl]2-Et3N

C H CH3

C

Si

n

RIM CF3COOH

C

n

CH2 m OH

C H

C

n

CH3

poly(p-PSPA)

SCHEME 15.13. AIP-RIM of phenylacetylene monomer (PSOPA, PSOMPA, and p-PSPA).

CHIRAL DESUBSTITUTION OF SIDE GROUPS IN MEMBRANE STATE

443

The enantioselective permeation of an aqueous solution of a racemic phenylalanine (PHE) through these desubstituted polymer membranes was examined. Similar to the original polymer membranes, all desubstituted polymer membranes showed (R)-isomer enantioselectivity in permeation. This result directly indicates the importance of the contribution of the chiral main chain for enantioselective permeation. Enhancements of the permeation rate were observed in the permeation through the desubstituted polymer membranes. These results show that molecular-scale voids generated by depinanylsilylation were retained and were effective in the enhancement of permeation. This method shows great promise to improve membranes that suffer from low permeability. 15.3.2.2 Poly(phenyleneethynylenes) Membranes. One-handed helical poly(phenyleneethynylenes) that have only a second-order structure as a chiral source were synthesized by in situ desubstitution [28]. That is, we synthesized a chiral poly(phenyleneethynylene)s that had optically active menthoxycarbonyl groups by polycondensations of (þ)-menthyl 3,5-diethynylbenzoate with (þ)-menthyl 3,5-diiodobenzoate using PdCl2(PPh3)2–PPh3–CuI (PMtMt) (Scheme 15.14), investigated the main-chain conformation of the obtained polymer in solution and in membrane by CD measurements, and then the in situ desubstitution of the polymer was performed. PMtMt was obtained in a good yield (yield: 74%, Mw ¼ 160  103, Mw/Mn ¼ 2.8) and showed the largest Cotton signal in the UV region. Because PMtMt had a enough molecular weight, self-supporting membranes can be fabricated using the solventcasting method. In the CD spectrum of PMtMt taken in chloroform/benzene (30:70 v/v)  at 10 C, large Cotton effects were observed in the absorption region of the polymer

I

+

I

toluene/Et3N

O O

O O

O O

PdCl2(PPh3)2, CuI, PPh3

n

O O

PMtMt O O

HCl aq.

THF, MeOH, KOH n

O O

O OH

O O- K+

RIM

n

r.t., 3 days O O- K+

n

r.t. a few minutes O OH

PMtMt

SCHEME 15.14. Synthesis of one-handed helical PMtMt (AIP) and RIM of PMtMt.

444

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

backbone, indicating an excess of one-handed helical conformation. However, as the ratio of chloroform was increased, the intensity of the Cotton signals decreased, and finally, the Cotton signals completely disappeared in chloroform. A thin membrane was prepared on a quartz disc using the spin-coating method. When toluene was used as a casting solvent, the membrane obtained showed a clear Cotton effect that was almost the same as that observed in solution but was accompanied by a slight blue-shift. However, no Cotton signal was observed when a membrane cast from chloroform solution was measured. RIM for the PMtMt membrane was examined as Scheme 15.14. Desubstituion was carried out by immersing a PMtMt membrane into an alkaline solution at room temperature for 3 days. Then the membrane was washed with methanol and treated with dilute hydrochloric acid to protonate the carboxylate groups. Finally, the membrane was washed with methanol again and dried under reduced pressure. In situ desubstitution of PMtMt proceeded a quantitatively yield. Confirmation of the complete reaction was attempted by comparing IR spectra of the membranes before and after the reaction. Thus, a broad and intense O–H stretching absorption (ns, O-H) in the region of 3500–2500 cm1 originated from carboxyl groups appeared, and absorptions at 2955 (ns, aliphatic C-H) cm1 derived from menthyl groups was reduced in the IR spectra of membrane after the reaction, but the broad absorption of ns, O-H was unclear because of overlapping. Therefore, we tried to check the completion of the reaction by gravimetry. As a result, the weight loss of the membrane upon desubstitution supported the completion of the reaction. For example, PMtMt was 9.57 mg; desubstituted PMtMt was 4.81 mg; calculated was 4.88 mg. To measure CD spectra of the desubstituted PMtMt membrane, a thin membrane was prepared using the spin-coating method on a quartz disc with a toluene solution and then treated as described previously. The desubstituted PMtMt membrane showed CD signals similar to those of the original polymer in the UV-vis region. This result indicates that the desubstituted PMtMt retains the same preferential onehanded helical conformation as those in the original polymers despite the absence of chiral pendant groups in the membranes. 15.3.3 Reaction in Polystyrene Monolith: Synthesis of Chiral Porous Materials Two chiral styrene monomers that have a (–)-dimethyl(10-pinanyl)silyl group and a (–)-menthoxycarbonyl group, (–)-PSSt and (–)-MtSt, respectively, were synthesized and then the preparation of chiral polystyrene monoliths was examined by W/O emulsion polymerization of (–)-PSSt/divinylbenzene or (–)-MtSt/divinylbenzene. Then, the removal of the chiral substituents, (e.g., (–)-dimethyl(10-pinanyl)silyl groups and (–)-menthyl groups), from the present monoliths was carried out, and the imprinting effect of the formed chiral cavity was investigated by enantioselective adsorption (Scheme 15.15) [29]. Then, the preparation of chiral styrene monoliths using (–)-PSSt and (–)-MtSt was carried out by using emulsion polymerization of a water-in-oil system that was prepared with a sun-and-planet–type blender.

CHIRAL DESUBSTITUTION OF SIDE GROUPS IN MEMBRANE STATE

AIBN sorbitan monooleate (as an emulsifier)

+

R=

RIM m

n

H2O

R

CF3COOH or KOH aq.

R'

O

,

(-)-PSSt

Monomer

R' =

H ,

COOH

(-)MtSt

Polymer

Water

Pore

1) Still standing Polymerization

W/O emulsion

de-poly[(-)-R'St] monolith

poly[(-)-RSt] monolith

O

m

n

R CH3 Si CH3

445

2) Removal of the water

Porous monolith

SCHEME 15.15. Synthesis and RIM of chiral poly[(–)-RSt] monoliths.

All polymerizations yielded cross-linking polystyrene gels in quantitative yields. The sizes and the total area of the pores were measured by the mercury intrusion method. Sharp distribution curves for the pore size were obtained, and all obtained chiral polystyrene monoliths had 2–3 mm of the pore radius. The total pore areas of the chiral monoliths were in the range of 1.15–3.33 m2/g, which was larger than that of the conventional porous polystyrene beads. In the next stage, we examined the depinanylsilylation of poly[(–)-PSSt] and de-menthylation (hydrolysis) of poly[(–)-MtSt] in gel state. The depinanylsilylation of poly[(–)-PSSt] was carried out by immersing it in CF3COOH. Depinanylsilylation proceeded quantitatively, and completion of the reactions were confirmed by IR spectra before and after the reaction. Thus, the characteristic absorptions at 1250 (ds, SiC–H), 1116 (nas, Si–CH3), 855 (nas, Si–CH3), and 812 (ns, Si–CH3) cm–1 completely disappeared, and the absorption at 3032 (ds, aliphatic 1 increased in the IR spectrum of de-poly[(–)-PSSt], which agreed well with C–H) cm the results of polystyrene synthesized directly by radical polymerization. Also, hydrolysis of poly[(–)-MtSt] was accomplished as follows: A piece of poly [(–)-MtSt] was heated in KOH aq./2-propanol for 3 days at reflux conditions. Then, the monolith was acidified by exposure into concentrated HCl aq. In the IR spectra of de-poly[(–)-MtSt], a broad and strong absorption, resulting from –OH stretching of a carboxyl group appeared, and the spectra agreed well with that of poly(4-vinylbenzoic acid) as synthesized. The conversions of depinanylsilylation and de-menthyl determined by weight reduction were 96% and 84%, respectively.

446

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

With the mercury-intrusion method, the macroporous structures of de-poly [(–)-PSSt] and de-poly[(–)-MtSt] were characterized. The density of the monoliths was slightly decreased after de-substituents, and total pore area increased (e.g., from 1.15 to 48.5 m2/g for poly[(–)-PSSt). In contrast, the average pore radius decreased in the original monolith. This result indicated that the molecular-scale voids were generated by the de-substituent in the monolith. The enantioselective adsorption experiments of a racemic trans-stilbene oxide were examined using the chiral polystyrene monoliths obtained. At first, the chiral substituents containing monoliths (i.e., poly[(–)-PSSt] and poly [(–)-MtSt]) were subjected to an enantioselective adsorption experiment. Then, both monoliths showed enantioselectivity to adsorb the (S, S)-isomer preferentially. The highest value of selectivity (a(s,s)) was of 1.49 (19.7% ee) when poly[(–)-PSSt] and acetone as a solvent for adsorption/desorption were used. Second, to clarify the chiral imprint effect in the present monoliths, no chiral group containing monoliths, (i.e., de-poly[(–)-PSSt] and de-poly[(–)-MtSt]) were subjected to enantioselective adsorption experiment. In the results, we were rewarded with the desired result. That is, de-poly[(–)-PSSt] and de-poly[(–)-MtSt] showed enantioselectivity in adsorption despite no chiral group contents of the monoliths being available. de-Poly[(–)-PSSt] and de-poly [(–)-MtSt] preferentially adsorbed the (S, S)-isomer as well as original monoliths. Using the de-poly[(–)-PSSt], the desirable result was obtained in that the adsorption quantity was increased as a(s,s) remained at a similar level. However, when the depoly[(–)-MtSt] was used, the adsorption quantity was decreased and a(s,s) was increased in comparison with poly[(–)-MtSt]. 15.4 SYNTHESIS OF CHIRAL POLYRADICALS 15.4.1 Molecular Design of Optically Active Helical Polyradicals Organic radicals are usually known as unstable transient intermediates in organic reactions. However, some organic radicals such as radical crystals of galvinoxyl [30] and steric hindered nitroxyl [31] are so stable that they remain in ambient atmosphere from a few months to a few years. Polymers bearing numerous free radical groups, so-called polyradicals, were used for polymer antioxidants, redox resin, and spin labeling [32]. Furthermore, they have recently been regarded as building blocks to construct a molecule-based ferromagnet [33]. Poly(phenylacetylene)s and poly(1,3phenyleneethynylene)s have been well investigated as a backbone structure of the polyradical for magnetic materials [34]. However, stereoregularities have not been mentioned. The optical activity of helical p-conjugated polyradicals will be possible candidates in combination with optic, electronic, and magnetic properties. Our goal is to develop new polyradicals with electronic, magnetic, and chiroptical properties through the fusion of optically active helical polymers with the control of hierarchical structures (Scheme 15.16). To synthesize such noble chiral polymers, we used two methods, AIP (see Section 15.2.1.1) and HSSP (see Section 15.2.2). In this section, two examples of

SYNTHESIS OF CHIRAL POLYRADICALS

447

X X X

Polyradical Magnetic property

Optically active helical polymer Optical activity

Chiral polyradical Magneto-chiral dichroism

SCHEME 15.16. Molecular design of optically active helical polyradicals.

synthetic methods of new polyradicals were used, one is AIP of monomers that have a radical group with comonomers with a chiral group as a chiral source (15.4.2), and the other is HSSP of monomers with a radical group using a chiral catalytic system (15.4.3). 15.4.2 Copolymerization of the Monomers Possessing Radical and Chiral Moieties Chiral polyradicals were obtained simply by the (co)polymerization of monomers possessing radical and chiral moieties. For example, an optically active helical poly (phenylacetylene) poly(p-PSPA-co-GPA) was synthesized by copolymerization of (4-ethynylphenyl)hydrogalvinoxyl (HGPA) and a chiral acetylene monomer p-PSPA using [Rh(nbd)Cl]2 catalyst (Scheme 15.17) [35]. The copolymer poly(p-PSPA-coHGPA) was obtained in good yield with a high molecular weight (Mn  105). The compositions of the copolymers were almost the same as the feed compositions of monomers. The CD spectra of the copolymers were different from that of the mixture of poly(p-PSPA) and poly(HGPA) and was the same as that of poly(p-PSPA). A bathochromic shift of the absorption edge was observed in the UV-visible absorption spectra with increasing amounts of HGPA. In all CD spectra of the copolymers, positive Cotton effects were observed in the absorption region (450 – 550 nm) of the backbone chromophore, and the peaks also shifted to a longer wavelength with the bathochromic shift of the absorption edge, indicating an excess of one-handed helical polyacetylene backbone. With a higher HGPA composition, a split-type CD signal appeared and increased its intensity in the absorption region (420 nm) of the hydrogalvinoxyl chromophore. In the CD spectra of the polyradical poly(p-PSPA-co-GPA) containing more than 20 mol% of p-PSPA, the Cotton effect was observed in the absorption region (470 nm) of the galvinoxyl radical chromophore and in (450 – 550 nm) the backbone chromophore. This result indicates the maintenance of the excess of a one-handed helix even after the oxidation reaction as well as the successful synthesis of an optically active helical polyradical. Another optically active helical poly(phenylacetylene) poly(HGPA-co-PEAGPA) was synthesized by the copolymerization of HGPA and PEAGPA (Scheme 15.17), which was synthesized to bond the chiral group to HGPA, using a [Rh(nbd)Cl]2 catalyst [36]. The Cotton effect indicated that the helix sense of poly(HGPA-co-PEAGPA)s could be controlled by the composition of HGPA and PEAGPA in the copolymers.

448

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

H

R

n

[Rh(nbd)Cl]2

R

poly(p-PSPA-co-HGPA )

p-PSPA + HGPA

poly(p-PSPA-co-GPA ) HGPA + PEAGPA

alkaline K3Fe(CN)6 aq.

poly(HGPA-co-PEAGPA ) PbO2 poly(GPA-co-PEAGPA ) O

CH3 Si CH2 CH3

R=

*

R=

*

OX

p-PSPA

HGPA: X=H GPA: X= PEAGPA: X =

O N H

SCHEME 15.17. Copolymerization of the phenylacetylene monomers possessing radical and chiral moieties.

