Organometallics in Process Chemistry (Topics in Organometallic Chemistry, 65) 303027960X, 9783030279608

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Topics in Organometallic Chemistry  65

Thomas J. Colacot Vilvanathan Sivakumar Editors

Organometallics in Process Chemistry Foreword by Phil S. Baran

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Topics in Organometallic Chemistry

Series Editors M. Beller, Rostock, Germany P. H. Dixneuf, Rennes, France J. Dupont, Porto Alegre, Brazil A. Fürstner, Mülheim, Germany F. Glorius, Münster, Germany L. J. Gooßen, Kaiserslautern, Germany S. P. Nolan, Ghent, Belgium J. Okuda, Aachen, Germany L. A. Oro, Zaragoza, Spain M. Willis, Oxford, United Kingdom Q.-L. Zhou, Tianjin, China

Aims and Scope The series Topics in Organometallic Chemistry presents critical overviews of research results in organometallic chemistry. As our understanding of organometallic structure, properties and mechanisms increases, new ways are opened for the design of organometallic compounds and reactions tailored to the needs of such diverse areas as organic synthesis, medical research, biology and materials science. Thus the scope of coverage includes a broad range of topics of pure and applied organometallic chemistry, where new breakthroughs are being achieved that are of significance to a larger scientific audience. The individual volumes of Topics in Organometallic Chemistry are thematic. Review articles are generally invited by the volume editors. All chapters from Topics in Organometallic Chemistry are published Online First with an individual DOI. In references, Topics in Organometallic Chemistry is abbreviated as Top Organomet Chem and cited as a journal. More information about this series at http://www.springer.com/series/3418

Thomas J. Colacot • Vilvanathan Sivakumar Editors

Organometallics in Process Chemistry With contributions by S. Achanta
E. R. Ashley
R. Bandichhor
D. Basu
T. J. Colacot
L. C. Forfar
F. Gallou
P. M. Gurubasavaraj
N. S. Hosmane
A. M. Hyde
N. U. Kumar
B. H. Lipshutz
P. M. Murray
H. G. Nedden
R. B. Rehani
H. W. Roesky
A. Santana Fariña
T. Schaub
V. Sivakumar
E. D. Slack
G. Talavera
P. D. Tancini
R. A. Watile
A. Zanotti-Gerosa Foreword by Phil S. Baran

Editors Thomas J. Colacot MilliporeSigma (A business of Merck KGaA, Darmstadt, Germany) Milwaukee, WI, USA

Vilvanathan Sivakumar Johnson Matthey Taloja, Maharashtra, India

ISSN 1436-6002 ISSN 1616-8534 (electronic) Topics in Organometallic Chemistry ISBN 978-3-030-27960-8 ISBN 978-3-030-27961-5 (eBook) https://doi.org/10.1007/978-3-030-27961-5 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

The interface of organic and organometallic chemistry still holds the most promise for changing the rules of retrosynthetic analysis and enabling heretofore unimaginable transformations. Indeed, reactions such as metal-mediated cross-coupling have revolutionized the practice of synthesis and brought forth countless advances that have improved the human condition from enabling new materials to life-saving medicines. The impact that the strategic use of organometallic chemistry in synthesis has had an unrivaled impact in the entire spectrum of the discovery process—from conception to commercialization. In this new book, on Organometallics in Process Chemistry for the series— Topics in Organometallic Chemistry published by Springer inspiring case studies of this phenomenon are expertly illustrated covering a wide range of topics as pertains to chemistry on process scale from small molecules to polymers. This expertly edited book by Thomas Colacot of MilliporeSigma (business of Merck KGaA), USA and V. Sivakumar of Johnson Matthey achieves the notable aim of covering this wide ranging area to provide perspectives to both newcomers and seasoned chemists alike. Thus, chapters cover both the introductory aspects of each subfield along with a deep dive into historical context and a look to the current state of the art. Those looking for inspiration or simply to catch up on this fast-moving area will therefore be rewarded with a didactically organized and graphically rich summary of the many opportunities, unanswered challenges, and beautiful solutions this field has to offer. Department of Chemistry Scripps Research Institute, La Jolla, CA, USA

Phil S. Baran

Skaggs Institute of Chemical Biology, La Jolla, CA, USA

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Foreword

Phil S. Baran was born in New Jersey in 1977 and completed his undergraduate education at New York University in 1997. After earning his PhD at The Scripps Research Institute (TSRI) in 2001, he pursued postdoctoral studies at Harvard University until 2003, at which point he returned to TSRI to begin his independent career. He was promoted to the rank of professor in 2008 and is currently the Darlene Shiley Professor of Chemistry. The mission of his laboratory is to educate students at the intersection of fundamental organic chemistry and translational science.

Preface

We are delighted to have the opportunity to be the editors of Springer’s second book on Organometallics in Process Chemistry for the series—Topics in Organometallic Chemistry. The earlier volume edited by R. Larsen appeared in 2004. Since then there has been a big gap in capturing some of the developments in organometallic chemistry relevant to organic processes. Our effort was to capture some of the most relevant applied areas in organometallic chemistry, relevant to organic synthesis with a heavy focus on process chemistry. Although Wilkinson’s contributions of the development of organometallic complexes such as RhCl(PPh3)3, RhH(CO)(PPh3)3, and Pd(OAc)2 made a significant impact in the area of organic process chemistry since 1960s, the area of organometallic chemistry remained as a discipline in inorganic chemistry with emphasis on structure elucidation, reactivity, and mechanisms for several years. During the recent 2–3 decades, transition metal-based organometallic chemistry has become a vital part of organic synthesis via homogeneous catalysis. Conversely, since the discovery of Grignard reagents and alkyl lithiums in the beginning of the last century, organic chemists have found their stoichiometric uses in organic synthesis. This book highlights the recent developments of main group organometallic compounds as well as transition metal complexes for applications such as drug development and fine chemical synthesis for varied applications. Since we are the volume editors, we decided to open the volume with a snapshot on the emergence of organometallics and their applications in process chemistry from a historical perspective, followed by the emerging technologies in organometallic chemistry geared for organic synthesis. This introductory chapter is followed by a comprehensive overview of the methods available for the generation of 3.1.0 bicycles using main group and transition metal organometallic chemistry by Dr. Ashley and Dr. Hyde (Merck Research Laboratories, USA). The subsequent chapter authored by Dr. Nedden and his colleagues from Johnson Matthey, UK, captures the structural diversity of ruthenium catalysts in asymmetric transfer hydrogenation processes. Dr. Bandichhor and coworkers from Dr. Reddy’s Laboratories Ltd., India, discuss on the process development case studies of some of the latest investigational and approved drug molecules. Then Dr. Colacot and team discuss the vii

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atom economical formation of mono- and bis-coordinated Pd(0) catalysts for their industrial cross-coupling applications in the pharmaceutical arena. Professor Lipshutz (University of California at Santa Barbara, USA) and his collaborator Dr. Gallou (Novartis, Switzerland) provide an overview of the greener approaches in using water as a solvent in developing organic synthesis via organometallic processes. Dr. Murray and his co-author Dr. Forfar (PhosphonicS, UK) give an overview on the all-important area of meeting metal limits in the active pharmaceutical processes, which is an important aspect to get the FDA approval of the drug. Dr. Schaub from BASF/CaRLa, Germany, elaborates on a flow chemistry approach for the manufacture of sodium acrylate. The volume is concluded with a chapter on organometallics in polymer chemistry processes from Dr. Gurubasavaraj (Rani Channamma University, India) with Prof. Hosmane (Northern Illinois University, USA) and Prof. Roesky (University of Gottingen, Germany). We strongly believe that the use of Organometallics in Process Chemistry will continue to grow and create greener and sustainable chemical processes. The emphasis will be on minimizing the precious metal loading by improving the catalyst efficiency, utilization of non-precious metal based catalysts, interdisciplinary approaches with the use of organometallics in conjunction with enzymes, and incorporation of emerging technologies such as flow chemistry and computeraided synthesis. We thank all the authors, peer reviewers, and Prof. Phil Baran, Scripps Research Institute, USA, for writing a foreword for the book, considering their busy schedules. We also express our special thanks to Dr. Charlotte Hollingworth, Senior Editor— Chemistry, Springer, and Ms. Alamelu Damodharan, Project Coordinator (Books) for Springer, SPi Global, for their patience and support in making this project a big success. MilliporeSigma (A business of Merck KGaA, Darmstadt, Germany) Milwaukee, WI, USA Johnson Matthey Taloja, Maharashtra India

Thomas J. Colacot

Vilvanathan Sivakumar

Contents

Organometallics in Process Chemistry: An Historical Snapshot . . . . . . . Vilvanathan Sivakumar, Rahul A. Watile, and Thomas J. Colacot

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Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry . . . Alan M. Hyde and Eric R. Ashley

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Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Garazi Talavera, Alejandro Santana Fariña, Antonio Zanotti-Gerosa, and Hans Günter Nedden

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Application of Organometallic Catalysts in API Synthesis . . . . . . . . . . . 115 Debjit Basu, Srinivas Achanta, N. Uday Kumar, Rajeev Bhudhdev Rehani, and Rakeshwar Bandichhor Process Economics and Atom Economy for Industrial Cross Coupling Applications via LnPd(0)-Based Catalysts . . . . . . . . . . . . . . . . 161 Eric D. Slack, Peter D. Tancini, and Thomas J. Colacot Organometallic Processes in Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Fabrice Gallou and Bruce H. Lipshutz Meeting Metal Limits in Pharmaceutical Processes . . . . . . . . . . . . . . . . 217 Laura C. Forfar and Paul M. Murray Sodium Acrylate from Ethylene and CO2: The Path from Basic Research to a System Appropriate for a Continuous Process . . . . . . . . . 253 Thomas Schaub Oxygen Effect in Heteromultimetallic Catalysis: Oxygen-Bridged Catalysts for Olefin Polymerization Process . . . . . . . . . . . . . . . . . . . . . . 271 Prabhuodeyara M. Gurubasavaraj, Herbert W. Roesky, and Narayan S. Hosmane

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Correction to: Organometallics in Process Chemistry: An Historical Snapshot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 Vilvanathan Sivakumar, Rahul A. Watile, and Thomas J. Colacot Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

Editors and Authors

About the Editors Thomas J. Colacot is currently working at MilliporeSigma, USA (business of Merck KGaA, Darmstadt, Germany), since May 2018 as a R&D Fellow, and Director—Global Technology Innovation (Lab and Specialty Chemicals). In 2018 he was named as one of the most outstanding researchers at Merck KGaA. Dr. Colacot received his PhD in Chemistry from the Indian Institute of Technology Madras in 1989, and was awarded the IIT Madras’ Distinguished Alumnus Award in 2016 for his technical contributions in the field of organometallic chemistry and catalysis. Immediately after his PhD, he held postdoctoral teaching positions, working on Gr. III–V chemistry for applications of performance materials in the electronics industry and metallocarborane for catalysis at the University of Alabama at Birmingham and Southern Methodist University, respectively. He also had combined teaching and research positions at Florida State University and Florida A&M University. Prior to joining MilliporeSigma Dr. Colacot has worked as Global R&D Manager/Technical Fellow in Homogeneous Catalysis at Johnson Matthey until May 2018. He is a co-author of more than 100 peer-reviewed publications and about 50 patents. He has also edited books such as “New Trends in Cross Coupling: Theory and Applications” (2014, RSC), “Organometallics in Process Chemistry—Topics in Organometallic Chemistry” (Springer, this volume), and Organometallic xi

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Chemistry in Industry (Wiley VCH, in press). He has also given over 400 presentations at national and international conferences, universities, and chemical and pharmaceutical companies. He is on numerous national committees and holds visiting professorships at various universities. His technical contributions to the field have resulted in many awards, among them the 2017 Catalysis Club of Philadelphia Award for outstanding contributions in catalysis, 2015 American Chemical Society National Award in Industrial Chemistry, 2015 IPMI Henry Alfred Medal by the International Precious Metal Institute, 2016 Chemical Research Society of India CRSI medal, and the Royal Society of Chemistry 2012 Applied Catalysis Award and Medal. In addition, Thomas holds an MBA degree and is a Fellow of the Royal Society of Chemistry. He co-authored two chapters of this book (chapters “Organometallics in Process Chemistry: A Historical Snapshot” and “Process Economics and Atom Economy for Industrial Cross Coupling Applications via LnPd(0) Based Catalysts”). Vilvanathan Sivakumar completed his PhD in Organometallic Chemistry in 2006 under the supervision of Prof. Balaji Jagirdar in the Department of Inorganic and Physical Chemistry followed by a post-doc position with Prof. Goverdhan Mehta in Organic Chemistry at the Indian Institute of Science, Bangalore. He joined Johnson Matthey in 2009 as Assistant Manager— Development. As a part of the R&D team in JM, he worked on the development of homogeneous and heterogeneous catalysts for a wide range of applications relevant to the pharma and agrochemical industries. In 2017, he became the Technical Services Manager which interfaces with customers, R&D, Sales and Marketing, and Production. He is a coauthor of chapter “Organometallics in Process Chemistry: A Historical Snapshot” of this book.

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About the Authors Srinivas Achanta was born in Nidadavole, India. He received his Bachelor of Technology in Chemical Engineering from Osmania University, India, and PhD in Chemistry under the guidance of Prof. V. B. Birman at Washington University in St. Louis, USA. After completing postdoctoral studies at York University, Canada, with Prof. M. G. Organ, he worked as a scientist in Jubilant Chemsys, TEVA API India Pvt Ltd, and currently working in Process Development in Dr. Reddy’s Laboratories Ltd., India.

Eric Ashley was born and raised in Helena, Montana, where he became an avid skier, hiker, soccer player, and budding chemist. After graduating high school, Eric traveled east to Harvard University where he completed an undergraduate chemistry degree in 2000 that included a stint in the labs of Prof. David Liu focused on molecular evolution of peptide nucleic acids. Eric then pursued PhD work with Prof. Brian Stoltz at Caltech in 2006, which culminated in the first total synthesis of the tetrahydroisoquinoline antitumor antibiotic lemonomycin. Eric then returned to Harvard for postdoctoral studies on base/hydrogen bond donor dual catalysis as an American Cancer Society Postdoctoral Fellow in the labs of Prof. Eric Jacobsen from 2006 to 2009. In 2009, Eric joined Merck Process Research in Rahway, New Jersey, where he has led the design and execution of new methods and synthetic routes spanning late discovery through clinical development. For his newest adventure, Eric has taken on the team build and leadership of the Discovery Process Chemistry group at Merck’s South San Francisco labs. When he is not mixing chemicals in the lab, Eric can be found racing ultramarathons, raising an 8-year-old, experimenting in the kitchen, and dreaming about skydiving.

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Rakeshwar Bandichhor, PhD, FRSC, CChem studied Chemistry and obtained PhD degree from University of Lucknow and worked at University of Regensburg, Germany, for a year during his PhD tenure. He did postdocs at University of Regensburg, University of Pennsylvania, and Texas A&M University. He has published more than 170 papers including patents and book chapters. He has won various awards and honors in his career, e.g., Chairman Excellence Award 2010, Anveshan Award 2011, ISCB Award 2012, Roll of Honor in Green Chemistry Area 2012, UK Travel Grant 2013, Green Innovation Award 2013, FRSC and CChem in 2014, Vice Chair, ACS-India (South) onwards 2016, CRSI Council Member onwards 2017, CRSI Bronze Medal 2018, etc. His interview featured in Nature Medicine 2013, 19, 1200–1203, in Process India (February 2014) and Business Standards (March 2014). He is also serving as BoS (Board of Studies) and BoG (Board of Governors) members of Institute of Science and Engineering, Jawharlal Nehru Technological University, Hyderabad (JNTU-H) starting from December 2017. He has also been appointed as honorary Visiting Professor at University of Delhi. He has recently been appointed as International Advisory Board Member of European Journal of Organic Chemistry. He has also edited a book entitled Hazardous Reagent Substituion: A Pharmaceutocal Industry Perspective published by Royal Society of Chemistry. Debjit Basu was born in India and obtained MS from Pune University in the year 2003. He joined Dr. S Chandrasekhar group at Indian Institute of Chemical Technology, India, receiving his PhD on research related to the organic synthesis of complex natural product. He came to France in 2009 and joined Dr. Prof. Jean Marie Beau group in ICSN, Paris, as researcher to investigate novel neuraminidase inhibitors targeting flu viruses. In 2010, he moved to Aurigene Discovery Technology, India, and led multidiscipline teams engaged in the design and development of synthetic routes for new pharmaceuticals. In 2012, he joined Dr. Prof. Daniel Rauh group in TU Dortmund, Germany, and was involved in various interdisciplinary areas of Chemical Biology. Currently, he is the technical lead of Process development of various Active Pharmaceutical Ingredients in Dr. Reddy’s Laboratories Ltd., India.

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Alejandro Santana Fariña received a BSc degree in Chemistry (2006) from Universidad Simón Bolívar in Venezuela where he also worked as an assistant professor in Chemistry. In 2008 he completed his MSc degree in Chemistry and later on his PhD in 2015 at University of Cádiz, Spain, under the supervision of Prof. Dr. José M. G. Molinillo and Prof. Dr. Francisco A. Macías, working on the synthesis and characterization of bioactive natural products. During his PhD, Alejandro completed an internship with Dr. Varinder Aggarwal’s research group at University of Bristol focused on asymmetric synthesis. In 2014, he began his industrial career working for MSD in Ireland. He then joined Aqdot Ltd. to optimize and scale up a critical synthetic process. Since 2017 Alejandro has been a Senior Chemist at Johnson Matthey in Cambridge where he has worked on synthesis and development of homogenous catalysts from laboratory scale to multi-kilogram scale. Laura Forfar completed a degree in chemistry at the University of Bristol and stayed to complete her PhD in 2014 with Dr. Chris Russell. On completion of her PhD, Laura joined PhosphonicS Ltd as a scientist, where she worked to develop new products and deliver client projects. Laura joined Paul Murray Catalysis Consulting Ltd in 2016. Laura uses experimental design to help clients with problematic chemical transformations and is involved with DoE training in a variety of chemical industries. Fabrice Gallou received his PhD from The Ohio State University (2001) in the field of natural products total synthesis. He then joined Chemical Development at Boehringer Ingelheim, USA, working as a process chemist responsible for route scouting and supply of early phase programs. He subsequently moved in 2006 to the Chemical Development group at Novartis, Switzerland, as a process development chemist, and became in 2008 responsible for global scientific activities, overseeing development and implementation of practical and economical chemical processes for large-scale production of APIs. His research interests rely in the research and development of sustainable synthetic methodologies intended for large-scale implementation. He

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published more than 150 peer-reviewed papers, book chapters, and patents, and won multiple awards, more recently the 2019 Swiss Chemical Society Senior Industrial Award, and the 2019 Yves Chauvin Award from the French Chemical Society. Antonio Zanotti Gerosa obtained his degree (Laurea, 1991) and PhD (Dottorato, 1994) at the University of Milano (Italy) under the supervision of Prof. S. Maiorana working on Fisher-type carbene– metal complexes. He later worked in Lausanne (Switzerland) with Prof. C. Floriani (1994–1997). In 1997, he joined Chirotech, later Dow (Cambridge, UK), where he became involved in the development of industrial applications of homogenous asymmetric catalysis, which included, in 1998, a secondment to the laboratory of Prof. R. Noyori in Nagoya University (Japan). In 2003, he joined Johnson Matthey as team leader. Currently, as R&D Director at Johnson Matthey, he leads a group of scientists developing new technologies in the areas of homogeneous hydrogenation and biocatalysis and collaborating with process development groups all over the world on new biocatalytic and chemocatalytic processes (homogeneous and heterogeneous catalysis). Prabhuodeyara M. Gurubasavaraj studied MSc in Chemistry at Gulbarga University, Gulbarga, and obtained PhD degree from Gottingen University, Germany, under the supervision of Herbert W. Roesky. He did his postdoc at Nara Institute of Science and Technolgy, Nara, Japan, as a JSPS Fellow. He then moved to University of Rochester, New York, to work in NIH sponsored project on bioinorganic chemistry. He has published more than 35 papers including most cited article in inorganic chemistry published in 2007 (ACS publication), patents, and book chapters. He has won various awards and honors in his career, e.g., UGC-NET Lectureship Award 2002, JSPS Postdoctoral Fellowship from Japan 2008, Raman Visiting Fellowship from India 2015, Young Scientist Award 2015, ViceChancellor Appreciation Award 2016, Listed in Marques Who’s Who World 2011, he is a life member and General Secretary (west Chapter) of Indian JSPS Alumni Association (IJAA), and a member of

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International EPR (ESR) Society. He is serving as BoS (Board of Studies) and BoE (Board of Examiner) for various universities, including Rani Channamma University. He has been appoined as advisory editorial member for various journals including Current Organocatalysis, Journal of Chemistry, etc. He has given more than 40 invited lectures at various conferences, seminars, and universities. Narayan S. Hosmane was born in Gokarn, near Goa in Karnataka state, Southern India, and is a B.S. and M.S. graduate of Karnatak University, India. He obtained a PhD degree in Inorganic Chemistry in 1974 from the University of Edinburgh, Scotland, under the supervision of Professor Evelyn Ebsworth. After a brief postdoctoral research training in Professor Frank Glockling’s laboratory at the Queen’s University of Belfast, he joined the Lambeg Research Institute in Northern Ireland, and then moved to the USA to study carboranes and metallacarboranes. After a brief postdoctoral work with W.E. Hill and F.A. Johnson at Auburn University and then with Russell Grimes at the University of Virginia, in 1979 he joined the faculty at the Virginia Polytechnic Institute and State University where he received a Teaching Excellence Award in 1981. In 1982 he joined the faculty at the Southern Methodist University, where he became Professor of Chemistry in 1989. In 1998 he moved to Northern Illinois University and is currently a Distinguished Faculty, Distinguished Research Professor, and Inaugural Board of Trustees Professor. Dr. Hosmane is widely acknowledged to have an international reputation as “one of the world leaders in an interesting, important, and very active area of boron chemistry that is related to Cancer Research” and as “one of the most influential boron chemists practicing today.” Hosmane has received numerous international awards that include but are not limited to the Alexander von Humboldt Foundation’s Senior U.S. Scientist Award twice; the BUSA Award for Distinguished Achievements in Boron Science; the Pandit Jawaharlal Nehru Distinguished Chair of Chemistry at the University of Hyderabad, India; the Gauss Professorship of the Göttingen Academy of Sciences in Germany; Visiting Professor of

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the Chinese Academy of Sciences for International Senior Scientists; High-End Foreign Expert of SAFEA of China; and Foreign Member of the Russian Academy of Natural Sciences. He has published over 370 papers in leading scientific journals and an author/editor of five books on Boron Science, Cancer Therapies, General Chemistry, Advanced Inorganic Chemistry (published in 2017 by Academic Press/Elsevier Publishers, Inc.), and Boron Chemistry in Organometallics, Catalysis, Materials and Medicine (published by World Scientific (UK) Publishing). He is also a Fellow of the Royal Society of Chemistry. Bruce H. Lipshutz began his academic career at the University of California, Santa Barbara, in 1979, where today he continues as a Distinguished Professor of Chemistry. His program in synthesis focuses on new reagents and methodologies, mainly in the area of organometallic chemistry. While these contributions tended to fall within the area of “traditional” organic synthesis, more recently his group has shifted in large measure towards the development of new technologies in green chemistry, with the specific goal being to get organic solvents out of organic reactions. To accomplish this, the Lipshutz group has introduced the concept of “designer” surfactants that enable key transition metal-catalyzed cross-couplings, and many other reactions, to be carried out in water at room temperature. Most recently, his group has turned its attention to developing new catalysts for key Pd- and Au-catalyzed reactions that enable C–C bond formation at the parts per million level of the metal, each catalyst being utilized in water under very mild conditions. The potential for his group’s work in this field to significantly influence, and possibly transform the way in which organic chemistry is performed in the future, led to a Presidential Green Chemistry Challenge Award in 2011, and more recently, the ACS GCI Peter J. Dunn Award.

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Paul Murray completed a degree in Natural Sciences at Trinity College Dublin and stayed to complete his PhD in 1998 with Prof. Brian McMurry. On completion of his PhD, Paul joined AstraZeneca as a development chemist working on various stages of the development process spanning process research to commercial manufacture. During his time at AstraZeneca, Paul looked at both the development of generic reaction conditions and the development of predictive catalysis to improve the optimization and understanding of catalytic reactions. In 2011 Paul set up CatScI with 4 former colleagues as a result of the R&D restructure at AZ, then in October 2013 Paul set up as an independent consultant. Paul Murray Catalysis Consulting Ltd provides expertise and training in catalysis, experimental design, principal component analysis, process development, and quality by design. In 2014 Paul joined PhosphonicS Ltd as Chief Technical Officer. Paul is responsible for the delivery of client projects as well as research and development within the technical team. Paul has extensive experience of using various metal removal techniques and PhosphonicS products in industrial applications prior to joining PhosphonicS. Hans Günter Nedden completed his PhD (Dr. rer. nat.) in chemistry at the University of Tübingen (Germany) under the supervision of Prof. U. Nagel in 1997, working on the synthesis of chiral PN ligands and use in Ni-catalyzed asymmetric cross couplings. After a second postdoctoral study with Prof. I. E. Markó in Belgium, working on catalysts for ethylene and propylene polymerization, he joined ICI Synetix in 2001, later to become part of Johnson Matthey. His core interest is in catalytic research and in the synthetic development of ligands and metal compounds with catalytic activity. As a senior scientist and team leader, he leads a team in Cambridge (UK) dedicated to bringing to market homogenous catalysts for hydrogenation and transfer hydrogenation.

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Uday Kumar Neelam studied chemistry at the National Institute of Technology, Warangal, India, where he completed his MSc. Later he joined as scientist at Dr. Reddy’s Laboratories Ltd., Hyderabad, India. Neelam completed his PhD. thesis in 2014 at Osmania University, Hyderabad, India, in the group of Dr. Rakeshwar Bandichhor in collaboration with Dr. Reddy’s Laboratories Ltd. He then worked with Marisa Kozilowski at UPenn, USA, as a postdoctoral fellow from 2014 to 2015. Presently, he is working as Tech Lead in API process R&D division at Dr. Reddy’s Laboratories Ltd., Hyderabad, India. Rajeev Bhudhdev Rehani is currently working as Senior Vice President and Global Head—API R&D at Dr. Reddy’s Laboratories Ltd., Hyderabad. He holds a Masters and a PhD degree in Organic Chemistry from Maharaja Sayajirao (M.S.) University of Baroda. He brings with him over 28 years of experience in the areas of academic research at M.S. University, followed by Process Chemistry of generic API’s at Sun Pharma’s R&D center at Baroda, leading to numerous DMF/ANDA filings for a gamut of small molecules of varying complexities, including peptides. Rajeev is very passionate about R&D collaboration cutting across crossfunctional domains, both within and outside the company, including external subject matter experts. He also has a number of patent publications to his credit and has delivered talks on emerging frontiers in Pharma Science and Technology. Herbert W. Roesky obtained his doctorate from Göttingen and worked at Du Pont in the USA before returning to his alma mater where he retired in 2004. He is primarily known for his pioneering work on fluorides of both transitional and normal metals. He has been a Visiting Professor at Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, Tokyo Institute of Technology, and Kyoto University, and he has also been a Frontier Lecturer at Texas A&M University at College Station, University of Texas at Austin, and University of Iowa at Iowa City. He is a member of the Academy of Sciences at Göttingen, the New York Academy of Sciences, the German Academy of Sciences

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Leopoldina in Halle, the Russian Academy of Sciences, Associéétranger de l’Académie des Sciences, and the Academia Europea in London. He served as Vice President of the German Chemical Society and as the President of the Academy of Sciences of Göttingen. More than 1700 peer-reviewed papers, articles, patents, and books record his research activity in the areas of inorganic chemistry and material sciences. He is also the recipient of several prizes, i.e., the prestigious Gottfried Wilhelm Leibniz Prize, the Alfred Stock Memorial Prize, the Grand Prix de la Foundation de la Maison de la Chimie, the Wilkinson Prize, and ACS awards in Inorganic and Fluorine Chemistry. Thomas Schaub was born in 1980 in Lahr (Black Forest) and received his PhD in 2006 in inorganic chemistry at the University of Karlsruhe, Germany, in the group of Udo Radius. After a Postdoc with David Milstein at the Weizmann Institute of Science (Israel), he started in 2008 as a research chemist in the Department for Synthesis and Homogeneous Catalysis at BASF SE in Ludwigshafen. Since 2014, he is heading the Catalysis Research Laboratory in Heidelberg and is a designated Principal Scientist since 2018 in the field of homogeneous catalysis. He is co-author of 38 scientific publications (thereof as 18 as reference author), three book chapters and co-inventor on 65 patent applications. Eric Slack started his chemistry career in 2007 at California State University Fullerton researching activation of strained carbocycles under the supervision of Christopher Hyland. Once he graduated with his Bachelor of Science in chemistry, he performed his graduate work in the labs of Professor Bruce Lipshutz researching organic transformations in aqueous media. After completing his Ph.D. studies, he began work in the homogeneous catalysis research labs of Johnson Matthey.

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Editors and Authors

Garazi Talavera completed her BSc (2008) and PhD (2012) from University of the Basque Country under the supervision of Prof. J. L. Vicario on the development of new organocatalytic methodologies towards the synthesis of biologically active polyfunctionalized hetero- and carbocycles. During her doctoral studies, she went on a secondment to the group of Prof. A. H. Hoveyda at Boston College working on the synthesis and application of chiral N-heterocyclic carbenes of silver and copper as catalysts. After her postdoctoral studies (2013–2016) at the Max-Planck-Institut für Kohlenforschung (Mülheim an der Ruhr, Germany) and the University of Göttingen with Prof. M. Alcarazo, she joined Johnson Matthey in Cambridge (UK). She is currently working on the development of homogeneous catalysts and ligands for industrial hydrogenation and transfer hydrogenation processes. Her research interests lie in organic and organometallic synthesis and homogeneous catalysis. Peter D. Tancini received his BS in Chemical Engineering from the University of Pittsburgh, Pittsburgh, PA. During his undergraduate studies, Peter worked for Computer-Aided Nano and Energy Lab (CANELa) under the guidance of his mentor, Dr. Giannis Mpourmpakis. At CANELa, Peter used computational chemistry to better understand early-stage nanoparticle growth and reaction kinetic mapping. Immediately following graduation, Peter joined Johnson Matthey at their West Deptford site under Dr. Thomas J. Colacot. Peter is presently working for Johnson Matthey as a Process Development Engineer designing robust processes for catalyst manufacture. Rahul A. Watile received his PhD in chemistry from the Institute of Chemical Technology (India) in 2014 under the supervision of Prof. B.M. Bhanage. After postdoctoral studies at the Stockholm University (2015–2017), he joined Johnson Matthey, Taloja, India, where he is currently an Assistant Manager and is involved in the development of new homogeneous catalysts, ligands and their scale-up and technology transfers and catalytic processes.

Top Organomet Chem (2019) 65: 1–30 DOI: 10.1007/3418_2019_34 # Springer Nature Switzerland AG 2019 Published online: 26 November 2019

Organometallics in Process Chemistry: An Historical Snapshot Vilvanathan Sivakumar, Rahul A. Watile, and Thomas J. Colacot

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Main Group Organometallics as Stoichiometric Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Organomagnesium Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Organolithium Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Transition Metal Organometallics in Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Hydroformylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Asymmetric Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Cross-Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Metathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 C H Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Emerging Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Photoredox Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Flow Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Ester Hydrogenation Under Greener Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Organic Electrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Computational Modelling for Reaction Predictability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The original version of this chapter was revised. A correction to this chapter is available at DOI 10.1007/3418_2019_35. V. Sivakumar (*) and R. A. Watile Johnson Matthey, Taloja, Maharashtra, India e-mail: [email protected] T. J. Colacot (*) Johnson Matthey, West Deptford, NJ, USA Affiliation at time of publication: MilliporeSigma (a division of Merck KGaA), Milwaukee, WI, USA e-mail: [email protected]

2 2 3 4 6 6 8 10 14 17 18 19 20 22 23 24 25 25

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Abstract The importance of organometallic chemistry for developing organic processes is briefly reviewed with a historical perspective, for the readers to appreciate the contents of this special volume. In addition to highlighting popular name reactions, a section was devoted to emerging technologies with a hope that some of these technologies might mature into real-world applications within a few years. Examples include photocatalysis, flow chemistry, electroorganic synthesis, and computational predictions. Keywords Cross-coupling · Earth-abundant metals · Electroorganic synthesis · Ester hydrogenations · Flow chemistry · Homogeneous catalysis · Organometallic chemistry · Pharmaceutical processes · Photoredox catalysis · Precious metals · Process chemistry

1 Introduction Process chemistry in general deals with the development of organic chemistry processes in an environmentally friendly and reagent-efficient manner to provide maximum economic benefits during the scale-up and subsequent manufacture. Organometallic compounds of main group metals are known for their high reactivity, which could be exploited safely with the latest developments in synthetic methodologies. On the other hand, newer catalytic activities of transition metal complexes are being expanded and fine-tuned by the improvisation of ligand design and catalyst engineering technologies geared toward specific transformations. Many organic reactions which utilized stoichiometric reagents under harsh reagents can be carried out efficiently with minimal steps using specialized organometallic complexes as catalysts. This volume gathers articles on the specific process chemistry applications by organometallics to synthesize both novel and generic pharmaceutical molecules, agrochemicals, fine chemicals, and performance materials. In order to get an overview about the applications of organometallics, in this chapter we shall provide a historical glimpse of the leading applications of both main group and transition metal-based organometallics with some highlights on the recently emerging technologies. Although there are some overlaps with certain chapters, we have tried to avoid any duplication in this chapter by omitting the topics discussed in those chapters, with a few exceptions.

2 Main Group Organometallics as Stoichiometric Reagents Early on the uses of organomagnesiums and organolithiums were well explored in organic processes. These reagents are still vital not only for the construction of new molecules but also for the development and improvement of organic processes, despite their high air and moisture sensitivity and pyrophoricity. For example,

Organometallics in Process Chemistry: An Historical Snapshot

3

Fig. 1 Victor Grignard, Nobel Prize 1912

there is a new trend in cross-coupling catalysis, where many of the coupling partners such as organozinc [1] and boron reagents [2] are derived from either Grignard or lithium reagents. The UCLA incident, where a young researcher was killed in 2009 while handing t-BuLi using a syringe without proper protection, caused a big alarm in the chemistry community (https://cen.acs.org/articles/87/web/2009/01/Researcher-Dies-Lab-Fire. html). Industrial accidents have also been reported with killing of operator and injuring workers during the production or handling of main group organometallic reagents (https://www.weddellandhaller.com/blog/2015/10/workplace-injury-atchemical-plant-after-several-prior-citations.shtml). Therefore, proper personal protection of the chemists and operators with the adequate training and handling techniques is required to avoid such tragedies. Safer handling of these reactive organolithium reagents in the lab as well in the plant has been discussed in a review article [3].

2.1

Organomagnesium Reagents

Even though organometallic chemistry had its origins in 1827 with Zeise salt [4], the first practically useful organometallic reagents were reported by Grignard during the late nineteenth century for which he got the Nobel Prize in Chemistry in 1912 (Fig. 1) [5]. These regents are known today as Grignard reagents, with the general formula R–MgX, and are being employed in many creative ways to form C–C, C–O, and C–N bonds. Knochel group has developed a robust magnesium-halogen exchange methodologies using isopropylmagnesium chloride or its lithium chloride adduct and isopropylmagnesium bromide as a starting material for other Grignard reagents [6, 7].

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N

N

Br

N

NH2 N + Cl

CyMgCl additon at 15 - 25 °C 20 °C hold for 2 h

Br N

N

N

HN

N

O

N

THF

O

N N Boc

2

N Boc

1

3

O Me

N N

HN

N

O

N

N N H

4

Palbociclib

Scheme 1 Regioselective nucleophilic aromatic substitution (SNAr) reaction mediated by a Grignard reagent

Despite their huge applications in organic synthesis, a few applications are highlighted below from the pharmaceutical industries. An elegant regioselective nucleophilic aromatic substitution (SNAr) reaction (Scheme 1) between the 2-amino pyridine 1 and the pyrimidine 2 gave an intermediate for palbociclib 4, a drug to treat advanced breast cancer [8]. Grignard reagents have been also used as coupling partners in the transition metal-catalyzed cross-coupling reactions to form C–C bonds, known as the Kumada-Corriu coupling [9], and this coupling approach has been used to design a manufacturing process for aliskiren 8, a direct renin inhibitor drug with the aid of a Fe catalyst (Scheme 2) [10].

2.2

Organolithium Reagents

The organolithiums are versatile reagents for alkylation, deprotonation, directed metalation, and dehalogenation. Several tons of these reagents are being made on a commercial scale, especially n-BuLi is produced in multi-ton quantities every year. Using n-BuLi other organolithiums could be easily made via lithium-halogen exchange. Schlenk prepared the organolithium reagents for the first time in 1917, and in the subsequent years, Ziegler, Gilman, and Wittig led the further developments to advance this field. In 1929, Ziegler found that certain alkyllithium compounds are less reactive to alkyl halides and prepared organolithiums directly from lithium metal and organic halides. In 1938 Gilman and Wittig independently discovered lithium-

Organometallics in Process Chemistry: An Historical Snapshot O

O MgCl

O O

+ Cl

5

Fe(acac)3, NMP THF, 0 - 5 °C

N 6

5

O

O N

O 7

O

O

NH2

O N H

O OH

8

O

O NH2

Aliskiren

Scheme 2 Kumada-Corriu coupling for the synthesis of aliskiren 1. sec-BuLi/DPBP MTBE, -75 to 70 °C 2. CO2

COOH N Boc

N Boc 9

10

N H N

N O

O N H

H N

N O

O

O

H N O

11 Telaprevir

Scheme 3 Stereoselective lithiation for the synthesis of telaprevir

halogen exchange reactions of organobromides with alkyllithiums or phenyllithium, and this transformation made the preparation of aryllithiums easier [11]. Although there are numerous applications on the use of organolithium reagents in process chemistry, a recent example involving a stereoselective lithiation as the key step for the synthesis of HCV protease inhibitor, telaprevir 11, is shown in Scheme 3 [12]. The direct use of organolithium reagents in cross-coupling reactions has been reported in the very beginning of the cross-coupling era, where Murahashi et al. revealed a palladium-catalyzed cross-coupling reaction of alkenyl halides with various organolithium compounds [13]. However these reactions were practiced neither at the lab nor at industrial scale due to their inherent problems such as functional group tolerance, reproducibility, and ease of handling in comparison to other cross-coupling reactions involving nucleophiles such as boronic acids.

