CATALYTIC METHODS IN ASYMMETRIC SYNTHESISAdvanced Materials, Techniques, and Applications

EDITED BY

MICHELANGELO GRUTTADAURIAFRANCESCO GIACALONEDepartment of Molecular and Biomolecular Sciences (STEMBIO)Section of Organic ChemistryUniversity of PalermoPalermo, Italy

A JOHN WILEY & SONS, INC., PUBLICATION

CATALYTIC METHODS IN ASYMMETRIC SYNTHESIS

CATALYTIC METHODS IN ASYMMETRIC SYNTHESISAdvanced Materials, Techniques, and Applications

EDITED BY

MICHELANGELO GRUTTADAURIAFRANCESCO GIACALONEDepartment of Molecular and Biomolecular Sciences (STEMBIO)Section of Organic ChemistryUniversity of PalermoPalermo, Italy

A JOHN WILEY & SONS, INC., PUBLICATION

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

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data

Gruttadauria, Michelangelo. Catalytic methods in asymmetric synthesis : advanced materials, techniques, and applications / Michelangelo Gruttadauria, Francesco Giacalone. p. cm. ISBN 978-0-470-64136-1 (hardback) 1. Asymmetric synthesis. 2. Catalysis. I. Giacalone, Francesco. II. Title. QD262.G78 2011 541'.395–dc22 2011006415Printed in the United States of America

oBook ISBN: 978-1-118-08799-2ePDF ISBN: 978-1-118-08797-8ePub ISBN: 978-1-118-08798-5

10 9 8 7 6 5 4 3 2 1

http://www.copyright.com/http://www.wiley.com/go/permissionshttp://www.wiley.com/

This book is dedicated to Prof. Renato Noto

CONTENTS

vii

PREFACE xi

FOREWORD xiii

CONTRIBUTORS xv

I NEW MATERIALS AND TECHNOLOGIES: SUPPORTED CATALYSTS, SUPPORTS, SELF-SUPPORTED CATALYSTS, CHIRAL IONIC LIQUID, SUPERCRITICAL FLUIDS, FLOW REACTORS, AND MICROWAVES 1

1 RECYCLABLE STEREOSELECTIVE CATALYSTS 3Carlos M. Monteiro, Alexandre F. Trindade, Pedro M. P. Gois, and Carlos A. M. Afonso

2 RECYCLABLE ORGANOCATALYSTS IN ASYMMETRIC REACTIONS 83Michelangelo Gruttadauria, Francesco Giacalone, and Renato Noto

3 SYNTHESIS AND CHARACTERIZATION OF SUPPORTED CHIRAL CATALYSTS 177Carmela Aprile, Hermenegildo Garcia, and Paolo P. Pescarmona

viii CONTENTS

4 SYNTHESIS OF CHIRAL CATALYSTS SUPPORTED ON ORGANIC POLYMERS 209Tor Erik Kristensen and Tore Hansen

5 SELF-SUPPORTED CHIRAL CATALYSTS 257Hongchao Guo and Kuiling Ding

6 CATALYSIS WITH CHIRALLY MODIFIED METAL SURFACES: SCOPE AND MECHANISMS 291Angelo Vargas, Cecilia Mondelli, and Alfons Baiker

7 CHIRAL IONIC LIQUIDS FOR ASYMMETRIC REACTIONS 323Annie-Claude Gaumont, Yves Génisson, Frédéric Guillen, Viacheslav Zgonnik, and Jean-Christophe Plaquevent

8 ASYMMETRIC REACTIONS IN FLOW REACTORS 345Munawwer Rasheed, Simon C. Elmore, and Thomas Wirth

9 ASYMMETRIC CATALYTIC SYNTHESIS IN SUPERCRITICAL FLUIDS 373Tomoko Matsuda

10 MICROWAVE-ASSISTED TRANSITION METAL-CATALYZED ASYMMETRIC SYNTHESIS 391Luke R. Odell and Mats Larhed

II RECENT ADVANCES IN ORGANOCATALYTIC, ENZYMATIC, AND METAL-BASED MEDIATED ASYMMETRIC SYNTHESIS 413

11 RECENT ADVANCES ON STEREOSELECTIVE ORGANOCATALYTIC REACTIONS. ORGANOCATALYTIC SYNTHESIS OF NATURAL PRODUCTS AND DRUGS 415Monika Raj and Vinod K. Singh