An optically active poly(1,3-phenyleneethynylene) GPSPE bearing galvinoxyl units and dimethyl(10-(1S)-pinanyl)silyl groups was synthesized via the synthesis of the hydrogalvinoxyl precursor polymer HGPSPE by condensation polymerization of (3,5dihalogenophenyl)hydrogalvinoxyl and 1,3-diethynylbenzene monomer bearing dimethyl(10-(1S)-pinanyl)silyl groups using a Pd(PPh3)4 catalyst (Scheme 15.18) [37].

I

n

I O

+

Pd(PPh3)4, CuI

Si

O

* *

Si OH

* *

OX

PbO2

HGPSPE: X = H GPSPE:

X=

SCHEME 15.18. Synthesis of the optically active poly(1,3-phenyleneethynylene)s HGPSPE and GPSPE.

449

SYNTHESIS OF CHIRAL POLYRADICALS

The molecular weight of the polymer HGPSPE (Mw ¼ 1.7  105, Mw/Mn ¼ 3.7) was improved by using the diiodo monomer instead of the dibromo monomer. The obtained polymer was soluble in chloroform, tetrahydrofuran, ethyl acetate, benzene, and toluene but was insoluble in acetone, diethyl ether, DMSO, DMF, alcohols, and aliphatic hydrocarbons. The polyradical GPSPE was obtained by oxidizing the polymer HGPSPE by treating of the polymer solution in degassed chloroform with fresh PbO2. The CD spectra of HGPSPE and GPSPE were measured in various solutions. In the CD spectrum of HGPSPE taken in ethyl acetate solution, clear Cotton effects were observed in the absorption region of the backbone and hydrogalvinoxyl chromophore, indicating an excess of one-handed helical foldamer conformation. However, the formation of GPSPE unfortunately became insoluble in ethyl acetate. Yet, Cotton effects were hardly observed in chloroform, THF, and benzene solution for both HGPSPE and GPSPE. But the CD signals appeared in CD spectra of the polymer and polyradical by adding of methanol to the chloroform solution, accompanying a bathochromic shift of absorption maxima of galvinoxyl chromophore and a hypochromic effect of absorption around 300 nm. An optically active poly(1,3-phenyleneethynylene)-based polyradical NNMtPE bearing nitronylnitroxide units and chiral menthyloxycarbonyl groups was directly synthesized by condensation polymerization of (3,5-diiodophenyl)nitronylnitroxide and homochiral menthyl 1,3-diethynylbenzoate using a Pd(PPh3)4 catalyst (Scheme 15.19) [38]. The polyradical NNMtPE was obtained in good yield (77%, Mw ¼ 2.6  103, Mw/Mn ¼ 1.3). In the CD spectrum of NNMtPE taken in benzene solution, clear Cotton effects were observed in the absorption region of the backbone, indicating an excess of one-handed helical foldamer conformation, whereas no Cotton effects were observed in chloroform solution. The CD signal intensity of NNMtPE in benzene increased and decreased with the addition of methanol and chloroform, respectively. An optically active poly(binaphthyl-6,6’-diylethynylene-1,3-phenyleneethynylene) GPENp with pendant galvinoxyl residues was synthesized via synthesis of the hydrogalvinoxyl precursor polymer HGPENp by condensation polymerization of (1,3-diiodophenyl)hydrogalvinoxyl and 6,6’-diethynyl-2,2’-dihexyloxybinaphthyl using a Pd(PPh3)4 catalyst (Mw ¼ 4.6  104, Mw/Mn ¼ 3.0) (Scheme 15.20) [39]. The polymer resulted in the corresponding polyradical with a high spin concentration by treating the polymer solution with PbO2. In the CD spectra of the polymer and polyradical taken in various solution, clear Cotton effects were observed in the

I I O

N

N O

n

Pd(PPh3)4, CuI

+ O

O * *

O

N

O

N O

O * *

*

*

NNMtPE

SCHEME 15.19. Synthesis of the optically active poly(1,3-phenyleneethynylene) NNMtPE.

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

450

OC6H13 OC6H13

I

I

+

OC6H13 OC6H13

Pd(PPh3)4, CuI

H

n

H O

OH

O

OX

HGPENp: X = H PbO2

GPENp:

X=

SCHEME 15.20. Synthesis of the optically active poly(binaphthyl-6,6’-diylethynylene-1,3phenyleneethynylene) HGPENp and GPENp.

absorption region of the binaphthyl chromophore, whereas no Cotton effect was observed in that of the galvinoxyl chromophore. 15.4.3 Synthesis of Chiral Polyradicals via HSSP of Achiral Monomers Although the copolymerization of a radical monomer and a chiral monomer is a simple approach to obtain the chiral polyradicals, the chiral monomer reduces the number of radical units in the polymer, which leads to a reduction of spin interaction. Therefore, HSSP using chiral catalysts or chiral initiators is a possible method to obtain various one-handed helical polyradicals because the process demands no chiral moiety in the monomer. This fact will result in increased flexibility of monomer design, besides obvious economic implications as a result of using only a catalitic amount of chiral compounds that are often expensive. Recently, optically active helical poly(HGPA) [14–16], poly(HGDHPA) [17, 40], poly(HNHHPA), poly (EHNHHPA), and poly(NHHPA-co-DoDHPA) [37] bearing stable radical precursor have been synthesized by HSSP of the corresponding achiral phenylacetylenes, using the rhodium complex catalyst, in the presence of chiral 1-PEA (Scheme 15.21). HSSP of the monomer HGPA was carried out in the presence of the [Rh(nbd)Cl]2 catalyst and (R)- or (S)-PEA. A red solid polymer was obtained in low yield with an average molecular weight of ca. 104, but in the CD spectrum taken in chloroform solution, clear Cotton effects were observed not only in the absorption region (450 – 600 nm) of the backbone chromophore but also in that of the hydrogalvinoxyl chromophore (420 nm). The CD spectra of the polymers obtained by polymerization using (R)- and (S)-PEA as a solvent resulted in mirror images of each other. These results indicate an excess of one-handed helical polyacetylene backbone. The Cotton effect in 420 nm showed split-type CD signals that were attributed to exiton coupling between the hydrogalvinoxyl chromophores. The sign of the CD signal in the absorption region (420 nm) of the hydrogalvinoxyl chromophore was calculated from the polymer geometry, and the result suggests that an excess of right-handed helix (P-helix) was induced by polymerization in the presence of [Rh(nbd)Cl]2

SYNTHESIS OF CHIRAL POLYRADICALS

Rh complex cat. (R)- or (S)- PEA

HGPA HGDHPA HNHHPA EHNHHPA NHHPA + DoDHPA

451

n

poly(HGPA) poly(HGDHPA) Oxidation poly(HNHHPA) poly(EHNHHPA) poly(NHHPA-co-DoDHPA)

poly(GPA) poly(GDHPA) poly(HNHPA) poly(EHNHPA) poly(NHPA-co-DoDHPA) HO

O

R

=

N OX R = OC6H13

OX

HNHHPA: X = H HNHPA: X =

HGPA: X = H GPA: X =

R = OCH2CH(C2H5)C4H9 EHNHHPA: X = H EHNHPA: X = R=H

HO

O

NHHPA: X = H NHPA: X = HO

O

OC12H25

HO

HGDHPA: X = H GDHPA: X =

OX

HO

DoDHPA

SCHEME 15.21. HSSP of the achiral phenylacetylenes bearing a stable radical precursor, using the rhodium complex catalyst, in the presence of chiral 1-PEA.

catalyst and (R)-PEA [15]. When excess amounts of (R)-PEA were added to the solution of achiral or racemic poly(HGPA) that were obtained by polymerization using triethylamine or racemic PEA as solvents, no Cotton effects were observed. Therefore, it was confirmed that HSSP occurred in the presence of the chiral PEA. Because the helical polyacetylenes possessing no chiral moieties except for helicity have two conformational enantiomers whose states are thermodynamically equivalent to one another, the conformational rotations of the polymers should lead to the full racemization of polymers on the intrachain and/or interchain. However, the optically active poly(HGPA) had an excess of one-handed helix kinetically stabilized by the achiral bulky side groups. The CD signals of optically active poly(HGPA)

452

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

remained for a long time in chloroform solution, and the half-life of the CD signal intensity was more than 3 days at room temperature [14]. However, CD and UV-vis absorption spectra of the optically active poly(HGPA) exhibited both thermo- and solvatochromism in the solution examined immediately after preparation [15]. The observation of chiroptical thermo- or solvatochromism is novel for one-handed helical polymers that possess no chiral moieties in the polymer chains because the helical polymers require both a high activation energy for the conformational rotations to the conformational enantiomer and the availability of intermediate conformational states with lower activation energies, whose CD signals become weakened in intensity or have an opposite sign compared with those of the helical conformation of the ground state. The [Rh(cod)Cl]2 (cod.1,5-cyclooctadiene) catalyst system for the HSSP of HGPA also yielded a red polymer, whose CD spectrum showed a larger Cotton effect, although the yield and molecular weight were lower than those of the polymer obtained by the [Rh(nbd)Cl]2 catalyst system [16]. Moreover, the CD signals of the polymers obtained by polymerization using [Rh(cod)Cl]2 and [Rh(nbd)Cl]2 were nearly mirror image of each other, except for the magnitudes of the signals, despite using the same chiral environment (i.e., in the presence of (R)-PEA [Scheme 15.22]). This result indicates that, for polymerization in the presence of (R)-PEA, poly(HGPA) from [Rh(nbd)Cl]2 and [Rh(cod)Cl]2 were assigned to P-helix and M-helix, respectively. The plausible polymerization mechanism related to the helix-sense-selectivity was proposed based on the aforementioned results and semiempirical molecular orbital calculation, in which each phenyl group of PEA was placed on the near side of the smaller nbd and the opposite side of the larger cod, respectively. This finding indicates that the helix sense in the HSSP was controlled by the bulkiness of achiral diene ligands in combination with chiral PEA as the chiral bias. The monomer HGDHPA was polymerized in the presence of [Rh(nbd)Cl]2 or Rhþ(nbd)[(h6-C6H5)B–(C6H5)3] catalysts, chiral PEA cocatalyst, and an achiral solvent. The red solid polymer poly(HGDHPA) was obtained by precipitation from the polymerization mixtures into methanol (Mw  105). The addition of copper (I) iodide (CuI) into the catalytic system improved the polymer yield. The effect of a CuI addition in the polymerization of HGDHPA was estimated as the transmetalation of copper acetylide to Rh accelerated complexation to polymerization active species. Moreover, the replacement of [Rh(nbd)Cl]2 by Rhþ(nbd)[(h6-C6H5)B–(C6H5)3] in the polymerization catalytic system seemed to enhance the reactivity remarkably probably because the elimination of tetraphenyl borate anion proceeded more readily compared with the chloride anion. Split-type–induced CD signals were observed for the THF solution of poly(HGDHPA) at 300 nm, indicating an excess of one-handed helical polyacetylene backbone. It is clear that HSSP occurred in the presence of chiral PEA because monomer HGDHPA has no chiral moieties and the CD signal at 300 nm was similar to that of the previously reported poly(DoDHPA). The CD intensity of poly(HGDHPA) was nearly constant even when the solution was heated to 60  C. But the CD signals decreased and disappeared in CD spectra of poly (HGDHPA) when adding DMF to the THF solution, which supported the notion that the rigid and one-handed helical conformation was stabilized by intramolecular

453

O

(R)-PEA

H

H 2N Cl Rh Rh Cl

HGPA

[Rh(cod)Cl]2

O

[Rh(nbd)Cl]2

Cl Rh Rh Cl

OH

(S)-PEA

H

NH2

(R)-PEA

H

H2N

right-handed helical poly(HGPA)

O

SCHEME 15.22. Achiral diene-ligands control the helix sense in the HSSP of HGPA.

left-handed helical poly(HGPA)

HO

(S)-PEA

H

NH2

OH

454

SYNTHESIS AND FUNCTION OF CHIRAL p-CONJUGATED POLYMERS

hydrogen bonds. This behavior is in contrast to the results for poly(HGPA) described earlier, whose CD signal intensity was dependent on temperature over the experimental range and decreased reversibly with an increasing temperature for the CD spectra of poly(HGPA) in the solution used immediately after preparation. The hydrogalvinoxyl units of poly(HGDHPA) were converted to the corresponding galvinoxyl radicals after treatment with fresh PbO2. The absorption maximum at 420 nm resulting from the hydrogalvinoxyl chromophore decreased, and a new absorption peak resulting from the galvinoxyl radical chromophore appeared at 470 nm. The polyradical poly(GDHPA) was stable enough to maintain the initial spin concentration under electron spin resonance (ESR) and CD measurement conditions. In the CD spectra of the polyradical, the Cotton effect was still observed at 300 nm, which indicates that maintenance of the excess of the one-handed helix and the successful synthesis of an optically active polyradical with a high spin concentration was achieved even after the oxidation reaction compared with the optically active helical copolymer–polyradicals described previously.

