Handbook of Asymmetric
Heterogeneous Catalysis
Edited by
Kuiling Ding and
Yasuhiro Uozumi


Further Reading
Ertl, G., Knözinger, H., Schüth, F.,
Weitkamp, J. (Eds.)

Handbook of Heterogeneous
Catalysis
8 Volumes
2008
ISBN: 978-3-527-31241-2

Maruoka, K. (Ed.)

Asymmetric Phase-Transfer
Catalysis
2008
ISBN: 978-3-527-31842-1

Mikami, K

van Santen, R. A., Neurock, M.

Molecular Heterogeneous
Catalysis

A Conceptual and Computational Approach
2006
ISBN: 978-3-527-29662-0

Sheldon, R. A., Arends, I.,
Hanefeld, U.

Green Chemistry and Catalysis
2007
ISBN: 978-3-527-30715-9

Cornils, B., Herrmann, W. A., Muhler, M.,
Wong, C.-H. (Eds.)

New Frontiers in Asymmetric
Catalysis

Catalysis from A to Z

2007
ISBN: 978-0-471-68026-0

2007
ISBN: 978-3-527-31438-6

A Concise Encyclopedia


Handbook of
Asymmetric Heterogeneous Catalysis

Edited by
Kuiling Ding and Yasuhiro Uozumi


The Editors
Prof. Dr. Kuiling Ding
Chinese Academy of Sciences
Shanghai Institute of Organic Chemistry
Fenglin Road
Shanghai 200032
China
Prof. Dr. Yasuhiro Uozumi
Institute for Molecular Science (IMS)
Myodaiji
Okazaki 444-8787
Japan

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Printed on acid-free paper
ISBN: 978-3-527-31913-8


V

Contents
Preface XIII

List of Contributors XV
1
1.1
1.2
1.2.1
1.2.2
1.2.3
1.2.4
1.2.5
1.2.5.1
1.2.5.2
1.2.5.3
1.2.5.4
1.2.6
1.2.7
1.3
1.4

2

2.1
2.2
2.2.1
2.2.2

An Overview of Heterogeneous Asymmetric Catalysis 1
Zheng Wang, Kuiling Ding, and Yasuhiro Uozumi
Introduction 1
Common Techniques for Immobilization of Homogeneous
Asymmetric Catalysts 4

Chiral Catalyst Immobilization on Inorganic Materials 4
Chiral Catalyst Immobilization Using Organic Polymers 7
Dendrimer-Supported Chiral Catalysts 8
Self-Supported Chiral Catalysts in Asymmetric Reactions 10
Chiral Catalyst Immobilization Using Nonconventional Media 12
Catalyst Immobilization in Water 12
Fluorous Phase-Separation Techniques in Catalysis 13
Catalytic Reactions in Ionic Liquids 14
Enantioselective Catalysis in Supercritical Carbon Dioxide 15
Phase-Transfer Catalysis 16
Immobilization of Chiral Organic Catalysts 16
Chirally Modified Metal Surface for Heterogeneous Asymmetric
Hydrogenation 17
Heterogeneous Enantioselective Catalysts in Industrial Research and
Application 18
References 19
Heterogeneous Enantioselective Catalysis Using Inorganic Supports
Santosh Singh Thakur, Jae Eun Lee, Seo Hwan Lee, Ji Man Kim,
and Choong Eui Song
Introduction 25
Asymmetric Reduction 27
Immobilization via a Covalent Link 31
Immobilization via Hydrogen Bonding, Ionic and Other
Interactions 34

Handbook of Asymmetric Heterogeneous Catalysis. Edited by K. Ding and Y. Uozumi
Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 978-3-527-31913-8

25



VI

Contents

2.3
2.3.1
2.3.1.1
2.3.1.2
2.3.1.3
2.3.1.4
2.3.2
2.3.3
2.3.4
2.3.5
2.4
2.4.1
2.4.2
2.4.3
2.4.4
2.4.5
2.4.6
2.4.7
2.4.8
2.4.9
2.5

3


3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13
3.14
3.15
3.16
3.17

Asymmetric Oxidation 40
Asymmetric Epoxidation (AE) of Unfunctionalized Olefins 40
Immobilization via a Covalent Link 45
Immobilization via Coordination, Ionic and Other Interactions 45
Immobilization by the ‘Ship-in-a-Bottle’ Approach 47
Supported Ionic Liquid Catalysis (SILC) 48
AE of Allylic Alcohol 49
Enone Epoxidation 51
Asymmetric Dihydroxylation (AD) and Asymmetric
Aminohydroxylation (AA) of Olefins 52
Asymmetric Aziridination of Olefin 53
Asymmetric Carbon–Carbon and Carbon–Heteroatom Bond