12 RECENT ADVANCES IN BIOCATALYSIS APPLIED TO ORGANIC SYNTHESIS 491Gonzalo De Gonzalo, Iván Lavandera, and Vicente Gotor

13 PEPTIDES FOR ASYMMETRIC CATALYSIS 529Matthias Freund and Svetlana B. Tsogoeva

CONTENTS ix

14 SILICATE-MEDIATED STEREOSELECTIVE REACTIONS CATALYZED BY CHIRAL LEWIS BASES 579Maurizio Benaglia, Stefania Guizzetti, and Sergio Rossi

15 RECENT ADVANCES IN THE METAL-CATALYZED STEREOSELECTIVE SYNTHESIS OF BIOLOGICALLY ACTIVE MOLECULES 625Catalina Ferrer, Xavier Verdaguer, and Antoni Riera

16 STEREOSELECTIVE NITROGEN HETEROCYCLE SYNTHESIS MEDIATED BY CHIRAL METAL CATALYSTS 671Sherry R. Chemler

INDEX 689

PREFACE

Catalytic asymmetric synthesis is the “ art ” of promoting the exclusive achieve-ment of an enantiomer over another with the help of substoichiometric amounts of a proper catalyst. This frontier fi eld of research experiences, day after day, an exponential growth, and in the meantime it evolves in a parallel manner in thousands of laboratories all over the world. This continued evolu-tion has led in the last decade to the astounding discovery of a new founda-tional pillar in the fi eld. In fact, similar to the well - established biocatalysis and organometallic catalysis fi elds, in the last decade a third column called organocatalysis is strongly helping chemists with new additional tools in the preparation of three - dimensional chemical structures. However, due to fast developments in the fi eld, with new concepts and methods almost daily being discovered, it is diffi cult to carefully describe it in a given moment.

In this book we tried to take an instant picture of the most recent methods, applications, and techniques exploited in asymmetric synthesis. We gathered an authoritative list of worldwide experts in their corresponding areas of inter-est and asked them to contribute to this project. In order to cover the more important aspects of asymmetric synthesis that in the last recent years have received considerable interest from the scientifi c community, the book has been divided in two parts.

In the fi rst part new materials and technologies are collected. Chapters 1 and 2 focus on the recycling of stereoselective catalysts and organocatalysts, respectively, which paves the way to more sustainable processes. Chapters 3 and 4 are devoted to the synthesis and characterization of covalently sup-ported chiral catalysts on both inorganic and polymeric organic supports. The

xi

xii PREFACE

most important aspect is that these materials can be easily separated from the reaction mixture and reused several times without affecting their effi ciency. On the other hand, very recently metal - organic supramolecular polymers, constituted by self - complementary units or by orthogonal supramolecular building blocks, have emerged as powerful microporous heterogeneous cata-lysts; these are highlighted in Chapter 5 . Next, chirally modifi ed metals employed in the asymmetric hydrogenation of prochiral double bonds with special emphasis on the mechanistic aspects of the processes involved are discussed in Chapter 6 . Then, in Chapters 7 – 10 , asymmetric catalysis in alterna-tive green reaction media such as ionic liquids or supercritical fl uids will be thoroughly addressed as well as the use of enabling technologies such as con-tinuous fl ow or microwave - assisted reactors.

In the second part the most relevant and recent advances regarding the three pillars of asymmetric catalysis will be described. Particularly, much atten-tion will be devoted to the synthesis of natural products mediated by organo-catalysts, metal - free organic compounds of relatively low molecular weight and simple structure (Chapter 11 ), as well as to the use of the more structur-ally complex enzymes (Chapter 12 ) or natural and synthetic peptides (Chapter 13 ), meant as simplifi ed versions of biocatalysts, in asymmetric catalysis.

Chapter 14 covers chiral silicon - based Lewis bases, which play an important role as promoters of a large variety of stereoselective reactions. Finally, the last two chapters cover the most recent and innovative advances in the fi eld of chiral metal catalysis with special emphasis on the applications for the synthesis of biologically active molecules (Chapter 15 ) and the stereoselective nitrogen heterocycle synthesis, since nitrogen heterocycles play a central role in many biologically active molecules.

This book will serve to introduce the reader to the wide fi eld of asymmetric catalysis, giving him or her an insight into the current status of the area. Moreover, the presence in one book of two interconnected and complemen-tary aspects may allow teachers to give a wider overview of the topic and, at the same time, give an advantage to the students.

We would like to acknowledge once again all the contributors, the efforts of whom have made the publication of this book come true. We want to thank also Jonathan Rose and all the people at Wiley - Blackwell that supported us during the whole adventure.

M ichelangelo G ruttadauria

F rancesco G iacalone Palermo March 2011

FOREWORD

There will always be a need for organic synthesis. New compounds will always be required for evaluation as pharmaceuticals, agrochemicals, dyestuffs, mate-rials, and for a host of other purposes. In the context of organic synthesis, the need for asymmetric synthesis to provide effi cient access to enantiomerically enriched materials is a supreme challenge and the development of catalytic processes for asymmetric synthesis is at the forefront of advances in this area.

