cover

Contents

Title Page

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. 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 empowering. 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 Pharmaceuticals, Inc., Ridgefield, CT, USA

Chris H. Senanayake, Chemical Development, Boehringer Ingelheim Pharmaceuticals, 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, CT, USA

William A. Szabo, Consultant in Drug Development, San Diego, CA, USA

Lamont Terrell, Heart Failure DPU, GlaxoSmithKline, King of Prussia, PA, USA

Oliver R. Thiel, Chemical Process Research & Development, Amgen, Inc., Thousand Oaks, CA, USA

Vince Yeh, Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA

Jingjun Yin, Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, USA

About the Authors

Editors

Professor Barry M. Trost

Born in Philadelphia, Pennsylvania in 1941 where he began his university training at the University of Pennsylvania (BA, 1962), he obtained a Ph.D. degree in Chemistry just three years later at the Massachusetts Institute of Technology (1965). He directly moved to the University of Wisconsin where he was promoted to Professor of Chemistry in 1969 and subsequently became the Vilas Research Professor in 1982. He joined the faculty at Stanford as Professor of Chemistry in 1987 and became Tamaki Professor of Humanities and Sciences in 1990. In addition, he has been Visiting Professor of Chemistry in Denmark (University of Copenhagen), France (Universities of Paris VI and Paris-Sud), Germany (Universities of Marburg, Hamburg and Munich), Italy (University of Pisa), Spain (Universities of Barcelona and Santiago de Compostela) and the UK (Cambridge University). In 1994 he was presented with a Docteur Honoris Causa of the Université Claude-Bernard (Lyon I), France, and in 1997 a Doctor Scientiarum Honoris Causa of the Technion, Haifa, Israel. In 2006, he was appointed Honorary Professor of the Shanghai Institute of Organic Chemistry.

Professor Trost's work has been characterized by a very high order of imagination, innovation and scholarship. He has ranged over the entire field of organic synthesis, particularly emphasizing extraordinarily novel methodology. Further, he has repeatedly demonstrated how his innovative methodology allows for the simplification of many complex target oriented syntheses leading to natural products of high biological activity. Early in his career, Professor Trost participated in the isolation and structure determination of the Cecropia Juvenile hormone. These studies helped to promulgate the concept that insect growth regulators can serve as ecologically preferable alternatives to pesticides. The long term goal and defining mission of Professor Trost's career has been toward enhancing synthetic effectiveness. He has virtually created whole new methodologies and strategies in organic synthesis. Among the areas which he has pioneered are the use of sulfur based reagents and transition metal, most notably palladium, and more recently ruthenium, catalysts in complex setting. More recently, his work has focused on enantioselective catalysts via the rational design of “chiral space.” This work requires a detailed grasp of the mechanistic nuances of organometallic reactions. As part of this program, he designed a new class of ligands that spontaneously forms dinuclear complexes that are proving to be especially effective at asymmetric catalysis. Another continuing theme, directed to the realities of organic synthesis in fostering commercial goals, is the strategy of “atom economy.” Thus, synthetic building blocks are combined to produce complex targets in high yield with a bare minimum of debris under the guidance of carefully crafted catalysts. In this way, organic synthesis can be brought to bear in process settings to reach substances of high complexity in a commercially feasible way which minimizes environmental impact. Barry Trost's triumphs in total synthesis include complex terpenoids, steroids, alkaloids, vitamins, antibiotics, nucleosides and macrolides. His syntheses are conducted with characteristic flair and serve as learning resources in addressing the limits of the methodology which he tends to develop independently.

