Handbook of

Chiral Chemicals
Second Edition

2006 by Taylor & Francis Group, LLC

 Handbook of
Chiral Chemicals
Second Edition

edited by
David Ager

Boca Raton London New York

A CRC title, part of the Taylor & Francis imprint, a member of the
Taylor & Francis Group, the academic division of T&F Informa plc.

2006 by Taylor & Francis Group, LLC

Published in 2006 by
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742

2006 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group

No claim to original U.S. Government works

Printed in the United States of America on acid-free paper
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International Standard Book Number-10: 1-57444-664-9 (Hardcover)

International Standard Book Number-13: 978-1-57444-664-7 (Hardcover)
Library of Congress Card Number 2005043716

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Library of Congress Cataloging-in-Publication Data

Handbook of chiral chemicals / edited by David J. Ager.2nd ed.

p. cm. Includes bibliographical references and index.
ISBN 1-57444-664-9 (alk. paper)
1. ChemicalsHandbooks, manuals, etc. 2. EnantiomersHandbooks, manuals, etc. I. Ager, David J.

TP201.H26 2005
661'.8--dc22 2005043716

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2006 by Taylor & Francis Group, LLC

Contents
Chapter 1 Introduction...................................................................................................................1
David J. Ager

Chapter 2 Amino Acids...............................................................................................................11

David J. Ager

Chapter 3 Microbial Pathway Engineering for Amino Acid Manufacture ................................31

Ian Fotheringham and Paul P. Taylor

Chapter 4 Carbohydrates in Synthesis ........................................................................................47

David J. Ager

Chapter 5 Terpenes: The Expansion of the Chiral Pool.............................................................59

Weiguo Liu

Chapter 6 Resolutions at Large Scale: Case Studies..................................................................75

Weiguo Liu

Chapter 7 New Developments in Crystallization-Induced Resolution.......................................97

Bernard Kaptein, Ton R. Vries, Jos W. Nieuwenhuijzen, Richard M. Kellogg,
Reinier F. P. Grimbergen, and Quirinus B. Broxterman

Chapter 8 The Role of cis-1-Amino-2-Indanol in Resolution Processes.................................117

Chris H. Senanayake, Dhileepkumar Krishnamurthy, and Isabelle Gallou

Chapter 9 Asymmetric Oxidations............................................................................................123

David J. Ager and David R. Allen

Chapter 10 Asymmetric Epoxidation of Olefins by Chiral Ketones..........................................147

Yian Shi

Chapter 11 Ozonolysis in the Production of Chiral Fine Chemicals.........................................165

Janine McGuire, Gary Bond, and Peter J. Haslam

2006 by Taylor & Francis Group, LLC

Chapter 12 Transition Metal Catalyzed Hydrogenations, Isomerizations, and
Other Reactions ........................................................................................................185
Scott A. Laneman

Chapter 13 Modular, Chiral P-Heterocycles in Asymmetric Catalysis......................................249

Mark J. Burk and James A. Ramsden

Chapter 14 Asymmetric Olefin Hydrogenation Using Monodentate BINOL- and

Bisphenol-Based Ligands: Phosphonites, Phosphites, and Phosphoramidites........269
Johannes G. de Vries

Chapter 15 Asymmetric Catalytic Hydrogenation Reactions with Ferrocene-Based

Diphosphine Ligands................................................................................................287
Hans-Ulrich Blaser, Matthias Lotz, and Felix Spindler

Chapter 16 Asymmetric Reduction of Prochiral Ketones Catalyzed by Oxazaborolidines ......305

Michel Bulliard

Chapter 17 cis-1-Amino-2-Indanol-Derived Ligands in Asymmetric Catalysis ........................319

Chris H. Senanayake, Dhileepkumar Krishnamurthy, and Isabelle Gallou

Chapter 18 Enantioselective Hydrogenation of Activated Ketones Using Heterogeneous

Pt Catalysts Modified with Cinchona Alkaloids......................................................345
Martin Studer and Hans-Ulrich Blaser

