High-throughput synthesis: principles and practices PDF
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HIGH-THROUGHPUT SYNTHESIS Copyright © 2001 Marcel Dekker, Inc. HIGH-THROUGHPUT SYNTHESIS Principles and Practices edited by Irving Sucholeiki Solid Phase Sciences Corporation Medford, Massachusetts MARCELDEKKER, INC. NEWYORK• BASEL Copyright © 2001 Marcel Dekker, Inc. Library of Congress Cataloging-in-Publication Data High-throughput synthesis: principles and practices / edited by Irving Sucholeiki. p. cm. Includes bibliographical references and index. ISBN 0-8247-0256-5 (alk. paper) 1. Combinatorial chemistry. I. Sucholeiki, Irving QD262 H54 2000 547’.2—151;dc21 00-050928 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquar- ters address above. Copyright © 2001 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OFAMERICA Copyright © 2001 Marcel Dekker, Inc. Foreword Preparing new compounds and finding their practical application have always been among the most important goals of chemical science. These compounds have supplied the materials for new pharmaceuticals, pesticides, dyes, plastics, cata- lysts, components of fragrances, etc. When it first became known that large series of compounds were needed to produce new pharmaceuticals, these compounds were prepared and tested one by one. This conventional method of research was in obvious contrast to the technical possibilities available even two decades ago, since fabricating large series of items through the use of production lines and automation was extensively applied in industry. The advent of combinatorial chemistry radically changed this situation. It brought about a revolution in phar- maceutical research that is gradually expanding to other fields in which new com- pounds or materials are produced. The title of this book, High-Throughput Synthesis: Principles and Practices, indicates the current importance of combina- torial methods. There are two main approaches for high-throughput synthesis: one of them comprises the real combinatorial methods; the other includes the parallel proce- dures. Real combinatorial methods apply tricks to substantially reduce the number of operations/compounds needed. The reduced labor requirement makes it possi- ble to prepare in less than a week more compounds than were made in the whole previous history of chemistry. These methods were responsible for the outbreak of the combinatorial revolution. In parallel procedures the number of operations needed to carry out a synthesis is practically the same as in the conventional approach, and for this reason productivity cannot be nearly as high as when the previously mentioned methods are used. The parallel execution of the reactions, however, as well as extensively applied automation and other advan- iii Copyright © 2001 Marcel Dekker, Inc. iv Foreword tages made this type of library synthesis very popular. The parallel method also proved indispensable in realization of one-pot reactions, in solution-phase synthe- ses, and in searching for new materials. The capability to synthesize a large number of new compounds or to make new materials by mixing compounds is very important in the present era, since new useful compounds and materials can be found experimentally by making and testing a large number of candidates. The practical application of new compounds or composite materials depends largely on molecular interactions, and the fact that the combinatorial methods are so extensively used nowadays just reflects how incomplete our knowledge is of the rules that govern these interactions. One hopes, however, that the analysis of the huge amount of data accumulating from testing combinatorial libraries sooner or later will help us to better understand the relationship between molecular interactions and structure. It will be very impor- tant to make these data publicly available and not store them in the safes of com- panies. In the long run, understanding molecular interactions will eliminate the need for combinatorial chemistry and open the way for safe application of molec- ular design and molecular engineering. This won’t happen very soon, and until it does we must stick to combinatorial chemistry. This book will certainly contribute to its more successful application. It was an excellent idea to present it in the cookbook format. Listing the chemicals and equipment used in the syntheses and description of the procedures and even the postsynthetic analyses in sufficient detail will be very useful for readers and will help them to design their own com- binatorial experiments. Árpád Furka Department of Organic Chemistry Eötvös Loránd University Budapest, Hungary