In recognition of his many contributions, Professor Trost has received a number of awards, including the ACS Award in Pure Chemistry (1977), the ACS Award for Creative Work in Synthetic Organic Chemistry (1981), the Baekeland Award (1981), the first Allan R. Day Award of the Philadelphia Organic Chemists' Club (1983), the Chemical Pioneer Award of the American Institute of Chemists (1983), the Alexander von Humboldt Stiftung Award (1984), MERIT Award of NIH (1988), Hamilton Award (1988), Arthur C. Cope Scholar Award (1989), Guenther Award in the Chemistry of Essential Oils and Related Products (1990), the Dr. Paul Janssen Prize (1990), the ASSU Graduate Teaching Award (1991), Pfizer Senior Faculty Award (1992), Bing Teaching Award (1993), the ACS Roger Adams Award (1995), the Presidential Green Chemistry Challenge Award (1998), the Herbert C. Brown Award for Creative Research in Synthetic Methods (1999), the Belgian Organic Synthesis Symposium Elsevier Award (2000), the Nichols Medal (2000), the Yamada Prize (2001), the ACS Nobel Laureate Signature Award for Graduate Education in Chemistry (2002), the ACS Cope Award (2004), the City of Philadelphia John Scott Award (2004), Thomson Scientific Laureate (2007), the Kitasato Microbial Chemistry Medal, and the Nagoya Medal (2008). He has held a Sloan Fellowship, a Camille and Henry Dreyfus Teacher-Scholar grant and an American-Swiss Foundation Fellowship as well as having been the Julius Stieglitz Memorial Lecturer of the ACS-Chicago section (1980–81) and Centenary Lecturer of the Royal Society of Chemistry (1981–82). Professor Trost has been elected a Fellow of the American Academy of Sciences (1982) and a member of the National Academy of Sciences (1980). He has served as editor and on the editorial board of many books and journals, including being Associate Editor of the Journal of the American Chemical Society (1974–80). He has served as a member of many panels and scientific delegations, and served as Chairman of the NIH Medicinal Chemistry Study Section. He has held over 120 special university lectureships and presented over 260 Plenary Lectures at national and international meetings. He has published two books and over 840 scientific articles. He edited a major compendium entitled Comprehensive Organic Synthesis consisting of nine volumes and serves as editor for ChemTracts/Organic Chemistry.

Dr. Matthew L. Crawley

Matthew Lantz Crawley obtained his B.A. degree from Williams College with a double major in political economy and chemistry under the guidance of Professor J. Hodge Markgraf. In 1998, he started his graduate studies with Professor Barry M. Trost at Stanford University, where his work focused on the development of asymmetric palladium-catalyzed reactions with applications in total synthesis. After completion of his Ph.D., Matthew joined the medicinal chemistry department of Incyte Corporation in Delaware, where he worked for several years. From late 2005 through 2010, Matthew worked at Wyeth Research in Pennsylvania (now Pfizer), first as a Senior Research Scientist and then as a Team Leader and Principal Research Scientist doing drug discovery in an array of therapeutic areas, including neuroscience, inflammation, and cardiovascular and metabolic disease. Most recently, while remaining active in chemistry through consulting, his work has focused on the healthcare sector where he is the Director of Electronic Medical Records for the Philadelphia based Main Line Health system. Matthew has authored or coauthored dozens of publications and is an inventor on several non-provisional and issued patents.

Authors

Dr. Chris H. Senanayake

Dr. Chris H. Senanayake was born in Sri Lanka and received a BS degree (First Class) in Sri Lanka. After coming to the United States, he completed his MS at Bowling Green State University with Professor Thomas Kinstle in synthetic chemistry. He obtained his Ph.D. under the guidance of Professor James H. Rigby at Wayne State University in 1987 where he worked on the total synthesis of complex natural products such as, ophiobolanes, and completed the first total synthesis of grosshemin in the guaianolide family. He then undertook a postdoctoral fellow with Professor Carl R. Johnson and worked on the total synthesis of polyol systems such as amphotericin B and compactin analogous, and the synthesis of C-nucleoside precursors.

In 1989, he joined the Department of Process Development at Dow Chemical Co. In 1990, he joined the Merck Process Research Group. After 6 years at Merck, he accepted a position at Sepracor, Inc. in 1996 where he was promoted to Executive Director of Chemical Process Research. In 2002, he joined Boehringer Ingelheim Pharmaceuticals. Currently, he is the Vice President of Chemical Development and leading a group of highly talented scientists, engineers, and administrative staff located in Ridgefield, CT.