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Pd2(dba) 3 (2.5 mol%) XPhos (10 mol%)

+ OMe

Li

Toluene, RT, 1 h

13 14

OMe

12

Scheme 4 Pd-catalyzed cross-coupling of alkenyllithium with an aryl halide

Recently, Feringa and co-workers to a certain extent resurrected this area via palladium-based catalytic systems containing modern ligands [14]. An example of direct cross-coupling of alkenyllithium compounds with an aryl halide is shown in Scheme 4 [15]. These types of reactions have not yet been practiced in industry unlike Suzuki or Buchwald-Hartwig coupling; however, it has the potential to grow as a useful method with careful choice of catalysts and substrates.

3 Transition Metal Organometallics in Catalysis The use of organometallics as catalysts indeed broadened the area of organometallic chemistry from a structural inorganic chemistry discipline to an important area in synthetic organic chemistry. Organic synthesis involving transition metal catalysts can not only shorten the number of synthesis steps in pharmaceutical processes but also enhance the sustainability and greenness of the commercial manufacturing processes [16]. In the following sections, we shall provide a glimpse of the wellestablished historical developments in catalysis relevant to process chemistry.

3.1

Hydroformylation

One of the first major industrial reactions to use homogeneous catalysts was the “oxo process” to make aldehydes from olefins. The hydroformylation of alkenes was originally discovered by Otto Roelen in 1938, while he was investigating FischerTropsch process. Hydroformylation as a process is one of the matured organometallic processes today, and its industrial capacity has reached to manufacture about dozen million tons per year, a number which keeps on increasing every passing year [17]. Hydroformylation process adds a molecule each of carbon monoxide and hydrogen to an olefin in the presence of a transition metal complex, such as cobalt or rhodium to form linear or branched aldehydes (Scheme 5). The ratio of isomers (selectivity) depends on many factors such as the metal precursor, ligand, their ratios, pressure, concentration, and rate of addition. The hydroformylation is an attractive transformation in process chemistry not only to increase the carbon chain length; the resultant aldehydes could be further

Organometallics in Process Chemistry: An Historical Snapshot CO/H2 [Rh] or [Co]

R 15

R

CHO

7

R

+

CHO 17 branched

16 linear

Scheme 5 The schematic representation of hydroformylation of alkenes Ph

Ph HN O

O HN

O N N O

P

P

Ph

O N N O

NH O

O NH

O

O

P

P

19 (R,R,R,R)-BIBOP ligand

Ph

18 (S,S,S)-bisdiazaphos, BDP ligand

Fig. 2 Examples of chiral ligands for asymmetric hydroformylation O Ph

O N H

Rh(acac)(CO)2/ Ligand 18 150 psi, 1:1 CO/H2 OMe THF, 80 °C, 22 h OMe 20

Ph

CHO N H

OMe OMe 21

Scheme 6 Asymmetric hydroformylation for the formation of a protected L-DOPA aldehyde

functionalized to alcohols, carboxylic acids, and amines [18]. The formation of amines by reductive amination has been reported for the synthesis of some of the APIs like cinacalcet [19], tolterodine [20], and penfluridol [21]. In recent years, more emphasis is given for the stereoselective and chiral hydroformylation technologies to access certain drug intermediates in an atomeconomical way [22]. However, control of both regio- and enantioselectivity of hydroformylation is still a challenging transformation to adopt on the industrial scale. Landis et al. have developed a family of chiral bisphosphine ligands, diazaphospholanes, for asymmetric hydroformylation. Of these (S,S,S)-bisdiazaphos, BDP ligand 18 in Fig. 2 has shown excellent selectivity toward the asymmetric hydroformylation, leading to a protected L-DOPA aldehyde 21 with 98% ee and 15.4:1 branch selectivity (Scheme 6) [23]. Senanayake et al. have used BIBOP ligand 19 for the enantioselective hydroformylation to achieve the synthesis of 4-methyl-3,4-dihydroisocoumarin 23 (Scheme 7) [24]. Dihydroisocoumarins are secondary metabolites produced by certain plants, fungi, and insects, and they exhibit noteworthy biological and pharmacological properties such as antimicrobial, antiallergic, and anticancer activities [25].

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COOEt

(i) Rh(acac)(CO) 2 (0.5 mol%) Ligand 19 (0.6 mol%) CO/H2, 60 °C

O

O

(ii) NaBH4 22

23

Scheme 7 Asymmetric hydroformylation for the formation of coumarin core

3.2

Asymmetric Hydrogenation

Although heterogeneous catalysts dominate the industrial hydrogenation processes, for chiral hydrogenations, one must adopt homogenous hydrogenations using specialized chiral ligands due to the nature of transition state, a critical step in chiral hydrogenation pathway [26]. Enzymatic hydrogenation, a complementary technology for chiral catalyst hydrogenations, could replace them in some specific transformations. For example, the blockbuster drug sitagliptin to treat type II diabetics is reported to be manufactured by enzymatic hydrogenation by Merck where the same transformation could be done under Rh-catalyzed conditions [27]. Wilkinson’s classical rhodium complex RhCl(PPh3)3 24 [28], in Fig. 3, popularly known as Wilkinson’s catalyst has been widely studied to understand the mechanism of homogeneous hydrogenation by identifying its intermediates in these reactions [29]. This understanding played a crucial role in the conceptualization and development of chiral homogeneous catalysts and ligands. Inspired by Wilkinson’s catalyst, Knowles developed a chiral phosphine ligand DIPAMP 25 which literally opened a new avenue in organic synthesis [30]. The work of Knowles and Kagan [31] influenced the chemical community to pursue this emerging technology in the 1970s and 1980s. A notable contribution in this area is from Noyori (Fig. 4) through the introduction of BINAP ligand 26 [32] for which he shared half of the Nobel Prize [33] with Knowles (Fig. 4), while the other half was given to Sharpless for chiral oxidations. BINAP class of ligands are easily tunable and are used in conjunction with metals such as Rh and Ru as preformed catalysts or in situ for several large-scale applications in pharmaceutical and flavors and fragrances industries [34] (Fig. 4).

O Ph3P

Rh

Ph3P

PPh3

O P

PPh2 PPh2

P

Cl 24

Wilkinson's catalyst

25 DIPAMP ligand

Fig. 3 Wilkinson’s catalyst and Knowles’ and Noyori’s chiral ligands

26 BINAP

Organometallics in Process Chemistry: An Historical Snapshot

9

Fig. 4 William Knowles (with permission PNAS November 22, 2005;102(47):16913–16915; Copyright (2005) National Academy of Sciences, U.S.A.), and Ryōji Noyori, Nobel Prize 2001

O

P Fe

O N

Cl

PPh2

27 Xyliphos

28 (S)-Metolachlor

Fig. 5 Xyliphos, an example for the Josiphos class of ligands and the pesticide (S)-Metolachlor

Apart from inspiring the development of chiral hydrogenation catalysts by the achiral hydrogenation catalyst which bears his name, Wilkinson’s indirect contribution to chiral hydrogenation is his work on the structural elucidation of ferrocene as a sandwich compound, for which he shared the Nobel Prize with Otto Fisher in 1973 [35]. Ferrocene due to its rigid structure has been used as a ligand backbone for chiral ligands [36]. An example is xyliphos 27 [37] of Josiphos class of ligands in Fig. 5 for the manufacture of a powerful pesticide, (S)-metolachlor 28 [38]. This class of ligands is one of the highly successful ligands in asymmetric hydrogenation, other than BINAP. In addition to the diphosphine ligand class of BINAP, Noyori also reported a class of non-phosphine-based chiral diamine ligands [39]. The diamine ligands have been used to form mixed diphosphine-diamine [40] and diamine-Ru catalysts such as 29 in Fig. 6. The triflate analog 30 [41] has been used in chiral process development of eliglustat 33 [42], a drug for treating type I Gaucher disease. The ruthenium catalyst 30 performs dynamic kinetic resolution-asymmetric hydrogenation (DKR-ATH) to create two chiral centers in a single step under transfer hydrogenation conditions (Scheme 8).

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O F3C S N Ru Cl O NH Ph

O S N Ru Cl O NH Ph Ph

Ph

29

30

Fig. 6 Noyori-type diamine chiral ruthenium catalysts for transfer hydrogenation reactions O

O

O

OH O OEt

HCOOH/Et2NH (5:2)

N

O 31

Ph

Ru catalyst 30 (5 mol%)

O

OEt N

O

Ph

Ph

Ph

32 OH

N

O O

HN

O

33 Eliglustat

Scheme 8 Catalytic asymmetric hydrogenation-DKR for eliglustat

The design and development of some of the privileged ligands and catalysts have been discussed in detail [43]. Asymmetric hydrogenation process development is highly important for the generic pharmaceutical companies to develop a reliable chiral process for obtaining a process IP to commercially produce the drug molecule. Some of the popular chiral drug molecules are shown in Fig. 7 [44]. A chapter on the structural diversity of ruthenium catalysts for asymmetric transfer hydrogenation processes is a part of this book.

3.3

Cross-Coupling

Currently, transition metal-catalyzed cross-coupling reactions are rated as the most versatile and powerful method for carrying out organic syntheses for the design and development of bioactive molecules [45]. Over the last two decades, this area has become more mature due to the availability of innovative technologies from the never-ceasing development efforts in academia and industry to identify new catalysts and ligands [46–53].

Organometallics in Process Chemistry: An Historical Snapshot

11

Fig. 7 Some of the popular chiral drug molecules (chiral centers created by chiral hydrogenation are highlighted)

Fig. 8 Akira Suzuki, Ei-ichi Negishi, and Richard Heck on stage, 2010 Nobel Prize

The anti-asthma drug montelukast [54], the antihypertension drug losartan [55], and the fungicide boscalid [56, 57] were the initial examples of industrial processes involving cross-coupling. The success and popularity of cross-coupling reactions led to the award of Nobel Prize to Richard Heck [58], Ei-ichi Negishi [59], and Akira Suzuki [60] in 2010 (Fig. 8).

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O P

O

P

P

38

39

tri-tert-butylphosphine

40 cataCXium A

BrettPhos

Fig. 9 Some of the bulky monodentate phosphine ligands

S N

N

N

Pd N

Cl

H N

O

O

42 41

Brexpiprazole

Fig. 10 Nolan’s Pd-NHC catalyst and the API brexpiprazole

Like any transition metal-catalyzed transformation, ligands exert a fine control over cross-coupling reactions. Some of the popular class of monodentate ligands are shown below in Fig. 9. Fu popularized the usefulness of the simple tri-t-butylphosphine ligand 38 for challenging cross-coupling reactions involving aryl chlorides [61] although there was a precedence on the use of tri-t-butylphosphine ligand by Koie [62, 63]. Buchwald designed a class of sterically demanding monodentate biaryl phosphine ligands 39 known as Buchwald ligands [64]. Beller and his team have developed a series of trialkyl- and dialkylarylphosphine ligands such as cataCXium A 40 [65]. Apart from the electron-rich alkyl phosphine ligands, N-heterocyclic carbene (NHC) ligands have also proven their usefulness in the challenging C–C and C–N bond formations [66]. Like phosphines electronic and steric properties of NHCs are also tunable. The Buchwald-Hartwig coupling stage in the pursuit of the drug molecule brexpiprazole 42 in Fig. 10 has been achieved using a Pd-NHC catalyst 41 [67]. Gilead’s miracle hepatitis C drug, Harvoni, where ledipasvir 47 is one of the two active ingredients, has two late-stage cross-coupling steps, a one-pot Miyaura borylation/Suzuki coupling involving two highly functionalized fragments (Scheme 9) [68]. Some of the recently approved drug molecules [69] have one or more crosscoupling steps in their manufacturing processes. Few such examples such as elagolix 48 [70, 71], tezacaftor 49 [72], abemaciclib 50 [73, 74], and darolutamide 51 [75] are shown in Fig. 11.

Organometallics in Process Chemistry: An Historical Snapshot Boc

O O B B O O

N

N NH

Br

13

Boc O

Pd(P(t-Bu2Ph)2Cl2 CH3CH2COOK i-PrOAc

43

N

N NH

B O

44

Boc

F

N

1) K3PO4, Water 2) Oxalic acid, EtOH/i-PrOAc

F

H N Br

N 45

Boc

Boc

F

N

F

N

N

H N

NH

N 46

O

O

O

NH O

N

O

HN

F

F

O

N

N

H N

NH

N 47 Ledipasvir

Scheme 9 Synthesis of ledipasvir

The two chapters titled “Application of Organometallic Catalysts in API Synthesis” and “Process Economics and Atom Economy for Industrial Cross-Coupling Applications via LnPd(0)-Based Catalysts” discuss the development of modern catalysts for cross-coupling applications for the manufacturing pharmaceutical molecules.

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Sonagashira coupling

Carbonylation O

Suzuki coupling

O

F

OH

F 3C

N

O

O

OH N

F

O HN

N F

H N

O

F

F

HO

O

49

HO

Tezacaftor, approved in Feb 2018

48 Elagolix, approved in Jul 2018

Miyaura borylation and Suzuki coupling

Buchwald-Hartwig coupling N N

N

N H

O

F

N

Cl N

N

N H

NC

N 50

N

N

OH N NH

51

F

Darolutamide, approved in Jul 2019

Abemaciclib, approved in Sep 2017

Fig. 11 Some pharmaceutical drug molecules involving cross-coupling processes in their manufacturing

3.4

Metathesis

Although the first metathesis reaction was reported in 1955 [76], Schrock’s group at MIT came up with the first viable metathesis catalysts in the late 1980s (Fig. 12) [77, 78]. In the 1990s Grubbs’ group at Caltech came up with Ru-based catalysts 53 [79] and 54 [80] (Fig. 13) with functional group tolerance and moisture and air stability, making these catalysts widely useful for organic synthesis and polymerization applications [81]. Hoveyda modified 54 with a tethered i-PrO electron-donating group 55 that decreased the initiation period [82]. Further modification of Hoveyda’s catalyst with electron withdrawing groups by Grela with a nitro group 56 [83, 84] and Zhan with a sulfonamide group 57 [85] has improved the activity and scope in various types of metathesis applications. These ruthenium-based catalysts which can

F3C F3C

N Mo O O F3C CF3 52

Fig. 12 Schrock’s catalyst

Ph

Organometallics in Process Chemistry: An Historical Snapshot

PCy3 Cl Ru

N

15

N

N Cl

Ru

Ru

Cl

Cl

Cl PCy3

O

PCy3

53 Grubbs I

54 Grubbs II

N

56 nitro-Grela

N Cl Ru

Ru

Cl

Cl O

55 Hoveyda-Grubbs II

N

N Cl NO2

N Cl

O

O S NMe2 O

57 Zhan-1B

Fig. 13 Some of the well-known commercial Grubbs-type ruthenium-based metathesis catalysts

Fig. 14 Richard Schrock, Robert Grubbs, and Yves Chauvin, Nobel Prize 2005 [91]

satisfy a wide variety of metathesis transformation demands have been discussed in detail [86, 87] and are commercially available. Chauvin [88], Schrock [89], and Grubbs [90] were awarded Nobel Prize in 2005 for their contribution for the development of metathesis technology (Fig. 14). Glecaprevir 60 used in combination pibrentasvir to treat chronic hepatitis C virus (HCV) genotypes 1–6 has been reported with a metathesis route (Scheme 10) [92]. To the best of our knowledge, metathesis methodologies are not widely employed currently in industrial scale to manufacture of pharmaceutical molecules unlike other catalytic transformations like cross-coupling and chiral hydrogenation. On the other hand, metathesis methods have been reported as one of the best methods for accessing several drug molecules under clinical trials and certain approved drug molecules such as rolapitant 61, bimatoprost 62, unoprostone 63 [92], and grazoprevir 64 (Fig. 15) [93].

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V. Sivakumar et al. F F

O O

F F N

O O

Zhan 1B 57

N

toluene, 110 °C

NH N O 58

N

O O O

O

N

NH N

COOMe

O 59

COOMe

F F N

O O O

N

O NH N O

NH

O

60

F

O F

H N S O O

Glecaprevir

Scheme 10 Synthesis of glecaprevir by metathesis

Fig. 15 Some pharmaceutical drug molecules reported with metathesis process as an option in their manufacturing (C–C bonds formed by metathesis reactions have been highlighted)

Organometallics in Process Chemistry: An Historical Snapshot

3.5

17

C2H Activation

There has been a significant effort in developing practical processes for C–H activation as it avoids the use of reagents such as Grignard or Negishi reagents, arylboronic acids, etc. The work of late Fagnou created a big splash in this area during the 2000s where he employed the intramolecular directing effect to functionalize the C–H bond via activation [94]. Seki et al. have developed intramolecular chelation-assisted C–H activation by ruthenium catalysts for the synthesis of angiotensin II receptor blockers (ARBs) such as losartan and valsartan [95]. Recently, Mehta et al. have disclosed a water-soluble ruthenium catalyst MCAT-53 [Ru2Cl2(HCOO)3(p-cymene)] 65 (Fig. 16) and applied it for the synthesis of an intermediate for the CETP inhibitor, anacetrapib 69 (Scheme 11).

.Na O Ru

O H

Cl Ru

Cl

O

H

O O H O 65

Fig. 16 MCAT-53 catalyst for C–H activation

F 3C

+ H N

O

F

O

MCAT-53 catalyst 65, HCOONa

F

O

Water

Br

N

F 3C 67

68

O

66

F

O

CF 3 N O

O

CF 3

CF 3 69 Anacetrapib

Scheme 11 Ruthenium-catalyzed C–H activation in water for the synthesis of anacetrapib

18

V. Sivakumar et al.

Me O

Cl N N

Ir

Ir

Ir

N

N 72

71

70

N

N

O Me

73

Fig. 17 Ir catalysts and ligands for C–H borylation

NH2 H

Bpin 0.5 mol % 70

74

N

N B2pin2, octane Boc

Cl

75

N Boc

N

N

1 mol % dtbpfPdCl2 2.5 equiv. Cs2CO3 IPA/Water (1:1), 80 °C

NH2

N

76

N H 77

87 % over 3 steps

Meridianin G

Scheme 12 C–H borylation/Suzuki coupling sequence for the synthesis of meridianin G

C–H borylation of arenes and heteroarenes represents a key strategy for the latestage elaboration of aromatic molecules [96]. Our group came up with a preformed Ir catalyst, Ir(COD)(phen)Cl 70 (Fig. 17), to carry out borylation of indoles very efficiently [97]. The earlier workers missed this system during the in situ studies as the phenanthroline ligand can form either an inactive cationic or highly active neutral complex depending on the solvent of choice. This new system avoids the use of relatively unstable [Ir(COD)(MeO)]2 71 precursor and the expensive ligands like di-t-butylbipyridine (dtbpy) 72 and 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4Phen) 73 [98, 99]. We have applied the Ir catalyst 70 to synthesize meridianin G 77 (Scheme 12), a marine alkaloid that belongs to a class of alkaloids which have shown antimalarial and antileishmanial activities [100].

4 Emerging Technologies Several emerging and breakthrough technologies are being applied to organometallic processes in the recent times to improve the throughput and to access novel reactive patterns. Few major ones are discussed in this section.

Organometallics in Process Chemistry: An Historical Snapshot

4.1

19

Photoredox Catalysis

Certain metal complexes can absorb light to bring it to higher energy level and transfer that energy to a substrate to make a chemical reaction to occur via radical formation (single electron transfer) and can facilitate both oxidation and reduction depending upon the electron acceptor/donor nature of the substrate [101, 102]. A typical ruthenium photocatalyst and its excited state are shown in Scheme 13. In collaboration with Eli Lilly, Stephenson group reported a visible lightmediated radical Smiles rearrangement to provide a general route to the difluoroethanol motif 81 (Scheme 14) while investigating a practical and efficient route for the synthesis of an antagonist of the opioid receptor like-1 [103]. MacMillan group has demonstrated that the photocatalysis is a versatile tool for late-stage and direct trifluoromethylation of widely prescribed pharmaceutical agents such as donepezil 79 (Fig. 18) [104]. 2Cl N N

N

visible light source λmax = 452 nm

N RuII

N

2Cl

N

metal-to-ligand charge transfer (MLCT)

N N

N RuIII

N

N N

-.

78

78* Excited state

Ru Catalyst

Scheme 13 Ru(bpy)32+ photocatalyst and its excited state

F O O O S

F Br

N

F F

NBu3 (1.5 eq), HCOOH (1.5 eq)

N

Ru catalyst 78 (0.1 mol%) blue LED, DMSO

80

81

Scheme 14 Radical Smiles rearrangement

CF3

O

O MeO

MeO

MeO

MeO 78 Trifluoromethylated precursor to Donepezil

Fig. 18 Late-stage functionalization of donepezil

79 Donepezil

N

OH

20

V. Sivakumar et al.

Molander group has reported a challenging C–C bond formation by a cooperative dual-catalyst system involving a photocatalyst and a transition metal catalyst [105]. Doyle’s group has also used a similar dual cooperative catalyst system for the cross-coupling of aryl chlorides with α-oxy sp3 C–H bond of cyclic and acyclic ethers [106]. These reactions were previously very difficult or impossible with the conventional cross-coupling methods.

4.2

Flow Chemistry

The flow chemistry is one of the most exciting field in process chemistry, which has grabbed a lot of attention with significant budget allocation in the pharmaceutical and fine chemical industries. IUPAC on its 100th year anniversary recently identified this as one of the emerging technologies in chemistry [107]. The major advantage of flow chemistry technology is that one can have a finite control over reaction conditions such as heat and mass transfer, solid-liquid interactions, and online purification of the intermediates. Using this technology, it is relatively safe to handle toxic, pyrophoric, and shock-sensitive materials. Also, many of the reaction steps could be combined under flow conditions with certain automation. Hence, the products which have been made in the batch reactors for years are being moved into the flow systems [108, 109]. Thaisrivongs and Naber and their team at Merck reported a flow chemistry reaction at pilot plant scale for the addition of an organolithium 83 to a chiral ketimine 84 in the pursuit of a pharmaceutical drug, verubecestat 86 (Scheme 15) [110]. The flow chemistry conditions allowed fast mixing of organolithium reagent and chiral ketimine as the desired selectivity is controlled by the rate of mixing of these two reactants.

+ −O O Li S NPMB H2 C

N

+

O S

1.0 equiv. DMPU THF

t-Bu

Br

t-Bu Br

F

83

O S

NH O O S NPMB F

84

85

NH2 F

N

H N

N O

86

N S O O

F

Verubecestat

Scheme 15 Organolithium addition process in the manufacture of the drug molecule verubecestat

Organometallics in Process Chemistry: An Historical Snapshot

21

+

O O − S Li NPMB H2C

-10 to -20 °C

-10 to -20 °C

83 (1.0 M) 1.7 equiv and 1.0 equiv DMPU

N

O S

t-Bu

Br F 84 (0.8 M) 1.0 equiv

Koflo static mixer

t-Bu Br

O S

NH O O S NPMB F 85

Fig. 19 Schematic representation of continuous process the addition of organolithium to a ketimine

A schematic representation of optimized continuous process at pilot plant scale is shown in Fig. 19. The system consists of a Y-shaped flow device followed by a Koflo static mixer. The preformed organolithium reagent at 20 C was used in this process. The flow conditions minimized proton transfers between the nucleophile and electrophile and between the unquenched product and the electrophile. The product was produced in more than 100 kg in a single batch in 88–89% yield with consistent assay. Seeberger and co-workers developed a continuous flow protocol for the preparation of efavirenz 87 (Fig. 20), an essential medicine for the treatment of HIV leading to a shorter and safer synthetic pathway, and gave the final product in 45% overall yield within a relatively shorter reaction period of 2 h [111]. The continuous flow synthesis of another drug to treat HIV, dolutegravir 88, an HIV integrase inhibitor has been reported with seven total steps in three separate flow operations [112]. A team SARCode has developed a flow chemistry protocol for the low-temperature carboxylation of an organolithium intermediate for the manufacturing of lifitegrast 89 [113], a drug for the treatment of signs and symptoms of dry eye. Landis group in collaboration with Eli Lilly has applied research scale pipes-in-series plug flow reactor for the synthesis of the popular drug naproxen 90 by the asymmetric hydroformylation of 2-vinyl-6-methoxynaphthalene [114]. A chapter on the process development of sodium acrylate from ethylene and CO2 under continuous process conditions is a part of this volume.

22

V. Sivakumar et al. O

F

N N

O N H

N H

O

CF3

Cl

F

O

HO

O

O

H

88 Dolutegravir

87 Efavirenz

Cl

O N H

N

O O

COOH

O

S O

O OH

O

Cl

90 Naproxen

89

Lifitegrast

Fig. 20 Few examples of drug molecules synthesized via flow chemistry processes

4.3

Ester Hydrogenation Under Greener Conditions

Ester hydrogenations are usually carried out by the addition of stoichiometric amounts of hydride-reducing agents such as LiAlH4, NaBH4, Red Al, etc. resulting in the formation unwanted salts. These classical methods are not sustainable considering their impact on environment. The development of active homogeneous catalytic systems which have functional group tolerance and can operate under milder conditions is essential to have a greener process. Flavors and fragrances industry firms like Firmenich [115, 116] and Takasago [117] have developed suitable catalysts for this transformation. Milstein and his team were the first one to come up with a practical ruthenium catalyst system for the hydrogenation of esters to the corresponding alcohols [118]. Later on his [119] and Beller [120] groups have utilized earth-abundant metals such as iron and manganese using PNP pincer ligands. Gusev et al. reported a set of highly active Ru-SNS catalyst systems 92–95 in Fig. 21 with high potential to replace the use of stoichiometric hydride reducing agents for the hydrogenation of esters to alcohols in industrial processes (Scheme 16) [121]. Et S

Cl Ru

N H

PPh 3 SEt

Cl 91

Et S

Ru N H

Et S

H PPh 3 SEt Cl

H Ru

N H

92

Fig. 21 Gusev’s Ru-SNS ester hydrogenation catalysts

AsPh 3

93

H CO Ru

SEt Cl

Et S N H

SEt Cl 94

Organometallics in Process Chemistry: An Historical Snapshot Catalyst 91 (0.05 mol%) ester (0.1 mol), KOMe (5 mol%) THF, H2 50 bar, 3 h, 40 °C

O O

23

OH 96

95

+

MeOH 97

Catalyst 91 (0.05 mol%) ester (0.1 mol), KOMe (5 mol%) THF, H2 50 bar, 3 h, 40 °C

O

OH

O

+

99

98

MeOH 97

Scheme 16 Ru-SNS catalyst catalyzed hydrogenation of esters

Gusev catalysts and similar systems have been licensed and made commercially available by Millipore Sigma (Merck KGaA) for catalog quantities (https://www. sigmaaldrich.com/technical-documents/articles/technology-spotlights/ester-hydroge nation.html) and Johnson Matthey for commercial quantities (https://matthey.com/ news/2018/partnering-with-greencentre-canada).

4.4

Organic Electrosynthesis

The electrosynthesis methods have attracted a great deal of attention as a powerful green tool for the organic synthesis, affording less chemical waste production, less chemicals spent, and often less reaction steps than conventional methods [122]. Collaborating with Pfizer and Asymchem, Baran and co-workers reported a nickel-catalyzed coupling between aryl (pseudo)halides and aliphatic amines in the absence of an external base and under ambient reaction conditions, through a simple and inexpensive experimental setup (constant current, undivided cell) and demonstrated this method to derivatize the drug amoxapine 101 (Scheme 17) [123]. Ackermann group has disclosed an electrochemical methodology to functionalize C–H and N–H bonds by water-tolerant Co catalysts at room temperature (Scheme 18) [124].

Br

O

Cl

+ N CF3 100

N

NiBr2(diglyme) (10 mol%) dtbpy (10 mol%) LiBr (4 equiv.)

O

Cl

(+)RCV/(-)Ni undivided cell cosntatnt current DMA, RT, 7 h, 86%

N N

HN

101 Amoxapine

102 F3C

Scheme 17 Derivatization of amoxapine

N

24

V. Sivakumar et al. O

O MeO H

H N H

PyO

(+)RVC/(-)Ptl constant current Co(OAc)2 4H2O (10 mol%)

MeO

+

OMe 104

PyO Me

H2O/MeOH (1:1) NaOPiv, 16 h, 23 °C

103

N

.

OMe

85% 105

Me

Scheme 18 Electrochemical C–H/N–H annulation

4.5

Computational Modelling for Reaction Predictability

There is a new trend where computational modelling has been applied to predict the catalyst and ligands for chemo- and enantioselective organic transformations [125– 127]. Ahneman et al. have applied “machine learning (ML)” methods to study the Buchwald-Hartwig of amination of isoxazoles employing Glorius fragment additive screening approach [128]. Wheeler group at University of Georgia have developed AARON (An Automated Reaction Optimizer), an open-source computational toolkit that aids in identifying the transition state and intermediate structures required to predict the enantioselectivities of asymmetric catalytic reactions [129]. Sigman et al. have developed multidimensional analysis tools for asymmetric catalysis by correlating reaction outputs such as electrochemical potential, enantio-/ site-/chemoselectivity, and ligand parameters with structural descriptors of the molecules involved [130]. His group has been able to selectively couple chloro- of the 4-bromo-2-chloropyridine selectively with aniline (Scheme 19) by predicting DMAPF ligand (Fig. 22) as the appropriate one for this transformation. This was contrary to the C–X bond dissociation energy concepts. However, lower selectivities Pd(dba)2 (5 mol%) aniline (1 equiv.) Ligand 106

Br N

Cl

NaOt-Bu (1.25 equiv.) Dioxane, 70-80 °C, 15 h

107

Scheme 19 Chemoselective Pd-catalyzed amine arylation

Me Me N Me P N Fe Me Me P N Me N Me Me 106

Fig. 22 DMAPF ligand

Br N 108

NHPh

Organometallics in Process Chemistry: An Historical Snapshot

25

were observed when aniline was changed to another amine or when the substrate was substituted with other groups [131].

5 Summary and Outlook Today organic chemists who want to do process chemistry cannot avoid metalcatalyzed reactions if they want to make a modern competitive process. At the moment precious metal organometallics as catalysts dominate the field of organic synthesis; however, there is a significant effort in utilizing earth-abundant metal-based catalysts. Among the several established and emerging technologies discussed above, combining enzymes with transition metal complexes for organic synthesis is also gaining attention [132]. Knowledge of biology and the role of enzymes via technologies to synthesize molecules may be important for the next generation of organometallic chemists to make the impossible possible such as the fixing of CO2 just as nature does it using a metalloenzyme, but more efficiently. With time synthesis of artificial metalloenzymes via directed evolution and protein engineering for solving some of the challenges in organic processes will also emerge [133, 134].

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86. Grubbs RH (2003) Handbook of metathesis. Wiley-VCH, Weinheim 87. Grela K (ed) Olefin metathesis theory and practice, vol 2014. Wiley, Hoboken, p 287 88. Chauvin Y (2006) Angew Chem Int Ed 45(23):3740 89. Schrock RR (2006) Angew Chem Int Ed 45(23):3748 90. Grubbs RH (2006) Angew Chem Int Ed 45(23):3760 91. CC BY 2.0, barney grubbs at https://www.flickr.com/photos/59957667@N00/82196494 92. Hughes D, Wheeler P, Ene D (2017) Org Process Res Dev 21(12):1938 93. Williams MJ, Kong J, Chung CK, Brunskill A, Campeau LC, McLaughlin M (2016) Org Lett 18:1952 94. Campeau LC, Stuart DR, Fagnou K (2007) Aldrichim Acta 40:35 95. Seki M (2016) Org Process Res Dev 20:867–877 96. Hartwig JF (2012) Acc Chem Res 45:864 97. Johansson Seechurn CCC, Sivakumar V, Satoskar D, Colacot TJ (2014) Organometallics 33:3514 98. Cho JY, Tse MK, Holmes D, Maleczka RE Jr, Smith MR III (2002) Science 295:305 99. Ishiyama T, Takagi J, Ishida K, Miyaura N, Anastasi NR, Hartwig JF (2002) J Am Chem Soc 124:390 100. Bharate SB, Yadav RR, Khan SI, Tekwani BL, Jacob MR, Khan IA, Vishwakarma RA (2013) Med Chem Commun 4:1042 101. Shaw MH, Twilton J, MacMillan DWC (2016) J Org Chem 81(16):6898 102. Douglas JJ, Sevrin MJ, Cole KP, Stephenson CRJ (2016) Org Process Res Dev 20(7):1134 103. Douglas JJ, Sevrin MJ, Cole KP, Stephenson CRJ (2016) Org Process Res Dev 20(7):1148 104. Nagib DA, MacMillan DWC (2011) Nature 480:224 105. Tellis JC, Primer DN, Molander GA (2014) Science 345(6195):433 106. Shields BJ, Doyle AG (2016) J Am Chem Soc 138(39):12719 107. Gomollón-Bel F (2019) Chem Int 41(2):12 108. Gutmann B, Cantillo D, Kappe O (2015) Angew Chem Int Ed 54:6688 109. Porta R, Benaglia M, Puglisi A (2016) Org Process Res Dev 20:2 110. Thaisrivongs DA, Naber JR, Rogus NJ, Spencer G (2018) Org Process Res Dev 22(3):403 111. Correia CA, Gilmore K, McQuade DT, Seeberger PH (2015) Angew Chem Int Ed 54:4945 112. Ziegler RE, Desai BK, Jee JA, Gupton BF, Roper TD, Jamison TF (2018) Angew Chem Int Ed 57(24):7181 113. Tweedie S, Venkatraman S, Zeller J (2019) Continuous flow carboxylation reaction. US Patent US10273212B2, 30 Apr 2019 114. Abrams ML, Buser JY, Calvin JR, Johnson MD, Jones BR, Lambertus G, Landis CR, Martinelli JR, May SA, McFarland AD, Stout JR (2016) Org Process Res Dev 20(5):901 115. Saudan LA, Saudan CM, Debieux C, Wyss P (2007) Angew Chem Int Ed 46:7473 116. Saudan L, Saudan C (2008) Hydrogenation of esters with Ru/bidentate ligands complexes (Firmenich SA) PCT Int Appl WO/2008/065588 A 117. Kuriyama W, Matsumoto T, Ogata O, Ino Y, Aoki K, Tanaka S, Ishida K, Kobayashi T, Sayo N, Saito T (2012) Org Process Res Dev 16:166 118. Zhang J, Leitus G, Ben-David Y, Milstein D (2006) Angew Chem Int Ed 45:1113 119. Zell T, Ben-David Y, Milstein D (2014) Angew Chem Int Ed 53(18):4685 120. Elangovan S, Garbe M, Jiao H, Spannenberg A, Junge K, Beller M (2016) Angew Chem Int Ed 55:15364 121. Spasyuk D, Smith S, Gusev DG (2013) Angew Chem Int Ed 52:2538 122. Yan M, Kawamata Y, Baran PS (2017) Chem Rev 117(21):13230 123. Li C, Kawamata Y, Nakamura H, Vantourout JC, Liu Z, Hou Q, Bao D, Starr JT, Chen J, Yan M, Baran PS (2017) Angew Chem Int Ed 56:13088 124. Tian C, Massignan L, Meyer TH, Ackermann L (2018) Angew Chem Int Ed 57:2383 125. Ahn S, Hong M, Sundararajan M, Ess DH, Baik MH (2019) Chem Rev 119:6509 126. Durand DJ, Fey N (2019) Chem Rev 119(11):6561 127. Wodrich MD, Sawatlon B, Solel E, Kozuch S, Corminboeuf C (2019) ACS Catal 9(6):5716

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29

Top Organomet Chem (2019) 65: 31–72 DOI: 10.1007/3418_2019_30 # Springer Nature Switzerland AG 2019 Published online: 13 August 2019

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry Alan M. Hyde and Eric R. Ashley

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Intermolecular Metallocarbenoid Cyclopropanation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Cyclopropanation of Electron-Rich Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Cyclopropanation of Less Electron-Rich Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Simmons–Smith Cyclopropanations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Michael-Initiated Ring Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Reactions Between Sulfur Ylides and Enone Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Reactions Between Sulfur Ylides and 1,4-Enedicarbonyl Substrates . . . . . . . . . . . . . . . . . 3.3 Reactions Between α-Halo Enolates and 1,4-Enedicarbonyl Substrates . . . . . . . . . . . . . . 4 Intramolecular Metallocarbenoid Cyclopropanation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 α-Diazocarbonyl Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Lithium Carbenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Nucleophilic Displacement Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Cyclization of Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Intermolecular Enolate Double Addition to Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32 38 38 42 48 49 50 51 53 56 56 61 62 63 66 68 69

Abstract Within the field of process chemistry, all available methods of synthesis are typically considered for the preparation of complex targets. Early in development, speed and flexibility are paramount, but as larger quantities of clinical candidates are required later in development, a route is typically chosen based on process robustness, product quality, and its overall efficiency with respect to several metrics. In this chapter we will highlight the preparation of active pharmaceutical compounds and intermediates containing [3.1.0] bicycles for which stoichiometric main group or catalytic transition metals were utilized to construct C–C bonds. We will focus on four broad classes of reactions: Intermolecular metallocarbenoid A. M. Hyde (*) and E. R. Ashley Department of Process Research and Development, MRL, Rahway, NJ, USA e-mail: [email protected]; [email protected]