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Akagi,K. Chem. Rev. 2009, 109 (11), 5354–5401. Liu,J.; Lam, Y.; Tang, B. Z. Chem. Rev. 2009, 109 (11), 5799–5867. Aoki,T.; Kaneko, T. Polymer J. 2005, 37(10), 717–735. Aoki,T.; Kaneko, T.; Teraguchi, M. Polymer 2006, 47 (14), 4867–4892. Yashima,E.; Maeda, K.; Iida, H.; Furusho, Y.; Naga, K. Chem. Rev. 2009, 109 (11), 6102– 6211. Aoki,T.; Kokai, M.; Shinohara, K.; Oikawa, E. Chem. Lett. 1993 (12), 2009–2012. Aoki,T.; Kobayashi, Y.; Kaneko, T.; Oikawa, E.; Yamamura, Y.; Fujita, Y.; Teraguchi, M.; Nomura, R.; Masuda, T. Macromolecules 1999, 32(1), 79–85. Aoki,T.; Fukuda, T.; Shinohara, K.; Kaneko, T.; Teraguchi, M.; Yagi, M. J. Polymer Sci. A: Polymer Chem. 2004, 42, 4502–4517. Teraguchi,M.; Suzuki, J.; Kaneko, T.; Aoki, T.; Masuda, T. Macromolecules 2003, 36(26), 9694–9697. Teraguchi,M.; Mottate, K.; Kim, S.Y.; Aoki, T.; Kaneko, T.; Hadano, S.; Masuda, T. Macromolecules 2005, 38(15), 6367–6373. Aoki, T. Prog. Polymer Sci. 1999, 24, 951–993. Aoki, T. Kaneko, T.; Maruyama, N.; Sumi, A.; Takahashi, M.; Sato, T.; Teraguchi, M. J. Am. Chem. Soc. 2003, 125(21), 6346–6347. Sato, T.; Aoki, T.; Teraguchi, M.; Kaneko, T.; Kim, S.Y. Polymer 2004, 5(24), 8109–8114. Umeda,Y.; Kaneko, T.; Teraguchi, M.; Aoki, T. Chem. Lett. 2005, 34(6), 854–855. Kaneko, T.; Umeda, Y.; Yamamoto, T.; Teraguchi, M.; Aoki, T. Macromolecules 2005, 38 (23), 9420–9426. Kaneko, T.; Umeda, Y.; Jia, H.; Hadano, S.; Teraguchi, M.; Aoki, T. Macromolecules 2007, 40(20), 7098–7102.

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CHAPTER 16

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS YASUHIRO MORISAKI and YOSHIKI CHUJO

16.1 INTRODUCTION Phosphine (PR3) is the general term for a three-coordinated organophosphorus compound consisting of three covalent bonds and an unshared electron pair. The structure of a phosphine is trigonal pyramidal, in which a phosphorus atom is located at one point. This is the same structure as that of amine (NR3); however, the p character of the sp3-hybridized orbital of the three bonds and the s-character of the sp3-hybridized orbital of the unshared electron pair of phosphine increase relative to those of amine. Therefore, the inversion energy of phosphine is higher than that of amine. As shown in Scheme 16.1, for example, it is estimated that the inversion energy of cyclohexylmethylpropylphosphine is 35.6 kcal/mol. In other words, when the racemization time of this phosphine is t, t1/2 is calculated to be approximately 450 h at 130
C in solution [1]. Thus, a phosphorus atom can act as a chiral center similarly to a carbon atom, and optically pure phosphine exists as a structurally stable compound. Based on this background, various optically active phosphines have been prepared [2] and used extensively for chiral ligands of transition-metal–catalyzed asymmetric reactions [3]. However, in the field of polymer chemistry, there have been few optically active polymers containing chiral “P” atoms in the main chain [4]. In addition, only a few optically active polymers containing chiral heteroatoms in the main chain have been synthesized, such as optically active polysulfoxides consisting of chiral “S” atoms [5], and optically active polycarbosilanes [6], polysiloxanes [7], and polycarbosiloxanes [8] consisting of chiral “Si” atoms.

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.

457

458

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

inversion energy 35.6 kcal/mol P P

SCHEME 16.1. Inversion of cyclohexylmethylpropylphosphine.

This chapter will focus on the chiral P atom and review the synthesis of optically active P-stereogenic oligomers as well as of P-stereogenic polymers containing chiral P atoms in the main chain. Related cyclic compounds prepared from P-stereogenic oligomers will also be highlighted.

16.2 P-STEREOGENIC OLIGOMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN P-Stereogenic bisphosphines are regarded as the minimum P-stereogenic oligomers. This class of phosphines can coordinate to transition metals as typical bidentate ligands, which catalyze the asymmetric hydrogenation of enamides, enol acetates, and olefins with high enantiomeric excess (ee) [3, 9]. Figure 16.1 shows the representative P-stereogenic bisphosphines, DIPAMP (S,S)-1 [9], 2,5-di(tert-butyl)-2,5-diphosphahexane (S,S)-2 [10], and 2,5-diphenyl-2,5-diphosphahexane (S,S)3 [11]. Although excellent reviews on their syntheses and applications to asymmetric reactions have been published [2, 3], there have been few reviews dealing in detail with P-stereogenic oligophosphines having four or more chiral P atoms. In this section, P-stereogenic oligomers containing 4, 6, 8, and 12 chiral P atoms in their backbone will mainly be discussed. 16.2.1 P-Stereogenic Tetraphosphines Containing Two Chiral “P” Atoms First, we begin by describing the synthesis of P-stereogenic tetraphosphines containing two chiral P atoms. As shown in Scheme 16.2, optically inactive tetraphosphine 6, i.e., a mixture of meso and racemic tetraphosphines, was synthesized with a yield of 99% by reacting 1,2-bis(phenylphosphino)ethane 4 with diphenylvinylphosphine 5 in the presence of KOtBu [12,13c]. Tetraphosphine meso-6 and racemi-6 were OMe

t Bu

Ph

P

Me

P

Ph

(S,S)-1

OMe

P t

P

Bu

(S,S)-2

Ph

Me

Me

P

P

Ph

(S,S)-3

FIGURE 16.1. Representative P-stereogenic bisphosphines.

Me

459

P-STEREOGENIC OLIGOMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN

Ph

Ph H

P

P

Ph

4

H

+

P

Ph

KOtBu

Ph

Ph Ph

99%

P Ph

5

P

P

P

Ph

Ph

meso-6 and racemi-6 Ph

Ph

P Ph

P

P

Ph P

Ph

Ph meso-6, 97%

recrystallization Ph Ph

P Ph

P

P

P Ph

P

Ph

Ph Ph

Ph

Ph

P

P

Ph P

Ph

Ph

racemi-6, 85%

SCHEME 16.2. Synthesis and separation of tetraphosphine 6.

separated by taking advantage of their different solubilities to give pure meso-6 and racemi-6 in 97% and 85% yield, respectively. The optical resolution of racemi-6 was achieved as shown in Scheme 16.3 [13a–c]. The reaction of racemi-6 with (R)-7 yielded the corresponding palladium complex, after which counter anion exchange from Cl to PF6 was carried out to produce a 1:1 mixture of two diastereomers (R)(R,R)(R)-8 and (R)(S,S)(R)-8. Repeated recrystallization afforded (R)(R,R)(R)-8 and (R)(S,S)(R)-8 in 93% and 64% yields, respectively [13c]. Successive treatment of the diastereomers with HCl and KCN to remove the palladium species afforded the optically pure P-stereogenic tetraphosphines (S,S)-6 and (R,R)-6, each containing two chiral P atoms in high yields (Scheme 16.3). Tetraphosphine 6 can coordinate to transition metals such as Au [13c,e], Ag [13b,c], Cu [13c], Ni [13f], Pd [13a,c,f], and Pt [13f] as a bidentate or tetradentate ligand [14]. Figure 16.2 shows the [Ag2{(R,R)-11}2](PF6)2 complex, which was synthesized in 92% yield by reacting (S,S)-6 with AgClO4 and carrying out the counter anion exchange with NH4PF6 [13b,c]. Single crystals of this complex were obtained, containing both double helix and parallel double helix conformers (Figure 16.2) in the unit cell. The photoluminescence behavior of the [Au2{(R,R)-11}2](PF6)2 complex was examined [13g]. This Au complex exhibited an intense yellow emission (lmax 580–620 nm) at 293 K in the solid state resulting from the ligand-to-metal charge-

460

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

N

Cl Pd

N

NH4PF6 recrystallization

(R)-7

racemi-6

2PF6–

N

Ph

Pd+ P

P Ph +

Ph

Cl

Cl

Ph

Ph

+

P

Ph P Ph

(S,S)-9 Ph

P Ph

P

Cl

Cl

Cl

90%

Pd

Ph

(R,R)-9

Ph

KCN

P Ph

P

Pd Cl

Ph

Ph

Pd

P Ph

P

Ph

Ph

(R)(S,S)(R)-8, 64%

Cl P

Ph P

96%

Pd+

Ph

N

(R)(R,R)(R)-8, 93%

Pd

HCl

P Ph

P P

Ph P

N

Cl

Ph

Ph

Pd+

Pd+

Ph

Ph

2PF6–

N Ph

P Ph P

Pd

Cl

P

Ph P

Ph

Ph

Ph

P

+ Ph P

Ph

P

P

Ph

Ph

Ph

(S,S)-6

(R,R)-6

SCHEME 16.3. Optical resolution of racemi-6.

transfer (LMCT) transitions, i.e., p*(Ph–Ph) to Au(d)–P(p) transitions associated with excited P-Ph dimer units. Furthermore, two kinds of emission were observed at 77 K in frozen EtOH resulting from the triplet LMCT transitions, i.e., p*(Ph) to Au (d)–P(p) transitions, in addition to the p*(Ph–Ph) to Au(d)–P(p) transitions. Ph Ph Ph2P Ph2P

P

P

P P Ph Ph

PPh2 PPh2

Ph2P

Ph

Ph2P Ph

Double helix

Ph

PPh2

P

P

P

P PPh2 Ph

Parallel double helix = Ag+

FIGURE 16.2. [Ag2{(R,R)-6}2](PF6)2: double helix structure (left) and parallel double helix structure (right).

461

P-STEREOGENIC OLIGOMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN

16.2.2 P-Stereogenic Hexaphosphines Containing Four Chiral “P” Atoms Optically active hexaphosphines 11 containing four P-stereogenic centers were synthesized as shown in Scheme 16.4 [13d,15]. The terminal tertiary phosphines

(S,S)-6

1) Na/NH3 2) NH4Br

H

1) 5 2) Me2S·BH3

Ph

Ph P

P

P

P

H(Ph)

Ph

Ph 10, 96% BH3

BH3 Ph

Ph Ph

P

P

P

Ph

BH3

P

+

Ph

P

Ph

P

P

Ph

Ph BH3

BH3 Ph

Ph

Ph P

P

Ph BH3

BH3

BH3

P

P

Ph

Ph BH3

BH3

BH3

mixture of 11-BH3 and 12-BH3, 78%

BH3

BH3

Ph

P

BH3

Ph

Ph P

P

Ph

Ph P

P

Ph

P

Ph

Ph

BH3

BH3

BH3

(R,S,S,R)-11-BH3, 16% BH3

BH3

+

Ph

P

BH3

Ph

Ph

P

P

Ph

Ph P

P

Ph

separation by HPLC

P

Ph

Ph

BH3

BH3

BH3

(S,S,S,S)-11-BH3, 16% BH3

BH3

+

Ph

P

BH3

Ph

Ph P

P

Ph

Ph P

P

Ph

P

Ph

Ph

BH3

BH3

BH3

(R,S,S,S)-11-BH3, 32% BH3

BH3

+

Ph

P

P

Ph

BH3

Ph

Ph P

P

Ph BH3

P

Ph

Ph BH3

(R,S,S,)-12-BH3, 4.2% (S,S,S)-12-BH3, 4.1%

SCHEME 16.4. Synthesis of hexaphosphines 11 and pentaphosphines 12.

Ph

462

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

of (S,S)-6 were converted to secondary phosphines by treatment with Na/NH3 and NH4Br to obtain tetraphosphine 10 in 96% yield. The reaction of 10 with diphenylvinylphosphine 5 in the presence of KOtBu afforded hexaphosphine 11 and pentaphosphine 12, and then, the phosphorus atoms were protected with BH3 to obtain a mixture of 11-BH3 and 12-BH3 in 78% yield. They were successfully separated by high-performance liquid chromatography (HPLC) into hexaphosphineboranes (R,S,S,R)-11-BH3 (16%), (S,S,S,S)-11-BH3 (16%), and (R,S,S,S)-11-BH3 (32%) as well as into pentaphosphine-boranes (R,S,S)-12-BH3 (4.2%) and (S,S,S)12-BH3 (4.1%). Coordinated boranes on phosphorus atoms can be removed by a strong base or acid. In the case of tertiaryphosphine-boranes with aryl substituents at the phosphorus, the boranes are removed by organic bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO) and morpholine. However, a strong acid such as HBF4 (and then the treatment with base) is effective for the removal of boranes from trialkyl-substituted phosphine-boranes [16]. Thus, deboranation proceeded by the treatment of (R,S,S, R)-11-BH3 with morpholine to yield (R,S,S,R)-11, and the reaction with [Cu(MeCN)4]PF6 afforded the corresponding Cu complex [Cu3{(S,R,R,S)-11}2] (PF6)3 in high yield, as shown in Scheme 16.5 [15]. A single crystal of [Cu3{(S, R,R,S)-11}2](PF6)3 was successfully obtained, and its crystal structure exhibited the parallel double helix structure, as illustrated in Scheme 16.5. Scheme 16.6 shows the synthesis of P-stereogenic tetraphosphine (R,S,S,R)-15BH3 containing four chiral P atoms and its complexation with Rh. P-Stereogenic secondary bisphosphine-borane 13 [17] was reacted with n BuLi and tosylate (R)-14 [18] to afford (R,S,S,R)-15-BH3 in 65% yield [19]. Coordinated boranes were removed by successive treatments with HBF4 and NaHCO3. Then, (R,S,S,R)-15 was subjected to complexation with 2 equiv of [Rh(nbd)2]PF6 (nbd ¼ norbornadiene) to obtain [Rh2{(S,R,R,S)-15}(nbd)2](PF6)2 in 46% yield [19], whereas complexation with 1 equiv of [Rh(cod)2]SbF6 (cod ¼ 1,5-cyclooctadiene) produced [Rh{(S,R,R,S)15}]SbF6 in 37% yield [19b] (Scheme 16.6). The [Rh2{(S,R,R,S)-15}(nbd)2](PF6)2 complex was used for the asymmetric hydrogenation of various prochiral dehydroamino acid derivatives [19a]. The representative reaction is shown in O N H

(R,S,S,R)-11-BH3

(R,S,S,R)-11 85%

Ph

[Cu(MeCN)4]PF6 97%

Ph2P

P

Ph P

Ph

P

P Ph

P

Ph P

PPh2

P

PPh2

(PF6)3 Ph2P

P Ph

Ph

Ph

= Cu+

SCHEME 16.5. Synthesis of [Cu3{(S,R,R,S)-11}2](PF6)3.