Formation 54
Pd-Catalyzed Asymmetric Allylic Substitution 54
Enantioselective Addition of Dialkylzincs to Aldehydes 58
Asymmetric Diels–Alder Reaction 59
Ene Reactions 61
Asymmetric Conjugate Addition 61
Aldol and Nitroaldol Reactions 63
Asymmetric Cyclopropanation 64
Friedel–Craft Hydroxyalkylation 65
Si–H Insertion 65
Conclusions 66
Acknowledgments 67
References 67
Heterogeneous Enantioselective Catalysis Using Organic Polymeric
Supports 73
Shinichi Itsuno and Naoki Haraguchi
Introduction 73
Asymmetric Alkylation of Carbonyl Compounds 74
Asymmetric Phenylation 79
Asymmetric Addition of Phenylacetylene 80
Asymmetric Addition to Imine Derivatives 81
Asymmetric Silylcyanation of Aldehyde 81
Asymmetric Synthesis of α-Amino Acid 82
Asymmetric Aldol Reaction 84
Enantioselective Carbonyl-Ene Reaction 87
Asymmetric Michael Reaction 87
Asymmetric Deprotonation 91
Enantioselective Diels–Alder Cycloaddition 92
Enantioselective 1,3-Dipolar Cycloaddition 94
Asymmetric Sharpless Dihydroxylation 94

Asymmetric Epoxidation 95
Hydrolytic Kinetic Resolution of Terminal Epoxide 100
Enantioselective Borane Reduction of Ketone 101


Contents

3.18
3.19
3.20
3.21
3.22
3.23
3.24
3.25
3.26
3.27
3.28
3.29
3.30
3.31
3.32

Asymmetric Transfer Hydrogenation 104
Enantioselective Hydrogenation of Ketones 107
Asymmetric Hydrogenation of Enamine 110
Enantioselective Hydrogenation of C=C Double Bonds 110
Enantioselective Hydrogenation of C=N Double Bonds 111
Asymmetric Allylic Alkylation 111
Asymmetric Allylic Nitromethylation 115

Asymmetric Cyclopropanation 116
Enantioselective Olefin Metathesis 118
Asymmetric Ring-Closing Metathesis 120
Enantioselective Reissert-Type Reaction 120
Asymmetric Wacker-Type Cyclization 121
Enantioselective Hydrolysis 121
Asymmetric Hydroformylation 123
Summary and Outlooks 123
References 124

4

Enantioselective Catalysis Using Dendrimer Supports 131
Qing-Hua Fan, Guo-Jun Deng, Yu Feng, and Yan-Mei He
General Introduction 131
Core-Functionalized Dendrimers in Asymmetric Catalysis 134
Asymmetric Hydrogenation 135
Asymmetric Transfer Hydrogenation 145
Asymmetric Borane Reduction of Ketones 147
Asymmetric Addition of Organometallic Compounds to
Aldehydes 149
Asymmetric Michael Addition 151
Asymmetric Allylic Substitution 152
Asymmetric Aldol Reaction 153
Asymmetric Hetero-Diels–Alder Reaction 155
Peripherally Modified Dendrimers in Asymmetric Catalysis 156
Asymmetric Hydrogenation 157
Asymmetric Transfer Hydrogenation 159
Asymmetric Borane Reduction of Ketones 160
Asymmetric Ring Opening of Epoxides 161

Asymmetric Addition of Dialkylzincs to Aldehydes and Imine
Derivatives 162
Asymmetric Allylic Amination and Alkylation 163
Asymmetric Michael Addition 166
Asymmetric Diels–Alder Reaction 167
Asymmetric Aldol Reaction 168
Asymmetric Hydrovinylation 169
Solid-Supported Chiral Dendrimer Catalysts for Asymmetric
Catalysis 170
Solid-Supported Internally Functionalized Chiral Dendrimer
Catalysts 170

4.1
4.2
4.2.1
4.2.2
4.2.3
4.2.4
4.2.5
4.2.6
4.2.7
4.2.8
4.3
4.3.1
4.3.2
4.3.3
4.3.4
4.3.5
4.3.6
4.3.7

4.3.8
4.3.9
4.3.10
4.4
4.4.1

VII


VIII

Contents

4.4.2
4.5

5
5.1
5.2
5.3
5.3.1
5.3.2
5.3.3
5.4
5.4.1
5.4.2
5.5
5.5.1
5.5.2
5.5.3

5.5.4
5.6

6
6.1
6.2
6.2.1
6.2.2
6.2.2.1
6.2.2.2
6.2.2.3
6.2.2.4
6.2.2.5
6.3
6.3.1
6.3.2
6.3.3

7
7.1

Solid-Supported Peripherally Functionalized Chiral Dendrimer
Catalysts 174
Conclusion and Perspectives 175
References 177
Enantioselective Fluorous Catalysis 181
Gianluca Pozzi
Introduction 181
Designing Fluorous Catalysts 182
C−O Bond Formation 184

Epoxidation 184
Hydrolytic Kinetic Resolution 186
Allylic Oxidation 187
C−H Bond Formation 189
Reduction of Ketones 189
Reduction of C=N and C=C Bonds 191
C−C Bond Formation 193
Addition of Organometallic Reagents to Aldehydes
Pd-Catalyzed Reactions 197
Cyclopropanation of Styrene 200
Metal-Free Catalytic Processes 203
Conclusions 205
References 206

193

Heterogeneous Asymmetric Catalysis in Aqueous Media 209
Yasuhiro Uozumi
Introduction 209
Chiral-Switching of Heterogeneous Aquacatalytic Process 210
Combinatorial Approach 210
Imidazoindole Phosphine 214
Design and Preparation 214
Allylic Alkylation 214
Allylic Amination 217
Allylic Etherification 218
Synthetic Application 219
Heterogeneous- and Aqueous-Switching of Asymmetric
Catalysis 222
BINAP Catalysts 222