32

A. M. Hyde and E. R. Ashley

cyclopropanation, Michael-initiated ring closures, intramolecular metallocarbenoid cyclopropanation, and those utilizing nucleophilic displacements. A comparative method assessment is presented to illustrate which targets are most amenable to a particular chemistry for obtaining high yields and controlling stereochemistry. Keywords Azabicyclo[3.1.0]hexane · Bicyclo[3.1.0]hexane · Cyclopropanation · Process chemistry

1 Introduction Bicyclo[3.1.0]hexane architectures and the related heterocyclic counterparts appear often, both in nature and active pharmaceutical agents (Figs. 1, 2, and 3). For those originating from natural isolates, the functions of these motifs have typically not been elucidated, a notable exception being the alkylation of DNA by the duocarmycins (e.g., duocarmycin A–adenine adduct, Fig. 3). In pharmaceutical research, the utilization of fused bicycles comprises a powerful tool for medicinal chemists, allowing the design of compounds that array key recognition elements in a Me

Me

R2

Me

R Me

Me H Me Me

Me

Me

lindenane sesquiterpenes

thujane monoterpenes

OMe

O Me

Me Me

H H

H

HO2C laurentristich-4-ol

Ph

O

cyclolauren-2-ol

H

O Me

Me Me

H OH

H

dichapetalin triterpenoids

N N H

O HO P O HO

H

HO MK-1903 NIACR1 agonist dyslipidemia

N

OH

MRS-2339 P2X receptor agonist cardioprotective

Cl

HN N

N N

H

drospirenone (Yasmin) contraceptive

NH2 N

H Cl

O

H

O

O

echinopine A

H CO2H

H Me

Me

R

H

Me

HO

crispatene

H HO

Me

O Me

R4

R1

Me

O

R3

MeHN O HO

N

N N

OH

F MRS-5698 adenosine A3 inhibitor neuropathic pain

Fig. 1 Bicyclo[3.1.0]hexane natural products and active pharmaceutical ingredients

F

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

33 H

H

O

F

H CO2H

H CO2H

H2N

F H 2N

MGS0028 mGluR2/3 agonist

O

O H S

S

H NH NH 2

O

H 2N

O

O OCHF2

SMe

MK-1642 FFAR1 agonist

H Me

O

CO2H

CO2H HO2C

H CO2H

H Ar

Me NH2 HCl

LY544344 eglumegad prodrug mGluR2/3 agonist

CO2H H

H NH O

HYDIA mGluR2/3 agonist

H

O

O

HO

F3C

LY214003 mGluR2/3 agonist

Me

H CO2H

MGS0008 mGluR2/3 agonist

CO2H HO2C

H

CO2H

N O

O

CO2H H

MRL oxaza series FFAR1/FFAR4 dual agonists

CO2H

N O

H

Me MK-8666 FFAR1 agonist

Fig. 2 Pharmaceutically active bicyclo[3.1.0]hexane carboxylic acids

defined orientation. Within the broad category of fused bicyclic compounds, the [3.1.0] series is particularly prized for its highly constrained, puckered architecture [1], which potentiates highly specific target binding and limited off-target activity while taking advantage of the generally low lipophilicity and high metabolic stability of cyclopropane rings [2]. In particular, they have been frequently incorporated when conformationally rigid amino acids [3–6] or nucleosides are sought [7–9]. Bicyclo[3.1.0]hexane compounds therefore have become common pharmacophores, appearing in synthetic bioactive molecules that modulate hormone signaling, ion channel activity, glycine transport, hepatitis C protease activity, neurotransmitter reuptake, and the activity of G-protein-coupled receptors such as the adenosine A3 receptor, niacin receptor 1 (NIACR1), metabotropic glutamate receptors (mGluRs) [10], and free fatty acid receptors (FFARs) to name a few. Structures bearing carboxylic acids appended to the cyclopropane are particularly common among the mGluR and FFAR clinical candidates (Fig. 2). Azabicyclo[3.1.0]hexanes are also widely represented in biologically active compounds including several marketed drugs (Fig. 3) [11]. While these compounds are attractive targets due to their biological activity, the bicyclo[3.1.0]hexane framework poses a formidable challenge to efficient synthesis. A primary source of this difficulty arises from the substantial strain energy of these compounds relative to their acyclic congeners (for experimental data on heats of formation for a variety of cyclopropanes, see [12]). Homodesmotic reaction schemes

34

A. M. Hyde and E. R. Ashley NH2 OMe

N

OMe O

DNA

OMe

NH

N

Me

N

N H

Me

N H

N

Me

Cl

H

O

H Cl

N

NH

amitifadine serotonin–norepiniphrine– dopamine reuptake inhibitor

cycloclavine

Me

F

HO2C

Me

H N

N F

O

H

H N

H

N H

NH2

F trovafloxacin (Trovan) broad-spectrum antibiotic

H N

t-BuHN O

N

O

NC

saxagliptin (Onglyza) DPP-4 inhibitor

F O

H 2N

HO

N H

Me

indolizomycin

OH

duocarmycin A–adenine adduct

Me

N

OMe

NH

N O

MeO2C

duocarmycin A

O

OMe

Me

O

HO

OMe

O O

MeO2C

N N

Cl

NH2 O H

O

N

N

H O

t-Bu

N

N

Me

Me boceprevir (Victrelis) HCV NS3 inhibitor

PF-03463275 glycine transporter type-1 inhibitor

Fig. 3 Azabicyclo[3.1.0]hexane natural products and active pharmaceutical ingredients

[13] that add ethane to C–C bonds allow for ready calculation of such ring strain values. Using this approach, we calculated the ring strain energies [14] of a small set of [3.1.0] bicycle containing cores that map onto target molecules that will be discussed. Instead of decomposing the molecules into completely acyclic pieces to obtain the total ring strain, we chose to only break open the cyclopropane unit at the peripheral position to obtain relative values for this particular ring of interest (Fig. 4, hashed lines indicate the bond being broken). As a benchmark, the reaction between cyclopropane and ethane to produce n-pentane is calculated to be exothermic by 30.2 kcal/mol (ring strain energies calculated with Spartan‘16 using ωb97X-D/6-31g (d,p)). Interestingly, the strain of the cyclopropane ring is mildly decreased (27.0 kcal/mol) relative to the parent structure by fusion to a cyclopentane ring (this finding is consistent with heat of combustion measurements [15]). Also nonintuitive is that the inclusion of heteroatoms (N, O, S) in the five-membered ring increases the cyclopropane strain energy by up to 4.3 kcal/mol. The presence of a carbonyl or fusion of a benzene ring does not add additional ring strain, although

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

35

Homodesmotic Reactions calculated with ω b97X-D/6-31g(d,p) + ethane

Me

Me

ΔH = –30.2 kcal/mol O HN enthalpic ring strain (kcal/mol) =

N H 27.0

O

28.9

31.3

26.6

N H 30.0

27.2

O

S 28.4

26.1

S

31.2

27.5

Fig. 4 Calculated strain energies of the cyclopropane component for [3.1.0] bicyclic systems relevant to discussed target molecules Polar ring fragmentation mechanisms X (1)

X

EWG

X

EWG

(2)

EWG

(4)

X EWG

EWG

X = CH for benzo-fuse O for ketone X

X (3)

EWG Z

Z

EDG

EDG

Z = O, NH, S

Radical ring fragmentation mechanism

(5)

R

R

Fig. 5 Decomposition pathways of [3.1.0] bicycles via fragmentation

experimentally these compounds may be more prone to fragmentation through the formation of reactive intermediates at the alpha or benzylic positions (see Fig. 5 for examples of general degradation pathways available to cyclopropylcarbinyl anions (Eqs. 1, 2) [16–18], donor–acceptor cyclopropanes (Eqs. 3, 4) [19, 20], and cyclopropylcarbinyl radical intermediates (Eq. 5)) [21]. Such ring openings are responsible for decomposition pathways for a number of bicyclo[3.1.0]hexane ring systems [22, 23]. Given the broad array of bicyclo[3.1.0]hexane analogues found in nature, it is tempting to consider biomimetic synthetic approaches to targets of interest. The biosynthesis of thujone and related bicyclo[3.1.0]hexane terpenes is thought to occur via a cationic cascade shown in Fig. 6 that begins with cyclization of geraniol

36

A. M. Hyde and E. R. Ashley Me

Me

Me

Me thujane family

OPP Me

Me

geraniol pyrophosphate

Me

Me 1

Me

Me 2

Me

Me 3

Fig. 6 Proposed biosynthetic pathway for the construction of thujane monoterpenes

pyrophosphate to initially generate carbocation intermediate 1 [24]. A subsequent 1,2-hydride shift is proposed to give isomeric intermediate 2; this is followed by a cyclopropane-forming cyclization event to give cation 3, which can eliminate or be further functionalized to provide the final terpene products. This sequence builds the bicyclic core in rapid fashion, but, given the current state of the art in controlling cationic cascades, a biomimetic strategy would not be expected to be highly successful in the context of complex target synthesis. Alternatively, one can envision building up the [3.1.0] bicyclic system through many other well-precedented synthetic transformations [25–28], and those that have been utilized in process chemistry efforts (for a review on cyclopropanation reactions in process chemistry, see [29]) are shown in Fig. 7. Of these, perhaps the most straightforward approach is the intermolecular cyclopropanation of a cyclopentene derivative with a metallocarbenoid, which allows the simultaneous formation of two C–C bonds and three stereocenters from relatively simple starting materials (Fig. 7a). The simplicity of this transformation makes it very attractive, but in practice, the success of the reaction is highly dependent on the electronic nature of the reactive partners. Electron-rich cyclopentenes are suitable partners for cyclopropanation when paired with electrophilic α-carbonyl carbenoids, but for electron-poor cyclopentenes, reactivity is significantly diminished. This lack of reactivity can be overcome in some cases with the use of odd-electron metallocarbenoids or, in other cases, by taking advantage of nearby directing groups that enable the successful application of electron-rich zinc carbenoids (i.e., the Simmons–Smith reaction). A variation of the carbenoid approach makes use of sulfur ylides or α-haloenolates in a two-step conjugate addition, nucleophilic displacement sequence (Fig. 7b). This is the method of choice for highly polarized substrates such as α,β-unsaturated ketones or 1,4-enedicarbonyl systems, as they undergo [3 + 2] cycloadditions with diazoalkanes to form dihydropyrazoles. Alternatively, intramolecular metallocarbenoid variants tackle the reactivity challenges by proximity, and the control of stereochemistry may be enhanced by constrained reactive conformations (Fig. 7c). Lastly, we have found in some particularly challenging systems that stereochemistry is best set for the leaving group at an earlier stage with the three-membered ring formed later by a stereospecific nucleophilic displacement reaction (Fig. 7d). In this chapter we will thoroughly address each of these synthetic strategies for overcoming the challenge of preparing [3.1.0] bicycles in an efficient and stereocontrolled manner. Particular attention will be paid to the ways in which the target structure dictates the most successful synthetic strategy. The tactics that

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry Fig. 7 Synthetic approaches used in process chemistry to access [3.1.0] bicycles. (a) Intermolecular metallocarbenoid cyclopropanation, (b) Michael-initiated ring closures, (c) intermolecular metallocarbenoid cyclopropanation, (d) nucleophilic displacement approaches

37

A R1

Y Z

X

R1

ML* catalyst (Y,Z = N2)

R2

R2 X

or Zn/Et2Zn (Y = Z = I)

B R1 R3

R1

R2

Base R3

LG LG = halogen or R2S+

X O

R2 X O

C R1

R2

R1

ML* catalyst

R2

N2

O

O

OH LiTMP

O

O

H

Li H

D R

LG Base

R

EWG

EWG

Cl

O

R

CN

Base

H HO

R NC

R HN

underlie these strategies will show the power and limitations of a variety of organometallic carbenoids as well as occasional methods to circumvent their use. The featured case study will be MK-8666, for which three of the strategies (A, C, and D) were evaluated. We should point out that a number of diverse methodologies have been developed recently outside the context of process chemistry to prepare bicyclo [3.1.0]hexanes, in many cases asymmetrically. These include Pt- and Au-catalyzed cycloisomerization of hydroxylated enynes [30], Au-catalyzed cycloisomerization of 1,5-enynes [31, 32], Ru-catalyzed redox cycloisomerization of hydroxy-1,6enynes [33, 34], Pd-catalyzed oxidative cyclization of allyl propiolates [35], Cu[36] and La-catalyzed [37] [3 + 2] cycloaddition with cyclopropenes, α-magnesiation and ring closure of 4-chloro N-Boc piperidine [38], and Pd- [39] or Co-catalyzed intramolecular C–H activation [40]. While these approaches will not be covered here, they should be considered for synthetic planning as they could be advantageous for particular targets.

38

A. M. Hyde and E. R. Ashley

2 Intermolecular Metallocarbenoid Cyclopropanation The direct cyclopropanation of cyclopentene derivatives employing electrophilic metallocarbenoids constitutes one of the most straightforward methods for the construction of bicyclo[3.1.0]hexane derivatives [41]. In general, styrenes are considered to be the easiest substrate class for obtaining high stereoselectivity, while five-membered ring systems including indene are more difficult [42]. In cases where high stereoselectivity for cyclopropanation of indene has been achieved, the diazo partner is typically disubstituted with specific examples including dienyl diazoacetates [43], cyanoamides [44], or nitroesters [45]. With these precedents in mind, the FFAR1 agonists discovered at MRL (i.e., MK-8666, MK-1642, and the MRL oxaza series, Fig. 2) provided a fertile testing ground for evaluating the strengths and limitations of such direct cyclopropanations. The presence of the carboxylic acid moiety pendant to the cyclopropane ring in all of these APIs invited the retrosynthetic disconnection to a diazoacetate and the five-membered ring alkene, while the substrate electronics and requirement for stereocontrol posed considerable challenges.

2.1

Cyclopropanation of Electron-Rich Heterocycles

In 2007 MRL claimed a series of antidiabetic compounds with the general structure 4, where X and Y were broadly construed as heteroatom or alkyl linkers and Z was a carboxylic acid or bioisostere (Fig. 8) [46]. The exemplified claims consisted largely of compounds of type 7, which contained a benzo-fused oxabicyclo[3.1.0]hexane core. This structural feature, coupled with the pendant carboxylic acid, rendered these compounds prime candidates for synthesis via catalytic intermolecular cyclopropanation of the corresponding benzofurans 5 with an electrophilic metal carbenoid derived from a diazoacetate ester (6) and an appropriate metal catalyst (Fig. 9). In particular, it was expected that π-donation from both the ring oxygen R4 Ar

X

R2 Z R1 Y

R3

4 X, Y = heteroatoms and alkyl linkers Z = carboxylates and bioisosteres

Fig. 8 MRL antidiabetic compounds O

O Ar

OR

+ O

O 5

N2 6

OH

1. Metal catalyst 2. Chiral SFC separation 3. Saponification

Ar

O

O 7

Fig. 9 General synthetic scheme to prepare benzo-fused oxabicyclo[3.1.0]hexanes

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

O F3C

+ O

O OCHF2

N2

O

O OCHF2

9

Ligand

O OEt

F3C

OEt

8

Catalyst

H

39

MK-1642

H

10 Temp

Yield

ee

exo:endo

Me

Me

N

N

O (CuOTf)2•toluene (1.7 mol %)

L1 (4.1 mol %)

ambient

(CuOTf)2•toluene (0.5 mol %)

L2 (1.25 mol %)

–10 °C

55%

90%

70%

92%

not reported

29:1

O

R

R L1 R=t-Bu L2 R=Ph

Fig. 10 Cyclopropanation toward MK-1642

atom and the 6-aryloxy substituent would raise the HOMO of the benzofuran, while the ester moiety would lower the LUMO of the carbenoid, allowing efficient cyclopropanation under catalytic conditions (for a review on how electronic effects dictate selectivity in Rh-catalyzed reactions of diazo compounds, see [47, 48]). In practice, rhodium tetraacetate was used for most examples, and single-enantiomer compounds were generally obtained by chiral SFC separation either before or after the saponification step. The immediate precursor of MK-1642 was originally obtained by cyclopropanation of benzofuran 8 using 5 equiv of ethyl diazoacetate and a Cu(I) tertbutyl bis-oxazoline catalyst based on the conditions reported by Evans (Fig. 10) [49]. This system gave moderate reactivity and selectivity, providing the desired bicyclo[3.1.0]hexane product 10 in 55% yield and 70% ee on gram scale. Silica gel chromatography was required to remove the undesired endo-diastereomer and diethyl fumarate by-product, and a subsequent chiral chromatography step provided enantiopure material. Despite the utility of this route for providing gram quantities of APIs, the two chromatographic steps were considered impractical for kilo-scale work. Therefore, a screen of metal salts, ligands, and conditions was conducted, revealing that the combination of [CuOTf]2•toluene (1 mol% copper) and 1.25 mol% phenyl bis-oxazoline ligand L2 served as a much improved catalyst for the reaction in all senses, providing the desired product in 90% yield and 92% ee. Moreover, only 2.6 equiv of ethyl diazoacetate were now required for full conversion, and the product was generated in greater than 29:1 d.r. favoring the desired exo isomer on multi-kilo scale (the process synthesis of MK-1642 was developed by Don Gauthier, Yong-Li Zhong, Rich Desmond, Amude Kassim, Jason Kowal, and George Zhou). The results obtained for the aryloxybenzofuran substrate class exemplify the potential of asymmetric cyclopropanation for rapid, efficient, and stereoselective synthesis of the [3.1.0] bicyclic core. The high electron density and stability of the reactive aryloxybenzofuran, as well as the natural activation of the metal carbenoid intermediate by the resident carboxylate group, facilitate the efficient and stereoselective cyclopropanation reaction.

40

A. M. Hyde and E. R. Ashley H

(1)

+ S

CO2Et N2

43% crude yield; 31% yield, >99:1 dr after crystallization

neat

(2)

N Boc

0.05 mol % Rh2(Oct)4

CO2R

+

N2

S

• HCl

H

11

H

H CO2R

N H Boc

temp (°C) % yield 20 61 20 23 –20 37

% ee 52 83 93

O

H

N L3

+

H CO2R N H Boc 13

H N

O

t-Bu

S

RO2C H

12 R Me t-Bu t-Bu

O

CO2Me

LY2140023

1 mol % Cu(OTf)2 2.2 mol % L3 1 mol % PhNHNH2 DCM

H

MeO2C H2N

CO2Et

O N t-Bu

Fig. 11 Cyclopropanations of thiophene (Eq. 1) and N-Boc pyrrole (Eq. 2) with diazoacetate esters

Similar reactions have also been disclosed on the monocyclic thiophene, N-acyl pyrrole, and furan ring systems (Fig. 11). Yields and selectivities are typically moderate in these cases, since partitioning of the reaction to alternative pathways can lead to a variety of undesired products. Cyclopropanation of thiophene with ethyl diazoacetate was investigated to prepare intermediate 11 for the synthesis of the schizophrenia drug LY2140023 by Eli Lilly and Company (Fig. 11, Eq. 1) [50]. The first iteration of this reaction utilized 0.3 mol% Rh2(OAc)4 and ethyl diazoacetate in neat thiophene to provide the desired ring system as a single diastereomer in 38% yield after preparative HPLC. Reactions using [(MeCN)4Cu] PF6 primarily gave dimerization of ethyl diazoacetate, while chiral Cu- or Rh-based catalyst systems gave very low yields and were deemed unviable. Ultimately, Rh2(Oct)4 was used for scale-up as it was more readily available and allowed for lower catalyst loadings (0.05 mol%) than Rh2(OAc)4. A hypothesis for why the reaction was completely selective for the exo-diastereomer was not proposed. At pilot scale, the remaining unreacted thiophene was removed by wiped-film distillation, after which a second-pass distillation provided 11 as a crude oil. The final isolation was accomplished by low-temperature crystallization from MeOH, giving pure 11 as low-melting solid (36
C) in 30–35% yield at up to metric ton scale. This intermediate was further functionalized to LY2140023, with the absolute stereochemistry being set through resolution of a later intermediate as its 2-phenylglycinol salt. The outcomes obtained in the prior example are better appreciated in the broader context of the limited literature on the reactivity between diazoacetates and fivemembered heterocycles. In their synthesis of the GABA analogue homo-β-proline, Reiser and co-workers investigated the cyclopropanation of N-Boc pyrrole with α-diazoesters. The active catalyst for this reaction was generated from mixture of Cu(OTf)2, phenyl hydrazine for in situ reduction to Cu(I), and bis-tert-butyl-aza(bis)

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

41

oxazoline ligand L3 that proved optimal when used in combination with the bulky tert-butyl diazoacetate (Fig. 11, Eq. 2) [51]. High enantioselectivity could be achieved at the expense of yield by lowering the temperature from 20
C to 20
C. The yield was depressed by a second cyclopropanation of the desired product 12 to form by-product 13. Notably, 13 was formed with low enantioselectivity, indicating that the minor enantiomer of 12 was preferentially converted to 13, thus reinforcing the trade-off between selectivity and yield. Furan systems have also proven challenging for intermolecular transition metal-catalyzed metallocarbenoid cyclopropanation. In a study by Wenkert and co-workers, the desired cyclopropanation was complicated by the formation of products likely arising from polar stepwise mechanisms involving zwitterionic intermediates 14 and 15 (Fig. 12, Eq. 1) [52]. Although either intermediate could convert to the desired product 16, the formation of exomethylene 17 and enal 18 highlights the difficulty in controlling this highly electron-rich substrate. Further

+ O

EtO2C

N2

CHCO2Et

CO2Et

O CO2Et RhLn

Rh2(OAc)4

2%

34% 16

14

(1)

O

17

O O O

EtO2C

CO2Et

RhLn

18 10%/20% (E/Z)

15

Ph

CO2Me N2

20

H

1 mol % cat. (2)

MeO2C

O 19

O

Ph O

Ph

MeO2C

hexanes, rt

CO2Me CO2Me

H

22

21

catalyst Rh2(S-DOSP)4 Rh2(S-BTPCP)4 Rh2(S-PTTL)4 Rh2(S-TCPTTL)4

21/22 55:45 93:7 30:70 >99:1

%ee nd 56 48 91

%yield nd 84 nd 81

Cl

Ph O

C12H25 S O

O

Ph

N O

OH

N O

Cl O

Cl

O OH

O

CO2Me

OH t-Bu

O N

Cl O

OH t-Bu

Br S-DOSP

S-BTPCP

S-PTTL

Fig. 12 Catalytic cyclopropanation of simple furans with diazoacetate esters

S-TCPTTL

42

A. M. Hyde and E. R. Ashley

evidence in this vein is found in Lehner, Davies, and Reiser’s report on cyclopropanation of ester-substituted furan 19 with phenyldiazoester 20. In this case, it was demonstrated that certain dirhodium catalysts could divert the reaction pathway from dieneone 22 to desired cyclopropane 21 while achieving high ee (Fig. 12, Eq. 2) [53].

2.2

Cyclopropanation of Less Electron-Rich Heterocycles

Encouraged by the relative success of asymmetric cyclopropanation applied to the preparation of MK-1642, we devised an analogous route to the headpiece of MK-8666, wherein azaindene 28 would serve as the cyclopropanation substrate (Fig. 13) (this route to MK-8666 was led by Mark Huffman, Hongming Li, Feng Xu, and Paul Bulger). While the pyridine nitrogen and the replacement of the ring oxygen with a methylene were expected to lower the azaindene HOMO relative to that of benzofuran 8, it was hoped that the incorporation of the bis-(PMB)-amino group might provide sufficient electron density on the alkene to facilitate the desired reaction. To test this hypothesis and provide early deliveries of MK-8666, azaindene 28 was readily accessed from the commercially available aminopyridine 23. In the first step, bis-alkylation of the amino group proceeded smoothly to provide 24, which was iodinated para to the amine with N-iodosuccinimide to give 25 in excellent yield. A selective Suzuki–Miyaura vinylation of the aryl iodide followed by Pd-catalyzed allylation of aryl bromide 26 gave styrene 27, which was converted

H 2N

N

KOt-Bu, PMBCl

N Br

PMB

THF 86% yield

23

N PMB

NIS, DMF Br

N PMB

2-MeTHF/heptane 93% yield

24

BF3K Pd(PPh3)2Cl2 (3 mol %) KHCO3, DMF/IPA/H 2O 70 oC 73% assay yield

26

Zhan-1b (1.75 mol %) MTBE 93% yield

N PMB

25 Me Me O Me B O Me

N PMB

Br

Pd(PPh3)2Cl2 (2 mol %) KF, DMF 65 oC 83% yield

N

N (PMB)2N

(PMB)2N

N PMB

28

Fig. 13 Synthesis of the MK-8666 indene intermediate 28

29

N PMB

N PMB 27

I Br

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry N2 N

CO2Et

H

2–5 mol % catalyst DCM

(PMB)2N

catalyst yield (trans) trans/cis 3:1 31% Rh2(OAc)4 1:1 nd Rh2(esp)4 2.3:1 23% Cu(acac)2 2.5:1 23% [CuOTf]2•PhMe/L4 7:1 28% [CuOTf]2•PhMe/L4a 4.4:1 9% [RuCl2(cymene)]2/L5b c 2.6:1 7% [RuCl2(cymene)]2/L5

CO2Et

N H

(PMB)2N

28 entry 1 2 3 4 5 6 7

43

30 % ee 58 77 29 48

CN O

O N

Ph

O

L4

Ph

i-Pr

O

N N

HN

N L5

i-Pr

a

tert-butyl diazoacetate used solvent=toluene c solvent=THF b

Fig. 14 Catalytic cyclopropanation of indene 28 en route to MK-8666

to indene 28 by ring-closing metathesis. Careful optimization of this ring-closure was required to identify conditions under which the indene could be isolated without extensive isomerization to 29; both acids and transition metals were found to catalyze this. Most crucially, filtration of precursor 27 through Celite removed an oiling impurity, which allowed for direct crystallization of 28 and minimized compound handling. This chemistry was sufficiently robust to provide kilogram quantities of indene 28, which allowed the team to study the cyclopropanation reaction in depth (Fig. 14). The use of Rh2(OAc)4 in dichloromethane provided 30 in 31% yield and 3:1 d.r., favoring the trans product. Chiral Ru- and Cu-based catalysts provided the product in modest enantioselectivities but always with poor yields and diastereoselectivities. Further optimization proved difficult, with no improvements observed under varied conditions or with alternate ligand architectures. While the use of the Rh2(OAc)4 to prepare racemic 30 coupled with downstream chiral salt upgrade was sufficient to complete early deliveries, it soon became clear that alternative routes would be necessary to ensure long-term supply of the drug substance. As the lead compounds MK-1642 and MK-8666 progressed through clinical studies, the medicinal chemistry team became interested in designing backup compounds with increased polarity in the tricyclic headpiece. To facilitate the preparation of these compounds, the process chemistry group undertook the synthesis of oxaza headpieces 31 and 34 (Fig. 15), which hybridized the beneficial pyridine and furan substructures of MK-8666 and MK-1642. It was proposed, somewhat naively, that these compounds could be accessed by cyclopropanation of the corresponding furopyridines 32 and 35. We further planned to synthesize the furopyridine precursors by the route of Chartoire et al. [54], which had provided high yields of the parent furo[3,2-b]pyridine (i.e., des-chloro 31). We began our synthesis toward 31 from commercially available bromopyridine 33, which was first acetylated to provide acetate 37 (Fig. 16). A two-step, one-pot

44

A. M. Hyde and E. R. Ashley O

H

31

O

Cl

N O

Cl

H

O 34

OH 33

N

OR

N Cl

O 32

H

Br

N

Cl

H

O

Cl

N

OR

N

Cl

35

Br OH

36

Fig. 15 Proposed retrosynthesis of polar tricyclic FFAR1/FFAR4 agonist headpieces

N Cl

Br

AcCl

OH

Et3N

33

Cl

Br

TMS

(PPh3)2PdCl2, CuI N

OAc

TMSCCH, THF

37

89% yield

Cl

OAc 38

N

KF, MeOH 12% yield

N

O

Cl 32

Fig. 16 The initial route to synthesize furopyridine 32

conversion of 37 to furo[3,2-c]pyridine 32 was then attempted, involving Sonogashira coupling with trimethylsilylacetylene followed by treatment with potassium fluoride in methanol. Disappointingly, the furopyridine was formed in only 12% yield along with substantial amounts of black tar that could only be removed by chromatography. We found that performing the reaction with slow addition of the starting materials to a mixture of catalysts and triethylamine held at 30
C resulted in formation of the Sonogashira product 38 in 54%; the balance of the material was primarily a double Sonogashira by-product from reaction at both the bromide and chloride. With sufficient material in hand, we investigated the cyclization reaction independently (Table 1). Treatment of purified silylacetylene 38 with potassium fluoride in methanol (entry 1) cleanly provided phenol 39, but, surprisingly, none of the cyclized compound 32. Importantly, no tar was observed in this transformation, indicating that 39 was inherently stable. The conversion of 38 to 39 could also be mediated by other bases, as long as protic solvent was present (entries 2 and 3). With unprotected intermediate 39 thus available, we investigated the cyclization step in isolation. Cyclization of 39 to 32 was observed when the Sonogashira catalysts were introduced to the phenol in the presence of potassium fluoride (entry 4); however, the

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

45

Table 1 Deprotection and hydroxylalkyne cyclizations to form furopyridine 32 TMS Reagent, Solvent

N

Temperature Cl

OAc 38

Entry 1 2 3 4 5 6 7 8

Cl

N

Reagent, Solvent

N OH

Temperature

39

Starting material 38

39

38

Reagents KF K2CO3 LiOH KF, CuI, Pd (PPh3)2Cl2 CpRu(PPh3)2Cl K3PO4 K3PO4 K3PO4

O

Cl 32

Solvent MeOH MeOH THF/ water THF Pyridine DMF DMF/ water DMF/ water

Temp (
C) 23 23 23

Yield of 39 94% 93% 94%

Yield of 32 – – –

23

–

14%

115 115 115

– – –

30% 67% 89%

100

–

94%

yield was only 14% at full conversion, and substantial tar was again generated, indicating that metal catalysis was central to both the productive cyclization and the acetylene degradation observed in the original two-step one-pot process. Use of CpRu(PPh3)2Cl in pyridine at elevated temperature provided a slightly improved 30% yield (entry 5) but was once again accompanied by tars; this observation prompted us to evaluate transition metal-free cyclization. We were pleased to find that the use of K3PO4 in DMF at 115
C facilitated efficient cyclization of the phenol, giving a 67% yield (entry 6). Moreover, these conditions proved amenable to reaction with silylacetylene acetate 38, provided water was included in the solvent mixture (entry 7). Ultimately, an optimized 94% yield of the furopyridine 32 was realized at slightly lower temperature (entry 8), and the reaction was performed as expected upon scale-up. We next turned to the cyclopropanation of 32 with our goal being selective formation of trans-Et-31 (Table 2) (in addition to the authors, Yonggang Chen contributed substantially to this work). Surprisingly, this substrate proved fully inert to rhodium- and copper-catalyzed cyclopropanation with ethyl diazoacetate (entries 1 and 2), indicating that the chloropyridine ring was too electron-withdrawing to allow the desired interaction of the alkene with an electrophilic carbenoid species. We therefore turned to catalysis by odd-electron metal species in hopes of potentiating a non-concerted radical cyclopropanation mechanism. To our delight, a variety of penta-coordinate 17-electron cobalt complexes mediated the cyclopropanation reaction (entries 3–12), with N-methylimidazole-modified salcomine providing the best results with 60% conversion and 2.6:1 trans:cis selectivity (entry 8).

46

A. M. Hyde and E. R. Ashley

Table 2 Cyclopropanation reactions of furopyridine 32 O N2 N O

Cl

O

Entry 1 2 3 4 5 6 7 8 9 10 11 12

Catalyst Rh2(OAc)4 Cu(OTf)2/L4 Salcomine R,R-Co(II)salen Co(II)-TMP Co(II)-TPP Co(II)-OEP Salcomine R,R-Co(II)salen Co(II)-TMP Co(II)-TPP Co(II)-OEP

H OEt

N

catalyst (10 mol %) ligand, base

32

O

H OEt

O

Cl

cis-Et-31

Conversion (%) 0 0 46 24 31 26 32 60 32 29 27 39

CN O

N

O N

HN

O

Ph

O

Trans:cis d.r. – – 2.9:1 0.9:1 1.9:1 1.9:1 1.7:1 2.6:1 1.0:1 2.0:1 2.1:1 1.6:1

N

N CoII

H

O

Cl

trans-Et-31

Base – – DMAP DMAP DMAP DMAP DMAP N-methylimidazole N-methylimidazole N-methylimidazole N-methylimidazole N-methylimidazole

OEt

N

+ H

t-Bu

Ph

N CoII O O t-Bu

R,R-Co(II)salen

salcomine

L4

MeO

N N

Et

N

N Et

N

N

Et

CoII N

Et

OMe

Et

Et

Et

t-Bu

t-Bu

CoII

N

N

CoII N N

N

Et MeO

Co(II)OEP

Co(II)TPP

OMe Co(II)TMP

The relative success of the cobalt systems for cyclopropanation was expected based on the pioneering work of Katsuki and Zhang [55, 56]. Computational investigation supports a non-concerted, two-step single-electron pathway for alkene cyclopropanation via “carbene radical” species [57, 58]. In our system, interaction of salcomine with ethyl diazoacetate would proceed with loss of nitrogen to form the odd-electron species 40 (Fig. 17). The SOMO of this species is of appropriate energy to overlap with the HOMO of 32, leading to ether-stabilized radical 41. Radical rebound regenerates salcomine along with the bicyclic products cis/trans-Et-31.

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

N O O

N CoIII O

N

O OEt

O

Cl OEt

N2

47

32

40 N

N

N

O

CoII O

O

N CoIII O

O O

OEt O

H N

H

O

Cl

O

H

OEt

N O

Cl

trans-Et-31

N OEt

Cl

41

H

cis-Et-31

Fig. 17 Single-electron mechanism for Co-catalyzed furopyridine cyclopropanation O N

+

N2

O

Cl

H

salcomine (1 equiv) N-methylimidazole (1 equiv)

O Ot-Bu

dichlorobenzene 60 °C 54% yield

32

Ot-Bu

N H

O

Cl

trans-t-Bu-31

TMS N Cl

Br

AcCl

OH

97% yield

N Cl

Br

(PPh3)2PdCl2, CuI

OAc

TMSCCH Et3N, THF, 30 °C 92% yield

42

36

N Cl

OAc 43

O N

K3PO4 (aq) DMF 88% yield

+ O

Cl 35

N2

H

salcomine (1 equiv) N-methylimidazole (1 equiv)

O Ot-Bu

dichlorobenzene 60 °C 50% yield

Ot-Bu

N Cl

O

H

trans-t-Bu-34

Fig. 18 Synthesis of dihydro-1H-cyclopropa[4,5]furo[3,2-b/c]pyridine carboxylate isomers 31 (Eq. 1) and 34 (Eq. 2)

In practice, we modified this reaction slightly to utilize tert-butyl diazoacetate and stoichiometric salcomine, which allowed the isolation of trans-t-Bu-31 as a single diastereomer after chromatography (Fig. 18, Eq. 1). In a similar manner, pyridinol 36 could be advanced to furo[3,2-b]pyridine 35 (Fig. 18, Eq. 2). This compound was also amenable to cobalt-mediated cyclopropanation, providing compound

48

A. M. Hyde and E. R. Ashley

trans-t-Bu-34 in moderate yield. Further optimization to reduce cobalt loading and incorporate chiral ligands would be important for large-scale manufacturing, but this chemistry was valuable for the early exploration of this chemical space.

2.3

Simmons–Smith Cyclopropanations

Many bicyclo[3.1.0]hexane derivatives lack a pendant carbonyl, which contraindicates α-diazoacetates as starting materials. In these cases, Simmons–Smith methylenation provides a powerful alternative, particularly when resident stereocenters are available to direct the diastereoselectivity of the reaction. In a set of salient examples from process chemistry, substantial quantities of both cis and trans derivatives of 2-azabicyclo[3.1.0]hexane-3-carboxylic acid were needed for different programs at Bristol–Myers–Squibb. The trans isomer 46 was prepared in >100 g quantities to support the development of HCV clinical candidates. A Simmons– Smith reaction was performed on dihydropyrrolidine 44, having a bulky TBDPS silyl protecting group that served to shield one face, providing 45 in >25:1 d.r. (Fig. 19, Eq. 1) [59]. The silyl ether was subsequently deprotected and oxidized to carboxylic acid 46 for further elaboration. Conversely, ester 47, having the cyclopropane in a cis relationship, was needed for the synthesis of the commercial DPP-4 inhibitor saxagliptin. During preliminary studies, it was found that good yields and selectivities could be achieved for a directed Simmons–Smith reaction of 47, providing intermediate 48 in 84% yield and 11:1 d.r. (Fig. 19, Eq. 2). The process development route to saxagliptin made use of amide 49 instead, as it allowed for higher d.r. and enabled a more direct route to form the nitrile substituent (Fig. 19, Eq. 3) [60]. While conceptually similar to the preceding reaction, it was found to be significantly more complicated in its mechanism. Simply adding 1 equiv each of diiodomethane and diethylzinc to substrate 49 gave 50 in low yields (25:1 d.r.

ICH2Cl Et2Zn (2)

Boc N

Boc N

toluene, –23 °C

CO2Et

CO2Et 47

48 84% 11:1 d.r.

(3)

1. H2O (0.2 equiv) CH2I2 (2.1 equiv), –10 °C 2. Et2Zn (2.1 equiv), 0 °C 3. TFA (0.5 equiv), –10 to 16 °C

Boc N

saxagliptin

Boc N

EtOAc O

NH2

O

49

NH2

50

H H t-BuO

I Zn

I

95% AY 45:1 d.r. 70% isolated yield >99:1 d.r.

