Applications of Transition Metal Catalysis in Drug Discovery and Development Applications of Transition Metal Catalysis in Drug Discovery and Development

APPLICATIONS OF TRANSITION METAL CATALYSIS IN DRUG DISCOVERY AND DEVELOPMENT APPLICATIONS OF TRANSITION METAL CATALYSIS IN DRUG DISCOVERY AND DEVELOPMENT An Industrial Perspective Edited by MATTHEW L. CRAWLEY Main Line Health Berwyn, Pennsylvania, USA BARRY M. TROST Stanford University Stanford, California, USA Copyright Ó 2012 by John Wiley & Sons, Inc. 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For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data: Applications of transition metal catalysis in drug discovery and development : an industrial perspective / edited by Matthew L. Crawley, Barry M. Trost. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-63132-4 (cloth) I. Crawley, Matthew L. II. Trost, Barry M. [DNLM: 1. Drug Discovery. 2. Catalysis. 3. Pharmaceutical Preparations–chemistry. 4. Transition Elements. QV 744] 615.109–dc23 2011047552 Printed in the United States of America ISBN: 9780470631324 10987654321 CONTENTS Preface vii Contributors ix About the Authors xi 1 Transition Metal Catalysis in the Pharmaceutical Industry 1 Carl A. Busacca, Daniel R. Fandrick, Jinhua J. Song, and Chris H. Senanayake (Boehringer Ingelheim Pharmaceuticals) 2 Selected Applications of Transition Metal-Catalyzed Carbon–Carbon Cross-Coupling Reactions in the Pharmaceutical Industry 25 Hong C. Shen (Roche) 3 Selected Applications of Pd- and Cu-Catalyzed Carbon–Heteroatom Cross-Coupling Reactions in the Pharmaceutical Industry 97 Jingjun Yin (Merck) 4 Asymmetric Cross-Coupling Reactions 165 Vince Yeh (Novartis) and William A. Szabo (Consultant in Drug Development) 5 Metathesis Reactions 215 Oliver R. Thiel (Amgen) v vi CONTENTS 6 Transition Metal-Catalyzed Synthesis of Five- and Six-Membered Heterocycles 257 Cheol K. Chung (Merck) and Matthew L. Crawley (Main Line Health) 7 Oxidative Catalysis 277 Lamont Terrell (GlaxoSmithKline) 8 Industrial Asymmetric Hydrogenation 315 Hans-Ulrich Blaser (Solvias) Index 343 PREFACE Designing structure for function is a key activity of a chemist approaching problems in fields ranging from material science to medicine. A critical aspect of such an endeavor is the ability to access the designed structure in a time-efficient manner. This requirement puts a major constraint on the level of complexity of the designed structure, which, in turn, may limit the performance of the compound especially in terms of selectivity. Another component of this issue is the ability to synthesize any compound that does prove to have desirable properties in a practical way. At the heart of both of these requirements is the ability to obtain the required compound in as few steps as possible from readily available commercial materials. The strategic route to produce the desired structure depends upon the toolbox of synthetic reactions. To be as efficient as possible, the synthetic reactions must be chemoselective (i.e., differentiate among various bond types including between multiple functional groups of the same type), regioselective (i.e., control orientation of approach of two reactants), and, where applicable, diastereoselective (i.e., control relative stereochemistry/geometry) and enantioselective (i.e., control absolute stereochemistry). In addition, practical synthetic reactions must maximize the generation of raw materials and minimize the generation of waste—an aspect referred to as being atom economic. In the ideal condition, the reaction should be a simple addition in an intermolecular process or an isomerization in an intramolecular process. In any event, any stoichiometric by-product should be as small and innocuous as possible. To the extent another reactant is necessary, it should be needed only catalytically. While some synthetic reactions do meet these requirements, such as the Diels–Alder and more recently the Aldol reaction, most synthetic reactions do not. Thus, a huge need for new synthetic methodology to meet these challenges exists. No application is more impacted by these issues as pharmaceutical research. vii viii PREFACE To obtain the rigorous performance requirements of pharmaceuticals, ever more complex structures will be needed. However, our toolbox remains limited. Catalysis has rapidly emerged as a critical approach to meet these challenges. In the first instance, improving the ability to perform existing reactions is a more efficient and atom-economic fashion is one approach. Good examples are the aforementioned Diels–Alder and Aldol approaches. In the Diels–Alder reaction, catalysis becomes the vehicle to deal with issues of regio-, diastereo-, and enantioselectivity. In the Aldol addition, catalysis becomes critical to perform this important reaction in its most atom-economic fashion as well as to address the issues of regio-, diastereo-, and enantioselectivity. In the second instance, generating new patterns of reactivity is even more powerful in meeting these goals. New reactivity allows the creation of strategies that previously did not exist. A good illustration is the transition metal catalyzed cross-coupling reaction. No single reaction has had such an immense impact in pharmaceutical research and development than this process in the last 40 years, the reaction being first disclosed in the 1970s. While aryl coupling reactions such as the Ullmann coupling did exist, the thought that two different aryl groups could couple in a chemoselective manner was only a pipe dream. This could evolve into being so powerful that almost any two subunits can be coupled in this C–C bond-forming process that it has become was unimaginable. In a very real sense, a major change in the practice of the science has occurred and has allowed the design of new structures for pharmaceutical applications that has already borne such fruit. How many more such reactions may exist is impossible to estimate. However, it is reasonable to deduce that many remain undiscovered as strong incentive for the future generations of scientists. This monograph provides an overview of where we are in meeting these challenges. Leading scientists who are themselves confronted with these problems provide a description of how far we have come. At the same time, their chapters reveal that, in spite of the progress, we have a very long way to go. Yes,we have gotten better, but that does not mean that we are anywhere near where we need to be. It is fair to predict that we are still in our infancy in making the synthesis of pharmaceuticals more empower- ing. While the imagination, determination, and skill of future efforts will be required for us to move forward in meeting these challenges, the immensity of the opportunities undoubtedly will mean that these activities will be critical for a very long time. BARRY M. TROST Stanford University Stanford, California, USA CONTRIBUTORS Hans-Ulrich Blaser, Solvias AG, Basel, Switzerland (ret.) Carl A. Busacca, Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA Cheol K. Chung, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, USA Matthew L. Crawley, Main Line Health, Berwyn, PA, USA Daniel R. Fandrick, Chemical Development, Boehringer Ingelheim Pharmaceu- ticals, Inc., Ridgefield, CT, USA Chris H. Senanayake, Chemical Development, Boehringer Ingelheim Pharmaceu- ticals, Inc., Ridgefield, CT, USA Hong C. Shen, Department of Medicinal Chemistry, Roche R&D Center Ltd., Pudong, Shanghai, China Jinhua J. Song, Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield,

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