DPEN Catalysts 224
Miscellaneous 226
References 229
Enantioselective Catalysis in Ionic Liquids and Supercritical CO2 233
Sang-gi Lee and Yong Jian Zhang
Introduction 233


Contents

7.2
7.2.1
7.2.1.1
7.2.1.2
7.2.1.3
7.2.2
7.2.2.1
7.2.2.2
7.2.3

Enantioselective Catalysis in Ionic Liquids 234
Asymmetric Reductions in Ionic Liquids 235
Asymmetric Hydrogenations of the C=C Bond 235
Asymmetric Hydrogenations of the C=O Bond 239
Asymmetric Transfer Hydrogenations 244
Asymmetric Oxidations in Ionic Liquids 245
Asymmetric Dihydroxylation 245
Asymmetric Epoxidations 248
Asymmetric Carbon–Carbon and Carbon–Heteroatom Bond Formation
in Ionic Liquids 250

7.2.3.1 Asymmetric Diels–Alder Reactions 250
7.2.3.2 Asymmetric Ring Opening of Epoxides 252
7.2.3.3 Hydrolytic Kinetic Resolution of Epoxides 254
7.2.3.4 Asymmetric Cyanosilylation of Aldehydes 255
7.2.3.5 Asymmetric Allylic Substitution 256
7.2.3.6 Asymmetric Allylic Addition 258
7.2.3.7 Asymmetric Cyclopropanation 259
7.2.3.8 Asymmetric Sulfimidation 262
7.2.3.9 Asymmetric Diethylzinc Addition 262
7.2.3.10 Asymmetric Fluorination 262
7.2.4
Enantioselective Organocatalysis 264
7.2.4.1 Asymmetric Aldol Reactions 265
7.2.4.2 Asymmetric Michael Addition 269
7.2.4.3 Asymmetric Mannich, α-Aminoxylation, and Diels–Alder
Reaction 270
7.3
Enantioselective Catalysis in Supercritical Carbon Dioxide
(scCO2) 274
7.3.1
Asymmetric Hydrogenation 274
7.3.2
Asymmetric Hydroformylation 279
7.3.3
Asymmetric Carbon–Carbon Bond Formation 282
7.4
Enantioselective Catalysis in the Combined Use of Ionic Liquids and
Supercritical CO2 283
7.5
Summary and Outlook 285

References 286
8
8.1
8.2
8.3
8.4
8.5
8.6
8.6.1
8.6.2

Heterogenized Organocatalysts for Asymmetric Transformations 293
Maurizio Benaglia
Introduction 293
General Considerations on the Immobilization Process 295
Phase-Transfer Catalysts 299
Nonionic Cinchona-Derived Catalysts 302
Lewis Base Catalysts 305
Catalysts Derived from Amino Acids 307
Proline Derivatives 307
Amino Acid-Derived Imidazolinones 312

IX


X

Contents

8.6.3

8.7
8.8

Other Amino Acids 314
Miscellaneous Catalysts 317
Outlook and Perspectives 319
References 320

9

Homochiral Metal–Organic Coordination Polymers for Heterogeneous
Enantioselective Catalysis: Self-Supporting Strategy 323
Kuiling Ding and Zheng Wang
Introduction 323
A Historical Account of Catalytic Applications of MOCPs 326
General Considerations on the Design and Construction of Homochiral
MOCP Catalysts 330
Type I Homochiral MOCP Catalysts in Heterogeneous Asymmetric
Reactions 333
Enantioselective C−C Bond-Forming Reactions 333
Carbonyl-Ene Reaction 333
Michael Addition 335
Diethylzinc Addition to Aldehydes 336
Enantioselective Oxidation Reactions 337
Epoxidation of α,β-Unsaturated Ketones 337
Sulfoxidation of Aryl Alkyl Sulfides 339
Asymmetric Hydrogenations 340
Hydrogenation of Dehydro-α-Amino Acids and Enamides 340
Hydrogenation of Ketones 342
Type II Homochiral MOCP Catalysts in Heterogeneous Asymmetric

Reactions 343
Enantioselective Hydrogenations 343
Asymmetric C−C Bond-Forming Reactions 346
Epoxidation 349
Miscellaneous 350
Concluding Remarks and Outlook 351
References 352

9.1
9.2
9.3
9.4
9.4.1
9.4.1.1
9.4.1.2
9.4.1.3
9.4.2
9.4.2.1
9.4.2.2
9.4.3
9.4.3.1
9.4.3.2
9.5
9.5.1
9.5.2
9.5.3
9.5.4
9.6

10


10.1
10.2
10.3
10.4
10.5
10.5.1
10.5.2
10.5.3
10.6

Heterogeneous Enantioselective Hydrogenation on Metal Surface
Modified by Chiral Molecules 357
Takashi Sugimura
Introduction 357
History of the Chiral Modification of Metal Catalysts 358
Cinchona Alkaloid-Modified Platinum Catalysis [1, 4] 359
Tartaric Acid-Modified Nickel Catalysis [49–52] 363
Cinchona Alkaloid-Modified Palladium Catalysis [83] 368
Aromatic α,β-Unsubstituted Carboxylic Acids 369
Aliphatic α,β-Unsubstituted Carboxylic Acids 374
2-Pyrone Derivatives 376
Conclusions 377