Senanayake's research interests focus on the development of new asymmetric methods for the synthesis of bioactive molecules and heterocycles and on catalytic, enzymatic, and mechanistic studies. He has published and lectured in the area of practical asymmetric synthesis and many disciplines of organic chemistry how to develop drugs on an economical, greener and practical manner in large-scale operation for rapid development of drugs.

Senanayake demonstrates the ability to define and optimize chemical research and development strategies and tactics. He is able to “connect the dots” between the purely scientific and commercial perspectives and set up creative and effective strategies for new and proprietary products in ways that build value for the organization and create a competitive advantage. He is an Editorial Advisory Board member of the Organic Process Research & Development Journal. In 2008, he was the chairperson of Stereochemistry Gordon Conference. In 2010, he received the prestigious Siegfried gold medal award for development of practical processes for APIs and Process Chemistry. In 2011, He was appointed as an editorial board member of the Advance Synthesis and Catalysis Journal.

Dr. Daniel R. Fandrick

Dr. Daniel R. Fandrick received his B.S. degree with a major in chemistry from the University of California, San Diego under the guidance of Professor Joseph M. O'Conner. In 2006, Daniel earned his PhD degree in organic chemistry at Stanford University under the mentorship of Professor Barry M. Trost. His graduate studies focused on the development of the dynamic kinetic asymmetric transformations of vinyl aziridines and allenes and their applications to total synthesis. After graduation, he joined the chemical development group at Boehringer-Ingelheim Pharmaceuticals Inc. in Ridgefield, Connecticut where he is a principle scientist. Dr. Fandrick has published over 30 papers and numerous patents. His research interests are in the development of transition metal catalyzed and sustainable methodologies to provide efficient assess to pharmaceutically useful scaffolds and chiral centers. At Boehringer-Ingelheim Pharmaceuticals, Inc. Dr. Fandrick developed the novel asymmetric propargylation methodologies which provide general access to chiral homopropargylic alcohols and amines.

Dr. Jinhua Jeff Song

Dr. Jinhua Jeff Song received his undergraduate education at Nankai University in Tianjin, China (1989 to 1992). After a brief stay at Rice University in Houston, TX, he moved to the Massachusetts Institute of Technology in 1993 and obtained his Ph.D. degree in 1998 under the supervision of Prof. Satoru Masamune. Subsequently, he joined the Department of Chemical Development at Boehringer Ingelheim Pharmaceuticals in Ridgefield, CT, where he is currently a Senior Associate Director in Process Research.

Dr. Song's research areas encompass natural product synthesis, asymmetric synthesis of chiral biologically active compounds, efficient methodologies for heterocycle synthesis, and novel N-heterocyclic carbene catalyzed reactions. He has published >40 research papers, review articles and book chapters including some “Most-Cited” and “Most-Accessed” papers. Over the years, Dr. Song has delivered invited lectures at various international conferences as well as academic institutions. Some of his work also received media attention and has been highlighted in the Chemical and Engineering News. Additionally, Dr. Song holds >15 patents on efficient synthesis of pharmaceutical agents.

