Table Of ContentHandbook of
Chiral Chemicals
S e c o n d E d i t i o n
© 2006 by Taylor & Francis Group, LLC
Handbook of
Chiral Chemicals
S e c o n d E d i t i o n
edited by
D a v i d A g e r
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
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© 2006 by Taylor & Francis Group, LLC
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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. Chemicals—Handbooks, manuals, etc. 2. Enantiomers—Handbooks, 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, José 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 Company’s 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 nature’s 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 there—it 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 Company’s 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
Contributors
David Ager Michel Bulliard
DSM Pharma Chemicals SynKem
Raleigh, North Carolina Chenôve Cedex, France
and
PharQuest LLC Mark Burk
Raleigh, North Carolina Diversa Corporation
San Diego, California
David Allen
Stepan Company Dainis Dakternieks
Northfield, Illinois Chirogen Pty Ltd
Parkville, Victoria, Australia
Nelson Barton
Diversa Corporation
Paul Dalby
San Diego, California
University College London
Department of Biochemical Engineering
Colin Bayley
London, UK
PharQuest LLC
Raleigh, North Carolina
Ben de Lange
DSM Research
Jens Beckmann
Advanced Synthesis, Catalysis and
Chirogen Pty Ltd
Development
Parkville, Victoria, Australia
Geleen, The Netherlands
Hans-Ulrich Blaser
Johannes de Vries
Solvias AG
DSM Research
Basel, Switzerland
Advanced Synthesis, Catalysis and
Development
Wilhelmus H.J. Boesten
Geleen, The Netherlands
DSM Research
Advanced Synthesis, Catalysis and
Development Grace DeSantis
Geleen, The Netherlands Diversa Corporation
San Diego, California
Gary Bond
University of Central Lancaster Michael East
Centre for Material Science Uquifa Inc.
Preston, UK Golf, Illinois
Quirinus Broxterman Henk Elsenberg
DSM Research DSM Research
Advanced Synthesis, Catalysis and Advanced Synthesis, Catalysis and
Development Development
Geleen, The Netherlands Geleen, The Netherlands
© 2006 by Taylor & Francis Group, LLC