Contents

Acknowledgments
References 377


377

11

Asymmetric Phase-Transfer Catalysis 383
Xisheng Wang, Quan Lan, and Keiji Maruoka
11.1
Introduction 383
11.2
Alkylation 384
11.2.1 Pioneering Study 384
11.2.2 Asymmetric Synthesis of α-Amino Acids and Their Derivatives 384
11.2.2.1 Monoalkylation of Schiff Bases Derived from Glycine 384
11.2.2.2 Dialkylation of Schiff Bases Derived from α-Alkyl-α-Amino Acids 391
11.2.2.3 Alkylation of Schiff Base-Activated Peptides 394
11.2.3 Other Alkylations and Aromatic or Vinylic Substitutions 396
11.3
Michael Addition 398
11.4
Aldol and Related Reactions 399
11.5
Neber Rearrangement 403
11.6
Epoxidation 404
11.7
Strecker Reaction 406
11.8
Conclusions 408
Acknowledgments 408
References 408

12

12.1
12.2
12.2.1
12.2.2
12.2.3
12.2.3.1
12.2.3.2
12.2.3.3
12.2.4
12.3
12.3.1
12.3.1.1
12.3.1.2
12.3.2
12.3.2.1
12.3.2.2
12.4

The Industrial Application of Heterogeneous Enantioselective
Catalysts 413
Hans-Ulrich Blaser and Bent Pugin
Introduction 413
Industrial Requirements for Applying Catalysts 414
Characteristics of the Manufacture of Enantiomerically Pure
Products 414
Process Development: Critical Factors for the Application of
(Heterogeneous) Enantioselective Catalysts 414
Requirements for Practically Useful Heterogeneous Catalysts 415

Preparation Methods 415
Catalysts 416
Catalytic Properties and Handling 417
Practically Useful Types of Heterogeneous Enantioselective
Catalyst 417
Chirally Modified Heterogeneous Hydrogenation Catalysts 418
Nickel Catalysts Modified with Tartaric Acid 418
Background 418
Synthetic and Industrial Applications 419
Catalysts Modified with Cinchona Alkaloids 420
Background 420
Industrial Applications 422
Immobilized Chiral Metal Complexes 428

XI


XII

Contents

12.4.1
12.4.2
12.4.3
12.5

Background 428
Complexes Adsorbed on Solid Supports 430
Toolbox for Covalent Immobilization 431
Conclusions and Outlook 435

References 435
Index

439


XIII

Preface
Stereoselective molecular transformation is a central theme in modern organic
synthetic chemistry. Among the many strategies applied to prepare desired organic
molecules in their optically active forms, catalytic asymmetric synthesis has been
widely recognized as a powerful reaction class. Compared to the impressive developments of homogeneous asymmetric catalysis – the most splendid of which were
awarded the Nobel Prize of 2001 – enantioselective organic synthesis with heterogeneous chiral catalysts has received only scant attention, in spite of the historical
appearance of a silk–palladium composite as the first heterogeneous enantioselective catalyst in 1956.1) During the past decade, however, in response to increasing
environmental concerns about the harmful and resource-consuming waste of the
heavy and/or rare metals that are frequently used as the catalytic centers of homogeneous catalysts, the importance of heterogeneous systems has again been realized and this area is presently undergoing very rapid growth.2) In addition, the
development of heterogeneous chiral catalysts has been attracting significant interest for their practical advantages: the safe and simple manipulation of work-up;
reduced contamination by catalyst residues in the products; and the recovery and
reuse of the costly chiral and/or metal resources. There is good reason to believe
that the development of asymmetric heterogeneous catalysis – including the
heterogeneous-switching of given homogeneous asymmetric processes and the
chiral-switching of heterogeneous nonasymmetric processes – offers a practical,
‘green’, clean and safe alternative to more conventional methods of accomplishing
many asymmetric processes.
This book, which comprises 12 review-type chapters, is intended to provide an
overview of the main research areas of asymmetric heterogeneous catalysis,
although the arrangement of the chapters is somewhat arbitrary. Chapter 1
(Z. Wang, K. Ding and Y. Uozumi) provides an introductory review to outline this
volume, which should give guidance to the broad readership. Chapters 2

(S.S. Thakur, J.E. Lee, S.H. Lee, J.M. Kim and C.E. Song) and 3 (S. Itsuno and
N. Haraguchi) mainly describe the development of chiral catalysts bound to
1)

For a review, see: Izumi, Y. (1971)
Angewandte Chemie – International Edition 10,
871–948.

2)

For a review, see: De Vos, D.E., Vankelecom,
I.F.J. and Jacobs, P. A. (eds) (2000) Chiral
Catalyst Immobilization and Recycling,
Wiley-VCH, Weinheim.