Modern advances in catalytic asymmetric synthesis include not only the recognition and application of organic catalysts together with improved ligands and transition - metal based catalysts, but also the introduction of solid sup-ported catalysts, fl ow systems, and homochiral organic liquids. Advances in biotechnology are also providing improved and more generally applicable enzymic processes for asymmetric synthesis. The need for innovative partition and extraction procedures has led to the use of supercritical fl uids and fl uorous reagents and solvents. Microwave heating can also provide much faster reac-tions than conventional heating and the demand for environmentally accept-able processes requires the minimisation of waste whether from reagents or solvents and so the use of recyclable catalysts and atom effi ciency are of para-mount importance not least for industrial processes.

So this is a large and rapidly evolving fi eld! In this timely and very broadly based volume of recent advances in asym-

metric synthesis, technological as well as chemical advances are presented. The use of solid supported and recyclable catalysts is discussed with a range of polymer and other solid supports considered in detail. The question of how to

xiii

xiv FOREWORD

convert a homogeneous catalyst into a heterogeneous one is addressed together with procedures for the characterisation of solid supported catalysts. The benefi ts of different catalyst supports are also presented alongside self - supported catalysts, chiral ionic liquids, and chirally modifi ed metal surfaces. Asymmetric synthesis in fl ow systems and in supercritical fl uids in considered together with microwave heating for asymmetric catalysis. Finally recent advances in asymmetric catalysis are presented in the context of many differ-ent types of reaction.

This book will be useful not only to experts in the fi eld but also to all syn-thetic organic chemists involved in asymmetric synthesis of chiral compounds. Post - graduate students and post - doctoral researchers will also fi nd it an invalu-able introduction to an important and burgeoning fi eld.

E ric J. T homas School of Chemistry The University of Manchester April 2011

CONTRIBUTORS

C arlos A. M. A fonso , CQFM, Centro de Qu í mica - F í sica Molecular and IN — Institute of Nanosciences and Nanotechnology, Instituto Superior T é cnico, 1049 - 001 Lisboa, Portugal; iMed.UL, Faculdade de Farm á cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649 - 003 Lisboa, Portugal.

C armela A prile , Facult é s Universitaires Notre - Dame de la Paix (FUNDP), 61 rue de Bruxelles, B - 5000 Namur, Belgium.

A lfons B aiker , Department of Chemical and Applied Biosciences, ETH Zurich, Switzerland, Wolfgang - Pauli - Str. 10, ETH H ö nggerberg, HCI E 133, CH - 8093 Z ü rich, Switzerland.

M aurizio B enaglia , Dipartimento di Chimica Organica e Industriale, Universit à degli Studi di Milano, via Golgi 19, 20133 Milano, Italy.

S herry R. C hemler , Department of Chemistry, The State University of New York at Buffalo, Buffalo, NY 14260.

K uiling D ing , State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.

S imon C. E lmore , Cardiff University, School of Chemistry, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom.

C atalina F errer , Unitat de Recerca en S í ntesi Asim è trica (URSA - PCB), Institute for Research in Biomedicine (IRB Barcelona), and Departament

xv

xvi CONTRIBUTORS

de Qu í mica Org à nica, Universitat de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain.

M atthias F reund , Department of Chemistry and Pharmacy, Chair of Organic Chemistry I, University of Erlangen - Nuremberg, Henkestrasse 42, 91054 Erlangen, Germany.

H ermenegildo G arcia , (b) Instituto de Tecnolog í a Quimica CSIC - UPV, Av. de los Naranjos s/n, Universidad Polit é cnica de Valencia, 46022 Valencia, Spain.

A nnie - Claude G aumont , Laboratoire de Chimie Mol é culaire et Thioorganique, UMR CNRS 6507, INC3M FR 3038, ENSICAEN & Universit é de Caen, 14050 Caen, France.

Y ves G é nisson , CNRS - UMR 5068, Synth è se et Physicochimie de Mol é cules d ’ Int é r ê t Biologique, Universit é Paul Sabatier, 118 route de Narbonne, 31062 Toulouse cedex 9, France.

F rancesco G iacalone , Department of Molecular and Biomolecular Sciences (STEMBIO), Section of Organic Chemistry, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy.

P edro M. P. G ois , iMed.UL, Faculdade de Farm á cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649 - 003 Lisboa, Portugal.