463

P-STEREOGENIC OLIGOMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN BH3

t

H

Bu

P t

OTs

BH3

t

Bu

n

P

P

Me

BH3 H

P

Me

65%

Bu

t

Bu

(R)-14

BuLi

BH3

t

t

P

P t

Bu

BH3

P

Me

Bu

BH3

(S,S)-13

BH3

(S,R,R,S)-15-BH3

t

t

Bu

Me P

Bu

Rh

P P Rh

2 equiv [Rh(nbd)2]PF6 1) HBF4·Et2O 2) NaHCO3

Bu

P

Me tBu

t

Bu

2PF6–

46% (S,R,R,S)-15

95% 1 equiv [Rh(cod)2]SbF6

37%

t

t

Bu

Me

P

Bu

P

SbF6–

Rh

Me P

P t

tBu

Bu

SCHEME 16.6. Synthesis of P-stereogenic tetraphosphine (S,R,R,S)-15 and its Rh complexes.

Scheme 16.7; the hydrogenation of 1-acetylamino-1-phenylethene was carried out in MeOH at room temperature under a H2 pressure of 2 atm in the presence of a catalytic amount of [Rh2{(S,R,R,S)-15}(nbd)2](PF6)2 to afford the (R)-product with 99%ee. In addition to Rh, (S,R,R,S)-15 can coordinate to various transition metals such as Pd and Ru with various modes of coordination [19b] (Figure 16.3). Interestingly, a

CO2Me NHCOCH3

+ H2 (2 atm)

[Rh2{(S,R,R,S)-15}(nbd)2](PF6)2 MeOH rt, 30 min

R

CO2Me

NHCOCH3

99% ee

SCHEME 16.7. Asymmetric hydrogenation catalyzed by [Rh2{(S,R,R,S)-15}(nbd)2](PF6)2.

464

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS tBu

But

Me P

Pd+

2SbF6–

P Pd

But Me P Cl Ru

P Me

P

+

t

t

Bu

Ru

P P t

tBu

Bu

Bu

Cl P Me t

Bu

tBu

But Me

P

P 2Cl–

Pd2+

Me P tBu

P t

Bu

t Bu But Ru Cl Cl Ru P P Cl P P Cl Pd t Me Me tBu Bu Cl Cl

FIGURE 16.3. (S,R,R,S)-15-metal complexes.

heterotrimetallic complex was obtained by simultaneously treating (S,R,R,S)-15 with 1 equiv of PdCl2(cod) and 1 equiv of RuCl2(h6-benzene), and its structure was confirmed by X-ray crystallography. 16.2.3 P-Stereogenic Oligomers Containing 6, 8, and 12 Chiral “P” Atoms For the following three reasons, P-stereogenic bisphosphine-boranes (S,S)-2-BH3 and (S,S)-3-BH3 are used as powerful building blocks for constructing P-stereogenic oligomers. First, they can be readily prepared with high ee (>99%). Second, their phosphorus atoms are protected by borane against oxidation, leading to their easy handling. Third, the electron-withdrawing feature of borane provides the reactivity of their methyl groups substituted at phosphorus atoms; therefore, the methyl groups can be easily deprotonated by alkyllithium reagents. As shown in Scheme 16.8, the reaction of (S,S)-2-BH3 with 1.2 equiv of s BuLi/()-sparteine formed mono- and dilithiated species, and the treatment with CuCl2 and aqueous NH3 afforded a mixture of P-stereogenic tetraphosphine-borane (S,R,R,S)-15-BH3 and hexaphosphine-borane (S,R,S,S,R,S)-16-BH3. They were separated by conventional SiO2 column chromatography to produce pure (S,R,R,S)-15BH3 and (S,R,S,S,R,S)-16-BH3 in 26% and 14% yields, respectively [20]. Although this reaction is not an asymmetric one, ()-sparteine served as a good activator for s BuLi. P-Stereogenic oligophosphines with more chiral P atoms can be accessed by this methodology based on the reactivity of the terminal methyl group substituted at the phosphine-borane. Two methyl groups of (S,R,R,S)-15-BH3 were lithiated by 5 equiv of s BuLi/()-sparteine, as shown in Scheme 16.9. Although an excess amount of s BuLi was used for the reaction, a monolithiated intermediate was apparently included. Thus, after treatment with CuCl2 and aqueous NH3, P-stereogenic octaphosphine-borane (S,R,S,R,R,S,R,S)-17-BH3 (29%) and dodecaphosphineborane (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3 (8%) containing 8 and 12 chiral P atoms,

P-STEREOGENIC OLIGOMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN

465

BH3 t

Me

BH3 t

Me

P t

Bu

P

Me

1.2 equiv. sBuLi/(–)-sparteine

Bu

P t

P

CH2–Li+

Bu

BH3 BH3

Bu

t

Bu

BH3 +Li–H

(S,S)-2-BH3

2C

P t

P

CH2–Li+

Bu

BH3

BH3 P

Me t

BH3

tBu

t

P

P

P

Me

t

Bu

Bu

BH3

1) CuCl2 2) aq. NH3

Bu

BH3

(S,R,R,S)-15-BH3, 26% + BH3 Me

P

t

BH3 tBu

Bu

P

tBu

P

P

tBu

BH3

BH3 P

tBu

P

Me

tBu

BH3

BH3

(S,R,S,S,R,S)-16-BH3, 14%

SCHEME 16.8. Synthesis of P-stereogenic tetraphosphine-borane (S,R,R,S)-15-BH3 and hexaphosphine-borane (S,R,S,S,R,S)-16-BH3.

respectively, were obtained [20c]. At the same time, (S,R,R,S)-15-BH3 was converted into a cyclic compound by intramolecular coupling reaction (vide infra). Differential scanning calorimetry (DSC) analysis of P-stereogenic oligophosphines (S,R,R,S)-15-BH3, (S,R,S,S,R,S)-16-BH3, (S,R,S,R,R,S,R,S)-17-BH3, and (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3 revealed their behaviors in the solid state under heating conditions, as shown in the DSC thermograms in Figure 16.4. Incidentally, it is reported that P-stereogenic bisphosphine (S,S)-2-BH3 exhibited only the melting point (Tm) at 169–171
C [10]. As shown in Figure 16.4a, (S,R,R,S)-15-BH3 behaved as a simple small molecule showing only the Tm at 207–208
C without a glass transition temperature (Tg). According to Figure 16.4b, (S,R,S,S,R,S)-16-BH3 possessed two different solid states. In the first cycle, (S,R,S,S,R,S)-16-BH3 exhibited only the Tm at 194
C similarly to (S,S)-2-BH3 and (S,R,R,S)-15-BH3. In the second cycle, (S,R,S,S,R, S)-16-BH3 consecutively showed the Tg at 59
C, recrystallization point (Tc) at 152
C, and Tm at 194
C. In the third cycle, the sample was cooled to ambient temperature after the Tc and before the Tm. In the fourth cycle, (S,R,S,S,R,S)-16-BH3

466

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

5 equiv. sBuLi/(–)-sparteine

(S,R,R,S)-15-BH3

BH3 Me

tBu

P

P

BH3

BH3 tBu

P

tBu

1) CuCl2 2) aq. NH3

tBu

Bu

P

P

P

tBu

tBu

BH3

BH3

t

P

BH3

BH3

P

Me

tBu

BH3

(S,R,S,R,R,S,R,S)-17-BH3, 29% + BH3 Me

P

tBu

P

tBu

BH3

BH3 t

P

Bu

P

P BH3

BH3 tBu

P

P

tBu

tBu

BH3

BH3

tBu

P

tBu

BH3

P

tBu

P

tBu

BH3

BH3 tBu

P

P

Me

tBu

BH3

BH3

(S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3, 8% + cyclic compound, 15%

SCHEME 16.9. Synthesis of P-stereogenic octaphosphine-borane (S,R,S,R,R,S,R,S)-17-BH3 and dodecaphosphine-borane (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3.

exhibited only the Tm at 192
C again without the Tg and/or Tc. Thus, P-stereogenic hexaphosphine (S,R,S,S,R,S)-16-BH3 behaved as a crystalline solid; however, it becomes an amorphous solid once it melted. In Figure 16.4c, (S,R,S,R,R,S,R,S)-17-BH3 exhibited the typical Tg at 53
C and Tc at 138
C in the first scan. In the second scan, the Tg appeared at 76
C. In Figure 16.4d, (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3 exhibited almost the same behaviors as that of (S,R,S,R,R,S,R,S)-17-BH3, and the Tg and Tc were observed at 78
C and 146
C, respectively, in the first scan. After cooling, the Tg appeared at a higher temperature of 105
C in the second scan. As shown in the XRD patterns (Figure 16.5), distinct changes in the crystallinity of P-stereogenic oligophosphines were observed, which are consistent with the DSC curves. A sharp diffraction pattern was observed for (S,R,R,S)-15-BH3 (Figure 16.5a). A pristine sample of (S,R,S,S,R,S)-16-BH3 exhibited a relatively broad diffraction pattern, and a sample after solidification of the melt showed a broader peak (Figure 16.5b). Amorphous diffraction patterns were observed for (S,R, S,R,R,S,R,S)-17-BH3 and (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3, as shown in Figures 16.5c and 16.5d, respectively. The DSC and X-ray diffraction (XRD) analyses of (S,R,S,S,R, S)-16-BH3 suggest that it is intermediate between a small molecule and a polymer, and that (S,R,S,R,R,S,R,S)-17-BH3 and (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3 acquire the features of a polymer.

467

P-STEREOGENIC OLIGOMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN BH3 Me

tBu

P

P

tBu

Me

m.p. 169–171 °C

BH3

(S,S)-2-BH3 BH3

(a) Me

BH3

tBu

P

P

P

tBu

P

tBu

BH3

BH3

tBu

(c)

Me

Me

tBu

BH3

tBu

1st

BH3 Me

P

100

tBu

BH3

tBu

P

P

tBu

BH3

150

0

200

50

BH3

tBu

BH3

tBu

P

P

tBu

BH3

P

(d)

Me

Me

P

100

tBu

BH3

tBu

P

P

tBu

BH3

BH3

150

BH3

tBu

P

P

tBu

tBu

P

BH3 P tBu

BH3

BH3

200

tBu

P

BH3 P tBu

BH3

exo Tg 59 °C Tc 152 °C

Tm 194 °C

tBu

P BH3

BH3 P tBu

tBu

P

Me

BH3

Tg 59 °C Tc 152 °C

Tm 192 °C

4th Tm 192 °C 150

temperature / °C

200

Tc 146 °C Tg 78 °C

1st

Tg 105 °C

endo

exo endo

BH3

(S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3

1st

100

Me

temperature / °C

(S,R,S,S,R,S)-16-BH3

50

P

Tg 76 °C

2nd

temperature / °C

0

BH3

BH3

exo 50

tBu

tBu

Tc 138 °C

endo

endo

Tm 208 °C

3rd

tBu

BH3 P

P

Tg 53 °C

2nd

2nd

P

P

(S,R,S,R,R,S,R,S)-17-BH3

Tm 207 °C

0

tBu

Bu

BH3

1st

(b)

BH3

t

P

P

(S,R,R,S)-15-BH3

exo

BH3

tBu

P

2nd

0

50

100

150

200

temperature / °C

FIGURE 16.4. DSC thermograms of (a) (S,R,R,S)-15-BH3, (b) (S,R,S,S,R,S)-16-BH3,

(c) (S,R,S,R,R,S,R,S)-17-BH3, and (d) (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3. Incidentally, optically inactive oligophosphines 2-BH3 and 15–18-BH3 were also synthesized from tert-butyldimethylphosphine-borane without ()-sparteine as a chiral ligand of Liþ, as shown in Scheme 16.10 [20c]. Their DSC charts and XRD diffraction patterns showed evidence of amorphous phases [20c]. Stereoregularity around the P atoms strongly affected the solid state properties of the oligophosphines. However, it was reported that the specific rotation [a]D27 (c 1.0 in CHCl3) of optically active bisphosphine (S,S)-2-BH3 was 9.1 [10]. The specific rotations ([a]D25) of (S,R,R,S)-15-BH3 and (S,R,S,S,R,S)-16-BH3 were 3.4 (c 1.0 in CHCl3) and 1.8 (c 0.5 in CHCl3), respectively [20c]. In this system, the specific rotation

468

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

(a)

BH3 Me

BH3

tBu

P tBu

tBu

P

P

P

tBu

BH3

Me

BH3

(S,R,R,S)-15-BH3

BH3

(b)

Me

BH3

tBu

P

P

P

tBu

tBu

P

tBu

BH3

BH3

tBu

P

P

tBu

BH3

Me

BH3

(S,R,S,S,R,S)-16-BH3

pristine sample

sample after solidification of the melt

BH3

BH3

t

t

Bu

Me

(c)

P

P

P

tBu

BH3 Bu P

tBu

BH3

BH3

tBu

P tBu

tBu

P

P

P

tBu

BH3

BH3

Me

BH3

(S,R,S,R,R,S,R,S)-17-BH3

BH3

(d)

Me

P tBu

tBu

P BH3

BH3 P tBu

tBu

P BH3

BH3 P tBu

BH3

tBu

P

P

tBu

P

tBu

BH3

BH3

tBu

P tBu

BH3

P

BH3 P tBu

BH3

tBu

P

Me

BH3

(S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3

5

10

20

30

40

2θ [degrees]

FIGURE 16.5. XRD patterns of (a) (S,R,R,S)-15-BH3, (b) (S,R,S,S,R,S)-16-BH3, (c) (S,R,

S,R,R,S,R,S)-17-BH3, and (d) (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3.