Handbook of Asymmetric Heterogeneous Catalysis. Edited by K. Ding and Y. Uozumi
Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 978-3-527-31913-8


XIV

Preface

inorganic and organic (polymeric) supports, respectively, via the heterogenization
of chiral organometallic and organic catalysts originally designed for homogeneous counterparts. In Chapter 4, Q.-H. Fan, G.-J. Deng, Y. Feng and Y.M. He
present details of dendritic chiral catalysts, where the dendrimer moiety – a new
class of highly branched polymer – often provides unique physical as well as chemical properties. Asymmetric heterogeneous catalysis in exotic liquid media is
addressed in Chapters 5, 6 and 7. Thus, fluorous liquid–liquid biphasic systems
with fluorophilic-modified chiral catalysts are reviewed in Chapter 5 (G. Pozzi),

while water-based reactions with hydrophilic (or amphiphilic) polymeric catalysts
are described in Chapter 6 (Y. Uozumi). The recent growth of chemistry with ionic
liquids and supercritical carbon dioxide is also significant, and nowadays this is
applied to heterogeneous asymmetric catalysis, which is detailed in Chapter 7
(S.-G. Lee and Y.J. Zhang). Although organocatalysis is a well-established class
of organic transformations, chiral-switching is an up-to-date topic in the area of
asymmetric catalysis. M. Benaglia introduces the heterogeneous-switching of
asymmetric organocatalysis, mainly with cinchona- and amino acid-derivatives, in
Chapter 8. The metal crosslinked assembly of chiral organic ligands forming chiral
coordination polymers realized self-supporting systems of chiral complex catalysts
where the catalytic activity and heterogeneous property are obtained in a single
step (Chapter 9, K. Ding and Z. Wang). The chiral-switching of metal catalysts is
a classic, yet immature, approach to asymmetric heterogeneous catalysis. Clearly,
while pioneering strides have been made, additional studies on the chiral modification of metal surfaces are warranted, and this topic is reviewed by T. Sugimura in
Chapter 10. The chiral-switching of phase-transfer catalysis (PTC) has been another
eagerly awaited subject, and a breakthrough in asymmetric PTC was recently
brought about by K. Maruoka, who contributes Chapter 11 together with his colleagues, X. Wang and Q. Lan. The final chapter of this volume is provided by H.-U.
Blaser and B. Pugin, who introduce the industrial application of heterogeneous
asymmetric catalysis.
We gratefully acknowledge the work of all authors in presenting up-to-date and
well-referenced contributions; indeed, without their efforts this volume would not
have been possible. Furthermore, it was a pleasure to collaborate with the WileyVCH ‘crew’ in Weinheim, who not only did an excellent job in producing the book
but also helped us in a competent manner in all phases of its preparation. We are
also grateful to Dr. Zheng Wang of Shanghai Institute of Organic Chemistry, who
put a lot of effort into editing this volume. The collaborative studies of K.D. and
Y.U. were partially supported by the Asian Core Program, sponsored by the Japan
Society for the Promotion of Science.
Kuiling Ding
Yasuhiro Uozumi


Shanghai and Okazaki
July 2008


XV

List of Contributors
Maurizio Benaglia
Università degli Studi di Milano
Dipartimento di Chimica
Organica e Industriale
via Golgi 19
20133 Milan
Italy
Hans-Ulrich Blaser
Solvias AG
P.O. Box
4002 Basel
Switzerland
Guo-Jun Deng
Chinese Academy of Sciences
Institute of Chemistry
P.R. Beijing 100190
China
Kuiling Ding
Chinese Academy of Sciences
Shanghai Institute of Organic
Chemistry
354 Fenglin Road
Shanghai 200032

P. R. China
Qing-Hua Fan
Chinese Academy of Sciences
Institute of Chemistry
Beijing 100190
P. R. China

Yu Feng
Chinese Academy of Sciences
Institute of Chemistry
Beijing 100190
China
Naoki Haraguchi
Toyohashi University of Technology
Department of Materials Science
Tempaku- cho, Toyohashi, 441- 8580
Japan
Yan-Mei He
Chinese Academy of Sciences
Institute of Chemistry
Beijing 100190
P. R. China
Shinichi Itsuno
Toyohashi University of Technology
Department of Materials Science
Tempaku- cho, Toyohashi, 441- 8580
Japan
Ji Man Kim
Sungkyunkwan University
Department of Chemistry

Cheoncheon-dong 300, Jangan-gu
440 -746 Suwon
Korea

Handbook of Asymmetric Heterogeneous Catalysis. Edited by K. Ding and Y. Uozumi
Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 978-3-527-31913-8


XVI

List Of Contributors

Quan Lan
Kyoto University
Department of Chemistry
Graduate School of Science
Sakyo
Kyoto 606 - 8502
Japan
Jae Eun Lee
Sungkyunkwan University
Department of Chemistry
Cheoncheon- dong 300,
Jangan-gu
440 -746 Suwon
Korea
Sang-gi Lee
Ewha Womans University
Department of Chemistry and

Nano Science
Seoul 120 -750
Korea
Seo Hwan Lee
Sungkyunkwan University
Department of Chemistry
Cheoncheon- dong 300,
Jangan-gu
440 -746 Suwon
Korea
Keiji Maruoka
Kyoto University
Department of Chemistry
Graduate School of Science
Sakyo
Kyoto 606 - 8502
Japan
Gianluca Pozzi
CNR-Istituto di Scienze e
Tecnologie Molecolari
via Golgi 19
20133 Milan
Italy