G onzalo d e G onzalo , Departamento de Qu í mica Org á nica e Inorg á nica, Instituto Universitario de Biotecnolog í a de Asturias, University of Oviedo, 33006 Oviedo, Spain.

V icente G otor , Departamento de Qu í mica Org á nica e Inorg á nica, Instituto Universitario de Biotecnolog í a de Asturias, University of Oviedo, 33006 Oviedo, Spain.

M ichelangelo G ruttadauria , Department of Molecular and Biomolecular Sciences (STEMBIO), Section of Organic Chemistry, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy.

F r é d é ric G uillen , CNRS - UMR 6014, COBRA, IRCOF, Universit é de Rouen, rue Tesni è re, 76821 Mont - Saint - Aignan, France.

S tefania G uizzetti , Dipartimento di Chimica Organica e Industriale, Universit à degli Studi di Milano, via Golgi 19, 20133 Milano, Italy.

H ongchao G uo , Department of Applied Chemistry, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China.

T ore H ansen , Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, NO - 0315 Oslo, Norway.

T or E rik K ristensen , Department of Chemistry, University of Oslo, NO - 0315 Oslo, Norway.

CONTRIBUTORS xvii

M ats L arhed , Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE - 75123 Uppsala, Sweden.

I v á n L avandera , Departamento de Qu í mica Org á nica e Inorg á nica, Instituto Universitario de Biotecnolog í a de Asturias, University of Oviedo, 33006 Oviedo, Spain.

T omoko M atsuda , Department of Bioengineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori - ku, Yokohama, Japan, 226 - 8501.

C ecilia M ondelli , Department of Chemical and Applied Biosciences, ETH Zurich, Switzerland, Wolfgang - Pauli - Str. 10, ETH H ö nggerberg, HCI E 133, CH - 8093 Z ü rich, Switzerland.

C arlos M. M onteiro , CQFM, Centro de Qu í mica - F í sica Molecular and IN — Institute of Nanosciences and Nanotechnology, Instituto Superior T é cnico, 1049 - 001 Lisboa, Portugal.

R enato N oto , Department of Molecular and Biomolecular Sciences (STEMBIO), Section of Organic Chemistry, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy.

L uke R. O dell , Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE - 75123 Uppsala, Sweden.

P aolo P. P escarmona , Centre for Surface Chemistry and Catalysis, K.U. Leuven, Kasteelpark Arenberg 23, 3001 Heverlee, Belgium.

J ean - C hristophe P laquevent , CNRS - UMR 5068, Synth è se et Physicochimie de Mol é cules d ’ Int é r ê t Biologique, Universit é Paul Sabatier, 118 route de Narbonne, 31062 Toulouse cedex 9, France.

M onika R aj , Indian Institute of Science Education and Research, Bhopal Transit Campus: ITI Campus (Gas Rahat) Building, Govindpura, Bhopal — 460 023 India.

M unawwer R asheed , Cardiff University, School of Chemistry, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom.

A ntoni R iera , Unitat de Recerca en S í ntesi Asim è trica (URSA - PCB), Institute for Research in Biomedicine (IRB Barcelona), and Departament de Qu í mica Org à nica, Universitat de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain.

S ergio R ossi , Dipartimento di Chimica Organica e Industriale, Universit à degli Studi di Milano, via Golgi 19, 20133 Milano, Italy.

V inod K. S ingh , Indian Institute of Science Education and Research, Bhopal Transit Campus: ITI Campus (Gas Rahat) Building, Govindpura, Bhopal — 460 023 India.

xviii CONTRIBUTORS

A lexandre F. T rindade , CQFM, Centro de Qu í mica - F í sica Molecular and IN — Institute of Nanosciences and Nanotechnology, Instituto Superior T é cnico, 1049 - 001 Lisboa, Portugal.

S vetlana B. T sogoeva , Department of Chemistry and Pharmacy, Chair of Organic Chemistry I, University of Erlangen - Nuremberg, Henkestrasse 42, 91054 Erlangen, Germany.

A ngelo V argas , Department of Chemical and Applied Biosciences, ETH Zurich, Switzerland, Wolfgang - Pauli - Str. 10, ETH H ö nggerberg, HCI E 133, CH - 8093 Z ü rich, Switzerland.

X avier V erdaguer , Unitat de Recerca en S í ntesi Asim è trica (URSA - PCB), Institute for Research in Biomedicine (IRB Barcelona), and Departament de Qu í mica Org à nica, Universitat de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain.

T homas W irth , Cardiff University, School of Chemistry, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom.

V iacheslav Z gonnik , CNRS - UMR 5068, Synth è se et Physicochimie de Mol é cules d ’ Int é r ê t Biologique, Universit é Paul Sabatier, 118 route de Narbonne, 31062 Toulouse cedex 9, France.