N O

O Zn NH O F3C

O TS-1

Fig. 19 Simmons–Smith cyclopropanations to form 2-azabicyclo[3.1.0]hexane-3-carboxylic acid derivatives

3 Michael-Initiated Ring Closure For instances when a target molecule contains at least two contiguous cyclopropane carbons with adjacent electron-withdrawing groups, Michael-initiated ring closure reactions are generally the favored option. In this approach, formation of an ylide or ylide equivalent in the presence of a Michael acceptor initiates a non-concerted bond forming cascade that delivers the cyclopropane product. While these reactions are not typically amenable to asymmetric catalysis, enantioenriched products can be accessed through the use of sulfur ylides that bear chiral substituents appended to the sulfur atom. Moreover, these reactions typically involve low-energy starting materials and intermediates, rendering them a potentially safer alternative to cyclopropanation with diazo compounds [62–64].

50

A. M. Hyde and E. R. Ashley

3.1

Reactions Between Sulfur Ylides and Enone Substrates

A large array of bicyclo[3.1.0]hexanes bearing carboxylic acid substitution appended to the cyclopropane ring have been evaluated as mGluR2/3 agonists for a variety of neuroscience discovery programs at Eli Lilly and Company. One of the early strategies to access this target class relied on cyclopropanation of α,β-unsaturated ketone 51 (Fig. 20, Eq. 1) [65] that was conveniently accessed in four steps from commercially available D-ribonolactone. In the key event, ethyl (dimethylsulfuranylidene)acetate (EDSA) (for the first examples of cyclopropanations using EDSA, see [66]), generated in situ from the sulfonium bromide salt 52 and DBU, was reacted with 51 to provide the desired exo isomer of 53 in 96% yield and >99:1 d.r. While the approach enabled a straightforward path to a single enantiomer Br Me

CO2Et S DBU Me 52 Me O O

(1)

S CO2Et Me EDSA

O

CHCl3

O

H2N CO2H H

H O CO2Et

O

51

CO2H

H

H LY354740

53 96% >99:1 d.r.

O

O H

sulfonium salt (2)

CO2Et

base H 54 Br Me

BF4 CO2Et

S Me

S O

+ S

CO2Et

O

55

52

CO2Et N2

56

(d) DBU, toluene, rt: 73% (a) 1.2 equiv DBU, toluene, rt: 78%, 97:3 d.r. 10:1 d.r., 14% ee (exo), 80% ee (endo)

(e) Cu(acac)2 (5 mol %), DCE, 60 °C: 74% 1:1 d.r., 81% ee (exo), 75% ee (endo)

(b) 1.2 equiv TMG, MeCN, rt: 89%, 99:1 d.r. (c) 0.2 equiv TMG, 2 equiv K2CO3 MeCN, rt: 89%, 99:1 d.r. O

CO2t-Bu

S

O H

58

(3) BocHN

BocHN CO2t-Bu 57

DCM/CF3CH2OH

t-BuO2C

CO2t-Bu H

59 64% 95:5 d.r. (exo/endo)

Fig. 20 Cyclopropanation of cyclopent-2-en-1-ones with sulfonium ylides to prepare mGluR2/3 agonists

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

51

of the API, this was overshadowed by a subsequent low-yielding double deoxygenation and olefin reduction to remove the glycol moiety. Alternatively, cyclopropanation of cyclopent-2-en-1-one using EDSA was carried out with high d.r. (97:3), providing racemic intermediate 54 in 78% yield (Fig. 20, Eq. 2a). The absolute stereochemistry was set in a later step through classical resolution of a hydantoin intermediate. A follow-up study demonstrated that improved yields were possible when the reaction was performed in acetonitrile with either 1.2 equiv of N,N, N0 ,N0 -tetramethylguanidine (TMG) or a combination of 0.2 equiv TMG and 2 equiv K2CO3 (Fig. 20, Eqs. 2b, c) [67]. Performing this reaction in asymmetric fashion has not yet proven generally feasible, although Aggarwal has demonstrated proof of concept using chiral sulfonium salt 55 that gave 4:1 d.r. and 38% ee (Fig. 20, Eq. 2d) [68]. Interestingly, the unwanted and minor endo product is generated in 84% ee. Also promising was a Cu-catalyzed reaction of ethyl diazoacetate using chiral sulfide 56, providing only a 1:1 d.r. but with good ee for both diastereomers (Fig. 20, Eq. 2e). For the preparation of analogues containing extra substitution at the 4-position, it was demonstrated that good diastereoselectivity (95:5) for 59 could be achieved by reacting sulfonium ylide 58 with ketone 57 (Fig. 20, Eq. 3) [69]. Intriguingly, the indicated exo-diastereomer was favored only if trifluoroethanol or an acid with a similar pKa was included; otherwise, the endo-diastereomer was produced. Regardless of the endo/exo ratio, cyclopropanation occurred with consistent facial selectivity on the enone, which is likely dictated by an attractive noncovalent interaction with the pendant carbamate group.

3.2

Reactions Between Sulfur Ylides and 1,4-Enedicarbonyl Substrates

In a case study demonstrating the virtues of flow chemistry, the process chemistry group at Boehringer Ingelheim developed a scalable synthesis of trans-(dioxo)azabicyclo-[3.1.0]-hexanecarboxylate (trans-60) (Fig. 21, Eq. 1). As a starting point, conditions were evaluated in which EDSA [70] was added in one portion to a solution of N-benzylmaleimide in toluene at reflux, which gave a 1:1 mixture of cis/trans-60 [71]. While modestly high yielding on gram scale (71%, entry 1), a lower yield was obtained upon scale-up to 38 g (58%, entry 2). Significantly, even lower yields were obtained if the reagents were mixed at room temperature followed by heating (33%, entry 3) or if EDSA was added slowly to a solution of Nbenzylmaleimide at 100
C (64%, entry 4). The mass balance for the low-yielding reactions was tracked to a variety of by-products and polymeric species resulting from further reaction of the zwitterionic intermediate 61 with EDSA (Fig. 21, Eq. 2). These experimental outcomes indicated that instantaneous addition and rapid mixing of the reagents at high temperature were necessary to achieve reproducibly high yields. As these constraints are not easily met in typical batch-mode reactors, a flow strategy was pursued. In screening experiments at 5 g scale using a Uniqsis system

52

A. M. Hyde and E. R. Ashley Me O

S CO2Et Me EDSA

Bn N

(1)

toluene

O

1 2 3 4 5 6 7 8

CO2Et H

O cis/trans-60 1:1 d.r.

mixing mode

scale (g)

fast addn. EDSA, batch 1.8 fast addn. EDSA, batch 36 fast addn. EDSA, batch 1.8 slow addn. EDSA (2 h), batch 1.8 microchip mixing, flow 5 5 microchip mixing, flow microchip mixing, flow 5 T + static mixers, flow 3300

O (2)

DBU

Bn N

O

entry

O

H

Bn N OEtO C 2

Me S Me

low temp poor mixing

temp (°C)

H

Bn N p-xylene 140 °C batch-mode

CO2Et H

O trans-60 96:4 crude d.r. 72% isolated yield >99:1 d.r. after crystallization

assay yield (%) 71 58 33 64 75 82 92 92

110 110 25 100 100 95 105 120 120

O

CO2Et

Bn N

O Bn N

CO2Et

O

61 O

O

CO2Et CO2Et

Bn N O

CO2Et CO2Et

+ polymers

CO2Et O

CO2Et O

Bn N

CO2Et CO2Et

N

O

Bn

O

Fig. 21 Cyclopropanation of N-benzylmaleimide with EDSA in batch vs. flow

with microchip mixer and Hastelloy reactor tube, it was demonstrated that higher reaction temperatures were critical for success. When holding the residence time at 2 min, the yield increased from 75% at 95
C to 92% at 120
C (entries 5–7). For pilot scale, a setup was used in which the two reactor streams were combined in a jacketed T-mixer and then flowed through a static mixer, followed by a tube-in-tube reactor at 120
C. Once optimized, this apparatus was used for a demonstration run to make 3.3 kg of cis/trans-60 in 92% yield (entry 8). With the crude cis/trans-60 mixture in hand, it was found that efficient epimerization could be accomplished by switching the solvent from toluene to p-xylene and treating the mixture with 0.25 equiv DBU at 140
C in batch mode to provide a 96:4 d.r. favoring the desired trans isomer. Following workup and crystallization from ethanol, trans-60 was isolated in 72% yield and >99:1 d.r.

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

3.3

53

Reactions Between α-Halo Enolates and 1,4-Enedicarbonyl Substrates

While targeting fluoroquinolone antibiotics that would eventually lead to the discovery of trovafloxacin, chemists at Pfizer evaluated alternative methods to prepare the same versatile building block trans-60. Its preparation was first reported by Brighty and Castaldi (Fig. 21, Eq. 1) [72]. Their route began with a [3 + 2] cycloaddition between N-benzyl maleimide and ethyl diazoacetate to provide dihydropyrazole 62 in 94% yield [73]. Subsequent pyrolysis/ring contraction was carried out neatly at 180
C, and after slurrying the product mixture in Et2O, trans-60 was isolated in 25–35% yield. Trans-60 was then exhaustively reduced with excess LiAlH4 to give aminoalcohol 63 in 88% yield. Another five steps then provided diamine 64 (an analog of diamine 64 has been produced by an aza-Kulinkovichde Meijere cyclopropanation; see [74]). The yields shown here correspond to scale-up experiments that were carried out to provide the first clinical batch of a GlyT1 inhibitor [75]. The process chemistry group quickly determined that this route was unsuitable for further deliveries. A second-generation synthesis was developed based on a route disclosed in a patent from the Chisso Corporation (Fig. 21, Eq. 2) [76]. A Michael-initiated ring closure between diethyl fumarate and ethyl chloroacetate at 40
C, promoted by K2CO3 in the presence of a phase transfer catalyst, provided triester 65 in 80% yield. Saponification with NaOH, followed by dehydration with Ac2O, provided anhydride 66 in 79% yield (two steps). Conversion to the benzyl imide and reesterification gave trans-60 in 70% yield (three steps). Six equivalents of Red-Al were then used to fully reduce all three carbonyls and provide aminoalcohol 63 in 90% yield. Despite the increased step count compared to Eq. (1), this sequence used very inexpensive starting materials and was simple to carry out, allowing it to be run on large scales without problems (Fig. 22). Continued process development resulted in a more direct route to the diamine fragment of trovafloxacin. A Michael-initiated cyclopropanation between N-benzyl maleimide and bromonitromethane allowed for the generation of intermediate 67 in >99:1 d.r. (Fig. 23) [77]. Use of a sulfur ylide was deemed unviable because the sulfonium salt of nitromethane is unstable, decomposing to the sulfide and methyl bromide. Because of this instability, the use of bromonitromethane in conjunction with a base was explored. Most bases tested in this reaction gave no product, while amidines such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,2-dimethyl1,4,5,6-tetrahydropyrimidine (DMTHP) provided low product yields between 15 and 36%. More extensive base screening revealed that the tetrabutylammonium salt of hindered phenoxide 68 [78], as well as TBAF, gave acceptable yields of 42–49%. In all cases, the product was obtained as a single diastereomer. Subsequent work by Ballini and co-workers showed that a 70% yield could be obtained using K2CO3 in MeCN with multiple dosing of the maleimide starting material, although this was only demonstrated on milligram scale [79]. It was proposed that the exceptionally high diastereoselectivity of this cyclopropanation arose from a combination of base-promoted epimerization and

54

A. M. Hyde and E. R. Ashley CO2Et HN N Bn

CO2Et

O

25 °C 94%

O

N Bn

O

HO

CO2Et

180 °C open vessel

N2

(1) O

N

H

25–35%

H

O

O

N Bn

LiAlH 4

H

THF 88%

N Bn

trans-60

62

H

63

O Boc

NH

H

F

HO2C N

H

N F

N H

H F

64

(2)

CO2Et +

NH2

trovafloxacin

K2CO3 BnEt 3NCl

CO2Et Cl

EtO2C

H

N

1. NaOH, toluene 2. Ac2O, AcOH

CO2Et

40 °C, DMF 80%

79%

CO2Et

EtO2C 65

1. BnNH 2, Et3N 2. HCl 3. TsOH, EtOH

O

70%

Red-Al (6 equiv)

H O

N Bn

O

H O

O

66

HO

CO2Et H

CO2H H

H

THF 90 %

H

trovafloxacin

N Bn

trans-60

63

Fig. 22 Synthetic routes developed by Pfizer for the construction of diamine 64 and aminoalcohol 63 for the synthesis of trovafloxacin

O

Br

NO2

O

base Bn N

H

Bn N toluene

O

O

NO2 H

67 > 99:1 d.r.

Me

Bases: DBU or tetramethylguanidine

N

O

N

Me

DMTHP 15–22% yield

36% yield

t-Bu

Bu4N t-Bu

Bu4NF

68 42–49% yield

45% yield

Fig. 23 Cyclopropanation of N-benzylmaleimide with bromonitromethane

decomposition of the minor diastereomer. Indeed, resubjecting the nitrocyclopropane product 67 to DMTHP revealed that it was unstable to the reaction conditions, first generating nitroenolate 69, which subsequently decomposed (Fig. 24). Unfortunately, a mechanistic rationale for the variation in effectiveness

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry O

H

Bn N O

55

O

spontaneous NH2

NH2

Bn N

H 70

O 71

nitro reduction O

O

H

Bn N

DMTHP

NO2

O

O N

Bn N

H

O

67

degradation O

69

BH3•THF 85% Raney Ni hydrazine

H Bn N

NO2 H

H Bn N

75%

NH2 H

72

73

Fig. 24 Decomposition pathways via fragmentation and successful formation of diamine 73

O Boc N 74

+

Bn

H

N Bn 75

Ti(Oi-Pr) 4 MeMgBr, CyMgBr THF

H Boc N

H NBn 2

H 76 35% yield

Pd(OH) 2/C, H2

Boc N

NH2 H

MeOH 77

90% yield

Fig. 25 The application of a Kulinkovich–de Meijere reaction for the preparation of diamine 76 and subsequent debenzylation

with varied bases was not established. All attempts to reduce the nitro functionality of 67 led to ring-opening products, likely owing to the facile formation of zwitterionic intermediate 71 from aminocyclopropane 70. This problem was circumvented by first reducing the carbonyls with borane to obtain intermediate 72 followed by nitro reduction using Raney Ni and hydrazine to reach the target diamine 73. Another route to the 3-azabicyclo[3.1.0]hexane-6-amine core using the Kulinkovich–de Meijere reaction was demonstrated by chemists at Genentech (Fig. 25) [74]. The alternatives discussed above were disfavored either due to safety concerns or inadequate stereoselectivity. When carrying out this reaction, titanium isopropoxide was first reduced with methylmagnesium bromide followed by treatment with cyclohexylmagnesium bromide to generate a titanacyclopropane complex of cyclohexene that readily exchanged with 2,5-dihydropyrrole 74. The new titanacyclopropane complex was reacted with N,N-dibenzylformamide (75) to provide diamine 76 in 35% isolated yield at 100 kg scale. The yield was lower than on small scale, which the authors attributed to physical losses during the filtration, workup, and crystallization steps. A stereoselectivity was not reported although they cite a report by others who obtained 98:2 d.r. on a similar substrate.

56

A. M. Hyde and E. R. Ashley

4 Intramolecular Metallocarbenoid Cyclopropanation While the direct intermolecular cyclopropanation of cyclopentene analogues with metallocarbenoids, ylides, or active halomethylenes may comprise the most direct approach to bicyclo[3.1.0]hexane derivatives, the experiences discussed in Sects. 2 and 3 illustrate that these reactions can be difficult to control and optimize. Intramolecular cyclopropanations offer potential advantages for reactivity and selectivity by constraining an alkene donor and carbenoid or ylide acceptor within a single molecule [80]. These approaches typically require somewhat more complex substrate synthesis, but this cost may be outweighed by gains in reactivity and selectivity.

4.1

α-Diazocarbonyl Substrates

The challenge of preparing the MK-8666 headpiece was clearly not solved through intermolecular cyclopropanation of the indene intermediate with ethyl diazoacetate, wherein low reactivity, modest enantioselectivity, and the isomerization of the starting material combined to limit development potential (Sect. 2.1). Under immense time pressure to support the drug substance demands of the clinical program, the process chemistry team investigated a wide range of alternative approaches. For one of these routes, it was proposed that the conversion of α-diazoketone 80 to cyclopropyl ketone 79 might be optimized to high yield and enantioselectivity due to the constrained geometries of the intramolecular system (Fig. 26). The potential value of this transformation further convinced the team to investigate both an efficient synthesis of substrate 80 and the deoxygenation of ketone 79 in order to reach key intermediate 78. The synthesis of 80 began with commercially available 5-bromo-2-chloroisonicotinic acid (81, Fig. 27). After substantial optimization, it was found that a Heck reaction of this free acid with tert-butyl acrylate could be catalyzed by palladium acetate in toluene at elevated temperature, providing efficient access to cinnamate ester 82. Following the precedent of Bio and co-workers [81] (the efforts toward the synthesis and cylopropanation of diazoketone 76 were led by Purakattle Biju, Artis Klapars, and Amude Kassim, in addition to this chapter’s authors), the free acid was converted to α-diazoketone 80 through the intermediacy of hydrazonoyl chloride 83. The desired α-diazoketone could be isolated as a crystalline solid, and analysis of its thermal properties (exotherm of 120.1 cal/g, onset temp of 124
C) indicated the possibility of safe handling with standard precautions. Diazoketone 80 proved amenable to cyclopropanation with Rh2(OAc)4 to provide racemic 79 in 70% yield. Full conversion was achieved with a variety of chiral rhodium dimer complexes under screening conditions, but the highest enantioselectivity observed was only 16% ee with Rh2(S-MPPIM)4 (Fig. 28). Ruthenium complexes of diphenylpybox gave slightly improved results, but copper

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry O O S

H Me

O

Me

CO2H

H

N

H

Cl

Me

78

MK-8666

H

CO2t-Bu

CO2t-Bu

N

N H

Cl

CO2t-Bu

N

H

O

57

Cl

N2

O

O

79

80

Fig. 26 Retrosynthesis of MK-8666 based on intramolecular cyclopropanation as the key step CO2t-Bu Br

N

OH

Cl

o

81

82

Cl O

N NH2

85% yield

83

CO2t-Bu

N

ZnBr2, i-Pr2NH

Cl

CN-N=PPh 3, H2O 80% yield

O

CO2t-Bu N

oxalyl chloride

OH

Cl

Cy2NMe, PhMe, 100 C 69% yield

O

CO2t-Bu

N

Pd(OAc) 2 (10 mol %)

Cl

N2 O 80

Fig. 27 Synthesis of α-diazoketone 80

catalysts proved substantially more selective. The catalyst derived from a diphenylsemicorin ligand (L4) and [CuOTf]2•toluene yielded the product in 72% ee, while the analogous BOX ligand with an isopropylidene backbone (L2) gave the product in a slightly higher 77% ee. Interestingly, a higher coordination number around copper, provided by PyBOX or salen ligands, greatly diminished both reactivity and selectivity. Moreover, the phenyl substituent on the oxazoline was optimal; both the 4-tert-butylphenyl substituted semicorin-derived catalyst and the tert-butyl BOX-derived catalyst were much less selective (47% and 42% ee, respectively). After optimization of conditions, it was found that the diphenyl-BOX catalyst could give as high as 87% ee under cryogenic conditions while maintaining moderate yield. Additionally, racemic 79 was much less soluble than the enantiopure compound, such that crystallization of the racemate provided mother liquors of 95% ee with high recovery of the desired compound. Deoxygenation of ketone 79 proved quite challenging, as expected, with many reaction conditions leading to a variety of ring fragmentation and dechlorination products (Fig. 29). For example, treating benzylic bromide analogue 85 with sodium dithionite in DMF/water quantitatively produced ring-opened olefin 86 from

58

A. M. Hyde and E. R. Ashley H

CO2t-Bu

N Cl

metal catalyst

N2

toluene, 20 oC

O

H

Cl O

80

79

CN

O

Ph

CO2t-Bu

N

Rh

O

O

N Rh

N

N Ph

O

MeO

N N Ru ClCl

O

O

O N

Ph

Ph

HN Ph

L4

Me

N

N

O

L2 Ph Ph [CuOTf]2•PhMe

[CuOTf]2•PhMe

4

Me O

Rh2(S-MPPIM)4 72 % ee

22 % ee

16 % ee

77 % ee 87% ee, 50% yield at –20 °C

CN O

O N

HN

O N

t-Bu

N

Ph t-Bu

N

O

N

N

OH HO

Ph

t-Bu

t-Bu

Me

Me

N

N

O t-Bu

O

t-Bu

t-Bu

t-Bu

L1

[CuOTf]2•PhMe

[CuOTf]2•PhMe

[CuOTf]2•PhMe

[CuOTf]2•PhMe

47 % ee

1 % ee

4 % ee

42 % ee

Fig. 28 Asymmetric catalytic intramolecular cyclopropanation of 80

H

CO2t-Bu

N H

Cl

Na2S2O4 DMF/H2O quantitative

Br

CO2t-Bu

N Cl

85

86

Bu4NBr H

H

CO2t-Bu 1. NaBH 4

N H

Cl

2. MsCl, Et3N 85% yield

O

CO2t-Bu

N H

Cl

AcOH 80% yield

OMs

79

84

O Me

Me

O

CO2t-Bu

N H

Cl 78

H

O S

H Zn dust

CO2H

N O

H

Me MK-8666

Fig. 29 Three-step deoxygenation of MK-8666 precursor 79 to form the headpiece fragment 78

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

59

fragmentation of the transient cyclopropylcarbinyl anion. However, it was subsequently found that benzylic mesylate 84 could be reduced to the desired product with zinc dust in glacial acetic acid. It is hypothesized that the success of these conditions is a result of rapid quenching and protonation of the reactive benzylic radical or anionic species. Intramolecular metallocarbenoid cyclopropanation has also proven valuable for the formation of a variety of related ring systems, notably in studies toward the stereochemically complex mGluR2/3 agonist MGS0028. Fluorobicycloketone 88 was prepared from diazoketone 87 using a copper-box catalyst in up to 65% ee (Fig. 30, Eq. 1) [82]. In a related diazoketone bearing a tetrasubstituted center at the β-position (89), substrate control was relied upon to selectively prepare stereoisomer 90. The tetrachlorophthaloyl protecting group was used for the amide because it was easy to remove and gave crystalline intermediates. With a Cu(TBS)2 catalyst, only 3:2 d.r. was realized, while Rh2(OAc)4 provided a respectable 9:1 d.r., albeit in a Me

Me

N

N

O

Ph

O N2

O L2

4 mol % Ph

O H F

2 mol % CuCl, AgOTf

(1) DCE, reflux 79% 65% ee

F 87

EtO2C

H 88

O

H

catalyst

NTCP

H F

F H 2N

TCPN

CO2Et

EtO2C

F 89

EtO2C

O

O

N2 (2)

CO2Et

H

CO2Et

HO2C

90

TCP = tetrachlorophthaloyl t-Bu O

O

t-Bu

Cu(TBS) 2

Rh2(OAc)4

DCE, 82 °C 3:2 d.r., 90% yield

CF3Ph, 100 °C 9:1 d.r., 50–55% yield

O

Cl 2

O

CO2Et F 91

O

O

Cl

Cl Cl

NTCP EtO2C

CO2H

N

Cu N

H

MGS0028 mGluR2/3 agonist

N Cl Cl

CO2Et F

O N

Cl

O CO2Et 92

Fig. 30 Intramolecular cyclopropanations for the preparation of MGS0028

O EtO2C

Cl 93

CO2Et F

60

A. M. Hyde and E. R. Ashley

modest 50–55% yield (Fig. 30, Eq. 2) (unpublished results). Other commercially available rhodium catalysts gave lower yields due to competitive dimerization to generate 91 or formation of epoxide 93 presumably arising from ylide 92. Performing this chemistry with alternative protecting groups such as phthaloyl, tetrabromophthaloyl, and N-benzyl-N-TFA gave similar outcomes. Although bicyclo[3.1.0]hexane derivatives are typically synthesized as the final active pharmaceutical agent, there are also cases where structures of this type are synthesized as versatile synthetic intermediates [83]. In one such example, kilogram quantities of bicyclic ketoester 97 were needed as a key building block in the anti-HIV drug candidate 100 (Fig. 31) [84, 85]. The absolute stereochemistry of diazoalkane 96 was set by a Mo(CO)6/L5-catalyzed allylic alkylation of carbonate 94 with sodium dimethylmalonate. A catalytic intramolecular cyclopropanation of 96 was then carried out to furnish ketoester 97 as a mixture with endo isomer 98. The reaction was highly efficient with dirhodium carboxylate salts, occurring at room temperature but with minimal diastereoselectivity in the product. Copper salts were less reactive, requiring heating to 75
C, but moderate d.r. was achieved for the desired exo isomer. The use of chiral ligands was not advantageous, inhibiting the rhodium catalysts and making the copper catalysts less selective. Ultimately, 3 mol% [(MeCN)4Cu]PF6 was utilized for a 1.32 kg scale-up, providing the product in 98% yield and 83:17 d.r. The mixture of 97 and 98 could be directly advanced by treatment with sodium acetate in acetic acid followed by sodium hydroxide. The cyclopropane ring of 97 O

O MeO

ONa

MeO

O

O

OMe

MeO

O

F

O

6 steps

OMe F

N2

10 mol % Mo(CO) 6 15 mol % 95

94 O N

F

96

O NH HN

O

MeO

84–91% yield 96–97% ee 19:1 branched:linear

N L5

O O catalyst

MeO

O O + F

96 97

catalyst Rh2(OAc) 4 Rh2(5R-MEPY) 4 CuCl Cu(OTf) 2 CuCl/AgOTf [(MeCN) 4Cu]PF 6

% conv. 100 90 99 100 100 100

NaOAc, AcOH F 98

d.r. 43:57 52:48 50:50 77:23 85:15 83:17

O

MeO

F 100 oC then NaOH 86–94% yield from 96

HO 99

Me

isolated yield N N

Et

Me

N 98% yield 100

Fig. 31 Synthesis of chiral bicyclic keto esters 97/98 and subsequent ring opening

N

Me CO2H F

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

61

was readily opened under these conditions and afforded cyclopentanone 99 after in situ saponification and decarboxylation. Comparatively, the endo cyclopropane of 98 did not ring open under these conditions, allowing for easy separation of the undesired material.

4.2

Lithium Carbenoids

Even the simplest bicyclo[3.1.0]hexane systems can provide significant and unforeseen synthetic challenges. Bicyclo[3.1.0]hexane-2-one 101 has been utilized as an intermediate in the context of many synthetic efforts, yet the reported syntheses of this compound itself were either lengthy or racemic (Fig. 32). A very simple approach is cyclopropanation of cylopenten-2-one 102 with trimethylsulfoxonium ylide. Although this provides the racemic ketone in 70% yield [86], no asymmetric version has been developed. Simmons–Smith cyclopropanation of chiral allylic alcohol 101 followed by oxidation was also untenable because there was not an efficient route to the chiral starting material. Similarly, a Simmons–Smith reaction with the tartrate-derived acetal 104 was deemed unsuitable because of long reaction times or low yields in the acetalization and cyclopropanation steps [87]. The intramolecular cyclopropanation of diazoalkane 105 was proven viable with dirhodium C-metallated aryl phosphines providing high yield with a moderate 70% ee and a Cu-semicorin system that gave the product in 75% ee [88, 89]. The rhodium-based method was deemed too costly, and the copper-based method was not efficient enough. In order to supply kilogram quantities of cyclopentanone 101, a much more efficient, highly asymmetric synthesis was called for [90]. Based on previous work by Hodgson et al., it was known that bis-homoallylic epoxide 106 could be selectively lithiated in a trans relationship to the aliphatic BnOH 2C

CH2OBn

O O

102

1. CH2I2, Zn(Cu) 2. hydrolysis

H2C S(O)(CH 3)2

no asymmetric variant

1. CH2I2, Zn(Cu) 2. oxidation

O H

H

O

104

long reaction times, modest yields

chiral Rh or Cu cat.

101 O

OH no good route to sm 103

N2

high cost or poorly selective 105

Fig. 32 Initial routes considered for the preparation of cyclopentanone 101

62

A. M. Hyde and E. R. Ashley

O

0.5 equiv TMP-H 1.1 equiv n-BuLi added over 4 h

OH O

H

Li

o

1 M in MTBE, 0 C H

95% yield 106

TS-2

107

TEMPO, NaOCl K2HPO4, KBr MTBE/water 95% yield

O H

H 101

Fig. 33 Cyclization of epoxide 106 by generation of a lithium carbenoid followed by oxidation of alcohol 107

chain using LiTMP. Spontaneous cyclization provided alcohol 107 with high diastereoselectivity and no loss of optical activity (Fig. 33) [91, 92]. This elegant cascade reaction provided the basis of all further development and was proposed to proceed via TS-2, although a non-concerted two-step mechanism is also possible. Though encouraging, the parent conditions were suboptimal for a multi-kilogram scale process since 2 equiv of LiTMP were required and high dilution (0.2 M) was necessary due to the low solubility of LiTMP in MTBE. The volume inefficiency was addressed by reversing the addition mode and adding n-BuLi to a solution of 106 and TMP. It was also found that, when the n-BuLi was added slowly, it could be reduced from 2 to 1.1 equiv and TMP could be decreased from 2 to 0.5 equiv while achieving a 95% assay yield. Quenching the reaction carefully with 1 equiv HCl proved critical, as 107 is sensitive to strongly acidic conditions, opening to a cyclohexene by-product. The synthesis could then be completed by oxidation of the secondary alcohol to the ketone; utilization of TEMPO/NaOCl with catalytic KBr in a biphasic MTBE/phosphate buffer (pH controlled at 8.5–10.5) allowed for clean conversion and 95% yield. This optimized procedure was successfully demonstrated at 7.5 kg scale and provided 101 as a solution in MTBE with >99.5% ee.

5 Nucleophilic Displacement Approaches An alternative approach to bicyclo[3.1.0]hexanes relies on an intramolecular SN2 reaction between an exocyclic cyclopentane enolate and a nucleofuge positioned at the γ position. While less convergent than intermolecular strategies, it can be more reliable in terms of stereospecificity and employment of well-established reactions to set the stereochemistry for earlier alcohol intermediates. If the cyclopentane contains a heteroatom, another disconnection becomes available in which an intermolecular double SN2 event to form the cyclopropane ring precedes cyclization to form the cyclopentane ring. While this strategy benefits from the commercial availability of enantioenriched epichlorohydrin, pathways are available for side reactions that must be managed.

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

5.1

63

Cyclization of Enolates

A nucleophilic displacement approach was demonstrated at MRL in efforts to prepare mGluR2/3 receptor agonists bearing α-fluorocarboxylic acid-substituted cyclopropanes [93]. To establish proof of concept, model ester 108 was prepared and treated with LDA (Fig. 34, Eq. 1) [9]. The generated enolate smoothly displaced the pendant tosylate to produce cyclopropane 109. With this precedent in place, amides 111a and 111b containing a cyclic sulfite were accessed by elaborating commercially available lactone 108 (Fig. 34, Eq. 2). Upon treating 111a with LiHMDS, cyclization was achieved to provide cyclopropane 112a in 38% yield. When applying this reaction to the fluorinated analogue 111b, no cyclized product was obtained under any conditions investigated. A quenching experiment with d4-AcOH indicated deprotonation did not occur, which suggests that the favored conformer of the starting material has the hydrogen in an unreactive position. Attempts to prepare the corresponding ester were unsuccessful due to recyclization to lactone 110. Therefore, an alternative route was developed from commercially available alcohol 113 that allowed access to epoxy-ester 114 (Fig. 34, Eq. 3). BnO

BnO OTs (1)

H

LDA

CO2Et BnO

BnO

F

108

H

F CO2Et

109 only product O O S O

H

HO

H

X

base O

(2) H O

N

TBSO

X X = H 111a X = F 111b

110

H

AcO (3)

CO2t-Bu BnO

112a : LHMDS, 38% yield 112b : no product with any base tested

HO

LDA Et2AlCl

O H

HO

57%

BnO

F

114

113

H

H O

TBSO

N

O

H

H

F CO2t-Bu

115

O

LHMDS Et3Al

H

HO

H

O

H

F

F

(4) HO 116

CO2Me

TBSO 117

CO2Me

96% TBSO

H

CO2Me

118

Fig. 34 Intramolecular SN2 displacement reactions of α-fluoroenolates

H2N HO2C

H

F CO2H

MGS0028

64

A. M. Hyde and E. R. Ashley

Treating this compound with LDA did generate the enolate, but no cyclization occurred. However, with inclusion of Et2AlCl, the desired product 115 was obtained in 57% yield. While this method could be used to access the final API, the high cost of the starting material, in combination with poor selectivity for the epoxidation step, precluded this from being a scalable option. A more efficient sequence was found by first converting hydroxyester 116 to epoxy ester 117 (Fig. 34, Eq. 4) [94]. Although inconsequential for the cyclization step, the fluorine was introduced stereoselectively, aiding isolation and characterization of the intermediate. In the key step, a 96% yield was obtained from reacting a combination of LiHMDS and Et3Al with 117 to provide cyclopropyl alcohol 116. This intermediate was taken on to the API MGS0028 through seven additional steps. As discussed in Sects. 2.1 and 4.1, a scalable route to MK-8666 was not achieved via catalytic cyclopropanation of α-diazoesters. As such, an intramolecular displacement strategy was evaluated, first using methoxypyridine alcohol 119. Unfortunately, treatment of hydroxyester 119 with base and activating agents produced only lactone 122 (Fig. 35) [81]. It was hypothesized that this undesired reaction likely occurs through ionization of 119 to first form the extended oxonium ion 121 which is intercepted by the pendent ester with concomitant loss of the t-Bu. Therefore, while reactions with 119 did not provide a path forward, the results prompted us to test a more electron-poor ring system that might provide superior performance. It was anticipated that chloropyridine 123 would be better-behaved in the reaction due to electronic deactivation provided by the chloride relative to the methoxy substituent in 119 (Fig. 36). Testing a series of activating reagent/base combinations revealed that 123 was a viable substrate for ring closure, provided that a relatively weak leaving group was used [95]. Phosphate esters were chosen (entries 4–7), with conditions employing diethyl phosphoryl chloride and LiHMDS in MTBE being optimal (entry 7) to provide the desired product 78 in 94% yield with only the exo-product formed. It was determined through modelling the displacement transition states that the endo-diastereomer was kinetically disfavored by >5 kcal/mol. Having demonstrated a high yielding and highly stereoselective cyclopropaneforming step, a complete synthesis was established incorporating this key transformation as outlined in Fig. 37. Commercially available 2-chloro-5-bromopyridine MsCl, SOCl2, or ClP(O)(OEt)2 Base

CO2t-Bu

MeO

MeO

N

H

Desired product Not formed

N OH

H

119

CO2t-Bu

120

MeO CO2t-Bu

MeO X

Main product along with degradation

N

N

O 121

O

122

Fig. 35 Unsuccessful attempts at nucleophilic displacement of 119 en route to MK-8666

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry CO2t-Bu

Cl

Cl

activator, base

H N

N solvent –10 °C, 16–24 h

OH 123 entry

65

CO2t-Bu

H 78

activating group

base

solvent

% yield

1 2 3

MsCl TsCl TsCl

Et3N Et3N LiHMDS

THF THF THF

0 0 5

4 5 6 7

(Me2N)2POCl (PhO)2POCl (EtO)2POCl (EtO)2POCl

LiHMDS LiHMDS LiHMDS LiHMDS

THF THF THF MTBE

30 60 70 94

Fig. 36 Optimization of nucleophilic displacement reactions en route to MK-8666

CO2t-Bu HO LDA, THF, –78 °C; DMF;

Br Cl

NaBH 4, EtOH 89%

N 124

Br

EtOAc 99%

125

CO2Me Br

Cl

n-BuLi

NaOMe DMA 90%

N

t-BuO2C

2 wt % KRED-264 NADP pH 9 phosphate buffer

LiCl, AcOH O

NMP, –90 °C 93%

CO2Me MeO2C 127

126

CO2t-Bu

MeO2C

CO2Me

Br

SOCl2

N

Cl

CO2t-Bu

Cl

Cl

N

Cl

N 128

O

NMP, 80 °C 87%

Cl

i-PrOH, 50 °C nitrogen sweep 93% 98:2 d.r., >99% ee

N 130

129

Me OH CO2t-Bu

H

CO2t-Bu H

O

N 133

Me

CO2t-Bu

S

O

Me

O O

132 H

LiHMDS MTBE, –10 °C 90%

N 131

Ar

O P Cl

EtO

OH Cl

EtO

H

Cl

2 mol % Pd(OAc) 2 2 mol % BrettPhos Cs2CO3, PhMe, 80 °C 92 %

N 78

1. aq NaOH THF, MeOH 2. tris base i-PrOH, MeOH 88%

Me O Me O

S

O

Me

H

O

OH OH

H MK-8666 Tris salt

Fig. 37 Final synthetic route to MK-8666

H 3N

N CO2

OH

66

A. M. Hyde and E. R. Ashley

124 was lithiated and trapped with DMF at the 4-position. Subsequent aldehyde reduction gave alcohol 125, and chlorination yielded benzylic chloride 126. Alkylation using commercially available malonate 127 provided triester 128. Bromine– lithium exchange using n-BuLi generated diester 129 in high yield, provided the temperature was kept very low (90
C). Krapcho decarboxylation using buffered LiCl then generated β-ketoester 130. To set the stereochemistry in 131, a dynamic kinetic reduction was developed using the evolved KRED-264 enzyme. Notably, four different enzymes were identified that could provide each of the four possible diastereomers; the first example of this feat is reported in the literature. The key cyclization was then carried out using diethylchlorophosphate and LiHMDS to provide headpiece 78. A C–O coupling was performed using a Pd(OAc)2/BrettPhos catalyst system to generate penultimate 133. Finally, ester cleavage followed by salt formation with tris base provided the MK-8666 tris salt.