Dr. Carl Busacca

Dr. Carl Busacca is a native of Milwaukee, Wisconsin, who graduated from high school in North Carolina, and then attended North Carolina State University, receiving his BS in Chemistry in 1982. He performed some undergraduate research in both laser resonance Raman spectroscopy, and the 60Co radiolysis of fluorocarbons. He then worked three years in Research Triangle Park, North Carolina doing organic synthesis for Union Carbide, before returning to graduate school, at Colorado State University. At CSU, he studied under Professor A.I. Meyers, earning his Ph.D. in 1989 following research into asymmetric Diels-Alder cycloadditions. In 1990, he entered the Pharmaceutical Industry working for five years as a medicinal chemist at Sterling Winthrop in Rensselaer, New York. At Sterling, he worked on novel anti-arrhythmics and Thrombin inhibitors, and carried out research supporting the existence of palladium carbenes as intermediates in cross-coupling reactions. He joined the Department of Chemical Development at Boehringer-Ingelheim Pharmaceuticals in Ridgefield, Connecticut as a process chemist in 1994. At Boehringer, Dr. Busacca worked first for Dr. Vittorio Farina, and then for Dr. Chris Senanayake, and he is currently Distinguished Research Fellow. He has worked extensively in the anti-viral area, developing inhibitors of various parts of the HIV and HCV machinery. Dr. Busacca's principal research interests include mechanistic organopalladium chemistry, ligand design, the development of new organophosphorus chemistry, asymmetric catalysis, applications of NMR spectroscopy to Process Research, and the design of efficient chemical processes. He is deeply interested in the nucleosynthesis of transition metals in supernovae.

Dr. Hong C. Shen

Hong C. Shen received his B.S. degree in chemistry from Peking University under the direction of Professor Yunhua Ye in 1997. He subsequently moved to University of Minnesota, where he developed a formal [3+3] cycloaddition with Professor Richard Hsung, and obtained his M.S. degree in 1998. Hong Shen then joined the research group of Professor Barry Trost at Stanford University. His work spanned from Ru- and Pd-catalyzed reactions to their applications in total syntheses of natural products. After obtaining his Ph.D. in 2003, Hong Shen assumed a senior research chemist position at Merck Research Laboratories, Rahway, New Jersey. He then took on an exploratory chemistry team lead working in the areas of cardiovascular, thrombosis, and metabolic diseases. Most recently he returned to China to pursue an exceptional opportunity as the section head for medicinal chemistry at Roche. Hong has authorship on more than 55 scientific publications and is an inventor on 17 patent applications. Hong is currently a visiting professor at Tianjin University.

Dr. Jingjun Yin

Jingjun Yin obtained a B.S. degree from the University of Science and Technology of China in 1994 and then went on to earn his Ph.D. degree in Organic Chemistry under the direction of Prof. Lanny Liebeskind at Emory University in 1999. After that, he moved to Massachusetts Institute of Technology as a postdoctoral fellow with Prof. Stephen Buchwald. In 2001, he joined the Process Research Department of Merck at Rahway, New Jersey focusing on designing efficient and practical syntheses of complex drug candidates with a special interest in transition-metal catalyzed reactions.

Dr. William A. Szabo

Bill Szabo received his undergraduate degree in Chemistry from Lehigh University, worked for 2 years as an R&D chemist at Johnson & Johnson's McNeil Laboratories, and earned a Ph.D. degree in Heterocyclic and Medicinal Chemistry from the University of Florida. He held a 2-year postdoctoral fellowship in natural product synthesis at Wesleyan University with Professor Max Tishler, former President of Merck Research Laboratories and an early pioneer in pharmaceutical process development. Bill was next recruited by Alfred Bader, cofounder of the Aldrich Chemical Company, and worked for 18 years at Aldrich in Milwaukee in various management positions in R&D, production, and advertising. He then relocated to St. Louis and spent 4 years in the sales and marketing of reagents and bulk pharmaceutical intermediates for Sigma-Aldrich, positions which included Sales Director for North America and Vice President of International Sales. In 1998, Bill took an early retirement and moved to San Diego. He has since been consulting in drug and business development. Bill has been active in the 2800-member San Diego Section of the American Chemical Society. He served as Chairman of its executive board in 2011.

Dr. Vince Yeh

Vince Yeh completed his B. S. degree from the University of British Columbia in 1994. Subsequently, he earned his Ph.D. in organic chemistry from University of Alberta in 2001 under the guidance of Professor Derrick Clive. He then moved to Stanford University for post-doctoral studies under Professor Barry Trost. During that time he contributed to the development of asymmetric direct aldol catalysts invented in the Trost labs. In 2003 he moved to Chicago to work for Abbott Laboratories in their Metabolic Diseases unit where he invented an advanced development candidate. In 2007, he worked for Astellas Pharmaceuticals where he established their first American preclinical chemistry research lab. Later that year, he moved back to California (San Diego) to pursue medicinal chemistry research at the Genomic Institute of Novartis Research Foundation. Vince holds numerous patents and has written a number of original research papers, reviews and book chapters in chemistry and medicinal chemistry.