PART I

NEW MATERIALS AND TECHNOLOGIES: SUPPORTED CATALYSTS, SUPPORTS, SELF - SUPPORTED CATALYSTS, CHIRAL IONIC LIQUID, SUPERCRITICAL FLUIDS, FLOW REACTORS, AND MICROWAVES

CHAPTER 1

RECYCLABLE STEREOSELECTIVE CATALYSTS CARLOS M. MONTEIRO , ALEXANDRE F. TRINDADE , PEDRO M. P. GOIS , AND CARLOS A. M. AFONSO

Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications, First Edition. Edited by Michelangelo Gruttadauria and Francesco Giacalone.© 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

3

1.1. Introduction 3 1.2. Chiral phosphines 5

1.2.1. Hydrogenation 5 1.2.2. Hydroformylation 13 1.2.3. Cycloaddition 14 1.2.4. Allylic substitution 15

1.3. Chiral alkaloids 17 1.4. Bisoxazolines 24

1.4.1. Py - BOX ligands 24 1.4.2. BOX ligands 26 1.4.3. Aza - BOX and phe - BOX ligands 33

1.5. Salen - type ligands 35 1.6. Enzymes 47 1.7. Chiral diamines, diols, and aminoalcohols 51

1.7.1. TsDPEN - type ligands 51 1.7.2. Chiral aminoalcohols 55 1.7.3. BINOL - type ligands 59

1.8. Conclusions 64 References 64

1.1. INTRODUCTION

Asymmetric catalysis constitutes an important subject, generating thousands of published works every year. Still, the application of such methodologies in

4 RECYCLABLE STEREOSELECTIVE CATALYSTS

the chemical industry is rather limited due to the high cost of the chiral ligands and/or noble metals used in such transformations. Additionally, sometimes the fi nal products contain high levels of metal contamination derived from cata-lysts descomplexation or degradation phenomena, which can became a serious drawback if the metal is toxic, particularly for the pharmaceutical and food industries. For these reasons, there are still advantages to using the chiral building blocks readily available in nature or by applying resolution of optical isomers [1] .

Stereochemical and chemical effi ciency of a certain transformation are, in principle, better reproduced and predicted in homogeneous catalysis than in heterogeneous catalysis. The presence of the heterogeneous support in a reac-tion vessel can create, in some cases, unpredictable results (negative vs. novel positive effects) [2] . The choice of the heterogeneous support for the catalysis is a crucial decision. Some properties like high thermal, chemical and physical stabilities, chemical inertia, and homogeneous - like behavior are highly desir-able. Furthermore, the catalyst is easily recovered using just fi ltration or extraction techniques that are impossible to be applied in homogeneous catalysis [3] .

Amorphous and ordered silicas, clays, and highly cross - linked polymers are the standard supports to heterogenize a homogeneous catalyst. The principal immobilization mechanisms consist of ligand grafting, metal coordination, microencapsulation, electrostatic interactions, and ion exchange [3] (see also Chapters 3 and 4 ).

It is possible to combine the advantages of homogeneous and heteroge-neous systems by running reactions with catalysts that have been chemically linked to soluble macromolecules like oligomeric and/or low cross - linked soluble polymers, poly(ethylene glycol) (PEG), and dendritic structures. The supported homogeneous catalyst can be precipitated at the end of the reaction by addition of a cosolvent and recovered like a heterogeneous system [3] .

The reutilization of asymmetric catalysts and the reactions media was pos-sible using greener solvents like water, ionic liquids (ILs), PEG, perfl uorinated solvents, and supercritical CO 2 ( sc CO 2 ), which constitute alternatives to vola-tile organic solvents. Water appears as the cheapest solvent, bearing unique characteristics that differ from the others solvents: it is cheaper, most abundant in nature, and proven to have some unexpected benefi cial effects in organic transformations [3, 4] .

The need to transfer the asymmetric catalysis methodology to large - scale synthesis technology is a crucial goal for synthetic organic scientists worldwide. There are many contributions toward achieving this goal in the literature [2, 5] . In 2002, Chan et al. combined all these type of transformations or chiral ligands [6] , or self - supported heterogeneous catalysts [7] , or solvent - free trans-formations [8] . In 2009, Trindade et al. [3] updated the earlier Chan et al. work [2] , covering a broader number of transformations and all type of catalyst recycling methodologies. Other reviews were published in the literature, where the majority focused on catalyst immobilization for both chiral and achiral

CHIRAL PHOSPHINES 5

organic transformations, but they do not cover all types of reported catalysts immobilization processes [9] . From the reviews that focus only on enantiose-lective catalysis, some cover only one transformation performed with hetero-geneous catalysts [10] .