5.2

Intermolecular Enolate Double Addition to Epichlorohydrin

When a heteroatom is present in the cyclopentane ring, as is the case for azabicyclo [3.1.0]hexanes, additional disconnections become available. In the first discovery route to synthesize 1-aryl-3-aza[3.1.0]bicycles, a Michael-initiated ring closure between a bromoenolate of 134 and an unsaturated ester 135 was used to construct the cyclopropane (Fig. 38, Eq. 1) [96]. Following this event, the esters were hydrolyzed, and a resolving base was then used to obtain a single enantiomer of

Ar +

RO2C (1)

1. NaH 2. KOH 3. resolution

135

R2 R3 R2

O

Ar

Rh2(OAc)4

R1

Ar O

R3

O

CO2H

O

136

R1

N2

Ar

urea

Ar HO2C

Br 134

(2)

CO2R

139

CN 142

N H 138 R2 R3

Cl

O

epichlorohydrin 98% ee

NaHMDS

N H 141 1. BH3•Me2S 2. SOCl2 3. NaOH

THF –15 °C to rt

Cl

OH

NC 139

95% assay yield 85:15 d.r. 96% ee

Fig. 38 Methods to prepare 1-aryl-3-azabicyclo[3.1.0]bicycles

R1

Ar

140

+

Ar

O

4. MeNHNH2 5. LiAlH4

O

Cl

Cl

N H 137

1. potassium phthalimide 2. (COCl)2, DMF 3. MeONHMe, Et3N

Cl (3)

Red-Al

Cl H Cl N H amitifadine

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

67

diacid 136. The diacid was converted to the succinimide 135 using urea and finally reduced to obtain the pyrrolidine products 138. Another discovery route was subsequently developed allowing for more varied substitution on the cyclopropane (Fig. 38, Eq. 2) [97]. The key step involved intramolecular cyclopropanation of diazoester 139 with catalytic Rh2(OAc)4. The drawbacks to this method are that it generates racemic material and the conversion of lactone 140 to aza[3.1.0]bicycle 141 required five additional steps. A more scalable process was developed that relied on the reaction between aryl acetonitrile 142 and enantiopure epichlorohydrin (Fig. 38, Eq. 3) [98]. Proper reaction conditions were found to be critical in ensuring high-fidelity chirality transfer when preparing cyclopropane 143. In the event, NaHMDS was added to a solution of epichlorohydrin (98% ee) and 142 at 20
C, providing the desired product 143 in 95% assay yield, 85:15 d.r. and 96% ee. Changing the counterion to potassium gave a similar result, but the product distribution was shifted to favor cyclobutanol 147 in the case of magnesium and a mixture of 147 and 149 for lithium (Fig. 39). The outcome was rationalized as follows: for sodium and potassium alkoxides of 146, the oxygen is sufficiently nucleophilic to displace the neighboring chloride, generating a mixture of cis/trans isomers 150a/b. In contrast, the lithium and magnesium salts of alkoxide 146 are insufficiently nucleophilic to undergo direct displacement. As a consequence, competitive proton transfer occurs which leads to regeneration of a nitrile enolate and then displacement of the chloride to give, as the major products, cyclobutanol 147 along with alcohol 149 resulting from quenching of the intermediate. OH

Ar CN 147 Ar CN

Counterion Mg++ Li+ Na+ or K+

CN

O

CN

Ar C1

145

Ar = e- poor O

Cl

Ar

ent-150

+

Ar = e- rich O

CN 144

C3

Favored Product(s) 147 147, 149 150a,b

O

Ar 146

CN

Cl

OH

Ar

148

NC

OH

Ar Cl 149

NC OH

Ar 150a

150b

major

minor

Fig. 39 Mechanistic rationale for product distribution in Fig. 38, Eq. (3)

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A. M. Hyde and E. R. Ashley

6 Conclusion The large number of bicyclo[3.1.0]hexanes and heteroatom-containing congeners that have emerged from drug discovery and natural product elucidation programs has inspired the invention of an array of methods aimed at the synthesis of this compound class. The varied structures of the target compounds have limited the potential of some methods while harmonizing elegantly with others. As key examples, catalytic intermolecular cyclopropanation with diazoesters formed key steps in the process syntheses of MK-1642 and saxagliptin; intermolecular Michael-initiated cyclopropanation was crucial for the process synthesis of trovafloxacin; application of a metallocarbenoid in an intramolecular setting underpins the process synthesis of Table 3 Summary of methods applied to the preparation of bicyclo[3.1.0]hexanes in process chemistry Methodology Transition metalcatalyzed cyclopropanation with α-diazocarbonyl reagents Simmons–Smith cyclopropanation

Sulfur ylide or α-haloenolate addition to Michael acceptors

Functional group pattern Typically requires an alpha ketone or ester

Inter/ intramolecular Both

Stereochemical considerations Chiral ligands are used, variable success rates depending on the system

Substitution on cyclopropane ring limited to alkyl, olefin partners should not be polarized Typically requires a ketone adjacent to the cyclopropane

Both but intermolecular is more common

Substrate-controlled d.r. often quite good

Intermolecular

Very limited progress toward asymmetric version, substratecontrolled d.r. can be quite good Relies on stereochemistry of epoxide

Use of lithium carbenoids

bicyclo[3.1.0] hexan-2-one core

Intramolecular

Enolate displacements

Very flexible

Intramolecular

Kulinkovich–de Meijere

A heteroatom substituted appended to the cyclopropane ring

Intermolecular

Relies on stereochemistry of alcohol precursor or epichlorohydrin, stereospecific High d.r. but no asymmetric variant

Drawbacks Requires preparation/use of potentially hazardous diazo intermediates Not atomeconomical: Waste of one or two iodides plus stoichiometric zinc Ylide stability may be a concern

Very limited in scope, requires the use of expensive LiTMP May require a more lengthy route

Yields are generally low to moderate

Organometallic Approaches to [3.1.0] Bicycles in Process Chemistry

69

the key building block bicyclo[3.1.0]hexan-2-one; and nucleophilic displacement strategies were pivotal to the successful development of process routes to MGS0028, MK-8666, and amitifadine. Importantly, the continued discovery of biologically active bicyclo[3.1.0]hexane derivatives will demand the continued exploration and development of new of methods for the efficient preparation of these frameworks. To aid in choosing among the methods presented, Table 3 lists the functional group patterns that dictate choice of method along with the ability to control stereochemistry. None of the methods presented are ideal for all cases, and careful consideration of all options is necessary to ensure synthetic success.

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Top Organomet Chem (2019) 65: 73–114 DOI: 10.1007/3418_2019_27 # Springer Nature Switzerland AG 2019 Published online: 28 July 2019

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation Reactions Garazi Talavera, Alejandro Santana Fariña, Antonio Zanotti-Gerosa, and Hans Günter Nedden

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 2 ATH Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3 ATH of Polyfunctionalized Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4 Diastereoselective TH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5 ATH of Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 6 ATH Through Dynamic Kinetic Resolution (DKR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Abstract In this review, we focus on synthetic applications of asymmetric transfer hydrogenation (ATH) of structurally complex ketone and imine substrates towards the synthesis of biologically active molecules and natural products with high levels of diastereo- and enantioselectivity. This approach should be interesting to a large scientific community from both academic and industrial assets, and specially lifescience businesses. Commercial supply of catalysts is key for industrial groups aiming to implement this technology in their production campaigns. Thus, relevant examples of industrial use of ATH are described. Keywords Dynamic Kinetic Resolution · Formic acid · Imine · Industrialapplication · Ketone · Process-optimization · Substrate diversity · Transfer hydrogenation catalysis

G. Talavera, A. Santana Fariña, A. Zanotti-Gerosa, and H. G. Nedden (*) Johnson Matthey Plc, Cambridge, UK e-mail: [email protected]; [email protected]; [email protected]; [email protected]

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1 Introduction Asymmetric transfer hydrogenation (ATH) is recognized as one of the most powerful and versatile synthetic tools for the preparation of optically active compounds, not only in academia but also in large-scale applications for the synthesis of fine chemicals and pharmaceuticals. Under these conditions, the production of highly enantiomerically enriched alcohols and amines has been achieved with outstanding efficiency. Applications of ATH have been regularly reviewed over the past years [1–8]. In this chapter, we focus on synthetic applications of ATH toward the synthesis of some important drugs and natural products, with particular focus on the development of the technology in recent years. Our survey highlights how a vast range of structurally challenging ketones and imines have been successfully submitted to ATH processes allowing access to highly valuable intermediates in chemical synthesis. ATH offers, in fact, three major advantages: 1. ATH’s broad scope and tolerance of a vast array of functional groups, which makes it particularly suited for application on the complex, poly-functionalized substrates typical of the life science industry 2. The fact that specialized pressure equipment is not required (unlike hydrogenation with hydrogen gas), making ATH easily applicable in the majority of industrial plants 3. The possibility to optimize reactions over an incredibly broad range of conditions, from reactions in water at various pH values to biphasic systems and to a variety of neat organic solvents, with different hydrogen donors and over a large spectrum of acid/base ratios The flexibility of ATH catalysts extends to applications with hydrogen gas (the so-called “phosphine-free” hydrogenation), but this area is outside the scope of the chapter [9, 10]. The main objective of this chapter is to focus on the examples and concepts involving Ru-catalyzed ATH reactions. However, some important applications based on Rh- and Ir-catalyzed processes are referenced as, in some cases, they provide the gold standard benchmark. Ruthenium(II)/η6-arene complexes were introduced by R. Noyori in the mid-1990s and have been since then the workhorses of ATH. Amino alcohols have been proven to be effective ligands (e.g., Fig. 1, C1 catalyst), but their use is much limited by their applicability in a restricted spectrum of reaction conditions. Ruthenium(II) catalysts containing monosulfonyl-1,2-diamine ligands (e.g., Fig. 1, C2 and C3 catalysts) have instead become the standard. The electronically equivalent Rhodium(III)/η5-pentadienyl complexes (e.g., Fig. 1, C4 catalyst), introduced soon afterward, have found more niche but equally important applications. Numerous investigations aimed at diversifying the structure of the ligand (sulfonyl group or diamine backbone) have been undertaken to achieve more efficient catalytic performance. Several successful examples of this strategy have been reported, but, from

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . R'

O

Ru NH2

Cl

R' RO2S

Ph

N

Ru NH2

Cl

R' RO2S

N

Ru NH2

Ph Ph

Cl

RO2S

N

M Cl NH2

Ph Ph

C1

75

Ph C2

C3

M = Rh (C4), Ir (C5)

R = a: Me (Ms), b: Tolyl (Ts), c: C6F5 (Fs), d: 2,4,6-(Me)3C6H3 (Mts), e: 2,4,6-(iPr)3C6H3 (Tris) R'= a': H, b':1,3,5-(Me)3C6H3 (mesitylene), c':1-iPr-4-MeC6H3 (p-cymene)

Fig. 1 Ruthenium (“first-generation”), Rhodium, and Iridium catalysts structures for ATH

the perspective of practical, industrial application, in each case the use of more complex, thus expensive, ligands must be justified by a significant technical advantage. Practice of the technology over the past 20 years has somehow narrowed the choice of “first-generation” Ru(II) catalysts to few structures that are commercially available on large scale by catalyst suppliers.1 A continuing search for more robust catalysts that will not degrade easily during the catalytic process, thus improving activity and chemoselectivity, has led to the introduction of the “second-generation” class of tethered catalysts (Fig. 2). To understand the scope of ATH and where the technology is heading, prior to our survey of modern applications of ATH, this chapter includes a brief discussion on the “second-generation” tethered catalysts. To compare the performance of “firstgeneration” and “second-generation” catalysts, we reference the results on several model compounds, despite these being outside our main focus on complex targets such as pharmaceutical intermediates and natural products.

2 ATH Catalysts In 1995 Noyori et al. discovered the use of Ruthenium(II)/η6-arene catalysts bearing amino alcohols and sulfonyl-1,2-diamine ligands [11, 12] using 2-propanol and formic acid/triethylamine mixtures as hydrogen donors. 2-Propanol is still a commonly used hydrogen donor, especially in academic papers, but the reversibility of the reaction makes it less preferred for industrial applications. Formic acid derivatives (triethylammonium or sodium salts) have the advantage of producing CO2 that is liberated from the reaction mixture driving the equilibrium toward the products. The technology was developed and patented by the Japan Science and Technology

1

While small-scale samples of ATH catalysts can be obtained by catalogue companies, Ru ATH catalysts figure prominently in the offer of large catalysts suppliers such as Johnson Matthey, Umicore, and Takasago.

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R' n

Ru

RO2S N

Cl

NH Ph Ph C6

R' Ru

Ts N

Cl

Ru

Ts N

NH

Cl

Ts N

NH

Ru

Cl

NH Ph Ph

C7

C8

C9

n

O RO2S N

Ru NH

Ph

Cl

MeN O 2S

N

Ru

Cl

NH2

C10

N

Ph

Ph Ph

H 2N

Ru

Ph

Ph C11

Cl

O

F F

S O2 F

F

C12

R = a: Me (Ms), b: p-MeC6H4 (Ts) , c: 2,4,6-(Me)3C6H2 (Mts), d: 2,4,6-(iPr)3C6H2 (Tris) R' = a': H, b': p-MeC6H4, c': 3,5-(Me)2C6H3, d': p-OMeC6H4, e': p-iPrC6H4 n = 1, 2

Fig. 2 Ru(II) tethered (second-generation) catalysts

Corporation with a group of Japanese industrial partners and licenced by a handful of western companies (including Johnson Matthey). Only a few years later, Ikaria and Blacker published the use of isoelectronic Rh(III) catalysts bearing the pentamethylcyclopentadienyl moiety (Cp
) [13]. The catalysts have been industrially employed by Avecia (now NPIL). In the early 2000s, Wills and co-workers improved on the antecedent of Noyori’s catalyst, introducing an additional tether in which the 1,2-diamine ligand is covalently linked to the η6-arene ring, thus benefiting from increased stability due to the three-point attachment of the ligand to the metal. Tethered complexes have proved to be highly active under transfer hydrogenation conditions. As an example of the enhanced performance of the tethered catalyst, Wills et al. have demonstrated that acetophenone can be fully reduced in 3 h using 0.5 mol% of C6ba0 and HCOOH/ Et3N as hydrogen donor at 40 C without any loss of enantiomeric excess. The use of catalyst C2bc0 under the same reaction conditions extends the reaction time up to 24 h (entries 1 and 2, Table 1) [14]. Along with the modification of the sulfonyl group, including the introduction of methanesulfonyl C6aa0 , 2,4,6-trimethylphenylsulfolnyl C6ca0 , 2,4,6-triisopropylphenylsulfonyl C6da0 [15], the structure of these complexes has been studied tuning the length and the backbone of tether as well as the diamine residue. In this sense,

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . .

77

Table 1 Application of first- and second-generation Ru(II) catalysts to ATH of ketonesa Ketone O

O

MeO

O O

O

O

O

O COOEt n-Bu

O

a

Cat. C2bc0 C6ba0 C6bd0 C10b C9d0 C2bc0 C6ba0 C11 C6aa0 C6da0 C6ba0 b C2bc0 C6ba0 b C10b

Mol (%) 0.5 0.1 0.1 0.1 0.5 0.5 0.5 1.0 0.2 0.2 0.2 0.5 0.5 0.1

T ( C) 28 40 60 60 40 28 40 40 40 60 40 28 40 60

t (h) 20 3 2 3 24 60 1.6 20 24 24 7 36 3 5

Yield/[conv.] >99% [100%] [100%] >99% [100%] >99% [100%] 95% [100%] [91%] [96%] >99% [100%] >99%

C2bc0 C6bd0 C11

0.5 0.1 0.5

28 60 60

22 2 2

>99% [100%] [100%]

96 94 96

C2bc0 C6bd0 C10a C11 C2bc0 C6bd0 C11 C6aa0 C6ba0 b C6bc0 C6ba0 b

0.5 0.1 0.1 0.5 0.5 0.1 0.5 0.2 0.2 3 0.5

28 60 60 40 28 60 40 40 40 25 25

36 3 24 5 48 5 20 24 5 48 48

93% [100%] 94% >99% >99% [99%] [100%] [95%] [100%] 87% 92%

83 99 97 >99 99 99 >99 98 95 99 >99

C2bc0 C2bb0 C10b C10a

1 1 1 1

60 60 60 60

18 18 18 18

22% 45% 98% 94%

ee (%) 98 96 96 97 98 97 94 93 95 92 95 98 98 98

86 90 98 94

H-donor: HCOOH/Et3N (5:2) Catalyst C6ba0 where n ¼ 2

b

complexes like C8 containing 1,2-cyclohexyldiamine or benzyl-bridged structures such as C9a0 have been synthesized. Achiral derivatives have also been prepared (C7). Likewise, the substitution pattern on the η6-arene ring has been addressed (C6bb0 , C6bc0 , and C6bd0 ) [16–18]. Additionally, new families of tethered catalysts have been introduced. The oxo-tethered ruthenium complexes (DENEB) (C10) were first published by Ikariya

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and co-workers [19]. In parallel Wills et al. have developed this type of complexes based on a different synthetic strategy [20]. A further type of variants has been introduced by Mohar et al. replacing the sulfonylamino groups by sulfamoylamino groups, e.g., C11 [21–23]. Most recently, another type of oxo-tethered catalyst C12 was devised by Kayaki et al. using an elegant synthetic approach [24]. These tethered complexes have shown improved turnover rates over the untethered version, demonstrating enhanced longevity of the catalytic species. Over the past 15 years, tethered catalysts have proven to be successful beyond initial expectations, giving rise, in both academia and industrial laboratories, to several innovative applications that could not be achieved using first-generation catalysts. The advantage of tethered catalysts over the previous generation catalysts is usually in terms of stability and increased activity, with achievable catalyst loadings often one order of magnitude lower than with previous catalysts. This can be in first instance attributed to their increased robustness toward deactivation under the reaction conditions when polyfunctionalized substrates are present or highly nucleophilic amine products are formed. The best performance of tethered catalysts does not necessarily occur under the same conditions as the structurally equivalent non-tethered catalysts (pH or acid/base ratio or choice of solvent). Tethered catalysts are found to remain active and stable for extended periods, while the non-tethered equivalents are prone to dissociation of the chiral ligand under low pH [2, 25]. The decomposition pathways of non-tethered catalysts have recently been studied using in situ flow NMR techniques [26]. The study demonstrates that Ru-hydride intermediates are prone to lose the η6-coordinated arene forming hydride-bridged Ru dimers and ultimately Ru nanoparticles. At early stages of an ATH reaction, this deactivation was shown to be of very little importance. An updated rate equation was established that adds to previous mechanistic studies cited in a summary of Sasson et al. [27]. Both studies [26, 27] agree that nanoparticles are formed from the Ru catalyst during the reaction. The view of Sasson, expressing that nanoparticles modified by the chiral ligand are the real catalysts, is not supported by the flow NMR study. Tethered catalysts stabilize the η6-coordinated arene by the tether and should be more stable to such deactivation. Wills’ tethered catalysts can be activated by hydrogen gas without requiring any modification and under neutral conditions [28]. This is a further difference to non-tethered catalysts and adds to the versatility of the use of these catalysts. The increased performance comes, of course, at the price of increased complexity of the catalyst. The best trade-off between technical results and catalyst cost contribution is often found on complex substrates such as pharmaceutical intermediates, where the use of tethered catalysts becomes more cost-effective. Representative results for model ketone substrates have been summarized in Table 1 to highlight the different catalytic performances of first- and secondgeneration (tethered) catalysts. This list has been designed to be illustrative rather than exhaustive; thus further examples are given in the references [1, 3, 10, 12, 14, 29–32]. Interestingly, most of the examples have shown that ketones bearing unsaturated substituents can be successfully reduced to the corresponding alcohols in excellent enantioselectivities. The origin of this observation has been explained in several

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . Scheme 1 ATH of bulky ketones 1 and 2 catalyzed by tethered catalyst C6ba0

O

C6ba' (0.5 mol%) HCOOH/Et3N

79 OH

40 °C, 32 h 1

2 95% conv., 77% ee Non-tethered cat:95% ee

0.25 mol% (Ru(p-cymene)Cl2)2 0.5 mol% (R,R)-TsDPEN 28 °C

68% conv., 85% ee

0.25 mol% [Rh(Cp)*Cl2]2 0.5 mol% (R,R)-TsDPEN RT

85% conv., 75% ee

0.01 mol% C6ba' 60 °C

100% conv., >95% ee

0.25 mol% (Ru(p-cymene)Cl2)2 0.5 mol% (R,R)-TsDPEN 28 °C

45% conv., 89% ee

0.25 mol% [Rh(Cp)*Cl2]2 0.5 mol% (R,R)-TsDPEN RT

59% conv., 94% ee

Scheme 2 Comparison of catalytic performance of second- and first-generation Ru(II) and Rh(III) catalyst on the ATH of α-chloro- and α-hydroxyacetophenone O NMe2

OMe

C2bc' (0.25 mol%) HCOOH/Et3 N (5:2)

OH NMe2

OMe

EtOAc, RT, 7 d OMe

OMe 7

8 55%, 98% ee

Scheme 3 Synthesis of (R)-macromerine via ATH of dialkylaminomethyl ketone 7

high reaction rates, and enantioselectivities (Scheme 2) [15]. Among other alphasubstituted acetophenones, α-hydroxyacetophenone has been reduced using catalyst loadings as low as 0.01% mol to give full conversion to the corresponding diol in >95% ee. In this particular case, the deactivation of the catalyst was expected to take place via the interaction between the hydroxy group and the metal center; however, the positive results obtained with a wide range of tethered catalysts have opened the way to carry out this transformation without including any protection/deprotection steps.

3 ATH of Polyfunctionalized Ketones As mentioned in the previous section, challenging substrates, such as ketones bearing electron-withdrawing groups at α position, have successfully been subjected to ATH by using Ru(II)-tethered catalysts. In this context, the cactus Coryphantha macromeris alkaloid (R)-macromerine has been synthesized in 50–73% yields and 97–99% ee by ATH of dialkylaminomethyl ketone 7 using RuCl[(R,R)-TsDPEN](η6-p-cymene) (C2bc0 ) as catalyst [37] (Scheme 3). A series of halo-substituted aryl methyl ketones have been transformed into the corresponding alcohols for the preparation of chiral halohydrines in the presence of

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . O X R 9

Ph Ph

OH

(Ru(p-cymene)Cl2)2/L1-2 HCOONa/H2O, 35 °C 35 °C, 5 h, S/C = 100

H N

81

∗

OH X

R

NHiPr

∗

R

(R)-10 R=o-Cl; X=Cl 93%, 99% ee

11, (R)-clorprenaline R=o-Cl

(S)-12 R=p-NO2; X=Br 88%, 93% ee

12, (S)-sotalol R=p-NO2

S O2 NH2 O

L1 (S,S,S)-Cs-DPEN Ph Ph

H N

S O2 NH2 O

L2 (R,R,R)-Cs-DPEN

Scheme 4 Synthesis of halohydrines via ATH of α-haloketones OH

OH Br

O

O Ph

O

O

H N

14

O

15, (R)-salmeterol OMe

OH O 2N

Br

CHO HN HO

BnO 16

O Ph

OH Ph HN

H N

O

O 16

S O2 NH2 L3 (S,S)-PEGBsDPEN

17, (R,R)-formoterol

Scheme 5 Access to (R)-salmeterol and (R,R)-formoterol by using halohydrine intermediates 14 and 15 formed via Rh(III)-catalyzed ATH

relatively high catalyst loadings of in situ generated Ru(II) complexes coming from (Ru( p-cymene)Cl2)2 and ligands L1 and L2 [38] (Scheme 4). The latter has been derivatized to (R)-clorprenalline and (S)-sotalol upon a regioselective opening of the corresponding epoxides with isopropyl amine. Rh-based catalysts have been more widely used for the reduction of α-haloketones. In a similar approach, (R)-salmeterol and (R,R)-formoterol have been synthesized using [Cp
RhCl2]2 and L3 for the preparation of the chiral intermediates shown in Scheme 5 [39–41]. As highlighted in the discussion in the previous section, “second-generation” tethered Ru(II) catalysts provide a viable alternative in the reduction of α-chloroand α-bromo-substituted ketones. Chemists at Teijin Pharma have demonstrated this by developing an enantioselective method for the synthesis of several α-hydroxyquinolinone derivatives via ATH catalyzed by oxo-tethered Ru(II)

82

G. Talavera et al. O

OBn

N H

O

CHCl3, 50 °C, 2 h

R=Cl, Br, NHCbz 18

O

N H

O

R

OBn

N H

O

19 56-99% conv., 69-95% ee HO

NHCbz

OBn

HO

C10b or its enantiomer (S,S)-C10a (1 mol%) HCOOH/Et3N

R

NHCbz

1. (S,S)-C10a (0.5 mol%) HCOOH/Et3N 2. IPA

OBn

N H

TBSO

O OH

21

20

NH2 . 2 AcOH

N H

O

22 4.2 kg

71%, 99% ee

Scheme 6 Synthesis of quinolinone derivatives 19 and 21 via ATH catalyzed by oxo-tethered enantiomeric catalysts C10. Preparation of key intermediate 22 for the β2-adrenergic receptor agonists OH O Br

O

C4b (0.2 mol%) HCOOH/Et3N (5:2)

O

OH Br

O

EtOAc, 0 °C 23

O HO O

24

O

R

70%, >99% ee 25, R=H : (-)-eriolanin 26, R=Me : (-)-eriolangin

Scheme 7 Rh(III)-catalyzed ATH of heteroaryl-substituted halo methyl ketone 23

complexes C10. This methodology has been also applied to a N-Cbz-protected ketone toward the preparation of a key intermediate for the β2-adrenergic receptor agonists (Scheme 6) [42]. The optimized process was obtained with the opposite enantiomer of the oxo-tethered Ru(II) C10a ((S,S)-C10a). Heteroaryl-substituted halo methyl ketones have been addressed by Metz and co-workers [43] where ATH was used as the key step for the total synthesis of the sesquiterpene lactones ()-eriolanin and ()-eriolangin using in situ prepared [Cp
RhCl TsDPEN] (C4b) and HCOOH/Et3N (1:1) as hydrogen donor (Scheme 7). α-Sulfonyloxy aryl ketones have been employed for the preparation of β1adrenergic receptor agonist such as (R)-tebamide, (R)-aegeline, (R)-octopamine, and (R)-denopamine via rhodium-catalyzed ATH [44] as shown in Scheme 8. When the transfer hydrogenation step is applied to an α-mesityloxy-substituted ketone bearing an electron-rich aromatic moiety such as benzofuranyl, the corresponding mono-mesylated diol can be prepared in excellent yield and good enantioselectivity [45, 46] (Scheme 9).

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . O

OH

C4b (0.2 mol%) HCOOH/Et3N (5:2)

OTs

83

OTs

(R)-28 R=OMe 92%, 94% ee

EtOAc, RT, 18 h R

(R)-29 R=OBn 88%, 95% ee

R 27

OH

OH

H N

NH2

OMe OMe

HO

HO

31, (R)-denopamine

30, (R)-octopamine

OH

OH

H N

Ph O

MeO

H N

Ph O

MeO

32, (R)-tembamide

33, (R)-aegeline

Scheme 8 Rh(III)-catalyzed ATH of α-sulfonyloxy aryl ketones 27 O OMs

O

34

C4b (0.2 mol%) HCOOH/Et3N EtOAc, 1 h

OH OMs

O

35 97%, 97% ee

Scheme 9 Rh(III)-catalyzed ATH of α-sulfonyloxy heteroaryl ketone 34

Polyfunctionalized substrates become particularly challenging since aspects such as side reactions and/or catalyst deactivation might have a significant impact on the final outcome. Complex ketones such as 36 have been submitted to transfer hydrogenation conditions (Scheme 10). As part of a research collaboration between Johnson Matthey and Eli Lilly and Company [47], it has been shown that homogeneous transfer hydrogenation of highly functionalized substrates offers the best chemoselectivity (compared to heterogeneous catalysis) when side reactions, like dechlorination or debenzylation (morpholine cleavage), are likely to occur. Some other methods have been reported to work sufficiently for early routes using silanes in trifluoroacetic acid as solvent. However, large amount of fluoride- and siliconcontaining waste are generated by following these protocols. Other attempts describe the use of volatile silanes which makes it inconvenient for large-scale syntheses. A hypophosphorous-iodine-reducing system has been found to create difficulties in the downstream chemistry. In this context, a variety of homogeneous achiral catalysts have been tested for this transformation, where the superior reactivity of the

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O

O N

N N N

Cl

N Cat, HCOONH4

N

EtOAc/H2O, 80 °C, 16 h

O

N

Cl

N OH

F

F

Cl

Cl 36

37 iPr

Me Ts

N

Ru NH2

Cl

Ts N

Cl

C7

C2-TsEN

Catalyst C2-TsEN C7 C7

Ru NH

S/C 1000/1 5000/1 10000/1

Conversion 60% 100% 99.5%

Scheme 10 Catalytic performance of achiral Ru(II) catalysts C2-TsEN and C7 as chemoselective transfer hydrogenation catalysts of ketone 36 tBu

O R

OEt

2

R1 O 38

(Ru(p-cymene)Cl2)2/L4 (0.2-1.0 mol%) HCOONa, CTAB (4 mol%)

O R2

NHTs

tBu

O

H2O/DCM 40 °C

tBu

NH2

R1 39 90-99%, 98-99% ee

tBu

L4 (1S,2S)-TsBuDPEN

Scheme 11 ATH of acylarylcarboxylates 38 catalyzed by in situ generated (Ru(p-cymene)Cl2)2/ L4 complex. Synthesis of chiral lactones

achiral tethered Ru(II) catalyst C7 has been demonstrated. Most likely, the excellent chemoselectivity shown by Wills’ catalyst speaks for its enhanced robustness against substrates that contain moieties that presumably coordinate the metal catalytic species. Several acylarylcarboxylates, under ATH conditions using aqueous HCOONa as hydrogen donor, lead to the corresponding chiral alcohol that subsequently reacts with the ester located at ortho position affording optically active phthalide frameworks, which are present in a wide range of natural products [48]. As shown in Scheme 11, the ligand of choice consists of a more sterically hindered TsDPEN containing tert-butyl groups on the phenyl substituents (L4), which was essential for the excellent catalyst performance in terms of the stereochemical outcome.

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . .

85

Pri H Me Ru

NTs

R H

tBu

N O O

H H

t

Bu

EtO

But

tBu

Fig. 3 Proposed transition state for the ATH of acylarylcarboxylates 38 catalyzed by (Ru(p-cymene) Cl2)2/L4

O OMe O 40

(Ru(p-cymene)Cl2)2/L5 HCOONH/Et3N DMF, 25 °C, 4 h, S/C = 200

iPr

OH OMe O 41 100% conv, 96% ee

Ph Ph

iPr

H N

S O2 NH2

iPr

L5 (S,S)-TrisDPEN

Scheme 12 ATH of α-keto ester 40 catalyzed by in situ formed Ru(II) catalyst containing sterically hindered ligand L5

A model for the transition state has been proposed (Fig. 3), where the neighboring ester functional group presumably plays a significant role on the stereocontrol participating in a hydrogen-bond interaction with the unprotected amino group of the ligand providing a well-defined and highly ordered transition state. This hypothesis has been supported by the results obtained using 2-methylacetophenone as substrate, where the transfer hydrogenation proceeds with a substantial decrease on the enantioselectivity (59% ee). α-Keto esters have been shown to be suitable substrates for reductions using ATH catalysts. Mohar and co-workers have studied the influence of sterically hindered NArSO2-DPEN-type ligands on the stereochemical outcome concluding that in some cases such as methyl mandelate, a significant increase of the chiral purity can be achieved by replacing Noyori’s well-known TsDpen ligand by bulky arenesulfonyl groups like (S,S)-TrisDpen (L5) (59% ee vs 96% ee) (Scheme 12) [49]. The increasing amount of research contributions on ATH has prompted pharmaceutical and fine chemical companies such as BIAL to implement this technology in their manufacturing processes. Thus, they have studied the catalytic asymmetric reduction of the API oxcarbazepine toward the synthetic intermediate 43 which leads to the preparation of eslicarbazepine [50]. In the manufacture of APIs, the substrate/ catalyst ratio deserves the maximum attention due to the tight residual metal limits that are tolerated. Also the cost contribution of the catalyst has to be considered, and therefore, low catalyst loadings are desirable for large-scale manufacturing purposes. As depicted in Scheme 13, the reaction takes place in the presence of in situ formed Ru(II) complex with (Ru( p-cymene)Cl2)2 and (S,S)-TsDAEN (L6). It has been demonstrated that for this particular reaction the use of a more electron-rich ligand

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G. Talavera et al. O

HO MeO

(Ru(p-cymene)Cl2)2/ L6, HCOOH/Et 3N N O

NH2

NHTs

20% DMF/EtOAc, reflux or 10% DMF/10% H2O/ EtOAc, reflux

N O

42

NH2

NH2

43 >90%, >97% ee

MeO L6 (1S,2S)-TsDAEN

Scheme 13 ATH of oxcarbazepine catalyzed by in situ formed Ru(II) catalyst containing electronrich ligand L6 (iPr)2N

O

O

(S,S)-C2bc' H2 / HCOOH

(iPr)2N

O

O

OH

O key intermediate to Lorlatinib

F F

44

AH: 5 mol% cat, H2, tbuOK, IPA, 50 °C, 64-72 h ATH: 0.25 mol% cat, HCOOH/Et3N, IPA, 50-55 °C, 2 h

F

45

46

100% conv, 98.5% ee 94%, >99.9% ee (upgraded)

Scheme 14 AH versus ATH on the synthesis of chiral intermediate 45

such as L6, where methoxy groups are installed on the phenyl rings, provides a catalyst of enhanced efficiency allowing catalyst loadings of S/C 500/1 to 3,000/1. Along with the performance of the catalyst, the reaction is also more productive within an optimal pH window. The operational aspect is key for this transformation for a high yielding preparation of 43 at a substantially low catalyst loading. Recently, Pfizer has published an interesting comparison between an enzymatic reduction, a pressure asymmetric hydrogenation and an asymmetric transfer hydrogenation on the synthesis of a key intermediate to Lorlatinib (Scheme 14) [51]. The chiral purity of intermediate 45 was considered crucial for the preparation of the final API. Several asymmetric reduction methods have been ruled out against ATH due to synthetic issues while preparing the starting materials, operational limitations, and cost-efficiency. The catalyst of choice, RuCl[(S,S)-TsDPEN](η6-p-cymene) ((S,S)C2bc0 ), has been demonstrated to be significantly more active under ATH conditions than it would be expected from academic literature on model substrates, enabling to reduce the catalyst loading from 5% mol to 0.25% mol. It has to be noticed that even though the strong directing group adjacent to the carbonyl group has been installed for synthetic purposes for the preparation of the required ketone, the presence of a bulky substituent definitely has a positive impact on the enantioselectivity of the ATH reaction. Moreover, similarly to the ATH of acylarylcarboxylates (see Fig. 3), secondary interactions between the adjacent amide substituent and the diamine ligand should not be ignored, which presumably facilitates a more rigid transition state and, thus, a better control of the stereoselectivity. The preparation of a partial structure of morphine has been published where an α,β-unsaturated cyclic ketone is reduced to the corresponding saturated alcohol in

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . O

87

HO

N

C2bc' (0.5 mol%) HCOOH/Et3N CO2Et

N

RT, 72 h

47

CO2Et

48 81%, >99.9% ee

Scheme 15 Selective reduction of α,β-unsaturated ketone 47 via Ru(II)-catalyzed ATH

C6ba' (10 mol%) HCOOH/Et3N

C7H15 O

C7H15 OH

DCM, RT, 1 h

49

50, (S)-Panaxjapyne A1 85%, 96% ee

OBn

OBn

BnO CO2Me OH 51 99%, 99% ee

OH

OH 52

97%, >99:1 dr, >99% ee

Scheme 16 Synthesis of diynols via ATH catalyzed by second-generation Ru(II) tethered catalyst C6ba0

the presence of C2bc0 with excellent enantioselectivity and high yield [52] without interfering with the carbamate present on the molecule (Scheme 15). The newly generated chiral center is then controlling the stereochemical outcome of further steps by its directing effects. Optically active conjugated diynols are interesting building blocks since their inherent chemical and biological properties given by the 1,3-diyne units. This scaffold has been found in numerous polyacetylenic natural products and has proved to have potential anticancer activities [53, 54]. Regarding the synthesis of these structures, it has been recently reported that ATH promoted by “second-generation” tethered catalysts provides an efficient and highly stereoselective method with the potential to be further explored. Although alkynyl ketones had been previously reduced with first-generation catalysts using 2-propanol, usually the pre-activation of the catalyst as 16-electron species is required. Wills et al. have accomplished the synthesis of (S)-panaxjapyne A1 in good yield and 96% ee by using C6ba0 and HCOOH/Et3N as hydrogen donor at room temperature [55]. The same catalytic system has been studied toward the asymmetric reduction of functionalized acetylenic ketones affording a wide range of synthetically relevant propargyl alcohols at 0.5 mol% and 0.2 mol% catalyst loadings [56] (Scheme 16).

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G. Talavera et al.