Ben t Pugin
Solvias AG
P.O. Box
4002 Basel
Switzerland
Choong Eui Song

Sungkyunkwan University
Department of Chemistry
Cheoncheon-dong 300, Jangan-gu
440 -746 Suwon
Korea
Takashi Sugimura
University of Hyogo
Graduate School of Material Science
Himeji Institute of Technology
3 -2-1 Kohto
Kamigori
Ako -gun
Hyogo 678 -1297
Japan
Santosh Singh Thakur
Sungkyunkwan University
Department of Chemistry
Cheoncheon-dong 300, Jangan-gu
440 -746 Suwon
Korea
Yasuhiro Uozumi
Institute for Molecular Science (IMS)
Myodaiji
Okazaki 444 - 8787
Japan
Xisheng Wang
The Scripps Research Institute
Department of Chemistry
10550 North Torrey Pines Road
La Jolla, CA, 92037

USA


List Of Contributors

Zheng Wang
Chinese Academy of Sciences
Shanghai Institute of Organic
Chemistry
354 Fenglin Road
Shanghai 200032
P. R. China

Yong Jian Zhang
Shanghai Jiao Tong University
School of Chemistry and Chemical
Technology
800 Dongchuan Road
Shanghai 200240
P. R. China

XVII



1

1
An Overview of Heterogeneous Asymmetric Catalysis
Zheng Wang, Kuiling Ding, and Yasuhiro Uozumi


1.1
Introduction

Driven by the ever-increasing demand for nonracemic chiral chemicals, the development of efficient methods to provide enantiomerically enriched products is
of great current interest to both academia and industry [1–3]. Among the various
approaches employed for this purpose, asymmetric catalysis constitutes one of the
most general and appealing strategies in terms of chiral economy and environmental considerations [4–9]. Over the past few decades, intense research in this
field has greatly expanded the scope of catalytic reactions that can be performed
with high enantioselectivity and efficiency. Consequently, thousands of chiral
ligands and their transition metal complexes have been developed for the homogeneous asymmetric catalysis of various organic transformations. Despite this
remarkable success, however, only a few examples of asymmetric catalysis have
been developed into industrial processes, and today most chiral chemicals are still
produced from natural chiral building blocks or through the resolution of racemic
mixtures. The main concern for this situation is the need for reusable chiral catalysts for industrial implementation. Due to the high cost of both the metal and
the chiral ligands, systems that allow the straightforward separation of expensive
chiral catalysts from reaction mixtures and efficient recycling are highly desirable.
Whilst this is particularly important for large-scale productions, unfortunately it
is usually very difficult to achieve for homogeneous catalytic processes. Another
major drawback often associated with homogeneous catalytic processes is that of
product contamination by metal leaching; this is particularly unacceptable for the
production of fine chemicals and pharmaceuticals. Heterogeneous asymmetric
catalysis – including the use of immobilized homogeneous asymmetric catalysts
and chirally modified heterogeneous metal catalysts for enantioselective reactions – provides a good way to resolve such problems and has recently attracted a
great deal of interest [10, 11]. In this chapter we will briefly survey the field of
heterogeneous asymmetric catalysis by summarizing the main features of some
typical techniques at an introductory level. When relevant, we will present our

Handbook of Asymmetric Heterogeneous Catalysis. Edited by K. Ding and Y. Uozumi
Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

ISBN: 978-3-527-31913-8


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1 An Overview of Heterogeneous Asymmetric Catalysis

personal comments on weighing up their strengths and limitations, though
without delving into too much detail. For in-depth discussions and a comprehensive elaboration of each technique, the reader is referred to excellent recent reviews
[12–16] and the ensuing chapters in this handbook, all of which have been written
by scientists with expertise in these areas of research. The application of immobilized biocatalysts (including enzymes) in enantioselective organic synthesis,
although representing an important field of catalytic research, is beyond the scope
of this book.
The term catalyst immobilization can be defined as ‘the transformation of a
homogeneous catalyst into a heterogeneous one, which is able to be separated
from the reaction mixture and preferably be reused for multiple times’. The main
goal for the development of an immobilized chiral catalyst is to combine the positive aspects of a homogeneous catalyst (e.g. high activity, high enantioselectivity,
good reproducibility) with those of a heterogeneous catalyst (e.g. ease of separation, stability, reusability). Over the past few decades, a number of strategies have
been developed for this purpose. Depending on whether the modifications are
made on the catalyst structure or on the reaction medium, the immobilization
techniques can be categorized into two general classes, namely heterogenized
enantioselective catalysts and multiphase (or monophase) catalysis in nonconventional media (Figure 1.1). The immobilized chiral catalysts can be further subdivided into several types:

•
•
•

Insoluble chiral catalysts bearing stationary supports such as inorganic materials
or organic crosslinked polymers, or homochiral organic–inorganic coordination
polymeric catalysts without using any external support.

Soluble chiral catalysts bearing linear polymer supports or dendritic ligands.
Chiral catalysts with some form of nonconventional reaction medium as
the ‘mobile carrier’, such as aqueous phase, fluorous phase, ionic liquid or
supercritical carbon dioxide (scCO2).

In the latter case, these liquids can form biphasic systems with the immiscible
organic product liquid, thus giving rise to the possibility of an easy isolation and
recovery of the chiral catalysts by phase separation. An important option to the

Figure 1.1 Immobilization of asymmetric homogeneous catalysts.