Chapter 19 Biotransformations: Green Processes for the Synthesis

of Chiral Fine Chemicals .........................................................................................359
David P. Pantaleone

Chapter 20 Combining Enzyme Discovery and Evolution to Develop Biocatalysts.................405

Mark Burk, Nelson Barton, Grace DeSantis, William Greenberg,
David Weiner, and Lishan Zhao

Chapter 21 One-Pot Synthesis and the Integration of Chemical and Biocatalytic

Conversions...............................................................................................................419
Paul A. Dalby, Gary J. Lye, and John M. Woodley

Chapter 22 Substitution Reactions ..............................................................................................429

David J. Ager

2006 by Taylor & Francis Group, LLC

Chapter 23 Industrial Applications of Chiral Auxiliaries...........................................................443
David R. Schaad

Chapter 24 The Role and Importance of cis-1-Amino-2-Indanol in Biological

Systems and Asymmetric Processes ........................................................................457
Chris H. Senanayake, Dhileepkumar Krishnamurthy, and Isabelle Gallou

Chapter 25 Enantiopure Amines by Chirality Transfer Using

(R)-Phenylglycine Amide .........................................................................................487
Ben de Lange, Wilhelmus H. J. Boesten, Marcel van der Sluis,
Patrick G. H. Uiterweerd, Henk L. M. Elsenberg, Richard M. Kellogg,
and Quirinus B. Broxterman

Chapter 26 Pericyclic Reactions .................................................................................................503

Michael B. East

Chapter 27 Asymmetric Free-Radical Reductions Mediated by Chiral Stannanes,

Germanes, and Silanes .............................................................................................531
Jens Beckmann, Dainis Dakternieks, and Carl H. Schiesser

Chapter 28 Metathesis Reactions ................................................................................................539

David R. Allen

Chapter 29 Synthesis of Homochiral Compounds: A Small Companys Role..........................559

Karen Etherington, Ed Irving, Feodor Scheinmann, and Basil Wakefield

Chapter 30 Commercial Synthesis of the Antiglaucoma Prostanoid Travoprost.......................573

Martin Fox, Mark Jackson, Ian C. Lennon, and Raymond McCague

Chapter 31 Synthesis of Large Volume Products .......................................................................589

David J. Ager and Colin R. Bayley

2006 by Taylor & Francis Group, LLC

Preface
The purpose of this book is to highlight the problems associated with the production of chiral
compounds at a commercial scale. With the movement by pharmaceutical companies to develop
single enantiomers as drug candidates, the problems associated with this subclass of organic
synthesis are being highlighted. As the stereogenic center can be derived from nature through the
use of chiral pool starting materials, the major classes of natural products are discussed.
Despite the explosion of asymmetric methods in the past 20 years, very few can be performed
at scale due to cost, thermodynamic, or equipment limitations. The major reactions that have been
used are covered. Resolution, whether chemical or enzymatic, still holds a key position. However,
this is changing as highlighted by a short discussion of the best-selling compounds of 2002
compared to 1996.
The most mature chemical method for large-scale asymmetric synthesis is hydrogenation. This
is highlighted by chapters on the uses of new ligands for hydrogenation as well as hydride reducing
agents. Although we have made considerable advances in this area, the general catalyst is still
elusive. Although the struggle goes on to identify the ultimate hydrogenation catalyst, for example,
the use of enzymes and biological systems for the production of chiral compounds continues to
increase at an incredible rate. Now that we have learned to manipulate natures catalysts, this area
will continue to grow and become more important in the production of fine chemicals.
The chapters have been grouped by topic, as shown in the table of contents. The first chapter
under a topic heading is a general introduction to that topic. These chapters are not intended to be
comprehensive reviews, but to critically discuss the options available at scale.
The first chapter of the book is a general introduction. Chapters 2 through 5 discuss how the
key subclasses of the chiral pool are obtained. The amino acid chapters are more specific as there
are other examples of amino acid syntheses contained within other chapters.
The next 23 chapters cover methods that can be used to introduce or control stereogenic centers.
In some cases, such as asymmetric hydrogenations, the approach is well established and has been
employed for the large-scale synthesis of a number of commercially important compounds. In other
cases, such as pericyclic reactions, the potential is thereit just has not been used. Two of these
chapters cover enzymatic methods, and this area seems to be more important as we understand
how to manipulate enzymes to allow them to catalyze new reactions or take new substrates. The
rush to market for pharmaceutical companies is forcing the chemical development time to be
minimized. This is leading to large-scale usage of chiral auxiliaries. The chapters on resolution
have a number of examples as illustrations. This methodology is still important to obtain chiral
compounds. Although, ultimately, it may not be the most cost-effective method, it can provide
material in a rapid manner, and can usually be scaled up. The introduction of large-scale chromato-
graphic techniques, as well as the availability of a large number of enzymes that can be used to
perform reactions on only one enantiomer, will ensure that this approach remains a useful tool in
the future. The remaining chapters discuss various examples and topics to augment other chapters
and provide a perspective of the different methods available. In two cases, ozonolysis and metathe-
sis, the technique need not directly introduce a new stereogenic center. They are, however, still
important reactions in the asymmetric context.
The final section of the book has three chapters that illustrate applications of the methodologies
to prepare specific compounds. One chapter is from a small company and describes a number of
projects; the second, from a large company for the synthesis of a relatively small volume product.
The final chapter covers large monetary value products.