Copyright © 2001 Marcel Dekker, Inc. Preface This book grew out of discussions that I had in the early months of 1998 with Anita Lekhwani of Marcel Dekker, Inc. She was interested in creating a follow-up to an earlier book they had published—High Throughput Screening, edited by John P. Devlin—which was a review of state-of-the-art biological screening. She asked me to develop a chemistry version of that book, tentatively entitled High Throughput Synthesis, that would be an edited review of the field of combinatorial chemistry. Because my experience with a couple of edited review-type books in the past had been that they tended to get out of date even before they went to print, my first reaction was not very positive. Then I realized that what the field of combinatorial chemistry needed was a practical laboratory manual that would describe the mechanics of how to make large numbers of compounds. Too often, published reviews and papers leave out detailed information that, although not crucial to the overall understanding of the author’s work, is important in reproduc- ing the methods used. This book would target not only chemists in industry but also graduate students and faculty members in academia who may want to incor- porate combinatorial or solid-phase chemistry methods into their graduate research program. I had envisioned a recipe-type cookbook modeled after one of my all-time favorite undergraduate chemistry textbooks, Vogel’s Textbook of Practical Organic Chemistry(4th ed., Longman Group, 1978). For those not having had the good fortune of using the book, it was an all-encompassing manual presenting the gamut of “how-to” methods in organic chemistry from preparing and running samples for infrared analysis to running multigram scale nitration reactions. The combinatorial cookbook would contain recipes or case studies sorted by category. For example, there would be a section called “high-throughput synthesis for drug v Copyright © 2001 Marcel Dekker, Inc. vi Preface discovery” that would contain case studies illustrating the mechanics of making a large number of compounds for biological study. Other sections would have case studies on other aspects of producing large numbers of compounds, such as purifi- cation strategies and automation methods. Each case study would be written by a contributing chemist(s) with an emphasis on procedure and with very little theory. However, for a cookbook in combinatorial chemistry to succeed it must assume some knowledge on the part of the reader, such as familiarity with the theory behind various aspects of combinatorial chemistry and/or multiple parallel synthe- sis. Because most universities do not offer a course in combinatorial or solid- phase chemistry, I felt that for the book to be of benefit to graduate students and scientists not familiar with the field of combinatorial chemistry, it would need to include introductory sections or reviews covering the topics brought out by the case studies. Therefore, this book begins with an introduction to solid-phase organic chemistry, which is followed in Chapter 2 by a series of practical case studies written by J. Manuel Perez of Solid Phase Sciences Corporation covering various qualitative and quantitative methods for determining the loading capacity on solid support. Chapter 3 provides a perspective on how combinatorial chemistry came about, by Michael Pavia of Millennium Pharmaceuticals, Inc., who was one of the industry’s pioneers in the use of combinatorial chemistry for small-molecule, non- peptide drug discovery. Chapter 4 covers the field of high-throughput synthesis for drug discovery. It begins with a review by Stephen Wilson and Kathryn Reinhard of New York University and is immediately followed by several case studies con- tributed by various chemists from both industry and academia. Chapter 5, on purification strategies, begins with an overview by Mark Suto of DuPont Pharmaceuticals, followed by a series of case studies that highlight var- ious methods for purifying combinatorial libraries. Chapter 6 covers the use of automation and robotics in the production of compound libraries. Its author is Paul D. Hoeprich, Jr., of Agilent Technologies (currently with Genicon Sciences), who has been involved from the beginning in the development of automated synthesiz- ers for general organic chemistry. Several case studies follow this review that, although not all based on the use of automated systems, are highly innovative techniques that readers may find useful in enhancing the efficiency of their com- pound library production. The book then takes a dramatic shift away from the theme of producing com- pounds for