1.1 Introduction

biphasic catalysis is asymmetric phase-transfer catalysis (PTC), where a nonracemic chiral additive is applied to increase the mobility of a given catalyst or reactant
into a favored phase and furthermore control the stereochemical outcome.
Although, in general, catalyst recycling is somewhat difficult in PTC systems, it
represents a distinct type of heterogeneous asymmetric catalysis.
In order to apply an immobilized chiral catalyst to a chemical process, it is often
necessary to make a critical evaluation in terms of its activity, productivity, enantioselectivity, stability, ease of recovery and reusability, and so on. An ideal immobilized catalyst should not only exhibit activity and selectivity comparable or
superior to its homogeneous counterpart, but also be easily recoverable from the
reaction stream without metal leaching, and reusable for many runs without any
loss of catalytic performance. Unfortunately, this is seldom found in real-world
cases, and numerous problems can occur during the immobilization of a homogeneous catalyst. For example, in a supported chiral catalyst, one often-observed
negative effect is the lower catalytic activity (even complete deactivation) compared
to a homogeneous catalyst, as a result of the poor accessibility of the active sites
in the solid matrix. On the other hand, the geometry of an optimized homogeneous catalyst can be unintentionally disturbed by interactions with the support,
and this often leads to a negative change in enantioselectivity. For these reasons,
it is a common practice to use a linker of sufficient length to connect the complex
and the support, so that the complex can move far away from the solid surface

and into the liquid phase.
One general requirement for the reusability of any recoverable catalyst is that
both the support material and the catalytic sites must be sufficiently stable to
maintain the catalytic activity during the recycling process. Any type of poor stability in the catalytic moiety or the linker part and/or incompatibility of the support
with the solvent may result in leaching of the metal and/or ligand. For this reason,
the support material and the linkage for immobilization should have good mechanical, thermal and chemical stabilities in order to withstand the reaction conditions
used in the catalytic process. In addition, the issue of the robustness of the complex
itself can be nontrivial. Immobilization is sometimes found to decrease complex
degradation by virtue of steric constraints imposed by the supporting matrix, and
thus may improve the stability of an immobilized catalyst relative to its homogeneous analogues. Nevertheless, this beneficial effect of immobilization on catalyst
stability cannot be taken for granted, as other factors – such as the presence of
strong acids or oxidizing or reducing reagents or other harsh conditions – may lead
to demetallation or ligand degradation of the complex. For these reasons, the
stability issue of an immobilized catalyst must be addressed on a case-by-case
basis, by including the data on catalyst leaching into the product phase for
assessing the potential degree of catalyst decomposition. Despite these difficulties,
major efforts continue to be made to develop more efficient and practical immobilization methods for homogeneous chiral catalysts. In this regard, numerous
immobilized asymmetric catalytic systems have been examined over a broad
range of reactions, and a number of innovative techniques for chiral catalyst
immobilization have emerged during the past two decades. In favorable cases,

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higher enantioselectivities and/or improved efficiencies were observed with a
heterogeneous than with its homogeneous analogue [17–19].


1.2
Common Techniques for Immobilization of Homogeneous Asymmetric Catalysts
1.2.1
Chiral Catalyst Immobilization on Inorganic Materials

By far the most commonly used immobilization method is to support the active
chiral catalyst onto or into an insoluble solid, which can be either an inorganic
solid or a organic polymer. Several distinct types of strategy, featuring covalent
bonds or noncovalent interactions (e.g. physisorption, electrostatic interactions,
H-bonding), have been employed for linking the complex to the solid support,
either onto the external surface or into the interior pores (Figure 1.2). Each of these
immobilization strategies has advantages and limitations with respect to the
others. Covalent bonding linkage (Figure 1.2a) is the most frequently used strategy
by far, and is generally assumed to furnish the strongest binding between the
complex and a support. However, it is synthetically demanding since generally
some special functionalization of the ligand is required, either for grafting to
a preformed support or for forming an organic polymer by copolymerization with
a suitable monomer. In contrast, a major advantage of noncovalent immobilization in general is the ease of catalyst preparation, often without the need for prior
functionalization of the ligand. Adsorption (Figure 1.2b) represents a very facile
immobilization method, as a simple impregnation procedure can be sufficient to
furnish the heterogenized catalyst. Nevertheless, catalysts immobilized via adsorption tend to be nonstable when only weak van der Waals interactions are present,
and this often results in extensive catalyst leaching due to the competing interactions with solvents and/or substrates. Immobilization by electrostatic interaction
(Figure 1.2c) is another common and conceptually simple technique, which is
applicable to heterogenization of ionic catalytic species. Here, the solid support
can be either anionic or cationic, and the catalyst is adsorbed by ion-pairing.

Figure 1.2 Schematic representation of the strategies for
immobilizing homogeneous chiral catalysts with solid
supports.