469

P-STEREOGENIC OLIGOMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN

BH3

1) 1.7 equiv. sBuLi 2) CuCl2 3) aq. NH3

BH3 t

P

Me

Bu t Me Me without (–)-sparteine

Bu

P

P

tBu

Me

BH3

2-BH3, 38%

BH3

2-BH3

1) 1.2 equiv. 2) CuCl2 3) aq. NH3

sBuLi

P

Me

BH3

tBu

tBu

P

P

tBu

P

Me

tBu

BH3

BH3

15-BH3, 30% BH3

BH3

t

t

Bu

+

P

Me

BH3

P

P

t

t

Bu

t

Bu P

P

Bu P

Me

t

Bu

Bu

BH3

BH3

BH3

16-BH3, 3%

15-BH3

1) 5 equiv. sBuLi 2) CuCl2 3) aq. NH3

BH3 P

Me t

BH3

tBu

P

P

BH3 tBu

P

P t

t

Bu

Bu

BH3

BH3

tBu

P

P t

Bu

P

Me

Bu

BH3

BH3

tBu

BH3

17-BH3, 20% BH3

+

P

Me

BH3

tBu

P

P

t

BH3 tBu

P t

t

Bu

Bu

BH3

P

BH3

BH3

tBu

P

P

t

Bu

BH3

P

P

t

Bu

BH3

tBu

BH3

BH3

tBu

P

P

tBu

P

Me

t

Bu

Bu

BH3

BH3

18-BH3, 9%

SCHEME 16.10. Synthesis of oligophosphine-boranes 2-BH3 and 15-18-BH3.

[a]D of P-stereogenic oligophosphine is expected to reach “0” as the number of chiral P atoms increases because long P-stereogenic oligophosphines are likely to be syndiotactic polymers. However, the [a]D25 of (S,R,S,R,R,S,R,S)-17-BH3 and (S,R,S, R,S,R,R,S,R,S,R,S)-18-BH3 exhibited positive values of þ5.2 (c 1.0 in CHCl3) and þ4.7 (c 0.5 in CHCl3), respectively [20c]. This result implies that chiral P atoms rotate the plane of polarized light counterclockwise, whereas the higher ordered structure of the optically active oligomers rotates it clockwise [21].

470

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

16.3 P-STEREOGENIC POLYMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN 16.3.1 P-Stereogenic Polymers Containing Chiral “P” Atoms in the Repeating Unit of the Main Chain As mentioned, the methyl group substituted at a borane-coordinated P atom can be lithiated by alkyllithium reagents, which enables us to prepare wide varieties of Pstereogenic phosphines with various functional groups. Scheme 16.11 shows the synthetic procedure for a bifunctional monomer with the P-stereogenic bisphosphine-borane unit. The treatment of (S,S)-3-BH3 with an excess amount of s BuLi with N,N,N0 ,N0 -tetramethylethylenediamine (TMEDA) formed a dilithiated intermediate. Nucleophilic substitution with m-iodobenzyl bromide afforded the corresponding P-stereogenic bisphosphine-borane (S,S)-19-BH3 in 59% yield [4d]. It is noted that the bisphosphine unit retains the configuration of the P-stereocenters during this reaction. Polymerization of (S,S)-19-BH3 with m-diethynylbenzene derivative 20 was carried out in the presence of a catalytic amount of Pd(PPh3)4/ CuI to produce P-stereogenic polymer 21-BH3 in 73% yield. A dodecyloxy group was employed for the solubility of the polymer in common organic solvents. The number-average molecular weight (Mn) and weight-average molecular weight (Mw) were calculated to be 7300 and 16,800, respectively, by gel permeation chromatography (GPC). Coordinated boranes were readily removed by DABCO to obtain polymer 21 in 80% isolated yield, as shown in Scheme 16.12. The reaction of 21 with PdCl2(cod) afforded polymer complex 21-Pd in 45% yield (Scheme 16.12). The quantitative removal of boranes and complete complexation with Pd were confirmed by 1 H and 31 P nuclear magnetic resonance (NMR) spectroscopy. A shift of the GPC curve of polymer 21-BH3 was observed as a result of the complexation; this result could be attributed to the compact structure of 21-Pd on account of the prohibition of the rotary motion of the bisphosphine-palladium unit. BH3

Me

P

BH3

Ph P

s

Me

Ph

BuLi/TMEDA +

Li–H2C

Ph

P

P

CH2–Li+

Ph

BH3

BH3

(S,S)-3-BH3 I

BH3

Br

Ph

I

P

P

I

Ph

BH3

(S,S)-19-BH3, 59%

SCHEME 16.11. Synthesis of bisphosphine-borane monomer (S,S)-19-BH3.

P-STEREOGENIC POLYMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN

471

OC12H25 (S,S)-19-BH3

Pd(PPh3)4, CuI

+

20 BH3 Ph

P

P

n

Ph

BH3

21-BH3, 73% Mw = 16800 Mn = 7300

OC12H25

N

Ph N

P

P

n

Ph

21, 80%

Ph

Ph

P

PdCl2(cod)

OC12H25

P Pd

Cl

Cl n

21-Pd, 45% C12H25O

SCHEME 16.12. Synthesis of P-stereogenic polymer 21-BH3 and its complexation.

The ultraviolet (UV)-vis absorption spectra and circular dichroism (CD) spectra of 21-BH3, 21, and 21-Pd in diluted CHCl3 (1.0  105 M) are shown in Figure 16.6. The UV spectra exhibited absorption peaks from 260 to 350 nm derived from the p-p* transition band of a m-phenylene-ethynylene moiety. Weak Cotton effects appeared in the CD spectra of 21-BH3 and 21, whereas polymer complex 21-Pd exhibited a clear Cotton effect (Figure 16.6). Flexible ethylene chains of 21-BH3 and 21 do not affect the polymer structure, which presumably resulted in the negligible Cotton effects. In the case of 21-Pd, the fixed structure of the P-stereogenic bisphosphine unit by complexation transfers the chirality to the m-phenyleneethynylene moiety. According to studies on the dependence of the CD spectrum of 21-Pd on the molecular weight [4d], the observed Cotton effect of 21-Pd originates from the chirality of the m-phenylene-ethynylene unit induced by the neighboring chiral P atom rather than by the chiral higher ordered structure of the polymer (e.g., a one-handed helix).

472 0.5

1

1.5

2

2.5

3

[θ ] x 10–4 / deg·cm2·dmol–1

BH3

P

Ph

P Pd

Cl

P

P

Ph

Ph

21-Pd

Cl

Ph

21

Ph

P

21-BH 3

Ph

P

BH3

C12H25O

OC12H25

OC12H25

n

FIGURE 16.6. UV-vis absorption spectra and CD spectra of 21-BH3, 21, and 21-Pd (CHCl3, 1.0  105 M).

λ /nm

-14 0 240 260 280 300 320 340 360 380 400

-12

-10

-8

-6

-4

-2

0

2

ε x 10–5 / L·mol–1·cm–1

n

n

P-STEREOGENIC POLYMERS CONTAINING CHIRAL “P” ATOMS IN THE MAIN CHAIN

473

Monomer (S,S)-22-BH3 was prepared by reacting the dilithiated intermediate with p-iodobenzyl bromide, which led to the P-stereogenic polymer 23-BH3 possessing rigid rod p-phenylene-ethynylene linkers by the Sonogashira–Hagihara coupling reaction (Scheme 16.13) [4a]. As shown in Scheme 16.13, the dilithiated intermediate from (S,S)-2-BH3 was directly reacted with comonomers such as o,m,p-xylylene dibromide and 4,40 -bis(bromomethyl)azobenzene to yield the corresponding P-stereogenic polymers 24a–c-BH3 [4b] and trans-25-BH3 [4c], respectively. The azobenzene units of trans-25-BH3 isomerized to the cis-form in solution by UV irradiation and reverted to the trans-form reversibly by heating (Scheme 16.14). The treatment of trans-25-BH3 with CF3SO3H and KOH removed the coordinated boranes, and the subsequent reaction with PtCl2(cod) afforded trans-25-Pt. It took longer for trans-25-Pt to recover from the cis-form to the trans-form than it did for trans-25-BH3 because of the reduced mobility of trans-25-Pt by the chelate coordination of the bisphosphine unit. No clear Cotton effect was observed in the CD spectra of trans-25-BH3, whereas trans-25-Pt exhibited a weak Cotton effect in the region of the p-p* band of the azobenzene unit induced by the chelate coordination of the P-stereogenic bisphosphine moieties. 16.3.2 Optically Active Dendrimers Containing the P-Chiral Bisphosphine Unit as the Core P-Stereogenic dendrimers (S,S)-26-BH3 and (S,S)-27-BH3 were obtained in 64% and 70% yield [22], respectively, with the convergent dendrimer synthetic method [23] by the reaction of the dilithiated intermediate with benzyl ether dendrons (Scheme 16.15). The CD spectra of (S,S)-26-BH3 and (S,S)-27-BH3 exhibited weak Cotton effects induced by the P-chirality of the core near the region of the p-p* band of benzene rings. Recently, nanosized phosphine ligands with flexible or rigid dendritic frameworks have attracted significant scientific interest because of their improved catalytic performance toward transition-metal–catalyzed homogeneous reactions [24]. P-Stereogenic dendrimers such as (S,S)-27-BH3 possess promising potential to be applied in asymmetric reactions for chiral nanosized ligands leading to unique chemo-, stereo-, and regioselectivities. Entries of P-stereogenic phosphines with third- and fourth-generation dendrons are anticipated. 16.3.3 Helical Polymers Containing Chiral “P” Atoms in the Terminal Unit Lithiated P-stereogenic phosphine can be employed as an initiator for the anionic polymerization of methacrylate monomers. Table 16.1 shows the synthetic schemes and polymerization results [25] of triphenylmethyl methacrylate (TrMA) initiated by (S,S)-2-BH3, (R,R)-2-BH3 [20c], and optically inactive bisphosphine 2-BH3 with 1 equiv of s BuLi. Anionic polymerization of TrMA proceeded smoothly to obtain the corresponding poly(TrMA)s in good yields (Table 16.1). It is well established that TrMA with a bulky triphenylmethyl group provides a stable one-handed helical polymer by initiator- as well as ligand-controlled anionic polymerization [26]. The

474

(S,S)-2-BH3

Br

BuLi/amine

s

I

N

BH3

P

Bu

t

Bu

P

BH3

Br

Bu

t

t

CH2–Li+

BH3

P

Bu

BH3

P

Bu

t

trans-25-BH3, 62% Mw = 5000 Mn = 3000

2C

P

BH3

Br

N

I

N

Br

n

Br

Bu

BH3

P

Bu

t

BH3

P

Bu n

24a-c-BH3 (a: ortho, 11%, Mw = 3200, Mn = 1000) (b: meta, 11%, Mw = 1900, Mn = 1500) (c: para, 15%, Mw = 2700, Mn = 1900)

t

P

t

23-BH3, 21% Mw = 10800 Mn = 6100

Bu

BH3

t

P

BH3

SCHEME 16.13. Synthesis of P-stereogenic polymers 23-25-BH3.

N

+Li–H

I

Bu

t

(S,S)-22-BH3, 15%

t

P

BH3

n

475

CYCLIC PHOSPHINES USING P-STEREOGENIC OLIGOMERS AS BUILDING BLOCKS

trans-25-BH3

1) CF3SO3H 2) KOH 3) PtCl2(cod)

tBu

tBu

P Cl

UV

Δ

P Pt

N N

Cl

n

trans-25-Pt UV

BH3 P tBu

t

Bu

N

tBu

N

t

Bu

P

P

BH3

Cl

cis-25-BH3

n

Δ

P Pt

N N

Cl

cis-25-Pt n

SCHEME 16.14. Complexation and isomerization of 25-BH3.

positive specific rotation of poly(TrMA)s 28a-c-BH3 increased with increasing molecular weight, suggesting that 28a–c-BH3 are the one-handed helical polymers. The screw sense of 28a–c-BH3 induced by the P-stereogenic phosphine unit at the initiation point was the same as that of the polymers initiated by 9-fluorenyllithium or n BuLi/()-sparteine according to the positive specific rotation [26]. Poly(TrMA) 29-BH3 polymerized from the enantiomer (R,R)-2-BH3 [20c] possessed a negative specific rotation of 74.8 (c 0.5 in THF), indicating that the opposite helical sense was induced. In addition, 30-BH3 did not rotate the plane of polarized light, and its specific rotation was zero. The CD spectra of 28b-BH3, 29-BH3, and 30-BH3 in diluted tetrahydrofuran (THF) (1.0  105 M) are shown in Figure 16.7. Poly(TrMA) 28b-BH3 exhibited a positive Cotton effect in the range of the p-p* band of phenylenes in the TrMA unit. It is reported that helical poly(TrMA) shows a Cotton effect in this range [27]; therefore, the positive Cotton effect of 28b-BH3 is consistent with its one-handed helical conformation. In Figure 16.7, 29-BH3 exhibited a negative Cotton effect at around 240 nm, which was the mirror image of that of 28b-BH3. Poly(TrMA) 30-BH3 from the optically inactive initiator did not exhibit any Cotton effect. Because the (S,S)-2-BH3 unit does not absorb UV light at this wavelength, these results suggest that the poly(TrMA) main chain forms a one-handed helix induced by the chirality of the P-stereogenic phosphine unit. 16.4 CYCLIC PHOSPHINES USING P-STEREOGENIC OLIGOMERS AS BUILDING BLOCKS 16.4.1 Stereospecific Synthesis of trans-1,4-Diphosphacyclohexane As described previously, borane coordinated to a phosphorus atom enables the lithiation of the methyl group. As shown in Scheme 16.16, treating (S,S)-2-BH3 with 2.2 equiv of s BuLi and amine such as ()-sparteine and TMEDA generated a

476

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

O BH3 O

P t

Bu

t

O

P

Bu

BH3

O

(S,S)-26-BH3, 64%

O

O

Br

BH3 sBuLi/amine

(S,S)-2-BH3

+Li–H

2C

P t

tBu

P

CH2–Li+

Bu

BH3

O O

O

O

O

O

Br

O

O

O

O

BH3 P

O

O

t

But

P

Bu

BH3

O

O

O O

(S,S)-27-BH3, 70% O

O

SCHEME 16.15. Synthesis of P-stereogenic dendrimers (S,S)-26-BH3 and (S,S)-27-BH3.