C2bc' (0.1 mol%) HCOOH/Et3N

O

OH

40 °C, 24 h O

OH

53

54 NaH, THF, 0 °C to RT, 12 h MsO

OTBDMS

OTBDMS O

OH 55 70%, >97% de, >99% ee

Scheme 17 Double catalytic ATH of diketone 53 catalyzed by C2bc0

The double catalytic asymmetric transfer hydrogenation of a 1,2-diketone can be carried out under Noyori’s conditions with only 0.1 mol% of C2bc0 and HCOOH/ Et3N as hydrogen donor. The resulting crude diol has been subsequently submitted to nucleophilic substitution with the mesylate counterpart shown in Scheme 17 toward the synthesis of the key chiral intermediate for the preparation of muricatacin [57, 58].

4 Diastereoselective TH Important contributions on diastereoselective transfer hydrogenation have been reported opening the way to optically active molecules of considerable structural complexity, either by the use of chiral homogeneous catalysts that provide the best matched/mismatched scenario or by following a substrate-control strategy with achiral catalytic species. In this context, monocarbocyclic oxylipins, solandelactone A and eicosanoid, have been prepared by exploiting a catalytic ATH of ketones containing a cyclopropyl moiety toward the corresponding diastereomerically enriched alcohols, thus generating the right stereocenter that is configurating the final lactone [59, 60] (Scheme 18). In both cases, Noyori’s catalyst C2bc0 promotes the reactions showing high diastereoselectivity and functional group tolerance. Cyclic β-alkoxyketones undergo asymmetric transfer hydrogenation in a fully diastereoselective manner in the presence of C2bc0 as shown in Scheme 19. In this case, HCOOH/Et3N was used as hydrogen source in ethyl acetate at 50 C [61]. Kobayashi and co-workers have reported the total synthesis of phoslactomycin B where ATH conditions are applied to a highly functionalized α-alkynyl-substituted ketone containing several protecting groups and a terminal olefin and strong base as indicated. By using Ru[(S,S)-TsDPEN](η6-p-cymene), which is prepared in situ from

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . R1

H

H

n

O

R2

C2bc' (1 mol%) KOH or K2CO3

R1

H ∗

H HO

IPA, 80 °C, 6 h

89

n

R2

56, R1=CON(Me)(OMe); R2=OTBDPS; n=5

57, 85%, 90% de

Sondelactone A

58, R1=CO2tBu; R2=OBn; n=3

59, 65%, 90% de

Eicosanoid

HO O

H H

HO

O

H

O

60 Sondelactone A

H O

O

61 Eicosanoid

Scheme 18 Diastereoselective transfer hydrogenation towards the synthesis of oxylipins 60 and 61

OH

O

O

O

C2bc' (0.5 mol%) HCOOH/Et 3 N

O

O

EtOAc, 50 °C, 3 h

62

63 96%, >99.9% de

Scheme 19 Diastereoselective reduction of β-alkoxyketone 62

PMBO

O

PMBO

OH

Ru(p-cymene)[(S,S)-(TsDPEN)] OTES

TMS

OTES

KOH, IPA

TBDPSO

TMS

TBDPSO 64

65 87%, 94% de

Scheme 20 Selective ATH of α-alkynyl-substituted ketone 64

(Ru( p-cymene)Cl2)2 and (S,S)-TsDPEN and strong base, the resulting alcohol is obtained as a mixture of diastereoisomers in 94% de and 87% yield [62] (Scheme 20). Hydroxyl alkyl azetidinones have been prepared starting from the corresponding optically active ketone. Teva Pharmaceutical Industries have developed an efficient synthesis of ezetimibe (Scheme 21) by using a sulfonyl DPEN-type ligand containing an isobutyl substituent (L7) instead of the well-established tosyl group [63]. Due to the structural complexity of this substrate, the acidity of the reaction mixture is an essential parameter to be controlled in order to avoid decomposition of the starting material and/or product of which stability under basic conditions is very

90

G. Talavera et al. OH

OH OH

O (Ru(p-cymene) Cl2)2/L7 HCOONa

F

F

EtOAc, pH = 6.4, 65 °C, 6 h

N

N O

O

F

F 67, ezetimibe >99% conv., 85% de

66 H N

iBu

S O2 NH 2

L7 (1S,2S)- iBu-SO2-DPEN

Scheme 21 Synthesis of ezetimibe via ATH promoted by in situ formed (Ru(p-cymene)Cl2)2/L7 complex

Boc N

Boc N N

ATH cat HCOOH/Et3N

N

DCM, RT

N

N N N OH

O 68

69 C2ac' (1 mol%); 91% de (crude mixture)

starting material contains 15% product trans/cis (1:14)

C2ac' (1 mol%); 76% de (crude mixture)

Scheme 22 Synthesis of key intermediate 69 towards the manufacturing of ipatasertib via ATH catalyzed by C2ac0

low. Therefore, the reaction has to be performed with a pH ¼ 6.4 that was reached by adding formic acid to an aqueous solution of sodium formate. The success achieved by performing the reaction under these ATH conditions overcomes many other disadvantages related to the synthesis of ezetimibe, particularly at large quantities, such as the use of pyrophoric bases (LDA, n-BuLi, etc.), reagents like Grignards or zincates that are sensitive to moisture, low temperature, and the need for chromatographic techniques. Genentech has implemented an asymmetric transfer hydrogenation step for the total synthesis and scale-up of ipatasertib (Scheme 22) [64]. This transformation in the presence of a non-chiral catalyst (i.e., Pd-/C-catalyzed TH) leads selectively to the cis isomer, the undesirable stereoisomer according to their medicinal chemistry route; thus, an asymmetric reduction had to be developed. Catalyst C2ac0 has offered good diastereoselectivity (91% de) toward the trans isomer, although for production purposes, material containing 15% of the over-reduced alcohol (trans/cis 1:14) has

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . O

RuCl[Ts-en{H}( p-cymene)] (0.1 mol%) HCOONa IPA, 40 °C, 6 h

O 70 300 g scale

91

O

OH 71, (R,R)-actinol 99.6% conv., 90% de, 98.9% ee

Scheme 23 Synthesis of (R,R)-actinol at multi-gram scale via ATH of (R)-levodione

been used. The reduction was carried out with >1 kg batches to obtain the desired alcohol with 76% de at 0.8 mol% of catalyst. Optically active cyclic ketones have also been transformed to the corresponding alcohols in a diastereoselective manner by using the first-generation achiral Noyori catalysts. In this context, the stereochemical outcome is controlled by the substrate under the same reaction conditions. Roche has produced (R,R)-actinol at multi-gram scale starting from (R)-levodione in the presence of RuCl[Ts-en{H}( p-cymene)] and HCOONa in IPA [65]. The process turns out to give the chiral alcohol in excellent yield and high diastereoselectivity after 6 h of reaction (Scheme 23).

5 ATH of Imines In comparison with the ATH of ketones, the reduction of C¼N bonds present several drawbacks that are essential to overcome in order to develop a highly efficient and stereoselective catalytic process promoted by organometallic compounds: 1. Unproductive ligand-imine binding. 2. Imine/enamine tautomerization required to be controlled for the stereoselectivity of the reaction. 3. Electronic properties of the substrate. Electron-rich imines are prone to be hydrolyzed in the presence of moisture and under acidic conditions. 4. Electronic and steric properties of the substrate due to the substituent directly attached to the nitrogen atom. 5. Poisoning of the catalyst by the resulting amines. Since the pioneering work reported by Noyori and co-workers [66] for the asymmetric transfer hydrogenation of cyclic imines, an increasing amount of scientific contributions to this field have been published due to the synthetic relevance and practicality of this particular transformation. Innumerable bioactive molecules bearing saturated nitrogen-containing scaffolds are demanded specially from the pharmaceutical industry, and this technology has proved to be cost-effective industrially viable for the preparation of APIs and their precursors.

92

G. Talavera et al.

R

(S,S)-C2ba' (1 mol%) HCOOH/Et3N

N

R

∗ NH

IPA

Ar

Ar

72

73 72-97%, 83-99% ee

R=H, 5-OMe, 6-OMe, 7-OMe, 6,7-(OMe)2 Aryl groups of different electronic and steric demand:

OMe

OMe

Me

Me Me

OMe

Me

OMe

I

Br

Cl

F

Br

Cl Cl

F

Scheme 24 ATH of 1-aryl-substituted 3,4-dihydroisoquinolines 72 catalyzed by (S,S)-C2ba0 MeO HO

HO N

MeO NH

HO OMe OH

74, (S)-(-)-stepholidine ATH: 84%, 95.6% ee

NH

MeO

HBr

NH OH

75, (R)-higenamine hydrobromide ATH: 62%, >99% ee

N NH2 H 76, (+)-crispine E ATH: 90%, >89% ee

Scheme 25 Tetrahydroquinoline structures synthesized under ATH conditions

In this context, Noyori has published together with its catalytic system a practical application of this basic research in the synthesis of precursors of the Merck drugs MK-0417 and L-699,392 [31]. A wide range of 1-aryl/alkyl-substituted 3,4-dihydroisoquinolines undergo ATH in high yields and enantioselectivities. Although early studies have pointed out that substrates bearing aromatic substituents show diminished enantioselectivities, several improvements have been done on this matter. Scalone and RatovelomananaVidal have accomplished the preparation of several aryl-substituted tetrahydroquinolines containing either electron-withdrawing or electron-donating groups on the phenyl substituents in moderate to excellent yields and enantioselectivities by using (S,S)-C2ba0 (Scheme 24) [67]. The number of reports on reductions of alkyl or benzyl-substituted scaffolds is notably higher. In this context, a variety of synthetic targets have been prepared successfully (Scheme 25) [68–70]. Nitrogen-containing heteroaromatic compounds such as 2-substituted quinolines can also be submitted to ATH conditions as depicted in Scheme 26 [71], although

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . .

93

C6ba' (0.5 mol%) HCOOH/Et3N N 77

R

MeOH, 28 °C R = Ph, tBu, Et, nPr, nBu, CH2CH2Ph,

N H

R

78 57-95%, 41-73% ee

Scheme 26 ATH of 2-substituted quinolines 77 catalyzed by tethered catalyst C6ba0

N N H

R

β-carbolines

O

N

NH

N H H

N H 80

79

ATH: 72%, >90% ee

ATH: 89%, 96% ee O

CO2Et

O NH

NH N H

N Me 81

HN N H

NH2

82

ATH: 89%, >90% ee

ATH: 75%, >90% ee

O N

NH

N N H

N H

84

MsOH

ATH: 96%, 93% ee O 83 ATH: 92%, >90% ee

Scheme 27 ATH of β-carbolines in the presence of Ru(II) and Rh(III) catalysts

with lower efficiency in terms of conversion and enantioselectivity. Notoriously, alkyl groups at the ortho position lead to lower enantiomeric excess values. The best stereoselectivity has been obtained with the substrate containing planar substituents such as a phenyl group (73% ee). It has to be noted that the partial reduction of these particular moieties under iridium-catalyzed asymmetric hydrogenation conditions has been carried out with excellent results [72]. The reduced conversions obtained via transfer hydrogenation compared to pressurized hydrogenation speak for the need of these substrates for harsher conditions due to their increased stability (aromaticity). As mentioned above, β-carbolines are likewise another substrate that can undergo ATH by using the popular HCOOH/Et3N combination and ruthenium and rhodium catalysts (C2- and C4-type catalysts) [73–76]. In Scheme 27 a selection of biologically active targets, of which stereocenters have been constructed via transfer

94

G. Talavera et al. MeO N Cl

MeO

(Ru(p -cymene) Cl 2)2/(S,S )-TsDPEN HCOOH/Et 3N

MeO

MeCN, 0 ° C, 10 h

MeO

85

N H

86, (R )-(+)-crispine A 96%, 92% ee

Scheme 28 ATH of iminium salt 85 towards the synthesis of (R)-(+)-crispine A

MeO MeO

N

MeO N

N H

MeO

H

87, (R)-(+)-octahydroindolo[2,3-a]quinolizidine ATH: 87% ee

88, (R)-(+)-harmicine ATH: 79% ee N

MeO MeO

H

N H H

89, (R)-(+)-desbromoarborescidine ATH: 90% ee

Scheme 29 Benzo[a]quinolizidine analogues synthesized under ATH conditions

hydrogenation of the corresponding imines, is shown. As depicted, Noyori’s conditions are compatible with a wide range of substituents going from linear to branched alkyl groups, unsaturated chains, aromatic scaffolds, and functional groups (i.e., esters and carbamates). Likewise, iminium salts can also be submitted to ATH. An excellent example describing the synthesis of the antitumor alkaloid (+)-crispine A via ATH has been reported by Czarnocki and Drabowicz [77]. Here, the iminium chloride salt of the corresponding tricyclic scaffold is reduced in the presence of in situ generated (S,S)C2bc0 catalyst to afford the expected heterocycle in 96% yield and 92% ee. When the same reaction conditions were applied to the enamine analogue, an increase in the yield and the enantiomeric excess can be observed (90% yield, >99% ee) (Scheme 28). Following the same procedure, some other alkaloids containing a benzo[a] quinolizidine ring have been prepared in moderate to good enantioselectivities (Scheme 29) [78]. An interesting example comes from DSM and Actelion Pharmaceuticals and their large-scale production of almorexant [79] where the advantages for ATH of imines are highlighted. The authors show how iminium salts can be efficiently reduced using ATH conditions (in contrast to asymmetric hydrogenation protocols) on a multikilogram scale affording the corresponding chiral amine in good enantiomeric excess (Scheme 30). This alternative is preferred to an asymmetric hydrogenation

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . MeO N

MeO

C2bc' (0.06 mol%) HCOOH/Et3N

MeO

DCM, reflux

MeO

95 MeO

NH

O N

MeO HCl

MsOH

CF3 90 18 kg scale

N H

CF3

CF3

92, almorexant

91 (87% AcOH salt), >89% ee

Starting imine

Process efficiency (concentration)

Catalyst cost

Flexibility (facilities)

ATH

Iminium

High

Ru/Noyori: low

Standard reactor

AH

Imine

Low

Ir/TaniaPhos: high

H2 and pressure reactor

Scheme 30 ATH versus AH for the synthesis of tetrahydroquinoline 91 on a multikilogram scale

OMe

OMe H OMe

O N O

OMe

O N

Cl

O

93

O

94, (S)-(+)-lennoxamine

catalyst: N N N N

N M

Cl

ATH vs AH: M=Ru, HCOOH/Et 3N, DMF, 1 h: 85%, 92-94% ee M=Ir, 5 bar H2, EtOH, 55 °C, 4 h: 78%, 92-96% ee M=Rh; 5 bar H2, EtOH, 55 °C, 4 h: 80%, 90-92% ee

Scheme 31 Asymmetric reduction of indolinium analogue 93. Comparison studies between Ru(II)-catalyzed ATH and AH promoted by Ir(III) and Rh(III) catalysts

method where the relative cost/kg of produced chiral intermediate is slightly higher. In addition, this technology proved to be even more cost-effective than a nonenantioselective hydrogenation/resolution process due to the overall yield achieved and the numerous solvent switches necessary for the recycling steps of the undesired enantiomer. An interesting case where comparison studies between an asymmetric transfer hydrogenation reaction using a Ru(II) catalyst and Ir and Rh promoted hydrogenation methods has been published [80]. On this report an asymmetric reduction of a tetracyclic indolinium skeleton toward the synthesis of (S)-()-lennoxamine is described for which a tetrazole-containing catalyst has been used (Scheme 31).

96

G. Talavera et al.

Cl

N N

NH2

O

1. C2ec' (2 mol%) K2CO3, HCOOH/Et3N, DCM

HCl

Cl

N N

NH

O

2. HCl

96 97%, 94% ee

O 95

Scheme 32 Intramolecular reductive amination of 95 under ATH conditions in the presence of C2ec0 Pri ArO2S

Pri

Me O N

ArO2S

Ru NH2 O

Ph

H

Me N

Ru NH2

H

+

CO2

Ph Ph

Ph 97

98

Scheme 33 Equilibrium between Ru-formate 97 and Ru-hydride species 98

Asymmetric transfer hydrogenation has also been applied to reductive amination processes. In this area, an interesting intramolecular one-pot ATH approach has been published by Wills, which has become the key step for the synthesis of the dual orexin inhibitor molecule suvorexant MK-4305 [81] (Scheme 32). This particular reductive amination has to overcome several issues listed below: 1. Preferred reduction of the in situ formed imine versus the ketone reduction (typical of reductive amination reactions) 2. Formation of a seven-membered diazepam ring 3. Intra- versus intermolecular process The excellent chiral induction obtained applying the ATH strategy has ruled out other methods such as the pressure hydrogenation reaction and catalytic procedures using chiral phosphoric acids or chiral borohydrides. It has to be noted the relevance of the bulky substituent on the sulfonamide moiety of the ligand for achieving high levels of enantioselectivity. Additionally, the equilibrium between Ru-formate and Ru-hydride species has been studied to conclude that as the catalyst concentration decreases, a lower [CO2] is in place and, thus, the equilibrium is preferentially displaced toward the Ru-H species (Scheme 33). Further mechanistic studies support the idea of a decremental effect of carbon dioxide, which is highlighted by the improved results obtained when this gas is being purged from the reaction mixture. Trapping carbon dioxide with a secondary amine toward the formation of the corresponding carbamate has proved to be beneficial to the reaction rate, although less effective than the gas removal. Optically active 2-arylaziridines can be prepared from the ATH of their corresponding saturated heterocycles as it has been demonstrated by the use of the complex formed in situ from (Ru( p-cymene)Cl2)2 and amino alcohol L8 as ligand [82] (Scheme 34).

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . .

N

H N

(Ru(p-cymene) Cl 2)2/L8

Ar

iPrOK, IPA 99

97

O O

Ar 100 up to 78% ee

N H

OH

L8

Scheme 34 Synthesis of 2-arylaziridines 100 via ATH catalyzed by in situ formed (Ru(p-cymene) Cl2)2/L8 complex

Ar

BF4-

O N R 101

C6aa'(5 mol%) HCOOH/Et3N

Ar

O N

DCM, 0 °C to RT, >16 h

∗

R 102 67-93%, 43-80% ee

R = Me, Ph

Scheme 35 ATH of arylisoxazolium tetrafluoroborate salts 101

N R

PMP

(S,S)-C2bb' (2 mol%)

CF3

HCOONa, H2O/DMF 40 °C, 8 h

103

HN R

PMP CF3

104 70-94%, 93-99% ee

Scheme 36 ATH of α-trifluoromethylimines 103 in the presence of first-generation catalyst (S,S)C2bb0

Wills et al. have reported an interesting contribution on the ATH of arylisoxazolium tetrafluoroborate salts yielding Δ4-isoxazolines in moderate to good yields and moderate enantioselectivities using C6aa0 . Interestingly, the authors have not observed side reactions related to probable ring-opening processes (Scheme 35) [83]. Acyclic imines present an increased amount of different isomers (geometrical isomers with regard to the C¼N bond together with the enamine-imine tautomers), and therefore, in contrast to ketones and their cyclic counterparts, the reduction of these substrates under ATH conditions suffers from different reaction rates and poorly stereodefined scenarios which generally lead to slightly lower conversions and enantioselectivities. Thus, the influence of the chemical nature of the substituents, particularly the group attached directly to the nitrogen atom, is certainly determinant. An excellent example explores the efficient application of ATH conditions to α-trifluoromethylimines in an aqueous system using (S,S)-C2bb0 to afford good to excellent enantioselectivities [84] (Scheme 36). The same skeleton had been previously converted into the corresponding chiral amines by using aminoindanol as ligand (Scheme 37), although in this case, an increased catalyst loading is necessary to reach relatively good enantiomeric excess values [85]. The authors demonstrated the role of the CF3 group in the reactivity,

98

G. Talavera et al. N

Cl

Cl

(Ru(arene)Cl 2)2/L9 NH2 OH

PMP

HN

HN

R

CF3 CF3

104 L9

Cl

105 ATH: 94% ee

Scheme 37 Synthesis of α-trifluoromethylimines 104 in the presence of in situ formed (Ru(parene)Cl2)2/L9 complex towards the preparation of fluorinated analogue 105

NBn

106

cat. (0.5 mol%) HCOOH/Et3N

NHBn

107 78%, 90% ee

O2S

NH N Ru Cl cat.

Scheme 38 ATH of exocyclic imine 106 catalyzed by a Ru(II) complex containing a “roofed” diamine as ligand

giving an enhanced electrophilicity to the iminic carbon, thus, providing higher chemical yields. Additionally, this transformation has demonstrated to be a powerful alternative for the preparation of enantiomerically pure aryltrifluoromethylamines that are of well-known interest in fields like medicinal or organofluorine chemistry. In Scheme 37 a fluorinated analogue of a potent plant disease control agent is depicted [86]. Another example describes the ATH of a benzyl-substituted exocyclic C¼N bond by using a Ru(II) catalyst bearing a “roofed” diamine as ligand (Scheme 38) for the synthesis of the chiral amine 107 in 78% yield and 90% ee [87]. As discussed above, good chemical conversion and stereoselectivity strongly depend on the chemical nature of the substituents. Protecting groups such as sulfonyl and phosphinyl are presented as an interesting manner to overcome the drawbacks related to the asymmetric reduction of mainly acyclic structures since their steric hindrance may lead to predominantly one geometrical isomer and, therefore, high levels of enantiofacial discrimination. Moreover, their electron-withdrawing character enhances the reactivity of the reaction due to the activation of the substrate. In this context, the asymmetric transfer hydrogenation of N-sulfinyl imines can be accomplished by using an in situ generated catalyst bearing ligand L9. This method provides highly enantiomerically enriched primary amines after the removal of the protecting group in good to excellent yields (Scheme 39) [88–91]. Due to the intrinsic chirality of the sulfur atom of the sulfinyl unit, the former reaction has been also studied in the presence of achiral amino alcohol L10 with which excellent results were obtained under similar reaction conditions [92–95].

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . .

N

O S

t Bu

R

Ar

1. (Ru(p-cymene)Cl2)2/L9 tBuOK, IPA 2. HCl, MeOH R = Me, Et, Pr, CH2Cl, (E)-CH=CHPh

108

99

NH 2 R

Ar

109 81-99%, 69->99% ee

Scheme 39 ATH of N-sulfinyl imines 108 catalyzed by in situ generated (Ru(p-cymene)Cl2)2/L9 complex

O

N

O S

R

S N

tBu

n n=2-4 R X = Cl, Br 111 70-92%, 97:3->99:1 dr

tBu

n

(Ru(p-cymene)Cl2)2

O

X 110

L10

∗

R

OH

H2 N

HN n n=1-3

X = CH2CO2Et 112 70-96%, 90->99% ee

Scheme 40 ATH of N-sulfinyl imines 108 by using achiral aminoalcohol L10 as ligand

N

O PPh 2 R

Ar 113

(Ru(p-cymene)Cl2)2/L9 tBuOK, IPA R = Me, Et

HN Ar

O PPh 2 R

114 85-90%, 80-82% ee

Scheme 41 ATH of N-phosphinyl imines 113 catalyzed by in situ generated (Ru(p-cymene)Cl2)2/ L9 complex

Following the same approach, several heterocycles have been prepared starting from halo-substituted sulfinyl imines as depicted in Scheme 40 [96]. Likewise, lactams are synthesized after the deprotection step when using N-sulfinyliminoesters. Interestingly, the opposite absolute configuration can also be achieved by simply changing the configuration of the sulfur atom on the starting material [97]. N-Phosphinyl ketimines have been subjected to the above-described ATH conditions (Scheme 41) to obtain the corresponding protected amines in excellent yields and moderate enantioselectivities [98, 99]. While good catalyst performances have been demonstrated with the judicious choice of protective group strategy, the ultimate goal of atom economy and streamlined synthesis is achieved by the direct transfer hydrogenation of unfunctionalized NH imines. This very ambitious transformation usually requires second-generation ATH catalysts, which are more active and less prone to deactivation.

100

G. Talavera et al. Br Br

Br

C6ba' (0.5 mol%) HCO2NH4

Br

DCM Br

NH OH

Br

115

NH2 OH

116 96%, 98% ee

N N H N N N iPr

N H O NHCO2Me

O

N O

iPr

MeO2CHN

Ph

117 MK-8742

Scheme 42 ATH of primary imine 115 catalyzed by tethered catalyst C6ba0 towards the synthesis of MK-8742

Merck has carried out the synthesis of the HCV NS5a inhibitor MK-8742 via a very efficient and highly stereoselective ATH protocol of a primary ketimine [81, 100, 101]. The catalyst of choice is the tethered C6ba0 that provides excellent yield and enantioselectivity at 0.5 mol% catalyst loading (Scheme 42) [102].

6 ATH Through Dynamic Kinetic Resolution (DKR) Historically, industry has had a preference toward the resolution of racemic mixtures in order to produce enantiomerically pure compounds. The use of conventional separation techniques and kinetic resolution methods by employing a resolution agent has been for decades the only alternative that was considered for large-scale purposes. Nevertheless, this approach has evident disadvantages, such as theoretical yields that can’t exceed 50% which leads to racemization/recycling cycles that have to be put in place or the issues related to low selectivity factors and high loadings of the resolution agents. The scientific community has developed an alternative which consists of combining the racemization and the kinetic resolution principles in the so-called dynamic kinetic resolution process (DKR). As illustrated in Fig. 4, an in situ racemization takes place, and thus, 100% of the racemic mixture can be converted into the desired enantiomer as long as the following conditions are observed: 1. The racemization of the starting material must be faster than the ATH reactions (Krac > K1 and K2).

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . X R2

R1

ATH K1

101

X R2

R1 ∗

R3

R3

Krac X

X R2

R1 R3

ATH

R2

R1 ∗

K2

R3

X = N, O

Fig. 4 General scheme of ATH of carbonyl compounds and derivatives via DKR

C10b (0.1 mol%) HCOOH/Et3 N DABCO

BocHN F

O

BocHN F

OH

THF, 50 °C, 24 h

F

F

118

119 93%, 96:4 dr, 99% ee

F

H 2N N N

N Ms

O F 120, omarigliptin

Scheme 43 ATH of aminoketone 118 under DKR conditions catalyzed by C10b

2. One enantiomer must react faster than the other one, and the reaction must be irreversible (K1 > K2 or K2 > K1). The ability to influence the rate of the reduction step is a key aspect. By modifying the transfer hydrogenation catalyst and conditions structurally complex chiral alcohols and amines bearing more than one stereogenic center can be readily accessible. Recently, Merck has published the multikilogram-scale process for the production of omarigliptin, a long-acting DPP-4 inhibitor for the treatment of type 2 diabetes. The ATH of a N-Boc-α-substituted ketone under DKR conditions is one of the key steps of this synthetic route which allows the preparation of the chiral 1,2-amino alcohol intermediate bearing two out of three stereogenic centers of the final target. The catalyst of choice is, in this case, the “second-generation” oxo-tethered Ru(II) complex C10b, which provided the desired molecule in excellent yield and stereoselectivity at 0.1 mol% catalyst loading. As discussed previously, the process experiments marked improvement regarding its catalytic efficiency when the generated carbon dioxide is purged with nitrogen during the course of the reaction [103, 104] (Scheme 43).

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G. Talavera et al. O

O (S,S)-C2bb' (0.2 mol%) HCOOH/Et 3N

O O Ar 121

O

DCM, 40 °C, 3 h

OH Ar 122 90-97%, 69:1- 90:10 dr, 99% ee

Scheme 44 Synthesis of phthalide analogues via ATH/DKR in the presence of (S,S)-C2bb0

O Ar

O

C2cc' (1.5 mol%) HCOOH/Et3N

OR DCM, 35 °C, 13-17 h NHBoc R = Me, Et 123

OH O Ar

OR NHBoc 124

80-99%, 6:1- >99:1 dr, 72-97% ee

Scheme 45 ATH of α-amino keto esters 123 under DKR conditions using C2cc0 as catalyst

Noyori’s catalytic system has been applied efficiently to the construction of phthalide derivatives containing functionalized 1,3-diol subunits, the most important motif in polyketides, bearing two stereogenic centers [105] (Scheme 44). Although both the conversion and the enantioselectivities are not noticeably influenced by the electronic and steric properties of the substituents on the aryl ring, the diastereoselectivity under these reaction conditions seems to be low to moderate. 1,3-Keto esters are one of the most studied motifs in ATH reactions under DKR conditions due to the high value of the different building blocks accessible upon asymmetric reduction of these structural units. Scientists at Merck have proven the applicability of this technology by preparing chiral β-hydroxy-α-amino acid derivatives with an anti configuration in one pot starting from the corresponding racemic α-amino β-keto esters. The catalyst that shows the best performance is Noyori’s analogue C2cc0 containing a very electron-deficient perfluorinated ligand. The latter has been demonstrated to be essential in order to obtain high stereoselectivity. The way to operate seems to be crucial to achieve high levels of enantioselectivity obtaining up to 91% ee when a slow and controlled addition of formic acid was performed and 73% ee when the popular HCOOH/Et3N (5:2) azeotropic mixture was used as the hydrogen source [106] (Scheme 45). Many other studies on several parameters and reaction conditions have been carried out by different research groups on the ATH of these particular frameworks [107–110]. This transformation has been also developed for racemic α-amino β-keto ester hydrochlorides [111]. Despite the broad scope regarding the aryl substituent on the ketone and the excellent results obtained when preparing some of the analogues (up to 90% yield, 99% ee), lower catalyst loadings are still desirable under these conditions (S/C ¼ 50). Likewise, this methodology can be extrapolated to α-chloro- [112], alkyl- [56], and alkoxy-substituted substrates [113] (Scheme 46) becoming an elegant and

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . (Ru(p-cymene)Cl2)2/(S,S)-TsDPEN HCOOH/Et3N

C6ba' (0.5 mol%) HCOOH/Et3N

OH O R1

103

OH O OR2

OEt O

Cl 126 50-85% 51:49-88:12 dr 59-98% ee X = Cl R = R1 = Aryl R' = R2 = Me, Et

O

R

R3

Me 127 92-97% >99% ee

OR' X 125

X = Me R= R3 R' = Et R3 = Ph, nBu, (CH2)2OBn, C(Me)2OBn

(S,S)-C2bc' (0.5 mol%) HCOOH/Et3N OH O R4

OMe OR5

128 80-100% conv 70:30-99:1 dr 74-99% ee

X = OR5 R = R4 = Aryl R' = Me R5 = Me, Et, Bn O

MsO

OH O

OEt

129 AZ-242

Scheme 46 ATH/DKR of α-substituted keto esters 125 in the presence of Ru(II) catalysts

powerful tool for the synthesis of important fragments such as syn-2-chloro-3hydroxy esters, α-methylated β-hydroxyesters, and vicinal syn diol derivatives. It has to be pointed out the group tolerance of this strategy to electron-rich and electron-poor aryl substituents, heteroaromatic compounds, and alkyl, alkenyl, and alkynyl residues. Benzo-fused cyclic ketones have been reduced via ATH/DKR in the presence of a cyclic analogue of the well-stablished RuCl[(R,R)-TsDPEN](η6-p-cymene), generated in situ from (Ru( p-cymene)Cl2)2 and L11. In the case of five-membered cyclic ketones, excellent results in terms of conversion and stereochemical control have been obtained. The same situation has been found with 2-methoxycarbonyl-1indanone, although when switching to 3- and 4-substituted regioisomers, the catalyst does not show any diastereoselectivity. Noticeably, non-functionalized substrates like 1-indanone, 1-tetralone, and 4-chromanone can be successfully reduced under the described conditions at S/C ¼ 1,000 catalyst loading [32] (Scheme 47). McErlean and co-workers have demonstrated that when the ester function is situated at the γ-position of the indanone framework, tricyclic structure 134 can be prepared upon a subsequent lactonization step of the resulting hydroxyester [114]. This intermediate has been further transformed into the strigolactone (+)GR24 and ()-GR24 (Scheme 48).

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G. Talavera et al. O

n = 1,2 130

OH n CO 2Me

(Ru(p-cymene)Cl2)2/L11 HCOOH/Et3N

Ph

n CO 2Me

DCE, 40 °C, 3-6 h

NH 2

NH S O2 L11

131, indanone derivatives 100% conv, 95:5-97:3 dr, >99% ee 132, tetralone derivatives >99% conv, 50:50-98:2 dr, >99% ee

Scheme 47 Synthesis of indanone (131) and tetralone analogues (132) via ATH/DKR

O

O

2)2/(S,S)-TsDPEN CO2Et 1. (Ru(p-cymene)Cl HCOOH/iPr2NEt, iPrOH, 40 °C

O

2. PPTS, reflux 134

133

80%, >99:1 dr, 92% ee

O

O

O

O O

135 (+)-GR24

Scheme 48 Synthesis of indanone derivative 134 via ATH/DKR towards the preparation of strigolactone 135 O

O Ar

136

(S,S)-C2bc' (2.5 mol%) HCOOH/Et3N

OH O Ar

dioxane, 50 °C 137

67-85%, 92:8->99: dr, 93-99% ee

Scheme 49 Synthesis of β-hydroxy ketones 137 under ATH/DKR conditions by using C2bc0 as catalyst

In a similar approach, 2-aroyl-1-tetralones have been subjected to ATH/DKR conditions affording β-hydroxyketones with good to outstanding stereoselectivities becoming an interesting alternative to asymmetric aldol reactions [115]. It is important to highlight the relevance of the extra level of rigidity that the fused ring system is offering for a good stereochemical control of the reaction (Scheme 49). β-Keto Weinreb amides have been shown to be good substrates for ATH under DKR conditions toward the synthesis of β-hydroxy-α-alkyl-substituted Weinreb amides. In this regard, the synthesis of an advanced intermediate of the crocacin family has been accomplished for which a ATH/DKR step seems to be essential for the construction of the anti-anti-syn stereotetrad structural motif [116]. In the

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . Ru(p-cymene)[(R,R)-(TsDPEN)] (1 mol%) IPA OH O O N R1 R2 141 R2 = Me, Et,

C2bc' (1 mol%) HCOOH/Et3N O

O

OH O N

R

O

N

R'

139 94% 94:6 dr 98% ee

Ph

,

75-95% 70:30-95:5 dr 65-98% ee

O H

O

O

Ph

138

O

R1 = CH2OBn, (CH2)2OBn,

105

OH H N H

OMe OMe Ph

O NH2

O

142, (-)-brevisamide

140, crocacin C

Scheme 50 ATH of β-keto Weinreb amides 138 under DKR conditions

presence of C2bc0 and HCOOH/Et3N as hydrogen source, the syn configuration of the desired structural unit has been obtained in high diastereoselectivity but moderate yield and enantiomeric excess. However, when the isolated 16-electron ruthenium complex Ru[(R,R)-TsDPEN](η6-p-cymene) is used a significant improvement can be observed with lowered catalyst loading. The synthesis of stereodefined δ-/γ-alkoxy-β-hydroxy-α-alkyl-substituted Weinreb amides containing two successive hydroxyl-alkyl stereocenters has been accomplished for the preparation of an intermediate of ()-brevisamide [117]. Interestingly, for this specific transformation, the presence of δ- or γ-benzyloxy or alkoxy groups is crucial for the reaction to occur. The key step has been scaled up to 10 g for the preparation of the pyran ring of the final target (Scheme 50). Morpholinone derivatives have been addressed adding 0.5 mol% of C2bb0 to efficiently obtain the corresponding chiral alcohols in excellent diastereo- and enantioselectivity. Four stereoisomers of the antidepressant reboxetine have been prepared using this protocol [118] (Scheme 51). Racemic β-substituted α-keto esters are suitable motifs for ATH under DKR conditions. Since the first case published by Johnson and co-workers [119], a plethora of enantiomerically pure α-hydroxy ester derivatives have been prepared applying this method. In an elegant fashion and using a bulky DPEN-type ligand (L12), polysubstituted γ-butyrolactones have been synthesized with full diastereocontrol in a one-pot ATH/lactonization sequence due to the presence of an ester group conveniently situated at the γ-position. Similarly, substrates containing an aryl ketone functionality have been chemoselectively reduced to the corresponding chiral alcohols [120]. Interestingly, enantioenriched syn chlorohydrines have been prepared using this strategy, becoming a big contribution to the catalytic asymmetric synthesis of such fundamental building blocks. Anti-α-hydroxy-β-amino acid derivatives are another high-value motif that has

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O N Bn

O

H

O

R DCM, 35 °C, 3 h

N Bn

OH

R

O 144

143

90-98%, 96:4-99:1 dr, 95-99% ee R=H

EtO

O

H

N Bn

O

O

145, (S,S)-reboxetine

Scheme 51 Preparation of (S,S)-reboxetine by ATH/DKR of morpholinone analogue 143

(Ru(p-cymene)Cl2)2/L12 R2 = CO2Me HCOOH/Et3N EtO2C

R1

O

O 147 82-94% >20:1 dr 78-93% ee R1 = Ar

R1

O

CO2Me

N H

PG

R2

EtO CO2Me

(Ru(p-cymene)Cl2)2/L12 HCOOH/Et3N

R2 =

R2 Ph

EtO

O

OH

146

Ph H N S O2 NH2

O

148 65 - 77% >20:1 dr 94 - 97% er R1 = Ph PG = Boc, Cbz Ph

L12

Scheme 52 ATH of β-substituted α-keto esters 146 under DKR conditions

been prepared via ATH/DKR. Except for the alkyl-substituted compounds, it is worth mentioning the excellent levels of diastereocontrol reached on these transformations and the great tolerance to electronically diverse aromatic systems [121, 122] (Scheme 52). In addition to the different functionalities that have been covered, phosphonates and sulfonamides also play an important role in ATH/DKR transformations. In this sense, racemic α-alkoxy-β-keto phosphonates have been reduced using C2bb0 and a HCOOH/Et3N (1:5) azeotropic mixture as hydrogen source yielding syn monoprotected 1,2-dihydroxy phosphonates in high yields and variable stereoselectivities depending on the different substituents [123] (Scheme 53).