1.2 Common Techniques for Immobilization of Homogeneous Asymmetric Catalysts

Various supports with ion-exchange capabilities have been used for this purpose,
including organic or inorganic ion-exchange resins, inorganic clays and zeolites.
Although this approach can provide relatively stable immobilized catalysts, it is
still limited to the catalysts which can lend themselves to immobilization through
electrostatic interaction. Furthermore, competition with ionic species (either
present in or produced during the reaction) in solution may result in catalyst
instability and leaching. Finally, the catalytic complex can also be entrapped within
the pores of some solid matrix (Figure 1.2d). In this entrapment methodology, the
size of the metal complex relative to that of the window or tunnel of a porous solid
is the factor of paramount importance, leading to a mechanically immobilized
catalyst. This can be accomplished by preparing the complex in well-defined cages
of a porous support, or alternatively by building up a polymer network around a
preformed catalyst. Although conceptually very elegant, the entrapment strategy
is relatively complex to implement compared with the other methods, and the size
of the substrate molecules may cause diffusion problems in the catalysis. In
summary, it is difficult to predict whether a covalent or a noncovalent immobilization would be preferential for a given catalyst. Although covalent bonding remains
the most popular approach to chiral catalyst immobilization (mainly due to stability advantages), examples illustrated in the following chapters in this Handbook
have shown that noncovalent immobilizations are gaining increasing recognition
as a feasible way to achieve good stability and reusability as well as high selectivity
and activity of an immobilized chiral catalyst.
One major drawback of the insoluble solid-supported chiral catalysts is that, in
many cases, lower reactivities and/or poorer enantioselectivities were obtained as
compared with the corresponding homogeneous catalysts. However, recent results
have shown that the reverse can also be true by correctly choosing the support/
complex combination, even though this was largely achieved by trial-and-error
rather than by rational design. A salient feature of the insoluble solid-supported

catalysts is their easy recovery. In a batch operation, the solid-supported catalyst
can be isolated from the reaction mixture by simple filtration, and in some cases
can be reused for subsequent reaction cycles until deactivated. Alternatively, the
heterogeneous catalysts can be employed in a continuous-flow reactor, with the
advantages of easy automation and little or no reaction work-up [20–23].
Inorganic solids such as silicas, mesoporous solids (e.g. MCM-41, SBA-15),
zeolites and clays have been widely used as supports for the immobilization of
various homogeneous chiral catalysts [14, 24–30]. Depending on the properties
of the complex and the structure of the support, the immobilization strategies can
encompass the whole spectra of aforementioned interactions, from physical
entrapment to covalent bonding. For example, zeolites are crystalline microporous
aluminosilicates with interior cavities accessible to small reactants from the
solution. A chiral metal complex with a suitable size can be assembled inside the
zeolite cavity and entrapped snugly there for catalysis, as escape by diffusion
through the small windows is very difficult. One advantage of the zeolite-entrapped
catalyst is that the zeolite can impose shape selectivity to the catalytic system; that
is, only those substrates with appropriate size and shape can reach the catalyst and

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react. Zeolite entrapment may also lead to a better catalyst stability as a result of
protection of the inert framework. However, zeolite entrapment of a homogeneous
chiral catalyst often leads to a decrease in enantioselectivity, presumably by a negative steric influence of the cage walls. Alternative inorganic solids were also examined as supports, for example, to immobilize the catalytic complex on the external
surface of an nonporous solid such as amorphous silica, or in the interior of
porous solids with void dimensions larger than zeolites. The immobilization of

an electrically charged homogeneous complex by electrostatic interaction with the
surface of the inorganic support is an attractive method owing to the experimental
simplicity of the procedure. In this regard, lamellar solids bearing charged layers
(clays such as montmorillonite K10, laponite or bentonite) have been used as supports to immobilize a variety of charged chiral metal complexes via simple anionexchange procedures.
Usually, these immobilization approaches do not necessarily require special
functionalization of the ligand part. In contrast, immobilization by covalent
binding of a catalyst to an inorganic support is generally accomplished by reacting
complementary functional groups – one located on the solid and the other at the
complex moiety – to create a new covalent bond connecting the solid and the
complex. Although a large variety of functional groups have been shown to be
applicable for this purpose, and despite strong immobilization (not necessarily)
being expected, the approach suffered from the major drawback of a need for
extensive organic synthesis. Therefore, immobilization by covalent binding would
be preferential only if the stability and reusability of the resulting catalyst were to
be significantly improved relative to other methods.
The use of inorganic solids can demonstrate certain advantages over other types
of support. In general, the rigid framework can prevent the aggregation of active
catalysts which sometimes leads to the formation of inactive multinuclear species.
The chemical and thermal stabilities of the inorganic supports are also superior,
rendering them compatible with a broad range of reagents and relatively harsh
reaction conditions. Compared with organic polymeric supports, inorganic solids
are generally superior in their mechanical properties, which makes them less
prone to attrition caused by stirring and solvent attack. One negative aspect of an
inorganic solid-immobilized chiral catalyst is the extreme difficulty in the characterization of the catalytic species, apart from common problems suffered by heterogenized catalysts.
The use of an inorganic support for the immobilization of homogeneous chiral
catalysts has been a steadily expanding area of research during recent years, as
evidenced by the numerous examples described in Chapter 2. In some cases, the
heterogenization of a chiral catalyst onto an inorganic material has not only provided a facile vehicle for catalyst recycling, but also has significantly improved the
catalytic performance in terms of activity, stability and/or enantioselectivity by
virtue of the site-isolation and confinement effect. Taken together, it is expected

that this immobilization technique will continue to play an important role in the
development of highly efficient heterogeneous chiral catalysts in the future.