477

CYCLIC PHOSPHINES USING P-STEREOGENIC OLIGOMERS AS BUILDING BLOCKS

TABLE 16.1. Results of polymerization of TrMA and specific rotation of the polymers O BH3

1 equiv. sBuLi

(S,S)-2-BH3

tBu

Me

P tBu

P

CPh3

BH3

O CH2–Li+

Me

P

P

(R,R)-2-BH3

tBu

2C

P

P tBu

TrMA Me

tBu

Me

P tBu

P

Me

O

O

29-BH3

Me

tBu

P

CH2–Li+

tBu

TrMA Me

P

P

tBu

BH3

BH3

Me

BH3 tBu

P

P tBu

BH3

BH3

1 equiv. sBuLi

BH3 tBu

P

n

BH3 BH3

Ph3C

CPh3

28-BH3

BH3

BH3 +Li–H

O n

tBu

BH3

1 equiv. sBuLi

O

tBu

TrMA

BH3

O

O

CPh3

n

30-BH3

2-BH3

Initiatora

Polymer

Initiator/TrMA

Yield/%

Mn

Mw/Mn

[a]25Db

(S,S)-2-BH3 (S,S)-2-BH3 (S,S)-2-BH3 (R,R)-2-BH3 2-BH3

28a-BH3 28b-BH3 28c-BH3 29-BH3 30-BH3

1/5 1/10 1/15 1/10 1/10

66 87 80 80 76

1500 2700 4200 2300 2400

1.3 1.3 1.3 1.2 1.2

þ16.9 þ83.3 þ109.6 74.8 0

a b

With 1 equiv of sBuLi. c 0.5 in THF.

dilithiated intermediate [28]. This intermediate was reacted with CuCl2 and aqueous NH3 to afford trans-1,4-di-tert-butyl-1,4-diphosphacyclohexane-diborane trans-31BH3 in 73% yield by the intramolecular coupling reaction. The same synthetic procedure was applied to (S,S)-3-BH3 to yield the trans-1,4-diphenyl-1,4-diphosphacyclohexane-diborane trans-32-BH3 (56%). By reacting trans-31-BH3 with excess CF3SO3H and subsequently with KOH, its boranes were removed to obtain trans-31 in 91% yield. The removal of boranes from trans-32-BH3 was carried out using DABCO to produce trans-1,4-diphenyl-1,4-diphosphacyclohexane trans-32 in 94% yield. X-ray crystallographic analysis revealed their solid state structures [28]. Figure 16.8 shows the structure of trans-32-BH3 as a representative example. The chair conformation with equatorial phenyl groups and axial boranes were confirmed. Diphosphacycloalkanes are generally obtained as a mixture of cis- and transstereoisomers and are separated by chromatography [29]. Concerning eight- or more-membered rings, the only method for the stereoselective synthesis of cisdiphosphacycloalkane was reported by Alder and coworkers [30]. The present system shown in Scheme 16.16 yields the 100% trans-isomer because of stereospecific synthesis. This is of considerable importance for organic and organometallic chemistry.

478

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS BH3

30

tBu

28b-BH3

Me

P tBu

O

O

P

CPh3

n

BH3

20

[θ ] x10-4 / deg cm2 dmol-1

BH3

10

30-BH3

Me

P tBu

O

tBu

P

O

CPh3

n

BH3

0

-10 Ph3C

29-BH3

-20

O n

O

tBu

P

BH3 P tBu

Me

BH3

-30 220

230

240

250 260 270 Wavelength / nm

280

290

300

FIGURE 16.7. CD spectra of 28b-BH3, 29-BH3, and 30-BH3 (THF, 1.0  105 M).

However, in order to obtain pure cis-diphosphacyclohexane stereospecifically, meso-bisphosphine-borane should be prepared as a precursor instead of (S,S)bisphosphine-borane, as shown in Scheme 16.17. However, no easy method for the stereoselective and stereospecific synthesis of the meso-bisphosphine-borane has been found. Accordingly, the following reaction method was attempted (Scheme 16.18) [28]. The coupling reaction of dimethylphenylphosphine-borane without ()-sparteine yielded a mixture of meso-32-BH3 and racemi-32-BH3. Isolation of pure meso-32-BH3 was unsuccessful, and an intramolecular coupling reaction of the mixture was carried out to obtain a mixture of cis-32-BH3 and trans-32-BH3. They could be separated by column chromatography on SiO2 to afford cis-32-BH3 and trans-32-BH3 in 16% and 17% yields, respectively. 16.4.2 Synthesis of 1,4,7,10-Tetraphosphacyclodocecane, 12-Phosphacrown-4 As mentioned briefly in Section 16.2.3, a cyclic compound was obtained in addition to P-stereogenic octaphosphine-borane (S,R,S,R,R,S,R,S)-17-BH3 and dodecaphosphine-borane (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3 by the reaction of (S,R,R,S)-15BH3 with 5 equiv of s BuLi/amine (Scheme 16.9). This cyclic compound 33-BH3 was identified as 1,4,7,10-tetra-tert-butyl-1,4,7,10-tetraphosphacyclodocecane-tetraborane, which was obtained in 15% yield by the intramolecular coupling reaction of

479

CYCLIC PHOSPHINES USING P-STEREOGENIC OLIGOMERS AS BUILDING BLOCKS

(S,S)-2-BH3

BH3

2.2 equiv sBuLi/amine +Li–H C 2

tBu

P

P

t

CH2–Li+

Bu BH3

1) CuCl2 2) aq. NH3

BH3 t

Bu

P P

1) CF3SO3H 2) KOH

t

Bu

tBu

P P

tBu

trans-31, 91%

BH3

trans-31-BH3, 73%

(S,S)-3-BH3

BH3

2.2 equiv sBuLi/amine

Ph +

Li–H2C

P

P

CH2–Li+

Ph BH3 BH3

1) CuCl2 2) aq. NH3 Ph

N N

P P

Ph

Ph

P P

Ph

trans-32, 94%

BH3

trans-32-BH3, 56%

SCHEME 16.16. Stereospecific synthesis of trans-1,4-diphosphacyclohexanes.

dilithiated (S,R,R,S)-15-BH3 [20a], as illustrated in Scheme 16.19. The reaction proceeded stereospecifically, and the resulting 33-BH3 possessed four tert-butyl groups at the upper and lower sides alternately against the phosphacrown ring (Figure 16.9) owing to the chirality of the P-stereogenic tetraphosphine precursor. B P

P B

FIGURE 16.8. Molecular structure of trans-32-BH3.

480

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

BH3 R

BH3 BH3

BH3 BH3

R

BH3

P

BH3

R P

P

R P

P R

P R

Me

P

Me

Me

P

R

R

BH3

meso

cis

SCHEME 16.17. Retro-synthesis of cis-1,4-diphosphacyclohexane-borane.

It is a simple but unprecedented structure consisting of four ethylene units and four phosphorus junctions instead of oxygen atoms in 12-crownether-4. 16.4.3 Synthesis of 18-Diphosphacrown-6 Although 12-phosphacrown-4 33-BH3 is the first synthetic crown ether derivative comprising –CH2CH2–PR– units, the chirality of the P-stereogenic precursor (S,R,R, S)-15-BH3 disappears from the phosphacrown ring after the reaction. Various optically active crown ether derivatives have been prepared [31] since the discovery of dibenzo-18-crown-6 in 1967 [32]; until recently, however, there have been no reports on the synthesis of optically pure crown ether derivatives containing chiral heteroatoms that interact directly with guests in the ring skeleton. Scheme 16.20 shows the synthetic routes for the optically pure P-stereogenic phosphacrown derivative with two chiral P atoms instead of oxygen as the chiral heteroatom [33]. Treatment of dilithiated (S,S)-3-BH3 with CO2 gas formed P-stereogenic dicarboxylic acid, which was then, without isolation, reduced using BH3

1) sBuLi 2) CuCl2 3) aq. NH3

BH3 Ph

P

Me

Me

Ph Me

P

Me

P

Ph

BH3

meso-3-BH3 mixture of BH3

46%

BH3

Ph Me

Ph

without (–)-sparteine

Me

P

P

Me

Ph

P

Me Ph

P

BH3

BH3

racemi-3-BH3 1) sBuLi 2) CuCl2 3) aq. NH3

separation by SiO2 column

BH3 Ph

BH3

P

BH3 P Ph

cis-32-BH3, 16%

+

Me

Ph

P P

Ph

BH3

trans-32-BH3, 17%

SCHEME 16.18. Synthesis of cis- and trans-1,4-diphosphacyclohexanes.

CYCLIC PHOSPHINES USING P-STEREOGENIC OLIGOMERS AS BUILDING BLOCKS

5 equiv. sBuLi/amine

(S,R,R,S)-15-BH3

BH3 +Li-H

2C

t

BH3

tBu

P

481

P

P t

Bu

BH3

P

tBu

P

CH2

tBu

-Li+

t

P

Bu

P

Bu

tBu

BH3

t

CH2-Li+ CH2-Li+

P=P 1) CuCl2 2) aq. NH3

Bu

P

BH3

P tBu

P

t-Bu

P

P

tBu

t-Bu 33-BH3, 15% + (S,R,S,R,R,S,R,S)-17-BH3, 29% + (S,R,S,R,S,R,R,S,R,S,R,S)-18-BH3, 8%

SCHEME 16.19. Construction of the 12-phosphacrown-4 skeleton.

BH3THF to afford the corresponding P-stereogenic dialcohol (S,S)-34-BH3 in 42% yield. Williamson ether synthesis was carried out between (S,S)-34-BH3 and triethyleneglycol bis(p-toluenesulfonate) with NaH to obtain the optically pure P-stereogenic 18-diphosphacrown-6-borane (S,S)-35-BH3 in 17% isolated yield. The coordinated boranes could be removed by treating (S,S)-35-BH3 with DABCO (Scheme 16.20). A pair of two conformers was formed by recrystallization of (S,S)-35-BH3 (Figure 16.10), and each of the conformers was rapidly interconverted in solution at room temperature. Two phenyl groups of one conformer occupied pseudoequaB P

P B

B P

P B

FIGURE 16.9. Molecular structure of 33-BH3.

482

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

1) excess sBuLi/TMEDA 2) CO2 3) H+

BH3 Ph

HOOC

(S,S)-3-BH3

P

COOH

P

Ph BH3

1) NaH BH3

2)

Ph

BH3·THF

P

HO

O

TsO

O

OTs

OH

P

Ph BH3

(S,S)-34-BH3, 42% BH3 BH3

Ph

Ph

Ph

P

N

P

O

O

O

O

P

N

O

O

Ph

P

O

(S,S)-35-BH3, 17%

O

(S,S)-35, 90%

SCHEME 16.20. Synthesis of P-stereogenic phosphacrown.

O

O

O O P P B

P B

P

B B

O

O

O

O

FIGURE 16.10. Molecular structure of (S,S)-35-BH3.

CYCLIC PHOSPHINES USING P-STEREOGENIC OLIGOMERS AS BUILDING BLOCKS

483

torial positions, and those of another conformer occupied pseudoaxial positions. The ring size of (S,S)-35-BH3 was slightly larger than that of 18-crown-6 because of the
longer P–C bonds, i.e., an average length of approximately 1.83 A. However, (S,S)-3-BH3 can be synthesized enantioselectively from dimethylphenylphosphine-borane [11] using ()-sparteine, which is a natural product extracted from scotch broom as a chiral ligand for lithium. Because of the difficulty of the enantioselective synthesis of (R,R)-3-BH3, an alternative synthetic route was adopted for the synthesis of (R,R)-35-BH3 (Scheme 16.21) [33]. One methyl group of dimethylphenylphosphine-borane was enantioselectively lithiated by s BuLi with ()-sparteine, and successive treatment with CO2 gas afforded the carboxylic acid intermediate. This was reduced by BH3THF to obtain (S)-36-BH3 in 71% yield with 87%ee. The remaining methyl group of (S)-36-BH3 was reacted with s BuLi with TMEDA, and the intermolecular homocoupling reaction by CuCl2 and aqueous NH3 yielded the crude dialcohol (R,R)-34-BH3. The undesirable impurities meso-34-BH3 and (S,S)-34-BH3 were successfully removed by the repeated recrystallization from hot toluene and hexane, and the optically pure P-stereogenic bisphosphine (R,R)-34BH3 was isolated in 36% yield with >99%ee. The reaction of (R,R)-34-BH3 and triethyleneglycol bis(p-toluenesulfonate) with NaH afforded optically pure (R,R)-35BH3 in 22% yield. 1) 1.2 equiv sBuLi/(–)-sparteine 2) CO2 3) H+

BH3 Ph

P

BH3

Me

Me

Me

P

BH3·THF COOH

Ph

1) 2.5 equiv s BuLi/TMEDA 2) Cu/Cl2 3) aq. NH3

BH3 Me

P

OH

BH3 Ph

HO

P

Ph

P

OH

Ph

BH3

(S)-36-BH3, 71%

(R,R)-34-BH3, 36%

BH3 BH3

1) NaH 2)

TsO

Ph

Ph O

O

P

OTs

P

O

O

O

O

(R,R)-35-BH3, 22%

SCHEME 16.21. Synthesis of P-stereogenic phosphacrown enantiomer.

484

P-STEREOGENIC OLIGOMERS, POLYMERS, AND RELATED CYCLIC COMPOUNDS

Cl

Cl

Ph

P

PdCl2(cod)

Pd

Pd P

Ph O

69%

O

O

O

(S,S)-35 Cl

Cl

P

PtCl2(cod) 58%

Pt

Pt

Ph

P

Ph O

O

O

O

SCHEME 16.22. Complexation of (S,S)-35 and molecular structures of Pd and Pt complexes.