This chapter provides an overview of our selection transformations and all types of catalyst (except organocatalysts) recycling methodologies described up to March 2010.

At the beginning of each paragraph, there is a small description of the ligand in question and its applications in asymmetric catalysis. In the text, maximum efforts were made to identify the best - reported catalyst recycle system using heterogeneous catalysts, homogeneous catalysts, and alternative reaction media. Also, the method for recovery, in terms of reactivity and enan-tioselectivity, will be highlighted, giving special attention to the recycling process. This recycling process will be analyzed both in terms of executability and effi ciency. In terms of effi ciency, at times the reader may encounter Y e (x) = . . . % and ee e (x) = . . . %. These percentages should be read as the yield (Y e ) or enantioselectivity (ee e ) erosion at run x. The percentages are calculated according to the following expressions:

Y xY Y x

Yee x

ee ee xee

e e( )( ) ( )

( )( )

( ) ( )( )

=−

=−1

11

1

1.2. CHIRAL PHOSPHINES

The wide synthetic applications of phosphine catalysts have motivated many investigations on enantioselective reactions, particularly hydrogenation, hydroformylation, cycloaddition, and allylic substitution. The search for new, particularly designed chiral phosphorus catalysts has become a goal of several research groups. Despite the high activity and enantioselectivity achieved by complexing these ligands with Ru, Rh, and Ir, their air sensitivity and high cost represent a drawback. To circumvent these limitations, more stable and recy-clable catalysts have been developed.

1.2.1. Hydrogenation

Rhodium(I) and chiral phosphine catalysts are widely used in asymmetric alkene hydrogenation due to their effi ciency in the preparation of enantio-pure compounds with excellent atom economy. Generally, methyl α - acetamidoacrylate (MAA), methyl α - acetamido cinnamate (MAC), and dimethyl itaconate are the model substrates chosen by the authors to perform asymmetric hydrogenation reactions (Fig. 1.1 ).

Ding and Wang prepared a self - supported heterogeneous catalyst for enamines hydrogenation from an Rh complex [Rh(Cod) 2 BF 4 ] and a bis - phosphoamidate derived from 1,1 ′ - bi - 2 - naphthol (BINOL) (Monophos) 1 .

6 RECYCLABLE STEREOSELECTIVE CATALYSTS

SCHEME 1.1. Hydrogenation reaction with self - supported heterogeneous catalyst.

O

OMe

NHAc

O

OMe

NHAc

catalyst (1 mol%)

H2, 40 atm, toluene 95.8% ee

O

O

PN

RhP

O

O

P

N

BF4

n

Linker

Linker =

N N N

O N

O

NNN

ON

O

H H H H

H

H

1 2 3

FIGURE 1.1. Main substrates used for asymmetric hydrogenation assays.

O

O

O

HN

methyl acetamidoacrylate

O

O

O

HN

methyl acetamido cinnamate (MAC)

O

O

O

O

dimethyl itaconate(MAA)

Excellent enantioselectivities were obtained with aromatic and alkylic enamines with this heterogeneous catalyst (equivalent to a homogeneous ligand) (Scheme 1.1 ). The catalyst was recycled fi ve times with a minimal 5% enantioselectivity erosion [11] . Two years later, Ding and Wang prepared a new self - supported polymer based on the same homogeneous catalyst (cata-lyst 2 ). This polymeric complex proved to be an effi cient heterogeneous cata-lyst for enamines hydrogenation reactions [substrate/catalyst (S/C) = 100, 40 atm H 2 , 91% – 96% enantiomeric excess (ee)]. It could be recovered by fi ltra-tion and reused with minimal ee erosion [12] .

More recently, the same authors developed a continuous - fl ow system using another self - supported catalyst 3 based on the same catalyst. Under experi-mental conditions (2 atm H 2 ), the α - dehydroamino acid methyl esters

CHIRAL PHOSPHINES 7

could be continuously hydrogenated in > 99% conversion (93 – 94 μ mol/h) in 97% ee for a total of 144 hours and an overall yield of 2.52 g (15.75 mmol). The immobilized catalyst also showed high enantioselectivity (96% – 97% ee) but was observed with lower reactivity in a batch recycling system during 10 cycles [13] .

In 2000, de Rege et al. performed the heterogenization of a [(( R , R ) - Me - DuPHOS)Rh(COD)] + catalyst in mesoporous crystalline material (MCM) - 41. This heterogeneous catalyst proved to be as selective as the free catalyst (up to 99% ee) for the asymmetric hydrogenation of amidoacrylic acids and proved to be recyclable without loss of activity or enantioselectivity [14] .