Dr. Oliver R. Thiel

Oliver R. Thiel received his undergrad education in chemistry at the Technical University in Munich, Germany, completing a thesis in the labs of Prof. Matthias Beller, focusing on rhodium catalyzed hydroaminations. He then pursued his Ph.D. at the Max-Planck-Institut für Kohlenforschung in Mülheim, Germany under the guidance of Prof. Alois Fürstner, graduating with a thesis on the application of ring-closing metathesis for the synthesis of complex natural products. From 2001 to 2003 he was a Feodor Lynen Postdoctoral Research fellow with Prof. Barry M. Trost at Stanford University, applying palladium-catalyzed reactions for the synthesis of Furaquinocins and a Bryostatin analogue. Subsequently he joined the Chemical Process Research and Development group at Amgen in Thousand Oaks, CA where he currently holds the position of Principal Scientist. His main areas of interest are the development of robust processes for active pharmaceutical ingredients, the application of catalytic reactions in organic synthesis and the development of hybrid modalities. Oliver has authored more than 30 publications.

Dr. Cheol K. Chung

Cheol Chung obtained his B.S. and M.S. degree from Seoul National University. After a brief stint at LG Chemical working as a researcher in the pharmaceutical division, he joined the laboratory of Professor Barry Trost at Stanford University where he studied the transition metal catalyzed transformations of alkynes and their application to natural products synthesis. After the completion of his Ph.D. in 2006, he moved to California Institute of Technology for postdoctoral training to further his knowledge in organometallic catalysis under the supervision of Professor Robert Grubbs. Since 2008, Cheol Chung has been senior research chemist in Process Research at the Merck Research Laboratories in Rahway, NJ.

Dr. Lamont Terrell

Lamont Terrell earned his B.S. degree in Chemistry at Texas Southern University in 1995. Under the direction and guidance of Professor Robert Maleczka, Jr. at Michigan State University, he studied organic synthesis, completed the total synthesis of the antileukemic natural product amphidinolide A and earned his Ph.D. in 2001. Upon completion of his graduate studies at MSU, he continued synthetic training with a two-year postdoctoral stint with Professor Barry Trost at Stanford University. The focus of his postdoctoral studies was the development of a catalytic dinuclear zinc asymmetric Mannich reaction. After completion of his postdoctoral studies, Lamont obtained a position with GlaxoSmithKline in the cardiovascular medicinal chemistry group, where he has been for the last 9 years.

Dr. Hans-Ulrich Blaser

Hans-Ulrich Blaser carried out his doctoral research with A. Eschenmoser at the Federal Institute of Technology (ETH) Zürich, where he received the Ph.D. degree in 1971. Between 1971 and 1975 he held postdoctoral positions at the University of Chicago (J. Halpern), Harvard University (J.A. Osborn), and Monsanto (Zürich). During 20 years at Ciba-Geigy (1976–1996) he gained practical experience at R&D in the fine chemicals and pharmaceutical industry, which continued at Novartis (1996–1999) and at Solvias where he was chief technology officer until 2009. Presently he acts a scientific advisor. His main interest is selective catalysis with emphasis on enantioselective catalysts. During his industrial carrier he has developed and implemented numerous catalytic routes for agrochemicals, pharmaceuticals and fine chemicals both as project leader and section head. He and his team received several awards for their contributions to industrial catalysis in general and enantioselective catalysis in particular, notably the Sandmeyer Prize of the Swiss Chemical Society in 1998, the Horst Pracejus Prize of the German Chemical Society (2009) and the Paul Rylander Award of the Organic Reaction Catalysis Society (2010).