P-Stereogenic phosphacrown (S,S)-35 formed 1:1 metal complexs with transition metals such as Pd and Pt in 69% and 58% yields, respectively [33]. Pd and Pt coordinated to the bisphosphine unit outside the phosphacrown ring (Scheme 16.22). The molecular structures revealed that their phenyl groups existed at two diagonal quadrants and occupied quasi-equatorial positions. Such a structure is observed in the case of a series of Rh-(P-chiral bisphosphine) complexes [3a, 9b, 10, 34]. Various phosphorus-containing cyclic compounds have thus far been prepared including crown ether derivatives consisting of –CH2CH2–Y– (Y ¼ P, O, S, and N) [35–39]; they were mostly covered in the excellent review by Caminade and Majoral [40]. Among these compounds, optical resolution of racemic P-stereogenic phosphacrown derivative racemi-36 was achieved [37]. As shown in Scheme 16.23, spontaneous crystallization of the racemi-Ni complex from racemi-36 was possible, Ph

Ph P

P

O

O

N

N H

N N

H

1) NiCl2·H2O 2) HBF4·Et2O 3) NaNCS

meso-Ni complex

racemi-Ni complex

spontaneous crystallization

SCHEME 16.23. Optical resolution of P-stereogenic phosphacrown derivatives.

REFERENCES

485

and the enantiomers were separated by the Pasteur’s method [41]. Thus, the synthetic methods shown in Schemes 16.20 and 16.21 are practical synthetic routes for Pstereogenic phosphacrown derivatives.

16.5 CONCLUSIONS This account has focused on the syntheses of optically active P-stereogenic oligomers and polymers. Cyclic compounds containing P atoms prepared from P-stereogenic oligomers were also described. Many of the P-stereogenic oligomers and polymers introduced here are synthesized by incorporating P-stereogenic bisphosphines into carbon frameworks as building blocks. This method does not require any asymmetric reactions and allows access to optically pure P-stereogenic oligomers and polymers as well as cyclic phosphines with stereoregulated P atoms. These P-stereogenic compounds create optically active spaces by the chiral P atoms and possess high affinity to transition metals characterized by the tertiary phosphines. The synthesis and investigation of these compounds have just begun. It is anticipated that continued efforts to synthesize optically active P-stereogenic oligomers, polymers, and cyclic compounds will lead to greater possibilities beyond chiral ligands for transition metals. REFERENCES [1] Baechler, R. D.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 3090–3093. [2] (a) Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev. 1994, 94, 1375–1411. (b) Johansson, M. J.; Kann, N. C. Mini-Rev. Org. Chem. 2004, 1, 233–247. (c) Grabulosa, A.; Granell, J.; Muller, G. Coord. Chem. Rev. 2007, 251, 25–90. [3] (a) Cr
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INDEX

Achiral diene ligands, 452, 453 Acid-catalyzed polymerization, 225, 228 Acrylamide, 21 Acrylate, 21 Acrylonitrile, 23 Addition polymerization, 21, 423–425 AIP-RIM, 439–442 Aldol reaction, 17, 20, 29, 35, 46, 49, 50, 52, 63, 66–74, 76, 77, 209, 218 Alkylation, 29, 30, 35, 46, 218 Alkynes, 232 Al-Li-BINOL complex, 340, 341 Al-Li-bis(binaphthoxide) (ALB), 293 Allylation, 28 AlMe3, 337–339 Alternating copolymerization, 408, 410–412, 415, 418 Amidine, 213 Amidinium-carboxylate, 287 a-Amination, 22, 49 Amine, 457, 475 Amine catalyst, 45 b-Amino acid, 230 Amino-pyrimidinone, 168

a-Aminoxylation reaction, 69 Anion-exchange resin, 21 Anionic polymerization, 21, 51, 473 ring-opening polymerization, 271, 273, 274 ArgoGel, 20 Aromatic ketimines, enantioselective reduction of, 258 Asymmetric-induced polymerization (AIP), 425 Asymmetric polymerizations, 2, 9–11, 241 of achiral N-substituted maleimides, 368 of chiral N-substituted maleimides, 372 of N-substituted maleimides, 365 radical polymerizations, of N-substituted maleimides, 378 Asymmetric reaction, 126, 127, 132, 142, 143, 145, 457, 458, 473 addition, 283–285 alkylation, 306 allylation, 259 allylic alkylation, 258 aminohydroxylation, 190

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.

489

490

INDEX

Asymmetric reaction (Continued ) Brown allylation, 183 carbonyl-ene reaction, 299, 317 Diels-Alder reaction, 283 epoxidation, 286 hydrogenation, 285, 458, 462, 463 hydrosilylation, 259, 261, 288 Michael reaction, 294 reduction, 288 Asymmetric synthesis, 126 Atomic force microscopy(AFM), 238 Atropisomerism, 268, 269 Aza-Morita-Baylis-Hillman reaction, 49 Azides, 232 Azobenzene, 418 Baeyer-Villiger oxidation, 415 Bed, 131–133, 142, 151 Biased library, 110 Biginelli reaction, 169 BINAP, 348 Binaphthol, 389–391, 403, 404 1,10 -Bi-2-naphthol (BINOL), 293, 324, 327–331, 337, 339, 358 Biocatalysis, 151 Biotins, 233 N,N0 -Bis(acrylamide), 21 Bis(oxazoline), 139, 140, 141 1,2-Bis(phenylphosphino)ethane, 458 Bisphosphine, 470, 471 Block copolymerizations, 229 Block copolymers, 251 Borane, 462, 464, 470, 478 Boron enolates, 163 a-Bromination, 25 Brønsted acid, 50 Bulk polymerization, 21 t-BuOOH, 344–347 b-Carbolines, 176 Carbon monoxide, 409, 412, 413 Cascade reaction, 52 Catalyst immobilization bottom-up approach, 66, 71, 74, 81, 84 postmodification strategy, 66, 71, 74, 83, 84 Catalyst(s), 125, 127, 132, 134–136, 143–145, 152

analog, 311 control, 409, 415 Cation-exchange resin, 21 Cationic polymerization, 21 C2 axis of symmetry acyclic olefin monomer, 366 cyclic olefin monomer, additional polymerization of, 366–367 C2 chiral biaryl, 267–270, 274, 277, 289, 290 binaphthyl, 268, 271, 277, 280, 283 spirobifluorene, 274, 277, 282 Cellulose, 20 Chain-end control, 409 Charge relay system, 226 Chiral, 126, 132, 133, 135–137, 139, 142, 147, 150–152 auxiliary, 158 catalyst, 223 center, 457 cocatalysts, 433, 434, 436 discrimination using poly(N-substituted maleimide), 378 imprint effect, 446 initiators, 236, 248 ligand(s), 119, 213, 218, 467, 483 memory, 262 multidentate ligand, 315 organocatalysts, 4–6 poly(diphenylacetylene) membranes, 441 polymer catalysts, 255 polystyrene monolith, 444–446 recognition, 209 stationary phase (CSP), 209, 378 surfactant monomer, 302 synthesis, 158 Chirality, 424, 426, 432, 433, 438 inducer, 22 of 1-mono-/1,1-disubstituted and 1,2-disubstituted olefins, 365 propagation of, 284 Chirogenic center, 415 Chlorination, 49 a-Chlorination, 25, 35 Chloromethylstyrene, 20 Cholesteric liquid crystals, 244 Chromatographic resolution, 239 Cinchona alkaloid, 22, 23

INDEX

Cinchona alkaloid quaternary ammonium salt, 23, 28, 29 Cinchonidine, 22 Cinchonine, 22 Circular dichroism (CD), 201, 203–205, 394, 410 spectroscopy, 225 spectrum, 471 Click reaction, 20, 232 CMHP, 347, 348 Column-based flush and flow system, 25 Combinatorial approach, 157 Combinatorial chemistry, 17 Combinatorial decoration, of natural products, 184 Condensation polymerization, 424, 448, 449 Configurational chirality, 409 Configurational isomerization, 207, 208 Conjugate addition of nitroalkene, 22 Conjugated polymer, 271, 272 p-Conjugated polymers, 423–425, 427 Continuous-flow reactions, 69 Continuous flow systems, 1, 3, 8, 18 Convergent method, 473 Corey-Bakshi-Shibata asymmetric reduction, 49 Cotton effect, 207, 213, 471, 473, 475 Coupling efficiency, 21 Coupling reaction, 18, 20 Cross-coupling, 271, 389–399, 403, 404 Crown ether, 480, 484 12-Crownether-4, 480 a-Crystal, 418 b-Crystal, 418 C2-symmetric ligand, 410 Cyanation reaction, 22, 136 Cyanine, 211, 212 Cyclic carbonate, 271, 273, 274 Cycloaddition, 22, 136 Cyclopropanation, 22, 139–141, 287, 288 Darzens condensation, 29 Decarboxylation, 22 Degree of cross-linkage, 21, 22 Dendrimer, 323, 355–357, 473 Dendrimer supported BINOL (DSB), 294 Dendrimer-supported chiral catalysts, 6 Dendritic catalysts, 71 Dendronized polymer, 323, 358, 359

491

Density functional theory(DFT) calculation, 244 Depinanylsilylation, 443, 445 Deprotection, 20, 22 Desymmetrization, 102, 111 meso-compound, 22 meso-cyclic anhydride, 27 Dialkylzinc, 132–135 enantioselective addition of, 256 Diarylprolinol, 49 Diarylprolinol silyl ether, 80–83 Diastereomer, 459 Diazomethane, esterification by, 242 Diblock copolymer, 252 Diels-Alder reaction, 20, 29, 35, 38–41, 136–139 a, w-Diene, 414 Differential scanning calorimetry (DSC), 465 Dihydropyrimidines, 170 Dihydroquinidine, 25 Diisopropylethylamine, 28 4-(Dimethylamino)pyridine (DMAP), 27 Dimethylpoly(ethylene glycol) (DiMePEG), 43 DIPAMP, 458 Dipeptide, 93, 103, 107, 109, 118 2,5-Diphenyl-2,5-diphosphahexane, 458 18-Diphosphacrown-6, 480, 481 1,4-Diphosphacyclohexane, 475, 477 1,3-Dipolar cycloaddition, 35, 38, 337, 338 Direct aldol reaction, 262 Direct asymmetric aldol reaction, 103 Directed library, 111 2,5-Di(tert-butyl)-2,5diphosphahexane, 458 Diversity-oriented synthesis (DOS), 188 DNA, 201 DNA-bound copper catalyst, 283 Dodecaphosphine, 466, 478 Double activation, 109 Double-helical, 287, 288, 459, 460 Dynamic helical polymer(s), 203, 207, 216 Dysidiolide analogs, 180 Electrospinning, 82 Emulsion polymerization, 21 Enamine catalyst, 53 Enantiomerically pure compound, 17

492

INDEX

Enantiomeric excess (ee), 458 Enantiomer-selective polymerization, 230 Enantiomorphic-site control, 409 Enantioselective adsorption, 444, 446 aldol reaction, 164 cycloaddition, 173 epoxidation, 257 permeation, 436, 438, 442, 443 pervaporation, 442 Suga-Ibata reaction, 191 synthesis, 157 Enantioselectivity, 209, 218 Enders cascade, 81 Enders cascade reaction, 52 Ene-thiol click reaction, 23 Enzyme, 18, 46, 92–94, 105 Epoxidation, 29, 35, 52, 341–348 Erythro-diisotactic structure, 367 Erythro-disyndiotactic structure, 367 ESR, 454 Ethylene glycol dimethacrylate, 21 Ethylene oxide, 21 Exciton-coupled circular dichroic method, 376 Exiton coupling, 450 Ferrocene, 237 Fluoresce, 231 a-Fluorination, 24 N-Fluorobenzenesulfonimide (NFSI), 24 Friedel-Crafts alkylation, 22, 35, 40 Fullerene(s), 213–216 Galf-life, 451 Galvinoxyl, 446, 447, 449, 450, 454 Ga-Na-bis(binaphthoxide) (GaSB), 293 Gas phase polymerization, 21 Gel, 127, 129, 130, 132–135, 137 Gel permeation chromatography (GPC), 470 Glass transition temperature (Tg), 465 Glycine Schiff base, 29 Green chemistry, 18 Grignard reaction, 20 Grignard reagents as initiators, 244 Hajos-Parrish-Eder-Sauer-Wiechert reaction, 17 a-Halogenation, 22

Helical conformation, 417, 419, 427, 431, 439, 440, 442, 444, 452 Helical foldamer conformation, 449 Helical polymers, 2, 3, 6–7, 9–11, 51, 52 Helical reversals, 203 Helical sense, 201, 203–205, 207, 213, 216 Helicity induction, 205, 207, 213, 218 Helicity memory, 203, 205, 208, 209, 213, 216, 218, 219, 242 a-Helix (alpha-helix), 92, 94, 97 Helix inversion, 203, 205, 213, 216, 253 Helix-sense-selective polymerization (HSSP), 10, 202, 218, 284, 425, 427, 429, 430, 433, 434 Helix-sense-selectivity, 452 b-Helix structure, 228 Heteroatom chiral polymers, 10 Heterocyclic compound libraries, 168 Hetero-Diels-Alder reaction, 174, 336, 337 Heterogeneous system, 18, 132, 147 Hetero Michael addition, 161 Hexaphosphine, 461, 462, 464–466 High performance liquid chromatography (HPLC), 209, 216 chemical-bonded-type chiral stationary phases (CSPs) synthesis, 384 Huisgen cycloaddition, 233 Hydrogenation, 349, 351, 353–355 Hydrogen bonds, 230, 237, 429–431, 434, 454 catalyst, 53 Hydrophosphonylation, 22 Hydrosilylation, 218 a-Hydroxylation, 22 cis-4-Hydroxy-L-proline, 69 trans-4-Hydroxy-L-proline, 65, 69, 72 Hyperbranched polymers, 2, 5, 6, 9–10, 389, 390, 394, 396, 397, 399, 400, 403 Imine, hydrocyanation of, 29 Iminium catalyst, 53 Immidazolidin-4-one, 35 Immobilization, 18, 21, 293 Au-MPC, 307 catalyst analog, 311 dendrimer, 294 dendron, 296 gold cluster, 307 metal-bridged polymer, 314 Micelle, 302