2006 by Taylor & Francis Group, LLC

 If the reader thinks that topics are missing, or if there seems to be a company bias, all major
fine chemical manufacturing companies were invited to submit chapters. Even if a methodology
has not been specifically covered in depth, the introduction chapter to the topic will most likely
contain a reference to follow for further reading.
This is the second edition of this book. The publishers asked me whether they should print
more of the first edition, or if I was willing to produce a second edition. I chose the latter course.
All chapters have been updated, some very significantly illustrating the speed of development in
this area. Additional chapters have also been added to highlight successes of the approaches in an
industrial setting.
I would like to thank all the contributors to this book. Some have had to wait patiently for
other contributors to catch up. I would especially like to thank my former colleagues from NSC
Technologies for writing and updating many of the chapters that are overviews. They have also
supplied numerous suggestions and ideas (and supported the hypothesis that the number of ideas
generated is directly proportional to beer consumption). I would also like to make special mention
of my new colleagues at DSM, who responded to my requests without hesitation and also provided
a number of useful suggestions and ideas. To all the contributors, thanks; this book could not have
been completed without you.

Dave Ager
Raleigh, North Carolina

2006 by Taylor & Francis Group, LLC

The Editor
David Ager was born in Northampton, England, in 1953. He received a B.Sc. from Imperial College,
London, and a Ph.D. from the University of Cambridge, working with Dr. Ian Fleming on orga-
nosilicon chemistry. In 1977 he was awarded a Science Research Council Postdoctoral Fellowship
that allowed him to collaborate with Professor Richard Cookson FRS at the University of Southamp-
ton. In 1979, he joined the faculty of the University of Liverpool as a Senior Demonstrator. This
was followed by an assistant professor position at the University of Toledo in Ohio. In 1986, he
joined the NutraSweet Companys Research and Development group, and became responsible for
the scale-up of new sweetener development candidates as a Monsanto Fellow. He is a founding
member of NSC Technologies, which became an independent unit of Monsanto in 1995 as part of
Monsanto Growth Enterprises. In 1999, NSC was sold to Great Lakes Fine Chemicals; Dr. Ager
was a Fellow with GLFC, responsible for the development of new synthetic methodology. After
leaving GLFC he worked as a consultant on chiral and process chemistry. He joined DSM at the
beginning of 2002 as the competence manager for homogeneous catalysis. Dr. Ager is a member
of a number of scientific advisory boards. He has over 80 publications including three books.

2006 by Taylor & Francis Group, LLC