The chiral ligands ( R ) - 2,2 ′ - bis(diphenylphosphino) - 1,1 ′ - binaphthyl (BINAP) [15] , ( R,R ) - Me - DuPhos [16] and (2 S ,4 S ) - BDPP [17] , and carbon - activated [18] supports were studied under Augustine et al. ’ s immobilization methodology [19] . Generally, the heterogeneous catalysts were found to be less active than their homogeneous partners under batchwise conditions but provided compa-rable levels of enantioselectivities (generally above 90% ee). The high degree of recyclability of these catalysts was also demonstrated (up to 11 cycles).

Hutchings et al. showed that achiral [Rh(cod) 2 ]BF 4 could be immobilized in mesoporous MCM - 41 by ion exchange, followed by chiral ligand coordina-tion [( R,R ) - Me - DuPhos]. Alternatively, they also immobilized directly the chiral rhodium complex. Both types of heterogeneous catalyst proved to be as effi cient as their homogeneous analogs (up to 99% ee) and could be reused nine times without enantioselectivity erosion in methyl itaconate hydrogena-tion (S/C = 250, 80 psi H 2 ) [20] .

Luna et al. grafted a Ru - (BINAP) (dpea) complex on the surface of amor-phous AlPO 4 support to achieve its recycling. It was tested in the successive liquid - phase enantioselective hydrogenation of dimethyl itaconate, MAA, and MAC (in dichloromethane, S/C = 45.4, 6.8 atm H 2 at 50 – 70 ° C, Table 1.1 ). This heterogeneous catalyst 4 (Table 1.1 ) provided the respective products with excellent enantioselectivities (99% ee) over several days and worked continu-ously (up to 10 cycles) [21] .

Other chiral phosphines immobilization in heterogeneous supports, such as acidic aluminosilacte (AlTUD - 1) [22] , phosphotungstic acid (PTA) on alumina [23] , and carbon nanotubes [24] , were reported. Excellent enantioselectivity ( > 96% ee) was obtained in this transformation, with good recyclability.

Fan et al. prepared and tested a chiral dendritic ligand 5 bearing a Pyrphos moiety linked to its core for the asymmetric hydrogenation of α - acetamido cinnnamic acid. After in situ catalyst formation [reaction between Rh(Cod) 2 BF 4 and the dendritic ligand 5 , Fig. 1.2 ], it furnished phenylalanines with excellent ee ’ s ( > 97% vs. 99% ee for nonsupported ligands) with all dendritic genera-tions. The catalyst was recovered by fi ltration and reused with constant ee. However, the conversion decreased considerably upon recycling (run 1: 94%, run 2: 55%) [25] . Similar chiral dendritic ligand was tested with analogous results, but improving in terms of reutilization. A drastic decrease of conver-sion was only observed on the fourth cycle [26] .

8 RECYCLABLE STEREOSELECTIVE CATALYSTS

FIGURE 1.2. Structure of the dendritic ligand 5 .

O

O

O

O

O

O

2

N

OPh2P

Ph2P

5

TABLE 1.1. Successive Hydrogenation Rates of Different Substrates

PPh2

Ph2P

N

N

NHN

Ru

Cl

4

Run Substrate Temperature

( ° C)

Reaction Rate

( μ mol/s) TOF (h − 1 )

Half Reaction Time (h)

Reaction Time (h)

1 Dimethyl itaconate 70.0 0.248 2.53 10.0 46.0 2 Dimethyl itaconate 55.0 0.062 0.63 76.0 144.0 3 Dimethyl Itaconate 70.0 0.023 0.24 96.0 216.0 a 4 MAA 70.0 1.023 10.45 2.2 9.0 5 MAC 70.0 0.039 0.40 96.0 288.0

a After 1473 hours (2 months approximately) continuously working, TON = 408.

Feng et al. reported the use of wet ILs as biphasic reaction media for MAA and MAC asymmetric hydrogenation [27] . The mixture of [omim]BF 4 /water (2 mL of IL to 2 – 3 mL of cosolvent) proved to be the best reaction media for MAA, affording higher levels of enantioselectivity and conversion (up to > 99% ee) than the traditional methanol/ i - propanol system (catalyst loading of 1 mol%), for all ferrocene - containing catalysts (Fig. 1.3 ). This biphasic system proved to be very stable, and only at the sixth cycle was an extension on the reaction time required to always achieve complete conversion with a consistent 99% ee. For more apolar substracts such as MAC, the organic

CHIRAL PHOSPHINES 9

FIGURE 1.3. Chiral biphosphine ligands for asymmetric hydrogenation reaction in [omim]BF 4 /water.