INDEX

monolayer, 307 MPC, 307 Imprinted nanogel, 74 Indolactam library, 187 Induced CD (ICD), 203, 205, 211–213, 216, 217 In-situ chiral desubstitution, 442 In-situ desubstitution, 442-444 Inversion energy, 457, 458 Inversion of the helical sense, 261 Ion exchange method, 21 Ion exchange reaction, 34, 41 Ionic bond, 32, 33 Ionic liquids, 41, 66, 69 Isocyanides, 224 trans-cis Isomerization, 270 2,20 -Isopropylidenebis(4-phenyl-2oxazoline), 390 Isotactic, 409–414, 416, 417, 419, 420 Isoxazolines, 173 JandaJel, 20 Jørgensen-Hayashi catalyst, 81, 83. See also Diarylprolinol silyl ether Julia-Colonna reaction, 95–97, 99 Ketone reduction, 334, 335, 336, 351, 353, 354, 355 Khellactones, 180 Kinetic resolution, 22, 27, 41, 91, 98–102, 111, 113, 283 La (OiPr)3, 347, 348 Lantern, 175 Ligand-to-metal charge-transfer (LMCT), 460 transition, 281 Light-harvesting, 231 Like, 409 Linear polymer supported BINOL (LPSB), 306 Liquid crystalline, 246 Liquid-phase combinatorial synthesis (LPCS), 159 Liquid phase polymerization, 21 Living polymerization, 245 MacMillan catalyst, 35 Macrobeads, 167

493

Macrocyclic compound libraries, 165 Macrocyclization, 165 Macromolecular helicity memory, 52 Macromonomers, 436, 437 Macroporous, 127, 129, 130, 136 Magnetic material, 446 Main-chain chirality, 2, 5, 9 Main-chain chiral polymers, 2, 4–6, 11, 35 Main-chain functionalized polymers, 2, 5 Majority rule, 203 Maleimide polymer structures of, 367 Mannich reaction, 22, 49, 69 Maruoka catalyst, 46 Melting point (Tm), 465 Membrane, 424, 426, 427, 432, 434, 436, 438–444 Memory effect, 203, 205, 209, 213, 216–218 Merrifield-like resin, 18, 20, 30, 41 Mesyl-terminated PEG, 37 Metal bridged polymer, 8, 314 Metallosalen complex, 279–283 Metal organic porous material (MOPM), 315 Methylenation, 416 Micelle derived polymer (MDP), 302 Michael addition, 22, 23, 43, 46, 49, 340, 341 Michael reaction, 66, 77, 79–83 Microenvironment, 18, 55 Microporous, 127, 129 Microreactor, 126 Mitsunobu reaction, 20 Molar optical rotation, 412 Molecular-scale voids, 441, 443, 446 Mono-hydroxyl-terminated PEG, 25 Monolayer protected metal cluster (MPC), 307 Monolithic, 129–131, 133, 137, 140, 151, 444–446 Montrmorillonite, 41 Morita-Baylis-Hillman reaction, 22 Multi-angle light scattering (MALS), 303 Multicomponent asymmetric catalysts (MAC), 7–8, 293 Nafion, 50 2-Naphthol, 389–394, 396, 403 Natural-product libraries, 176

494

INDEX

Nickel-catalyzed polymerizations, 225 Nickel complexes, 224 Nitroaldol reaction, 22 Nitrone, 337, 338 Nitronylnitroxide, 449 Nitrophenyl ester, enantioselective hydrolysis of, 256 Noncovalent immobilization, 55 Nuclear magnetic resonance (NMR), 470 Number-average molecular weight (Mn), 470 Number-up, 126 O2, 341, 342, 343 Octaphosphine, 464, 466, 478 a-Olefin, 409, 418 Olefins, dihydroxylation of, 25, 50 Oligo(ethylene glycol), 21 Oligopeptide, 287 One-handed helical polymers, 424, 425, 431, 436, 439, 452 One-handed helicity, 434, 438 One-handed helix, 471, 475 One-pot sequential reaction, 106, 117 Optical activity, 201, 202, 205, 207, 212, 213, 217 Optically active phosphine, 461, 467 Optically active polymer, 34, 457 Optical resolution, 224, 246, 459, 460 using poly(N-substituted maleimide), 381 Optical resolution membrane, 424, 426, 436–438 Organocatalysis, 17, 147 Organocatalyst(s), 209, 218 Organonickel initiator, 251 Oxa Diels-Alder reaction, 175 Oxidation, 49, 143, 145 Oxidative cross-coupling, 389, 391, 392, 394, 396, 399 polymerization, 389, 392–399 m-Oxodititanium complex, 299, 317 Palladium, 407, 411 Palladium initiator, 244 PEA, 429, 430, 432, 433, 438, 450–453 Pentablock copolymer, 253 Pentaphosphine, 461, 462 Peptide-based isocyanides, 226

Peptide library, 100, 109, 111, 112 Persistence length, 207 Perylene diimide (PDI), 231 Phase-transfer catalyst (PTC), 23, 28, 29, 34, 35 Phenylacetylenes, 423–427, 429, 431, 432, 434–439, 441, 442, 448 Phenylene-ethynylene, 471, 473 Phosphine, 457, 462, 473 Phosphoramide, 27 Phosphorus atom, 457, 475 Photovoltaic devices, 231 Piperazinediones, 169 Poly(acetylene)s, 203, 205, 207, 219, 242, 255, 256 Poly(acrylamide), 20 Poly(acrylate), 20 Poly(acrylic acid), 20 Polyaddition, 21 Poly(1-alkene-alt-CO), 419 Poly(allylamine), 216 Poly(amino acid), 50, 93, 94, 96 Polyaniline, 217 Poly(BINAP), 348, 349, 351, 352, 354 Poly(binaphtyl-salen complex), 279 Poly(BINOL), 324–331, 333–347 Poly(carbodiimide)s, 203 Polycarbonate, 271, 273, 274 Polycarbosilane, 457 Polycarbosiloxane, 457 Poly(4-carboxyphenyl isocyanide), 207, 218 Polychloral, 202 Polycondensation, 21 Poly(ethylene glycol) (PEG), 20, 66, 68, 76, 79, 83 Poly(ethylene glycol-acrylamide) (PEGA), 76 poly(ethylene imine), 20 Poly(ethylene oxide) (PEO), 20 Polyguanidine, 202 Poly(isocyanate), 203, 285 Poly(isocyanide)s, 52, 208, 209, 218, 219, 224 Polyketone, 407, 409–411, 413–420 Polymer, 457, 466, 469, 471, 475, 477 Polymer catalyst, 209, 218 Polymer-coated mesocellular form (MCF), 40

INDEX

Polymeric chiral organocatalyst, 5 Polymeric chiral salen ligand, 5 Polymer-immobilized catalysts/ reagents, 192 Polymer-immobilized chiral organocatalyst, 17 acidic, 50, 51 basic, 27, 28 cinchona alkaloid, 23–27 cinchona alkaloid quaternary ammonium salt, 28–35 diarylprolinol silyl ester, 49 MacMillan catalyst, 35–42 Maruoka catalyst, 46 peptide, 50 poly(amino acid), 50 prolinamide, 49 proline, 49 pyrrolidine, 42–46 Polymer-immobilized peptides, 50 Polymerizability, 22 Polymer matrix, 18 Polymer support, 17, 21 bisBINOL, 296 Poly(methacrylate)s, 255, 259, 285 Poly(methyl methacrylate) (PMMA), 213–215, 219 Poly(N-acryloxy succinimide), 20 Poly(N-(4-ethynylbenzyl)ephedrine), 284 Poly(N-propargylamide), 288 Poly(N-substituted maleimide) absolute stereochemistry of, 372 Polypeptide, 29 Poly(phenylacetylene)s (PPA), 52, 203, 205, 207, 209, 211, 216, 287, 423–427, 429, 435, 436, 439, 446, 447 membranes, 439–443 Poly(phenyleneethynylene), 424, 425, 443 Poly(1,3-phenyleneethynylene), 446, 448, 449 Poly(phenyl isocyanide), 289 Poly(1-phenylvinylene)s, 423 Poly(propylene-alt-CO), 409–411, 413, 416 Poly(quinoxaline-2,3-diyl)s, 202, 218, 288 Poly(quinoxaline)s, 244 Polyradical, 446–454 Polysilanes, 203 Polysiloxane, 457

495

Poly((S)-N-a-methylbenzylmaleimide) X-ray diffraction (XRD) diagrams for, 375 Polystyrene, 217 Poly(styrene-alt-CO), 409, 411, 419 Polystyrene based catalysts cross-linked, 67, 69, 79, 81 linear, 65, 70, 73, 76, 82 Polysulfoxide, 457 Poly(t-butyl isocyanide), 201 Polytopic ligand, 279 Poly(trityl methacrylate), 259 Poly(vinyl alcohol), 20 Porphyrins, 209–211, 231, 236 Privileged structures, 168 Prolinamide, 27, 49 Proline, 46 Protonation, 22 P-stereogenic bisphosphine, 458, 464, 465, 470, 473 P-stereogenic oligomer, 458, 464 P-stereogenic polymer, 458, 470, 473, 474 Pyrene, 233 Pyrrolidine, 41, 43 Quaternarization reaction, 34 Quaternary ammonium salt, 6 Quinazoline alkaloids, 178 Quinidine, 22 Quinine, 22, 23 Quinoline, 22 Quinoxalinones, 172 Racemization, 248, 451, 457 Radical copolymerization, 20, 23, 33 Radical polymerization, 21 Reagent(s), 125, 126, 130–132, 135, 145, 150 Recrystallization point (Tc), 465 Reduction, 52, 141, 142, 415, 416 Reused, 261 Reversible addition-fragmentation chaintransfer polymerization, (RAFT), 73 Reversible switch of helical chirality, 255 Rhodamine dye, 233 RIM, 427, 431, 432, 439–445 Ring-opening polymerization, 21 Robinson annulations, 46, 49, 63, 67, 77

496

INDEX

Ruthenium complex, 288 Salen complex, 279, 287 Salt-bridge, 212, 287 Sarcodictyins, 186 Scale-up, 126 Scanning tunneling microscopy (STM), 303 Scavenger(s), 125, 150 Screw-sense selectivity(ies), 234, 236, 241, 249–251 polymerization, 226, 236, 247 Secondary structure, 91, 94, 99, 119 Selectfluor, 24 Selective cyclic aromatization(SCAT), 438–439 a-Selenenylation, 49 Self-supporting-membrane-forming abilities, 436 Sergeants and soldiers effect, 203 S factor, 43 Side-chain chirality, 2, 9 Side-chain functionalized polymers, 2 Silyl enol ester, 24 Site isolation, 53 Size-exclusion chromatograph (SEC), 303 Solid-phase organic synthesis (SPOS), 159 Solid-phase peptide synthesis, 17, 18, 50 Solid phase polymerization, 21 Solution polymerization, 21 Solvatochromism, 452 Solvent-dependant induction of helical sense, 238 Sonogashira-Hagihara coupling, 473 (–)-Sparteine, 465, 466, 469, 480, 483 Specific rotation, 467, 475 Spirobifluorene, 274, 277 Spirochromanones, synthesis of, 77 Spirocyclic compound libraries, 160 Spiroketal, 417, 418, 420 Stability, 136, 137, 138, 151, 153 Star-branched polymer, 53 Static helical polymers, 202, 203, 218 [2þ2] Staudinger reaction, 23 Stereochemical diversification, 174 Stereo-combinatorial synthesis, 182 Stereocomplex, 419 Stimuli-responsive, 270 Strecker reaction, 22

Styrene, 407–409, 411–413, 419 N-Substituted maleimides anionic polymerization mechanism of, 371 Sulfonamide, 25 a-Sulfonylation, 22 Supercritical, 142, 151 Suspension polymerization, 21, 40 Suzuki-Miyaura coupling reaction, 20 Syndiotactic, 407, 409, 411, 413, 414, 419 Syndiotactic polymer, 469 TADDOL, 135, 136, 137, 138 Taxoid library, 185 TentaGel, 20 TentaGel resin, 76, 77 N-Terminal prolyl peptide, 103, 107, 119 N,N,N0 ,N0 -Tetramethylethylenediamine (TMEDA), 470, 475 Tetrapeptide, 100–102, 105, 111 Tetraphosphine, 458, 459 Thermochromism, 452 Thermotropic liquid crystal, 239 Thiohydantoin, 171 Threo-diisotactic structure, 367 Threo-disyndiotactic structure, 367 Ti(OiPr)4, 327, 328, 337, 347, 358 Transfer hydrogenation, 51, 256 p-p* Transition band, 471 Transition metal catalyzed polymerization, 21 Transmission electron microscopy (TEM), 308 Triblock copolymer, 252 Tripeptide, 99, 101–103, 105, 107, 109, 119 Triphenylmethyl methacrylate (TrMA), 473, 477 b-Turn (beta-turn), 92, 99, 100, 102, 105, 111, 115–117 Ultraviolet (UV)-vis absorption spectrum, 471 Unlike, 409 a, b-Unsaturated ketones, 341–348 Vibrational CD, 213 Vinyl ether, 337, 338

INDEX

Wang resin, 20 Weight-average molecular weight (Mw), 470 Wieland-Mischler ketone, 46 Williamson ether synthesis, 481 Williamson reaction, 20, 23, 41 W/O emulsion polymerization, 444 X-ray diffraction (XRD), 207, 466

497

Yb(OiPr)3, 346, 347 Ytterbium trifluoromethansulfonate, 392 ZnEt2, 327–332, 334–336, 341–346, 351, 354, 355, 357, 358, 360 ZnMe2, 332 ZnPh2, 332–334