biological study to producing molecules for other uses. There is a chapter on new materials (Chapter 7) by Xiao-Dong Xiang of Lawrence Berkeley National Laboratory and one (Chapter 8) on new catalyst development by Richard Willson, David Hill, and Phillip Gibbs of the University of Houston. Both chap- ters contain case studies that apply high-throughput synthetic methods to either the development of new materials or the discovery of new catalysts. In Part IV, the book turns from currently practiced methods to possible Copyright © 2001 Marcel Dekker, Inc. Preface vii future applications or methods in the area of high-throughput synthesis. Chapter 9, by Nicholas Hodge, Luc Bousse, and Michael Knapp of Caliper Technologies, covers the area of microchemistry and further expounds on the “lab-on-a-chip” concept. Chapter 10, by David Walt of Tufts University, delves into the uses of fiberoptic sensors as a way to screen for compounds. Finally, Chapter 11 covers the application of some new solid-phase technologies for improving the automa- tion of solid-phase organic synthesis. Chapters 9–11 do not contain case studies, since they discuss methods or concepts that are still relatively new and under development. Alas, the reader may find that not every aspect of high-throughput synthesis has been covered in this book. For instance, there is no chapter on the planning of a combinatorial library through diversity analysis, nor on cataloging the library once it has been made. There are several reasons for this, not the least of which was the need to keep the book to a reasonable length. Another reason was my interest in focusing the book solely on the “hands-on” mechanics of production. Since there are already some good books out there that focus on those other sub- jects, I did not feel that there was a dire need to include them in this book. Even Vogel’s textbook had its limits! For those who find other omissions or flaws in either the content or the format of the book, I suggest that they contact Marcel Dekker, Inc., with their comments and/or suggestions so that they may be incorpo- rated into future editions of this book. There are many whom I would like to thank, most notably the many contrib- utors of case studies without whose participation this book could never have been created. I would also like to express my gratitude to Marcel Dekker, Inc., for hav- ing kept the faith over these past two years. Lastly, I thank my wife for her patience and understanding during all those work-at-home weekends. Irving Sucholeiki Copyright © 2001 Marcel Dekker, Inc. Contents Foreword Árpád Furka iii Preface v Contributors xiii Introduction H. Mario Geysen xix Part I Theory and Methods in Solid Phase Organic Synthesis Chapter 1 An Introduction to Solid Phase Organic Synthesis 3 Irving Sucholeiki Chapter 2 Methods of Analysis to Determine the Progress of a Chemical Reaction on Solid Support 27 J. Manuel Perez Part II High-Throughput Synthesis forDrug Discovery Chapter 3 High-Throughput Organic Synthesis: A Perspective Looking Back on 10 Years of Combinatorial Chemistry 43 Michael R. Pavia Chapter 4 Techniques and Strategies for Producing Compound Libraries for Biological Screening 55 Stephen R. Wilson and Kathryn Reinhard ix Copyright © 2001 Marcel Dekker, Inc. x Contents Case Study 4-1 A l-Turn Mimetic Library: Development and Production 65 Petr Kocis, James B. Campbell, Richard B. Sparks, and Richard Wildonger Case Study 4-2 Production of an a-Ketoamide-Containing Library via Convergent Parallel Synthesis 85 Alan P. Kaplan and Carmen M. Baldino Case Study 4-3 Manual Solid Phase Synthesis of a Fully Encoded, 46,656-Member Benzimidazole Library 93 David Tumelty, Lun-Cong Dong, Kathy Cao, Lanchi Le, and Michael C. Needels Case Study 4-4 Protease Substrate Specificity Mapping Using Membrane-Bound Peptides 109 Richard A. Laursen, Caizhi Zhu, and Yongjun Duan Case Study 4-5 Characterization of the Epitope Specificity of Antibodies Using Membrane-Bound Peptides 117 Richard A. Laursen and Zhengxin Wang Case Study 4-6 Rapid Parallel Synthesis Utilizing Microwave Irradiation 123 Brian M. Glass and Andrew P. Combs Chapter 5 High-Throughput Purification Strategies 129 Mark J. Suto Case Study 5-1 Fluorous Scavenging 135 Bruno Linclau and Dennis P. Curran Case Study 5-2 Polymer-Assisted Solution Phase Synthesis of a-Ketoamides 143 John J. Parlow, Thomas A. Dice, and Michael S. South Case Study 5-3 Ion Exchange Resins for the Preparation of Amide Libraries 153 Mark J. Suto Chapter 6 Automating High-Throughput Organic Synthesis 157 Paul D. Hoeprich, Jr. Copyright © 2001 Marcel Dekker, Inc.
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