Fe Fe FeFe

Ph2P

N

Ph2P

Ph2PPtBu2

PPh2PPh2

Ph2P

N

N

PhPh

PPh2Taniaphos Josiphos Walphos Mandyphos

TABLE 1.2. Asymmetric Hydrogenation of Enamides

R

COOCH3

NHCOCH3

Rh-(S,S)-Et-DuPHOS

H2

RCOOCH3

NHCOCH36 7

Entry Substrate (R) Solvent System (v/v) ee (%) a

1 6a (C 6 H 5 ) PEG600/MeOH (1:3) 97.6 2 6a (C 6 H 5 ) PEG600/MeOH (1:4) 98.1 (98.6) 3 6b (3 - Cl - C 6 H 4 ) PEG600/MeOH (1:3) 97.0 (98.6) 4 6c (4 - Cl - C 6 H 4 ) PEG600/MeOH (1:3) 97.1 (98.8) 5 6d (4 - CH 3 O -

C 6 H 4 ) PEG600/MeOH (1:3) 98.6 (99.0)

6 6e (H) PEG600/MeOH (1:3) 98.2 (99.6)

a Data in parentheses were obtained by using MeOH as solvent under otherwise identical conditions.

cosolvent toluene was added to the wet IL in order to achieve high enantioselectivity.

Chan et al. showed that PEG could be added to methanol to conduct ruthe-nium - and rhodium - mediated hydrogenation of 2 - arylacrylic acids and enamides (Table 1.2 ). This solvent mixture proved to be as effi cient as the original solvent used in this transformation, providing excellent levels of enantioselectivity (quantitative yields, up to 98.6% ee). Furthermore, it added the possibility of recycling the homogeneous catalysts during nine effi cient cycles [28] .

Chiral phosphines also have a great potential for asymmetric hydrogena-tions and reductions of ketones (Scheme 1.2 ). Several chiral phosphines were described mixed with 1,2 - diphenylethylenediamine (DPEN) - type ligands type with very good results. Some of the supported ligands provided excellent levels of chiral induction (up to 98% ee).

One of the most successful immobilizations techniques was carried out by Noyori et al. when they anchored a BINAP derivative to a polystyrene polymer. The ruthenium complex 8 (Fig. 1.4 ) with this ligand and DPEN were used to hydrogenate acetoacetates with 97% ee during 10 consecutive cycles.

10 RECYCLABLE STEREOSELECTIVE CATALYSTS

FIGURE 1.4. Structures of ruthenium complex 8 and ligand 9 .

SPHN

O

Ph2P

PPh2

HN

NH

Ru

Cl

Cl

PPh2

PPh2

NH

HN

HN

O

NH

ONHO

i-PrO

n

8 9

SCHEME 1.2. General substrates and methods for hydrogenation/reduction of ketones.

R

O

aromatic ketones

O O

O

acetoacetates

hydrogenation

hydride reductions

∗

R

OH

∗OH O

O

R'R'

or

Lemaire et al. immobilized diAm - BINAP in a polymer copolymer using di - isocyanates as the linker. The most rigid copolymer ligand 9 (Fig. 1.4 ) was used in ruthenium - mediated hydrogenation of acetoacetates with excellent performance and near - perfect selectivity (S/C = 1000, 40 atm hydrogen pres-sure, 50 ° C, 16 hours, 99% ee). This heterogeneous catalyst (in methanol) was reused three times without any change on its performance [29] .

Lin et al. were interested in preparing hybrid materials containing organic linkers and metal nodes. The catalyst Ru(4,4 ′ - (PO 3 H 2 ) 2 - BINAP) (DPEN)Cl 2 coordinated to a zirconium salt (ZrOt - Bu 4 ) was synthesized for such purposes. With this heterogeneous catalyst in hand, the hydrogenation of aromatic ketones was conducted with higher enantioselective than its homogeneous counterpart and achieved excellent performance (0.1 mol%, 700 psi of H 2 , 20 hours to give up to 99.2% ee). Furthermore, the catalyst was reused seven times [30] .

Bergens et al. reported the fi rst polymeric asymmetric catalyst prepared by ring - opening metathesis polymerization (ROMP) of trans - RuCl 2 (Py) 2 (( R,R ) - Norphos)) and cycloctene. The living ends of the polymer were cross - linked with dicyclopentadiene and the pyridine ligands with chiral DPEN ligand and deposited on BaSO 4 (catalyst 10 ). It was tested in 1 ′ - acetonaphthone hydro-genation (S/C = 500, 4 atm H 2 , Scheme 1.3 ), being reused up to 10 cycles with