Structural Diversity in Ruthenium-Catalyzed Asymmetric Transfer. . . O R1

C2bb' (0.5 mol%) O HCOOH/Et3N P(OR3)2 35 °C, 2-6 h OR2

R1

OH O P(OR3)2

R1 = Ar, Me, Et, (CH2)2Ph R2 = Bn, Me R3 = Me, Et

149

107

OR2 150

95-99%, 60:40-99:1 dr, 44-99% ee

Scheme 53 Asymmetric reduction of α-alkoxy-β-keto phosphonates 149

Ar R1 O

(Ru(p-cymene)Cl2)2/L12 O Ar HCOOH/Et3N P(OMe)2 R1 DMSO, RT, 10 h R1 = Me, Et, ,

151

,

O P(OMe)2 OH 152

Ph ,

84-94%, 5:1->20:1 dr, 97-99% ee

Scheme 54 Asymmetric reduction of acyl phosphonates 151

Cl O O S NH n O 153

Cl

(Ru(p-cymene)Cl2)2/(S,S)-TsDPEN HCOOH/Et3N dioxane, RT, 24 h

OH O S NH n O

∗ ∗

n=1 154, 88%, >99:1 dr, 98% ee n=2 155, 91%, >99:1 dr, 99% ee

Scheme 55 ATH/DKR of indanone and tetralone derivatives 153 containing a sulfonamide group

Acyl phosphonates have been converted into their anti-α-hydroxy phosphonate derivatives promoted by a first-generation-type catalyst bearing the bulky ligand L12 to give very high enantioselectivities [124] (Scheme 54). Indanone and tetralone analogues bearing a sulfonamide group (153) deliver diastereo- and enantiomerically pure β-hydroxysulfonamides [125], chiral synthetic synthons of high value not only due to their synthetic versatility but also their biological properties (Scheme 55).

7 Conclusions The impact of the ATH strategy on the chemoselectivity of the reactions has been evidenced by the amount of diverse examples described along this chapter. In this review, we have focused on selected examples either coming from industry or describing the preparation of natural products. In most cases, these are targets of much higher structural complexity than the simple substrates reported in academic environment to provide proof of principle of the technology. Diastereoselective

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reductions and dynamic kinetic processes target molecules with several stereogenic centers. The efficient reduction of complex substrates always involves optimization either of the reaction conditions or of the catalyst’s structure. The latter is a powerful tool but ultimately any increased complexity of the catalysts must lead to very significant technical advantages (increased enantio- or chemoselectivity, activity, reduced loading) to be economically viable. “First-generation” ATH catalysts bearing sulfonyl-diamine ligands have been optimized by acting on the structure of the backbone or of the sulfonyl group. A few cases can be highlighted where older, less commonly used ligands, such as chiral amino alcohols, still play a role. The need to work on substrates of increased complexity brings into the picture “second-generation” ATH catalysts, such as the tethered catalysts, which provide increased and, in some cases, unique performance. A number of the examples we have reported highlight the advantages of ATH if compared to non-chiral methodologies as well as compared to pressure hydrogenation catalysts. What is usually not addressed in the academic literature is the required trade-off between performance (activity or enantio- or diastereoselectivity) and the increasing complexity of the catalyst (which has a bearing on catalyst cost and commercial availability). This aspect very much concerns the industrial chemists and plays a crucial role in the practical choice of which technology to apply. While the ever-growing body of available literature on many different substrates and under many different experimental conditions strongly supports the choice of ATH as a robust and effective catalytic methodology, it still remains the task of the synthetic chemists, through their experience and judicious experiments, to assess on a case-by-case basis the value brought by the different catalysts and experimental conditions.

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Top Organomet Chem (2019) 65: 115–160 DOI: 10.1007/3418_2019_31 # Springer Nature Switzerland AG 2019 Published online: 27 September 2019

Application of Organometallic Catalysts in API Synthesis Debjit Basu, Srinivas Achanta, N. Uday Kumar, Rajeev Bhudhdev Rehani, and Rakeshwar Bandichhor

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Asymmetric Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 α-Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 β-Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Chiral Carboxylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Chiral Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Chiral Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 C-H Functionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Cyclopropanation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Hydroformylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Cross-Coupling for the Formation of Carbon-Carbon and Carbon-Heteroatom Bonds . . . 6.1 Cycloaddition Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Transition Metal-Catalyzed Transformations in Batch and Continuous Mode . . . . . . . . . . . . 8 Conclusion and Prospect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

115 116 117 119 123 125 128 130 134 136 137 137 140 156 156

Keywords Active pharmaceutical ingredients (API) · Catalysis · Organometallic

1 Introduction Inherent creativity in synthetic organic chemists is hallucinogenic and found to have potential to impact global healthcare industry incredibly by executing contemporary organometallic strategies to manufacture the products of varied interest. Application D. Basu, S. Achanta, N. U. Kumar, R. B. Rehani, and R. Bandichhor (*) Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Qutubullapur, Telangana, India e-mail: [email protected]

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of organometallics in chemical industry has intensely perfected the manufacturing of the materials right from trade goods to very personalized medicines without generating significant amount of waste. In pursuit of drug development, two types of challenges are encountered. The first one is related to design of the molecules, and the second is related to the manufacturing of these at commercial scale. Contemporary organometallics in the context of drug development and process research have advanced the toolbox of enabling technologies for addressing these challenges posed during drug development. In particular, transition metals in different oxidation states along with or without fully decorated chiral or achiral ligands are evidently well placed in synthetic organic chemistry landscape. These metals technically enable the scientists to architect various C-C and C-X bonds to achieve the synthesis of simple to highly complex framework toward rendering the manufacturing of the life-saving medicines in a sustainable manner. Success in organometallic strategy depends on strategic route selection featuring fit-for-purpose catalysts aiming at chemoselective, regioselective, and stereoselective products of choice. There are other critical process parameters that need to be under control to further ensuring the successful material production. Most of the catalytic processes offer very many advantages over stoichiometric reagent-based approaches. Through these strategies, material production can be achieved with high atom efficiency along with substantially minimized PMI (process mass intensity) and in a cost-effective manner. In particular, transition metal-catalyzed processes have been extensively utilized in the pharmaceutical industry [1, 2]. They have been employed for library preparations, discovery syntheses, and large-scale manufacturing of active pharmaceutical ingredients [3]. When compared with the traditional methodology, metal-catalyzed reactions provide greater efficiency with tolerance to numerous functional groups and also provide high enantio-, diastereo-, and chemoselectivity. The most commonly applied transition metal-catalyzed reactions and their application to the synthesis of chiral building blocks are discussed in this chapter.

2 Asymmetric Hydrogenation Asymmetric hydrogenation is the most significant asymmetric technology utilized to establish chirality in pharmaceutical products. Asymmetric hydrogenation can be considered as one of the powerful strategies for installation of chirality into drug substances [3]. In this context, Ru-, Rh-, and Ir-catalyzed asymmetric hydrogenation has found numerous applications in the large-scale synthesis of API. Application of asymmetric hydrogenation for the construction of nonnatural amino acids, chiral carboxylic acids, chiral amines, and chiral alcohols will be discussed in this section.

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α-Amino Acids

In the past few years, nonnatural amino acids have found numerous applications as pharmacologically active products and as chiral building blocks. While the traditional synthetic approaches toward amino acids, namely, resolution by diastereomeric crystallization, enzymatic resolution of derivatives, and separation by chiral chromatography, are amenable to scale-up, all of them suffer from the major limitation where 50% is the highest hypothetical yield. Enantioselective catalytic asymmetric hydrogenation and enzymatic synthesis have addressed this limitation, and both continue to provide an attractive and potential method for the preparation of these building blocks. The synthesis of unnatural N-Boc D-phenylalanine derivative 11 using catalytic Rh asymmetric hydrogenation on 150 kg scale was reported by Fox et al. [4]. Two potential routes were envisioned for the assembly of this compound, both differing mainly on the stage at which piperidine moiety is appended on to the molecule. Introduction of the piperidine moiety after the asymmetric hydrogenation was chosen as late-stage hydrogenation would not provide a handle to remove residual metal impurities. The key steps in the synthesis include selective monoreduction of one aldehyde group of terephthalic dialdehyde followed by Erlenmeyer condensation to generate azlactone 6. Subsequent ring opening/o-deacetylation with methanol provided N-acetyl dehydroamino acid exclusively as the (Z)-geometric isomer. Asymmetric hydrogenation of enamide 7 using [((R,R)-Ethyl-DuPhos)Rh(COD)] BF4 proceeded with 95% yield and >98% ee. Mesylation/displacement of the benzyl alcohol with cis-2,6-piperidine followed by Boc group introduction and basic hydrolysis for the deprotection of acetyl group led to the desired Boc-protected amino acid derivative 11 as shown in Scheme 1. Another application of asymmetric hydrogenation on multikilogram scale is the synthesis of α-amino ester moiety present in the calcitonin gene-related peptide (CGRP) antagonist. There is a severe unmet need for the long-term treatment of migraine headaches, and CGRP antagonists are under investigation as potential antimigraine agents [5]. Compound 21 was identified as a potent and effective competitive CGRP antagonist for clinical evaluation and was required on kilogram scale for taking it to the next phase of development. Two novel routes, namely, biocatalytic route using transaminase and catalytic asymmetric hydrogenation, were explored by the discovery group to address the need for material [6]. While each route offered different advantages, Rh-catalyzed asymmetric hydrogenation (Scheme 2) provided a fast and clean reaction with excellent volumetric efficiency in addition to having fewer steps when compared with the biocatalytic route using transaminase. The discovery route had significant issues: firstly the use of isolated amido acrylate 14a which was prone to polymerization, secondly the use of ICl for iodination which produced colored impurities, and finally the indazole ring interfered with asymmetric hydrogenation. These issues were systematically addressed by using amido acrylate 14a as a solution instead of isolation, the use of benzyltrimethylammonium dichloroiodate (BTMACl2I) as a replacement for ICl,

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Scheme 1 Synthesis of unnatural N-Boc-D-phenylalanine derivative HO

HO

ClCO2Bn, NaHCO3 NH2 HCl

MeO2C

MTBE/H2O

NHCO2Bn

MeO2C 14

13

MsCl, Et3N THF, 90% 14a

NH2 HCl

NH2 BTMACl2I, K2CO3 MeOH/DCM then HCl/IPA, 81%

MeO2C

NH2

NH2 HCl 1. MSA, DCM

Pd(OAc)2, K2CO3 THF/H2O, 66%

I 16

15

NHCO2Bn

2. aq K2CO3 17

NHCO2Bn

80%

18

NHCO2Bn CO2Me

CO2Me crude

NH2 MSA

1. H2, Et-FerroTANE-Rh DCM/MeOH 2. MSA, 96.1%, 99% ee

Et

Et P P Et

Fe Et

P Et (+)-(R,R)-Et-DuPHOS

HN N

1. H2, Pd/C, MeOH, DCM

1. K2CO3, EtOAc, H2O

NHCO2Bn CO2Me

2. HCl/IPA

2. i-AmONO, KOAc, HOAc, EtOAc, 72%

19

Et Et P Et (+)-(R,R)-Et-FerroTANE

Scheme 2 Synthesis of CGRP antagonist

HCl HN N

NHCO2Bn 20

CO2Me

84%

NH2 HCl 21

CO2Me

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and finally deferring the installation of indazole moiety until after the hydrogenation step. However, the downstream processes still provided challenges during the execution of asymmetric hydrogenation and are the highlights of the synthesis. For example, the variability in reaction rate was addressed by incorporating a hot filtration of the enamide 18 in ethyl acetate to remove residual chloride ions followed by crystallization before proceeding to hydrogenation. The catalyst life was improved by changing the ligand from DuPHOS to Et-FerroTANE ligand. Unfortunately, despite these advantages, exhaustive purification of the enamide substrate to achieve a high turnover number (TON) of the Rh catalyst and the use of a proprietary catalyst from a single vendor and stringent limits on the residual metal content (Pd and Rh) in the final API led to the selection of biocatalytic route for further development for material generation.

2.2

β-Amino Acids

The application of asymmetric hydrogenation to the synthesis of β-amino acids did not garner as much attention as it did with the synthesis of α-amino acids. One of the reasons is the additional steps required for accessing these basic building blocks. Figure 1 summarizes the various strategies used for the synthesis of β-amino acids from β-keto esters [7]. In this section large-scale application of routes 2, 3, and 4 will be discussed. Generalized anxiety disorder (GAD) is a psychiatric disorder which can impact normal social functioning. Drugs like gabapentin (Neurontin) [8] and pregabalin OH R

OLG CO2R'

R

23

CO2R' 24

N3 R

CO2R' 25

Route 1

O

NH2

Route 2

CO2R'

R

R

22

CO2R' 26

Route 3 NH2 CO2R'

R 27

Route 4

R

NHAc CO2R' 28

R

NHAc CO2R' 29

Route 1. Asymmetric hydrogenation via β-chiral alcohols followed by SN2 with azides and reduction Route 2. Direct reductive amination of β-keto ester Route 3. Asymmetric hydrogenation of an unprotected b-enamine ester Route 4. Asymmetric hydrogenation of enamides

Fig. 1 Various routes to β-amino acids

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1. CDI, EtOAc

Me

30

Me

32

CO2Et

2. EtO2CCH2CO2K, MgCl2 Et3N, EtOAc, 40 oC

NHAc CO2Et

1. NH4OAc, EtOH

O

CO2H 31

1. [Rh(1,5-COD)(R)-TCFP)]BF4 H2 (0.5 bar), EtOH, MeOH 2. 6N HCl 3. IPA/toluene

Me

BF4

62%, >98% de

33

2. Ac2O, Pyridine Isooctane, 86%

NH2 HCl COOH

Imagabalin hydrochloride

Rh P

P

[((R)-TCFP)Rh(COD)]BF4

Scheme 3 Synthesis of imagabalin hydrochloride

(Lyrica) [9] which are used to treat this disorder are α2δ ligands and act on the voltage-dependent calcium channel to decrease the release of neurotransmitters such as glutamate and norepinephrine. Imagabalin hydrochloride (PD-0332334) 33 was identified as a promising candidate in this regard and development of a scalable and cost economical route for supporting preclinical and clinical activities was of utmost importance. Medicinal chemistry route used (S)-(
)-β-citronellol from the chiral pool as the starting material, and the β-amino acid moiety was constructed by a diastereoselective enolate alkylation followed by a Curtius rearrangement [10– 12]. To overcome the limitations of the medicinal chemistry route, a secondgeneration route was developed wherein the two stereocenters (5R and 3S) were introduced through diastereoselective asymmetric Michael and aza-Michael addition reactions [10–14]. While the second-generation route provided multikilogram quantities, major limitations were the use of cryogenic conditions and the loss in yield due to diastereomer enrichment through crystallization. This necessitated the search for an alternative route. Finally, a more expedient and cost-effective route using Rh-catalyzed asymmetric hydrogenation was developed and demonstrated on metric tons scale with an overall yield of 40–47% over four steps from (R)-3methylhexanoic acid 30 [15]. Synthetic sequence includes esterification to obtain 31 followed by condensation of keto ester with ammonium acetate to afford enamine intermediate 32. The resultant 32 was subjected to asymmetric hydrogenation to give rise 33 as shown in Scheme 3. Human immunodeficiency virus (HIV) is a viral infection that if left untreated leads to terminal medical condition called acquired immunodeficiency syndrome (AIDS). Antiretroviral drugs are medication for HIV treatment and are classified into six categories, namely, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INSTIs), fusion inhibitors (FIs), and chemokine receptor antagonists (CCR5 antagonists). Developed by Roche, R05114436 is a promising CCR5 receptor antagonist candidate for HIV treatment. Retrosynthetic analysis of 43 leads to three key building blocks, β-amino ester 36, pyrrolidine 39, and carboxylic acid derivative of 42. Stereoselective synthesis of β-amino ester 36 via highly enantioselective reductive amination reaction using Ru catalyst is the highlight of

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the synthesis [16]. Unfortunately, attempted synthesis of β-amino ester either by using resolution of the racemic 36 via diastereomeric salt formation and enantioselective hydrogenation of the unprotected enamine was unsuccessful. In the end, a highly enantioselective asymmetric hydrogenation with ruthenium catalyst and (R)-MeOBIPHEP as ligand was used to install the benzylamine stereocenter present in RO5114436. The crude mixture with 95–96% ee was further enriched to >99.5% ee by recrystallization and converted to the API in a series of straight forward steps as shown in Scheme 4. Synthetic landscape includes homologation of 34 to obtain keto ester 35 followed by in situ enamine intermediate that was subjected to asymmetric hydrogenation to afford enantiomerically pure intermediate 36. Resultant 36 was converted to Boc-protected amine 37 followed by reduction to obtain corresponding aldehyde 38. Reductive amination in presence of amine 39 on 38 leads to the formation of advanced intermediate 40. Boc deprotection followed by tartrate salt formation gave rise stereochemically enriched penultimate API 41. Free base of salt 41 followed by acylation in presence of 42 afforded final API 43 in good yields. (S)-3-Amino-4-methoxy-butan-1-ol is a useful starting material in fine chemical industry. Previously reported syntheses used commercially available aspartic acid and L-homoserine benzyl ether as the starting materials for executing the synthetic routes [17]. Chromatographic purifications at several stages and the use of Ag2O were some of the limitations that necessitated search for new scalable route. The construction of β-amino alcohol is the key aspect, and both reductive amination of βketo ester 44 and asymmetric hydrogenation of enamine 45 were evaluated from a common starting material. Commercially available methyl 4-methoxyacetoacetate 44 was chosen as the common starting material for the synthesis. Notable feature of this compound is the already installed methyl ether moiety needed in the final product, thus avoiding additional steps to establish this functionality at a later stage [18]. The common intermediate from both the routes leading to (S)-3-amino4-methoxy-butan-1-ol is the β-amino ester 48. The desired substrate for asymmetric catalytic hydrogenation was isolated as a single Z-isomer of the unprotected enamine 45 by treating the β-keto ester 44 with ammonia gas with high purity (GC > 99%) after distillation. Subsequent enantioselective catalytic hydrogenation using [Ru(OAc)2((R)-MeOBIPHEP)] catalyst, 1 equiv of AcOH in MeOH at 60 bar, 80 C, S/C 1000 led to the β-amino ester with high enantioselectivity (97% ee). Further enrichment of the enantioselectivity was achieved via crystallization from ethyl acetate/heptane with 99.4% ee and 54–64% yield of 48 (Scheme 5). Alternatively, direct reductive amination of the β-keto ester in the presence of ammonium acetate using [Ru(OAc)2((R)-3,5-Xyl-MeOBIPHEP)] catalyst produced 48 with comparable enantioselectivity (98% ee). Further crystallization led to enrichment of ee to 99%. It is possible that a similar active species, primary imine, in both the routes is presumably the reason for the comparable enantioselectivities. In the end, (S)-3-amino-4-methoxy-butan-1-ol was prepared via asymmetric reductive amination and asymmetric hydrogenation with ee values of 97–98% which was upgraded to 99% by crystallization. Subsequent reaction sequence includes Boc

37

NH2

41

N

N

O HO

HO

2. DMSO/SO3.Pyr Et3N, DCM

NHBoc CO2Et 1. Red-Al, Me-THF

EtOAc, KO Bu, THF

t

Scheme 4 Synthesis of CCR5 receptor antagonist

F

F

F 34

CO2Et

O

O

F

OH OH

F

Bn

O OH

N

O Cl

42

O

1. 3 N NaOH, Me-THF 2. Et3N, Me-THF 3. Conc. HCl, aceton/water

HO

O

HN

O

Na(OAc)3BH, DCM

39

F

F

43

HN

40

NHBoc

O

O

N

N

N

N

O

O

76% from 9 (5 steps)

1. 3N HCl, Toluene, 50 oC 2. L-tartaric acid, EtOH/EtOAc

36

F

45% (2 steps) 100% ee PPh2 PPh2

NH2 HCl (Boc)2O, Me-THF CO2Et Sat.aq.NaHCO3

H2, NH4OAc, CF3CH2OH, (R)-MeOBIPHEP, Ru(II)(OAc)2 Toluene, 75 oC, 100 psig

MeO (R)-MeOBIPHEP MeO

CO2Et

NHBoc CHO

38

35

O

122 D. Basu et al.

Application of Organometallic Catalysts in API Synthesis NH3 gas neat, 20-32 oC

O CO2Me

MeO

NH2 CO2Me 45 methyl (Z)-3-amino-4-methoxybut-2-enoate MeO

44 methyl-4-methoxyacetoacetate

90-93% distillation

H2, 60 bar 46, S/C 1000 1 equiv AcONH4 MeOH, 80 oC

Ar MeO MeO

98% ee crude 56-61% cryst 99% ee cryst

MeO

123

H2, 60 bar 46, S/C 1000 1 equiv AcOH MeOH, 80 oC

Ar

P P Ru(OAc)2 ArAr

97% ee crude 54-64% cryst 99.4% ee after cryst

46: Ar = Ph

NH2 HOAc CO2Me 48 Boc2O, Et3N MeOH or DCM

MeO

NHBoc CO2Me 49

LiBH4 or NaBH4 MeOH, THF

NH2 HCl

NHBoc MeO

1.25 M HCl in MeOH MeO OH

50

80-85% (3 steps)

51

OH >99% ee

Scheme 5 Synthesis of (S)-3-amino-4-methoxy-butan-1-ol

protection to obtain intermediate 49 followed by reduction to obtain 50. Resultant 50 is subjected to Boc deprotection and HCl salt formation leading to final compound 51.

2.3

Chiral Carboxylic Acids

Diabetes is a metabolic disorder which results in high blood sugar levels over a prolonged period. Three main types of diabetes are known, namely, type 1, type 2, and gestational diabetes. Among three main types of diabetes, type 1 diabetes accounts for 90% of the cases in. According to projection by World Health Organization (WHO), by 2030, diabetes will be the seventh leading cause of death worldwide. Hence, there is an unmet need for new medication for the treatment of diabetes. Identification of small molecules which can activate glucokinase (GK) for the treatment of type 2 diabetes is long known [19]. Roche’s R4940 showed promising results in clinical trials, and hence, a large-scale synthesis for the supply of this molecule to continue further development was required. Retrosynthetic analysis of R4940 showed that it can be assembled by two chiral building blocks, trisubstituted α-aryl β-alkyl carboxylic acid 52 and the pyrazine diol (structure not shown). While several successful stereoselective syntheses of α-alkyl β-aryl carboxylic acids and α,β-diaryl carboxylic acids using asymmetric hydrogenation are known (for α-alkyl β-aryl carboxylic acid derivatives, see, for instance, [20–25]; for α,β-diaryl carboxylic acid derivatives, see [26–28]; for α,β-diaryl carboxylic acid derivatives and α-alkyl β-aryl carboxylic acid derivatives, see [29–34]), only few examples of α-aryl β-alkyl carboxylic acids are reported. The major limitation is the

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Cl

Cl

OH aq H O , HCO H 2 2 2 O

MeS

50 oC, 93%

OH

i. Ac2O, AcONa, THF, 40 oC, 25 h

O

MeO2S

54

53

52

CHO

ii. Cy2NH, Me2CO, heptane, 72% Ru(OAc)2 (S)-L, S/C 50000 MeOH, 50 bar, 50 oC, 17 h

MeO2S MeO 56 MeO

PAr 2 PAr 2

OH NHCy2 O

MeO2S 55

E/Z 98.4:1.6

i. aq H2SO4 Cl

92.1% ee

Cl

OH NHCy2 O 57

Cl

OH

ii. 2-PrOH, rt to -10 oC 96.9% ee, 92.5%

O

MeO2S 58

R4940

L, Ar = 3,5 Me-C6H3

Fig. 2 Synthesis of R4940

moderate enantioselectivities observed during the hydrogenation of α-aryl β-alkyl acrylates primarily with Rh and Ir catalysts [35–39]. However, the use of Ru catalyst for the synthesis of these substrates has seen limited application and is the notable feature of this synthesis [40]. The synthesis of the key intermediate acrylic ester 55 required for asymmetric hydrogenation was prepared in two steps starting from the commercially available 3-chloro-4-(methylthio) benzene acetic acid 52. Oxidation to the sulfone followed by Perkin reaction with the carboxaldehyde 54 provided the crude desired compound. The crude product was further purified by converting it to dicyclohexylamine salt 55 and isolated as a 98.4:1.6 E/Z mixture. Attempted asymmetric hydrogenation with Rh, Ir, and Ru catalysts and various ligands (e.g., 56) provided ee values (in the range of 91–94%) less than the desired target 57 in 95% yield. Further enrichment of optical purity was achieved by crystallization from 2-propanol. Fortunately, due to the high S/C ratio (~50,000), additional measures to control the amount of Ru catalyst in the API fragment 58 were not required as it was already below the ICH allowed limit for residual metal content (10 ppm). In the end the desired target 58 was achieved using a highly efficient Ru-catalyzed asymmetric hydrogenation with 97–99% ee after crystallization (Fig. 2). Cardiovascular diseases (CVD) are the number one cause of death globally. Coronary artery disease (CAD) is within the group of CVDs and occurs when the supply blood to heart muscle becomes hardened and narrowed due to the buildup of cholesterol and fatty acids. Phospholipase inhibitors are used for treating CAD, and AZD2716 was identified as a potential candidate by AstraZeneca [41]. A costefficient synthesis of enantiomerically pure α-chiral carboxylic acid present in the drug was the major limitation in the first-generation synthesis which utilized resolution of the racemic active pharmaceutical ingredient (API) leading to 50% loss of API in the last step. An attractive alternative strategy is the asymmetric hydrogenation of alkenoic acids to generate enantiomerically pure carboxylic acids. The chiral α-methyl carboxylic acid moiety present in AZD2716 was prepared by Rh-catalyzed

Application of Organometallic Catalysts in API Synthesis

Br

OH

MeOH/toluene, 19 bar, H2, 20 oC Rh-J-505 cat (1 mol%), 48 h

NH2

O

Br

O B B

62

O

O

OH

O

59

(R)

1.

125

R2P

PR'2

2. HCl

Fe

97% ee, 75% (overall)

63

O

Pd(dtbpf)Cl2, KOAc dioxane, 90 oC

90% ee 60 R = t-Bu 61 R' = 2-MePh Bn

Bn O

B

Pd(dtbpf)Cl2, K2CO3 water/dioxane, 100 oC

O

NH2

NaOH, 2-propanol

CN

O 57% (over 2 steps)

Bn OH 64 (R)

O

OH

OH CN

65 Cl

66

O

67 AZD2716 O

1. Org. Process Res. Dev. 2011, 15, 353. Fig. 3 Synthesis of AZD2716 [19]

asymmetric hydrogenation with 90% ee [42]. Further enrichment in ee was achieved by salt formation with (R)-1-phenylethylamine followed by crystallization to 97% ee. Compared with the first generation of synthesis (8% overall yield), enantioselective large-scale hydrogenation provided AZD2716 with an overall yield of 22% (Fig. 3).

2.4

Chiral Amines

Urinary incontinence (UI) is uncontrolled leakage of urine and can significantly impact the quality of the social life of a person. Urinary antispasmodics are used to control the symptoms of urge incontinence due to overactive bladder. Solifenacin succinate salt (Vesicare) is an approved drug to treat overactive bladder [43]. Industrial synthesis of solifenacin involves a classical resolution of the racemic amine 73 via the corresponding tartrate salt. The desired enantiomerically enriched chiral amine 73 is then converted to API. The racemic amine 73 so far is prepared from the amide 70 using Bischler-Napieralski cyclization followed by achiral reduction of the imine 72. These resolution-based approaches to separate racemic API or the corresponding intermediates have a major limitation of loss of 50% of the precious API irrespective of the stage at which resolution is achieved. Stereoselective synthesis of the chiral amine can address this limitation. Notable feature of this synthesis is the reduction of phenyl substituted imine 72 which known to be a challenging substrate for asymmetric reduction. Only a very limited number of transfer hydrogenation and hydrogenation catalysts have been reported to be successful for 1-aryl-3,4-dihydroisoquinolines. Ir-catalyzed asymmetric hydrogenation of the 72 (HCl salt of 71) was utilized for the synthesis of 1-(S)phenyl-1,2,3,4-tetrahydroisoquinoline present in the API [44]. Successful validation

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D. Basu et al.

H N

O NH2 68

CH2Cl2, Et3N

+

0-5 C then reflux 69

93% 72

N

88%

70

60%

N HCl

POCl3, P2O5 Xylene, 140 oC

o

2-phenylethan-1-amine

HCl. TBME

O

Cl 71

[Ir(COD)Cl]2-(S)-P-Phos (S/C = 850/1 - 1275/1) i-PrOH/H2O = 1/3 N

NH THF/H3PO4 (1.8 equiv) 60 oC, 20 bar H2 Quant, 97% ee

83 oC to 0-5 oC 95%, 98% ee

O O

73

N

74 Solifenacin

Fig. 4 Asymmetric hydrogenation process for the preparation of solifenacin

Fig. 5 Synthesis of (S)-1-(2-(methylsulfonyl)pyridin-4-yl)propan-1-amine

of this technology on 200 g scale led to the isolation of the hydrogenated intermediate amine 73 with 97.8% HPLC purity and 97% ee. Further recrystallization from i-PrOH/water (1/3) led to the upgrade of enantioselectivity from 97% ee to 98% ee, in 95% yield (Fig. 4). A highly enantioselective Rh-catalyzed enamide hydrogenation was utilized for the synthesis of (S)-1-(2-(methylsulfonyl)pyridin-4-yl)propan-1-amine 80, a chiral intermediate in the drug development program in Boehringer Ingelheim [45]. Notable achievements in the synthesis include (1) short and efficient synthesis of the starting material 2-sulfonyl 4-pyridyl ethyl ketone, (2) direct condensation of the ketone with propionamide resulting in a highly diastereoselective Z-isomer, (3) Rh-catalyzed asymmetric enamide hydrogenation with in-house-developed ligand MeO-BiBOP, and (4) a mild epimerization-free deprotection using Koenig’s procedure (Fig. 5). Congestive heart failure (CHF) is a condition that leads to the buildup of fluid around the heart and leads to “heart failure.” The most common cause is coronary artery disease (CAD) and myocardial infarction (heart attack). As discussed in the earlier section, this is the leading cause of mortality and morbidity in the industrialized world. Etamicastat 84 is a selective dopamine β-hydroxylase (DBH) inhibitor and currently in clinical development for the treatment of hypertension and heart failure. (R)-3-Amino-6,8-difluorochroman 83 is a common intermediate in all known syntheses reported so far, and a highly stereoselective route to this

Application of Organometallic Catalysts in API Synthesis

127 S

Ru or Rh NHCOOR Biphosphine catalyst, H2 F Solvent, additive

F

F

O 82

R= Me, Et, t-Bu, CH2Ph

NCHOOR

F

O F

NH N

O F

83

NH2.HC l

84

Fig. 6 Multikilogram production of etamicastat

CN

COOMe

Yield: 82% (2 steps) MeOOC

MeOOC

MeOOC 85

1. Ni-Al2O3 H2 (1.0 MPa) 2. Ac2O, NaOAc

86

O N H 87

NH2 HOOC 88

Tranexamic acid

Fig. 7 Synthesis of tranexamic acid

intermediate is of utmost importance, and several routes were developed and summarized. Synthesis of this pivotal intermediate via the asymmetric reduction of methyl (6,8-difluoro-2H-chromen-3-yl)carbamate 82 has been identified as the most economical and effective route. Both Ru and Rh catalysts were screened, and Rh catalysts (both isolated and formed in situ) exhibited low enantioselectivity during the hydrogenation of the prochiral ene carbamate 82 when compared with Ru catalysts. Scale-up experiments with the best Ru catalyst were demonstrated on 5 kg scale for Ru (R)-C3-TunePhos(acac)2 and with CatASiumTMT3/[Ru (p-cymene)Cl2]2 on 1 kg scale [46, 47] (Fig. 6). Raney nickel is used in a large number of industrial processes and in organic synthesis because of its stability and high catalytic activity at room temperature. Raney nickel, also called spongy nickel, is a fine-grained solid composed mostly of nickel derived from a nickel-aluminum alloy. It is typically used in the reduction of compounds with multiple bonds, such as alkynes, alkenes, nitriles, dienes, aromatics, and carbonyl-containing compounds. Additionally, Raney nickel will reduce heteroatom-heteroatom bonds, such as hydrazines, nitro groups, and nitrosamines. It has also found use in the reductive alkylation of amines and the amination of alcohols. A practical example of the use of Raney nickel in industry scale is shown in Fig. 7 for the reduction of nitrile functionality to its corresponding amine derivative. Yuanyuan Xie et al. have successfully developed a direct and efficient method for the preparation of key intermediate methyl 4-(acetamidomethyl)benzoate 87 by one-pot hydrogenation and acylation in acetic anhydride using Ni/Al2O3 as a catalyst for the synthesis of tranexamic acid 88 [48]. The reaction went smoothly using catalyst Ni–Al2O3 with anhydrous sodium acetate as cocatalyst and acetic anhydride as solvent at 50 C under hydrogen pressure of 1.0 Mpa. Thus they have shown the efficient usage of Raney nickel for the reduction of nitrile group by circumvent the usage of toxic reagents (CrO3, Cl2), solvent (CCl4), and expensive catalyst (PtO2).

128

2.5

D. Basu et al.

Chiral Alcohols

Antiemetics are the class of drugs used for relief vomiting and nausea resulting due to pregnancy, chemotherapy, motion sickness, or something else. Aprepitant [49, 50] 91 and fosaprepitant [51] 92 are two antiemetic drugs which operate by blocking neurokinin-1 (NK1) receptor. (R)-1-(3,5-Bistrifluoromethyl)phenyl ethanol 90 is a key intermediate in these drugs [52]. Although several routes to this intermediate are reported, there is still a need for scalable and cost-effective route for this intermediate. Using in-house-developed ligand (4R,5R)-(+)-4,5-bis (diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxoane-(R,R-Diop)-2R-(αmethylmethanamine)-4,7-dimethyl-1H-benzo[d] imidazole (R-DMe-BIMAH), a practical scalable process using Ru-catalyzed asymmetric reduction was developed. The robustness of this process was demonstrated by validating on multikilogram scale in pilot plant with 65–70% yields and ee 98.00–98.75% [53] (Fig. 8). Chronic respiratory diseases (CRDs) affect millions of people every year and if not treated lead to death. Most common are chronic obstructive pulmonary disease (COPD), asthma, occupational lung diseases, and pulmonary hypertension. Airway narrowing is known to onset bronchial asthma and COPD, and treatment with β-adrenoceptor (β-AR) agonists is the first-line medication. Indacaterol, abediterol, and carmoterol are the most common (β-AR) agonists and GSK961081, a combination of β-adrenergic receptor and a muscarinic receptor antagonist (indacaterol, [54, 55]; abediterol, [56]; carmoterol, [57–59]). A common moiety present in these drugs is the chiral β-amino-α-hydroxyquinolinone. Construction of the chiral alcohol in this moiety has been achieved from the corresponding prochiral ketone using Corey-Bakshi-Shibata (CBS) reduction in GSK961081 and Ru-catalyzed asymmetric transfer hydrogenation (ATH) in indacaterol and abediterol. A scalable synthesis of this key intermediate, chiral β-amino-α-hydroxyquinolinone 96, was reported by using the novel chiral Ru catalyst (Ms-DENEB) via asymmetric transfer hydrogenation. Starting with the commercially available quinolinone derivative 93, the key intermediate was prepared in 41% yield over four steps. A notable feature is the application toward the preparation of various analogues on multikilogram scale demonstrating the versatility of this process [60] (Fig. 9). O

OH

F3C

RuCl2[(R)-Diop][(R)-D-Me-BIMAH] CF3

H2, 30 atm, 25 oC t-BuOK, toluene S/C/Base = 1000/1/50

89 F

N

HN N O

O

65-70%, 98-98.75% ee

O HO N N O P N OH H

CF3 H N

i-PrOH/hexane

CF3

O N

CF3

O

CF3

O 91 Aprepitant

F3C

CF3 92 Fosaprepitant

Fig. 8 Synthesis of 3,5-bistrifluoromethyl phenyl ethanol

F

90

129

Fig. 9 Synthesis of β2-adrenergic receptor agonist

Application of Organometallic Catalysts in API Synthesis

130

D. Basu et al.

Fig. 10 Manufacturing route to omarigliptin (MK-3102)

As discussed in the earlier section, type 2 diabetes has high mortality rate, and it is important to develop diverse novel cost-effective therapies. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs used for treating type 2 diabetes mellitus and may represent a cost-effective option compared with sulfonylureas and insulin. Sitagliptin (Januvia), vildagliptin (Galvus), saxagliptin (Onglyza), and linagliptin (Tradjenta) are some of the DPP-4 inhibitor drugs approved by FDA. Developed by Merck, omarigliptin 109 recently received marketing authorization in Japan for treating type 2 diabetes. An elegant approach to the synthesis of omarigliptin on commercial scale was accomplished by a series of Ru-catalyzed reactions highlighting the impact of metal-catalyzed reactions in demonstrating dominance in the stereoselective synthesis of drugs [61]. Highlights of this synthesis are (1) DKR reduction delivering 24:1 dr and >99% ee; (2) an improved isomerization-based synthesis of N-Boc-1-mesyl pyrazole fragment 109 which afforded 30:1 regioselectivity; and (3) a telescoped Boc deprotection of 109 and reductive amination to avoid handling of mutagenic 1-mesylpyrazole BSA salt, which also improved the overall diastereoselectivity and efficiency of the route. Starting from glycine ester 102, the overall yield of this synthesis of 109 is 29% (Fig. 10).

3 C-H Functionalization Cholesterol when present in high levels in blood is characterized by a condition called hypercholesterolemia. Two main types of cholesterol are known: low-density lipoprotein (LDL) cholesterol (“bad cholesterol”) and high-density lipoprotein

Application of Organometallic Catalysts in API Synthesis

131

(HDL) cholesterol (“good cholesterol”). Atherosclerosis, accumulation of cholesterol-rich fatty deposits in arteries, is caused by the presence of high levels of LDL cholesterol. The accumulation of angiotensin causes arteries to become narrow or blocked and restrict the flow of blood to the heart and brain. It is a leading cause of illness and death worldwide and has unmet new therapeutic medication. Treatment involves the use of cholesteryl ester transfer protein (CETP) inhibitors, and Merck’s anacetrapib 120 is a promising candidate in this regard, and a largescale synthesis to support its pharmacological evaluation was needed. Anacetrapib contains a biaryl unit along with oxazolidinone moiety in the core structure. Increasing prevalance of biaryls in many pharmaceutical drugs led to the discovery of several methods for their construction. General methods for their assembly mostly involve the use of cross-coupling reactions, for example, Suzuki, Mizoroki-Heck, Negishi, and Stille coupling reactions. Unfortunately, these conventional methods have drawbacks: (1) prefunctionalization of either one or both coupling partners, (2) generation of toxic waste due to the by-products from the cross-coupling reactions, and (3) poor atom economy. Most of these concerns can be addressed by the use of C-H activation technology due to its high atom economy. However, examples on the application of C-H activation technology on preparative scale are limited due to high catalyst loading and lack of reproducibility. An interesting example that addressed some of these potential pitfalls in the application of C-H activation technology to scale is shown in Fig. 11. Biaryl alcohol 117 was identified as the key intermediate leading to the API (anacetrapib) which was envisioned to be constructed using the directed arylation of the bromoanisole 115 and oxazoline 111 [62]. The synthesis of these compounds is shown in Fig. 11. Ru-catalyzed direct arylation reaction between these two building blocks 111 and 115 was achieved in NMP as the solvent. Unfortunately, scale-up of the optimized process suffered from poor reproducibility of the results. Careful examination of the reaction conditions, solvents, and reagents led to the identification of the presence of an impurity, γ-butyrolactone, present as an impurity in NMP. The amount of γ-butyrolactone was different in various batches of NMP, and the variation in results was traced to this impurity through careful experimentation. Control experiments with γ-butyrolactone-free NMP proceeded poorly ascertaining the importance of the role of this impurity. While the variability of the results could be traced to the impurity, however, active species and the role were not clear. This is due to the stability of this impurity in basic conditions of the reaction, and γ-butyrolactone can undergo hydrolysis to the open-chain carboxylate which could be the active species enhancing the reaction rate. This hypothesis was confirmed by the addition of carboxylate additives particularly in direct arylation reactions. An independent experiment run with the addition of a cocatalyst, AcOK, proved equally effective in accelerating the reaction by facilitating the ligand exchange through hydrogen bonding (autocatalytic pathway). This discovery and understanding of the beneficial role of the impurity from solvent led to a robust process to anacetrapib which was demonstrated on multikilogram scale and is the first example on the application of direct arylation reaction on scale. In conclusion, the search for a better catalytic

NH2

MeO

OH

O

N

Me

Me

F

+

CaCl2 (cat), xylene 125 oC, 86%

HO

CN

Fig. 11 Synthesis of anacetrapib

117

F3C

111

F3C

110

F 3C

115

10 oC to RT

DMF, SOCl2

Br

MeO

MeO

114

Me OH Me

F

F3C 118

MeO

Cl

Me Me

F

F3C 116

119

O O

F3C

H N Me

DMF, NaHMDS Heptane cryst

AcOK (10 mol%), NMP, 120 oC

CF3

MeO

2. MeMgCl, THF 0 oC, 94%

F3C

O

N

Br

1. AcCl/AlCl3, DCE, 0 oC, 86% MeO

[RuCl2(benzene)]2 (1 mol%) Me PPh (2 mol%), K PO (2 equiv) 4 3 3 Me

F

DCE, -10 oC, 88% Br

(HSiMe3)O, TFA

Me

120

O

Me

Anacetrapib

CF3

Me Me

F

2. NaBH4, H2O 0 oC to RT

1. ClCO2Me, DIPEA THF, -60 oC

F3C

N O

MeO

Me

F

113

THF, 65 oC, 90% Br

F MeOK (1.2 equiv) F

112

F

132 D. Basu et al.

Application of Organometallic Catalysts in API Synthesis

133

Fig. 12 Structure of SPT inhibitor 1

O O N Me

H N 121

O

t

F

F

H2SO4, MeOH, NO2 reflux, 5.5 h 89%

HOOC

NO2

79%

MeOOC

NO2

COOtBu

BuOOC

NH2

H2, Ra/Ni, rt, 88%

MeOOC 124

123

122

t

COOtBu

BuOOC

CH2(CO2t-Bu)2, NaH, THF, 0 °C to rt

N

N

MeOOC 125

O NCbz

t

BuOOC

(i) NaBH(OAc)3, HOAc, DCE, rt, 72 h; (ii) chromatography 82%

COOtBu H N

(i) p-TsOHoH 2O, toluene, reflux, 2 h; (ii) chromatography NCbz

MeOOC

81%

126

O N

NCbz

121

MeOOC 127

Fig. 13 Medicinal chemistry route to oxindole 127

system and understanding the role of low-level impurity arising from the solvent led to the development of a robust process for the synthesis of anacetrapib. A scalable method for the preparation of oxindole 127, a key intermediate en route to a serine palmitoyltransferase inhibitor, compound 121, is presented. A three-step, chromatography-free route has been designed that takes advantage of Buchwald’s palladium-catalyzed C-H functionalization to cyclize an αchloroacetanilide to form the five-membered ring. This process has been successfully carried out in our kilogram laboratory facility on 10 kg scale in 76% yield [63]. Compound 121 (Fig. 12) is a molecule designed to inhibit the serine palmitoyltransferase (SPT) enzyme [64–66]. It has been proposed that inhibition of SPT may elevate levels of HDL cholesterol (HDL is commonly referred to as “good” cholesterol; see [67]). This effect is associated with decreased cardiovascular health risk, and therefore, compound 121 represents a potential treatment for heart disease [68, 69]. The original medicinal chemistry route for synthesizing the target 121 involved a key oxindole intermediate 127 which was accessed through a five-step synthetic process (Fig. 13). The synthesis started with the esterification of 3-fluoro-4nitrobenzoic acid (122) in MeOH as solvent and catalytic H2SO4 to provide methyl ester 123 in 89% yield. This intermediate then underwent reaction with di-tert-butyl malonate and NaH as base to generate intermediate 124 after fluoride displacement via SNAr in 79% yield [70, 71]. The nitro group was hydrogenated with Ra-Ni as catalyst to afford aniline 125 in 88% yield [72, 73], which underwent reductive amination with 1-benzyloxycarbonyl-4-piperidone to give secondary amine 126 in 82% yield after chromatography. Indole 127 was produced in 81% yield after treating 126 with p-TsOH•H2O in toluene at reflux followed by chromatography. Four additional steps completed the synthesis of 121 from 127. Even though this route was satisfactory for the preparation of small batches of 121, the need for kilo quantities of material to support clinical studies required the development of either

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D. Basu et al.

Cl

O N

NCbz

Pd(OAc)2 (10 mol %), 2-di-(tertbutylphosphino)biphenyl (20 mol %), TEA, MeTHF:IPA (4:1 v/v), 70-75 °C, 2.5 h, 76%.

MeOOC

128

MeOOC

O N

NCbz

127

Fig. 14 Preparation of 127 via C-H functionalization

an optimized or a new route. The team focused attention on the preparation of oxindole 127 as a key advanced intermediate en route to 121. Before we could test Buchwald’s C-H activation method [74] for the preparation of oxindole 8, they prepared the α-chloroacetanilide 128 compound. This was expediently accomplished in two steps from commercially available methyl 4-aminobenzoate, a considerably cheaper starting material than 3-fluoro-4-nitrobenzoic acid (122), and 1-benzyloxycarbonyl-4-piperidone (Fig. 14). Initial efforts at applying Buchwald’s method [74] toward cyclizing compound 128 gave incomplete reaction and significant side products. A major breakthrough came when the reaction was performed in a 2-MeTHF/2-propanol mixture. Initially, the reaction was carried out with a 1:1 (v/v) ratio to provide oxindole 127 in 49% yield after 1.5 h at 80 C. However, when a 4:1 (v/v) mixture of 2-MeTHF and 2-propanol was tested, complete cyclization occurred in less than 1 h at 70–80 C to afford 127 in 70% yield on gram scale.

4 Cyclopropanation Any pain lasting more than 12 weeks is often defined as chronic pain. Activation of transient receptor potential vanilloid 1 (TRPV1), an ion channel, is linked to chronic inflammatory pain. TRPV1 antagonists inhibit the transmission of pain signals. A scalable synthesis of two complex TRPV1 antagonists 139, 140 utilizing asymmetric Ru-catalyzed cyclopropanation using thermally unstable ethyl diazoacetate is shown in Fig. 15. The most challenging step in the synthesis proved to be the stereoselective construction of trisubstituted cyclopropyl carboxylic acid 134 [75]. In contrast to the number of examples on the stereoselective cyclopropanation of styrene-type substrates, only one example on vinyl pyridine substrates is reported. More importantly, the stereoselectivity is sensitive to the degree of substitution on the alkene, and poor trans/cis ratio or poor ee was observed with increasing substitution on the double bond. With the case in hand, the inferior trans/cis selectivity (70/30) and poor enantioselectivity (ee ~65%) were presumably the result of competitive coordination or ligation of the pyridine to the chiral ruthenium catalyst. Unfortunately, a high-through-put screen of reaction with various other transition metal catalysts (Cu, Co, and Pd) and different oxazoline-substituted ligands failed to improve the enantio- and diastereoselectivity suggesting the cyclopropanation of substituted vinyl pyridines is still an underdeveloped area in organic catalytic cyclopropanation. Screening of several chiral bases led to identification of quinine wherein the trans/cis selectivity enriched to >95:5 with no upgrade of the

N

o

Fig. 15 Synthesis of TRPV1 antagonists

2. (S)-1,2,3,4-tetrahydro-1-naphthylamine, 2-propanol, 50 oC, 77%

1. 2 M HCl (aq), MTBE, 25 C, 100%

N CF3 133 trans/cis 70:30, ee 65%

EtOH, LiOH, H2O rt, 81%

CF3

N CF3 136 trans/cis 99:1, ee 93%

HO

O

N CF3

NH2 HCl

O 132

MeO2SHN

X

O

139: X = F 140: X = Cl

N H

ethyldiazoacetate (EDA), toluene, 80 oC, 80%

N N RuCl2 N

N CF3 135 trans/cis >95:5, ee 65%

HO

O

131

50% T3P in EtOAc, DIPEA 50 oC, 63-77%

MeO2SHN

137: X = F 138: X = Cl

X

Quinine, MTBE, 55 oC, 75%

Dean-Stark, 75%

TsOH. H2O, Toluene

HO N CF3 134 trans/cis 85:5, ee 65%

O

HO

O

CF3 acetone, 99%

BuLi, Toluene, -60 oC

130

N

n

129

EtO

Br

O

N

CF3

Application of Organometallic Catalysts in API Synthesis 135

136

D. Basu et al.

enantioselectivity. Further enrichment in enantio- and stereoselectivity was achieved by traditional crystallization methods using (S)-1,2,3,4-tetrahydro-1-naphthylamine as the chiral base.

5 Hydroformylation Hypertensive heart disease is a health problem caused due to high blood pressure (hypertension) that is associated with moderate mortality and morbidity. Angiotensin II in blood causes blood vessels to contract, thereby increasing the blood pressure. Angiotensin-converting enzyme (ACE) inhibitors and neutral endopeptidase (NEP) inhibitors are medications that decrease the production of angiotensin II in blood. A key intermediate present in ACE/NEP inhibitors Ilepatril and omapatrilat is [(S)-2-amino-5-[1,3]dioxolan-2-yl-pentanoic acid [(S)-allysine ethylene acetal]. While several syntheses are reported a large scale, a cost-effective and scalable synthesis of this intermediate with high yields is still desirable. The chemical synthesis of this intermediate was reported in eight steps from 3,4-dihydro-2Hpyran. Alternative routes using biocatalysis, phenylalanine dehydrogenases, amidases, D-amino acid oxidases, and hydantoinases have also been reported. All of these routes proceed via a common intermediate glutaraldehyde monoacetal obtained in low yields (99% ee. The undesired (R)-isomer was recycled via racemization through azlactone (Fig. 16).

Application of Organometallic Catalysts in API Synthesis

137

Fig. 16 Synthesis of (S)-allysine ethylene acetal

6 Cross-Coupling for the Formation of Carbon-Carbon and Carbon-Heteroatom Bonds 6.1

Cycloaddition Reaction

Copper is a versatile transition metal that has been used as a building material by human civilizations for over 6,000 years. Copper is also an essential element, responsible for important biological processes. In the late 1980s and early 1990s, the topics centered on copper nitrene reactivity (e.g., aziridination), copper carbene chemistry, conjugate additions, and cross-coupling reactions. Some of the most highly cited papers of all time on this topic are reviews on conjugate addition, cross-coupling, and [3 + 2] “Click” reaction applied to bioconjugation. A concise catalytic asymmetric synthesis of idasanutlin was developed by Pankaj D. Rege et al. which employs a Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition reaction [77]. Idasanutlin (Fig. 17) is a mouse double minute 2 (MDM2) homologue protein antagonist discovered by Roche. MDM2 (also known as E3 ubiquitin-protein

138

D. Basu et al. Cl F

COOMe

CN F

Cl

+

152

COOH Cl F

Cl

N

AgF, Et3N, ClCH2CH2Cl

F

Cl

97%

Aq.NaOH, MeOH THF, Chromatography Cl

H N

O

NH

F 80% Cl

157

49%

O

O

COOMe

CN F

Chiral SFC separation

CN F 155

Cl

NH

F

81%

H N

O

Methyl-4-amino-3methylbenzoate, Ph2POCl, DIPEA, CH2Cl2 Cl

NH

F

CN F 154

Cl

NH CN F 156

2M NaOH, MeOH Cl NH

31% 153

COOH

COOMe Cl

CN F

COOH

158 Idasanutlin

Fig. 17 Ag-catalyzed synthesis of idasanutlin

ligase MDM2) is an important negative regulator of the p53 tumor suppressor protein. Idasanutlin (1) is designed to bind to MDM2 to potentially prevent the p53-MDM2 interaction and thereby result in activation of p53. Idasanutlin 158 shows efficacy in xenograft models, and clinical trials of this compound are ongoing. In the original synthesis, 158 was prepared in five steps and 10% overall yield from 152 (Fig. 17) [78]. This process was deemed not suitable for large-scale preparation due to several issues: (1) the low overall yield; (2) the use of stoichiometric amount of silver fluoride, which caused the formation of silver mirror on the wall of the glassware; (3) the use of a Class I solvent; and (4) the chromatographic purification, especially the chiral supercritical fluid chromatography (SFC) for the isolation of the desired enantiomer. Therefore, upon selection of 158 as a clinical candidate, process research activities commenced to meet the demands of clinical trial supply and eventually develop a commercial manufacturing process. These efforts initially resulted in an asymmetric cycloaddition reaction using Ag(OAc)2 with (R)-MeOBIPHEP4 as a chiral ligand. Although the Ag-catalyzed process gave 161 in good quality on a 100 kg scale, a more efficient process was required to support the increasing API demand (Fig. 18). The limitations of the Ag-catalyzed approach warranted continuation of development efforts in search of a more robust scalable process for commercial manufacturing. Along with Ag-based catalysts, Cu-based catalysts are widely employed in asymmetric [3 + 2] cycloaddition. In an effort to address the disadvantages of the Ag-catalyzed process and primarily to improve the diastereo- and enantioselectivity of the cycloaddition reaction and issues related to precipitation of Ag salts, the use of Cu catalysts was investigated. As reported by Shu et al. [79], the initial focus of this investigation was Cu(II)-based catalyst systems, and a process using Cu(OAc)2/(R)-BINAP (1.3% catalyst loading) delivered 163 with an er of approximately 94:6 on a 30 g scale. During further development, the Cu(OAc)2 catalytic system was found to give inconsistent results when starting materials of representative quality were employed. During their studies of Cu(II)-catalyzed systems, Shu et al. had noted that the Cu(I)-based catalyst system also provided encouraging results, so CuOAc was tested as an alternative to Cu(OAc)2 in the [3 + 2] cycloaddition reaction. Using only 0.50 mol% CuOAc in combination with

Application of Organometallic Catalysts in API Synthesis COOEt

Cl

AgOAc, Ligand, 4 oC, MeTHF, Not isolated

F O NH

O

+

F

O + Intermediates

NH

F

COOEt

CN F

Cl 159

H N

O Cl

N

CN Cl

139

160 H N

O Anh. LiOH, 60 oC, n-Heptane

161 O

i. LiOH, i-PrOH-H2O, 70 oC ii. Filter off lithium salt of racemate iii. AcOH-H2O, 70 oC

Cl NH

F

92-96% (ee: 68%)

COOEt

CN F 162

Cl

158 42% (ee: >99%

Fig. 18 Ag-catalyzed synthesis of idasanutlin Cl

O

F

O O O

+ HN

CN

N

F

Cl

H N

O

Exo selective [3+2] cycloaddition

O THF/EtOAc (Rac filtrate) Cl Cryst CH3CN/H2O

NH CN F 161

COOH

COOEt

CN F

Cl

THF, EtOH, Aq.NaOH Cryst from 2-PrOH/H2O 83% for two steps (Hydrolysis/Isomerization)

163

O

Cl

Cl

O

O

NH

F

160

159

F

CuOAc (0.5mol%), R-BINAP (0.53mol%), 2-MeTHF, Et3N.

H N

Cl

Cl

O

THF (polish filt) Cryst CH3CN,/H2O

NH

F 79% (Racemate removal)

H N

CN F

COOH

93%

158 Idasanutlin

(Recrystallization)

Crude 158

Fig. 19 Cu-catalyzed synthesis of idasanutlin

0.53 mol% (R)-BINAP led to smooth conversion of stilbene within 6 h, and the overall amount of diastereomers was raised to 90–93% with a fairly constant ratio between the single diastereoisomers. In contrast to Cu(OAc)2, the CuOAc system did not require any premixing or aging of the metal-ligand complex. The selectivity of the cycloaddition reaction was found to be very robust, and within the temperature range of 0–40 C, no change in selectivity was observed. The optimized Cu(I)catalyzed synthesis was demonstrated in the industrial scale and was used for the manufacture more than 1,500 kg of 158 (Fig. 19). The copper-catalyzed addition of azides and alkynes to form triazoles has been hailed as the crème de la crème of click chemistry – a way to assemble molecules via rapid, irreversible reactions. The copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) approach has been widely used in the different spheres of the science such as bioconjugation, oligonucleotide synthesis, construction of bolaamphiphilic structures, DNA labelling, and drug discovery. This high-yielding and mild reaction was well suited for the rapid exploration of a range of novel substituted macrolides through the attachment of different side chains to an N-alkynylated macrolide core such as 166 [80] (Fig. 20).

140

D. Basu et al. O

O O HO

O OH O

HO

O

O O

164

N

N

O

HO

O

O

O

F

F +

N3

N 165

OH

O OH

N

CuI (5 mol%), (i-Pr)2NEt, THF NH2

89%

O

HO

N

N

N

N

N

NH2

O

O

O

O O O

166

OH

Fig. 20 Click synthesis of macrolide

7 Transition Metal-Catalyzed Transformations in Batch and Continuous Mode Xudong Wei et al. have demonstrated a safe, scalable, and highly efficient coppercatalyzed conjugate addition of 2-trifluoromethylphenyl Grignard reagents to acetyl pyridinium salts as a key transformation step for the synthesis of sodium-hydrogen exchange type I inhibitor (NHE-1) 179 in a five-stage process with 43% overall yield [81]. Sodium-hydrogen exchangers (NHEs) are ion transporters expressed in a variety of cells that maintain intracellular pH homeostasis by the electroneutral exchange of intracellular hydrogen for extracellular sodium. The NHE-1 inhibitors are proven to improve myocardial contractility and metabolic status as well as to reduce arrhythmia, apoptosis, necrosis, and intracellular overload of sodium and calcium ions (Fig. 21). The original synthetic route to compound 179 from medicinal chemistry consisted of 14 synthetic steps and, while suitable for medicinal chemistry’s requirements, had a low overall yield (20%). In addition to the requirement of several chromatographic purifications, some costly reagents such as triflimide, octamethyl2,20 -bi(1,3,2-dioxaborolane), and Boc-protected guanidine were also employed. The acetyl pyridinium salts were formed instantaneously and precipitated out while acetyl chloride was added to a light-yellow solution of pyridine and 10 mol% CuI in THF (Fig. 22). 2-Trifluoromethylphenyl Grignard reagent was then added slowly into the slurry at
5 to 0 C. The addition was highly exothermic, indicating the rapid reaction between 2-trifluoromethylphenyl Grignard reagent and the acetyl pyridinium salt. The reaction provided an excellent conversion (>90%), assay yield (90%), and regioselectivity. The mole ratio of 1,4-addition adduct 181 to 1,2-addition adduct 183 was 97:3. Further experiments showed that the excellent regioselectivity can even be maintained in the presence of only 0.1 mol% CuI. Christopher Wise et al. have developed a non-cryogenic copper-catalyzed addition of Grignard reagents to epoxides in highly regioselective manner (Fig. 23) [82]. The developed process provides robust reaction conditions which limit the formation of impurities and has been applied successfully on >20 kg scale. The protocol has been demonstrated with a range of commercially available epoxides and Grignard reagents to provide the products typically in >90% yield.

CF3

167

N

N

Br

176

171

CF3

CF3

85% Ac

N

172

Br

OTf

1. TFA 2. AcCl

50%

1. NaNO2 2. CuCN

168

N

COOMe

NH2

Boc

NTf2

B B O

O

CF3

177

173

Br

Ac

NHBoc

75%

H2 N

O B O

N

COOMe

169

N

CF3

Boc

COOMe K CO , NH 2 3

92%

MeOH/HCl

CF3

CN

72%

KOAc, PdCl2.dppf, Dioxane

O

O

Fig. 21 Synthesis of sodium-hydrogen exchange type I inhibitor (NHE-1)

95%

Boc

85%

1. Nitration 2. Fe/HCl

70%

THF, -78 oC

Pd/C, HCOONH4

170

Br

Boc

O

LiHMDS,

178

Boc

CF3

N

O N H

NHBoc

NH

N

85%

TFA

Boc

Pd(PPh3)4, K2CO3

O

85%

174

O B

Ac

N

175

CF3

CF3 179

O

COOMe

N H

NH2

NH

Application of Organometallic Catalysts in API Synthesis 141

142

D. Basu et al.

F3C O

iPrMgBr (1.1 eq), Acetyl chloride (1.1 eq) Pyridine (1.5 eq), CuI (0.1 mol%), THF F3C 180

O

76%

Br

N

+

CF3

N 181

182 (181:182 = 97:3)

Fig. 22 Synthesis of key intermediate 181 Fig. 23 Copper-catalyzed addition of Grignard reagents to epoxides

O OBn

MgX (1.5 eq), CuX (5 mol%), THF X = Cl, I

OH OBn

~90%

184

183

N

Br

185

S

OMe

N

OMe

NH

O (1.5 eq),

CuCl (10 mol%), DMEDA (20 mol%), K2CO3 (2 eq), Pyridine, 100 oC, 20 h

100% (conversion)

N N O 186

N N

S

OMe

N

OMe

O

S N N

187 Histamine-3 (H3) antagonist

Fig. 24 Synthesis of histamine-3 (H3) antagonist

Jeffrey M. Kallemeyn et al. have reported a scalable process for the preparation of histamine-3 (H3) antagonist API in multikilogram scale having the key feature as copper-catalyzed C-N cross-coupling reaction (Fig. 24) [83]. The team has found that the protection of keto functionality as dimethyl acetal derivative 185 was necessary to suppress formation of impurities. The screening of various ligand led to the N,N0 -dimethylethylenediamine (DMEDA) as the best choice of ligand, and 2:1 loading of ligand/catalyst was found to result in the fastest reaction, while the solvent survey found pyridine to be the most effective solvent for this conversion. Similar copper-catalyzed C-N coupling has been demonstrated in industrial scale by Ioannis N. Houpis et al. in the synthesis of integrase inhibitors of immunodeficiency viruses. The key transformation is being the selective C-N coupling of a sulfonamide to a heteroaryl bromide in the presence of potentially competing amide and carbamate functionalities. The transformation was accomplished with CuI catalysis using bipyridine as the ligand in the presence of base [84]. Stefan G. Koenig et al. have developed a simple, ligand-free copper-catalyzed C-N bond formation process for the synthesis of D-amino acid oxidase inhibitor. The novel ligand-free Cu(I) amination was demonstrated at 50 g scale where Cs2CO3 (1.5 eq) was used as a base and CuI (0.3 eq) in toluene to achieve full reaction completion within 2 h. This was followed by diamine workup to remove the benzoyl protecting group and residual copper catalyst. The final product was crystallized directly from the reaction mixture, providing the target compound in up to 60% overall yield following five chemical steps and two isolations (Fig. 25) [85]. Neera Tewari et al. have reported a large-scale synthesis of cinacalcet hydrochloride using iron-catalyzed C-C coupling [86]. The novel process involves C-C bond formation by coupling of the intermediate 192 with in situ prepared

Application of Organometallic Catalysts in API Synthesis

O O

OEt NHBz

Cs2CO3 (1.5 eq), CuI (0.3 eq) Toluene, reflux, 2 h

N Bz 189

Br 188

Ethylene diamine (2 eq) 30 min, rt

O

O

143

OEt

O

O N H 190

76% over 2 steps

O

O N H 191

OEt

OH

D-Amino Acid Oxidase Inhibitor

Fig. 25 Synthesis of D-amino acid oxidase inhibitor 1. H N

Cl

, Mg, I2, THF, reflux

Br CF3 2. iron acetyl acetonate, NMP -50 to -55 °C

H N

F3C

Yield: 61%

192

Pd/C, H2

H N

F3C

193 194

Cinacalcet Hydrochloride

.HCl

Fig. 26 Synthesis of cinacalcet hydrochloride

Me

CF3 N Cl

195

MgBr, Fe(acac)3 THF, NMP 0-5 oC then 20 oC Yield: 94-96%

Me

CF3

F

CF3

O N

N 196

197 N Cl Me Dual NK-1/Serotonin Receptor Antagonist H

Fig. 27 Synthesis of dual NK-1/serotonin receptor antagonist

[3-(trifluoromethyl)phenyl] magnesium bromide from 3-bromobenzotrifluoride at
50 to 0 C using catalytic quantity of iron acetylacetonate/N-methyl-2-pyrrolidone (NMP) to give a mixture of cis and trans unsaturated cinacalcet in the ratio 1:10 (Fig. 26). Product was isolated as trans unsaturated cinacalcet hydrochloride in 99% purity with 1% of cis isomer, and both the isomers on reduction afford cinacalcet hydrochloride. No other by-products are formed during the reaction. Similar, iron(III)-catalyzed Grignard coupling has been demonstrated in multikilogram scale by Christina Risatti and his team for the preparation of dual NK-1/ serotonin receptor antagonist (Fig. 27) [87]. Peter Mullens et al. have evaluated two approaches to the chemical development and large-scale preparation of a pyrimidyl tetrazole intermediate 203 [88]. The firstgeneration route featured an iron-catalyzed cross-coupling between 4-butenylmagnesium bromide and a 4-chloropyrimidine derivative to afford an alkene-bearing pyrimidine intermediate. The chemoselective Fürstner-type Fe-catalyzed cross-coupling achieved commercial availability of 4-butenylmagnesium bromide and 5 mol% of iron acetylacetonate under condition that were relatively mild, and the reaction was readily scaled with the yield at kilo scale reproducing the laboratory yield (73%). This route was rapidly defined and used to prepare the initial 0.3 kg of the pyrimidyl tetrazole intermediate, which supported early toxicology and clinical studies of a drug candidate. However, it was found that impurities generated during this step had a significant deleterious effect on the downstream Heck reaction.

144

D. Basu et al.

Cl Cl

N

NH2

ps 2 ste

Br

MgBr, Fe(acac)2 N,N'-DMEDA, Acid wash

NPMB2

N N

Yield: 73% 1st generation route

199

NPMB2

N N

Br

6 ste

N

N 198

N N N N

ps

200

N

3 step

COOEt

s

CuI, Ligand, Cs2CO3 NPMB2 THF, DMAc, 60 oC

N

EtOOC I 201

N

Yield: 100% 2nd generation route

N EtOOC

N COOEt 202

NPMB2

5 ste

ps

HOOC 203 Pyrimidyl tetrazole intermediate

Fig. 28 Synthesis of pyrimidyl tetrazole intermediate

A second-generation, eight-step route to the pyrimidyl tetrazole intermediate was defined and demonstrated on multikilogram scale in a 21% overall yield. The key transformation in this sequence was a copper(I)-mediated cyclization of an iodopyrimidine, affording the bicyclic core of the target in quantitative yield (Fig. 28). Alongside a number of other important metals, nickel technology is widely used in the catalyst industry. Modern nickel-based catalysts have wide range of applications to meet the ever-increasing demand for process efficiencies from a number of major industries. Catalyst manufacturers achieve this through a range of different technological solutions, including new materials, new forms of catalyst, and different production processes. Nickel compounds provide a technological pathway for the production of a number of modern nickel-based catalysts. In 1983, Nozaki and Hiyama reported the synthesis of stereospecifically generate allylic alcohols by Cr(II)-mediated “Barbier-type” coupling reaction, using alkenyl iodides and aldehyde as coupling substrate [89, 90]. During model studies aimed at using this remarkably functional group-tolerant reaction to couple two highly oxygenated alkenyl iodide and aldehyde fragments in the synthesis of palytoxin, Kishi found that the success of the coupling was highly dependent on the Cr(II)Cl2 batch used. This reproducibility problem was solved by the addition of catalytic quantities of Ni(II)Cl2. Nozaki subsequently reported that batches of Cr(II)Cl2 effective in promoting the alkenyl iodide/aldehyde coupling contained ca. 0.5 mol% Ni on the basis of Cr. The Nozaki-Hiyama-Kishi (NHK) reaction has since become one of the most widely used synthetic methods for forming allylic alcohols in the context of highly functionalized substrates (Fig. 29). In the reaction Nickel is used in catalytic quantity as nickel salt. In the reaction mechanism, the catalytic nickel(II) chloride is first reduced to nickel(0) with two equivalents of chromium(II) chloride (as sacrificial catalyst) forming chromium(III) chloride. This followed by the oxidative addition of nickel into the carbon to halide bond forming an alkenylnickel R1-Ni(II)-X intermediate followed by a transmetallation step exchanging NiX with a Cr(III) group to an alkenylchromium R1-Cr(III)-X intermediate and regenerating Ni(II). This species reacts with the carbonyl group in a nucleophilic addition (Fig. 30). The NHK reaction has been successfully used in the production scale synthesis of eribulin mesylate by Eisai Corp as shown in Fig. 31 [91]. The lysophosphatidic acid receptor, LPA1, has been implicated as a therapeutic target for fibrotic disorders [92]. BMS-986020 (219), a small molecule antagonist of

Application of Organometallic Catalysts in API Synthesis O

145

OR1 I

MeO

OR

OR2

+

NiCl2 (10 mol%), CrCl2 (4 eq) DMSO, RT

204

OHC

OR O

OR1

RO OR

Yield: 81%

OR O

MeO

OR RO OR

O

OR'

OMe

OH 206

OMe

205

Fig. 29 Nickel-catalyzed Nozaki-Hiyama-Kishi (NHK) reaction Fig. 30 Catalytic cycle in Nozaki-Hiyama-Kishi (NHK) reaction

the receptor, is currently undergoing clinical trial as a possible treatment for pulmonary fibrosis. The process development for the synthesis of BMS-986020 (219) via a palladium-catalyzed tandem borylation/Suzuki reaction is described [93]. During the initial synthetic route development, a traditional Miyaura borylation posed significant processing challenges including incomplete conversion even under high catalyst loadings as well as difficulty in the removal of residual metals arising from the catalyst stoichiometry. Evaluation of conditions culminated in an efficient borylation procedure using tetrahydroxydiboron followed by a tandem Suzuki reaction employing the same commercially available palladium catalyst for both steps. Palladium-catalyzed borylation-Suzuki sequence using the phosphine ligand 4-(di-tert-butylphosphanyl)-N,N-dimethylaniline (AtaPhos) [94–100] obviated the shortcomings of the prior routes to 219. This methodology addressed shortcomings of early synthetic routes and was ultimately used for the multikilogram scale synthesis of the active pharmaceutical ingredient 219. Further evaluation of the borylation reaction showed useful reactivity with a range of substituted aryl bromides and iodides as coupling partners. These findings represent a practical, efficient, mild, and scalable method for borylation (Fig. 32). A three-step commercial manufacturing route has been developed for palbociclib, a highly selective, reversible inhibitor of CDK4/6 [101]. The second step, which utilizes a Heck coupling to install the enol ether side chain, is described. A highly regioselective catalyst was identified for this transformation along with reaction conditions that ensure robustness upon scale-up. Effective removal of palladium was accomplished via filtration of insoluble metal and an extractive chelation step. Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, involved in cellular progression from growth phase (G1) into the phase-associated

207

CHO

208

OTBS

(S)-ligand, Et3N

O

OMe

O

O

O

O

213

CHO

TBSO

2. EDA; 3. SiO2, IPA 48%

Fig. 31 Synthesis of eribulin

TBSO TBSO

O

N

O

TBSO

OTs

OTBS

O

O 1.CrCl2, NiCl2, MeCN,THF, TBSO

Br

I

OTBS

O

OTBS

70%

MsO

TBSO TBSO CrCl2, NiCl2, MeCN, THF, Et3N

209

N O

O

OMe

O

O

O

210

OTf

O

214

TBSO

O

OTBS

OH

OTBS

O OTBS

55%

O

HO

O

O

O

O

O

O

O H O

212

H O

H

OPv

O

215 Eribulin mesylate

O

O

PhO2S OMe

MeO

TBSO TBSO

MsOH.NH2

211 O 1. CrCl2, NiCl2, MeCN, THF, (S)-ligand, Et3N 2. EDA; 3' KHMDS, THF

TBSO

PhO2S OMe OTBS

146 D. Basu et al.

Application of Organometallic Catalysts in API Synthesis

147

Br CO2H

CO2H

B2(OH)4 AtaPhos2PdCl2 DIPEA

COOH

Br

O Me

218

MeOH, MeTHF 50 °C Palladium loading: 0.2-0.5 mol%

216

O N

O

Ph

Me

K3PO4

H2O/MeTHF 50 °C 95% isolated Yield Over 2 steps

B(OH)2 217

O N

O Me

O

Ph

Me

219 BMS-986020

Fig. 32 Synthesis of BMS-986020 Me

Me NH2 N

Me Br

N Cl

+ N N 220

Br

N N

HN CyMgCl, THF

N

N N Boc

N

HN N

N Boc

222

N

O

HCl, nBuOH Anisole, H2O, 70 oC

HN

O N

N

O

N

90% N

N

N

O

84%

88%

221

N

Me

N

O Pd(OAc)2, DPEPhos, DIPEA, nBuOH, 95 oC

N Boc

N

223

N H

224

Fig. 33 Commercial manufacturing process for palbociclib

with DNA replication (S) [102–105]. Palbociclib is marketed under the brand name IBRANCE®. The discovery chemistry route is highly convergent, even though more than two equivalents of 221 were required for good yield in the SNAr coupling and lack of regioselectivity 223 in the Heck reaction resulted in challenges for impurity control. During commercialization, synthesis of the penultimate intermediate was attempted by palladium-catalyzed amination and the construction of pyridinone ring through Friedländer annulation, Larock annulation reaction, and Knorr cyclization. However, none of these approaches were cost-effective compared to the enabling route. The final proposed commercial manufacturing process for palbociclib is illustrated in Fig. 33. The Heck reaction is developed to produce kg quantities of the penultimate intermediate 223. For the reaction, key challenges included selection of a catalyst/ ligand system which provided high selectivity and identification of appropriate reaction conditions to ensure process robustness. Bromide 220 is slurried in n-butanol (6 vol) and treated with n-butyl vinyl ether (3 equiv), diisopropylethylamine (2.4 equiv), lithium triflate (1 equiv), and PdCl2(dppf)•dichloromethane adduct (0.04 equiv) at 95 C under nitrogen. These conditions can be used to produce enol ether 223 in 75–82% isolated yield. However, several key impurities are also formed in the reaction that is difficult to purge. While the lithium triflate additive was found to suppress formation of the impurities to a certain extent, typical lab-scale reactions under these conditions still form 1% of the des-bromo impurity 225, 0.2–0.4% of the vinyl impurity 226, and 0.1–0.3% each of the regioisomer impurities 227 and 228 (Fig. 34).

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D. Basu et al. Me

Me

N HN

Me

N N

N

HN

O

N

N

N

O

O

N

N Boc

225

N

N

N

N Boc

N

HN

N

N

O

N

N Boc

226

227-228

Fig. 34 Formation of impurities in palbociclib synthesis O F

Br

O

N

O O

F

N Me

N NH N NH2

Br 230 Four steps (E isomer)

+

Me

N NH N

NH2 231 O Five steps (99%ee)

O 229 MR antagonist LY2623091

Fig. 35 Synthesis of MR antagonist LY2623091

David Mitchell and his team from Lilly Research Laboratories describe practical pilot plant convergent synthesis of MR antagonist LY2623091 [106]. Mineralocorticoid receptor (MR) antagonists have been evaluated as treatment for hypertension, congestive heart failure, and chronic kidney disease including diabetic nephropathy [107–109]. Marketed MR antagonists include eplerenone, spironolactone, and nifedipine to name a few [110, 111]. More recently, LY2623091 (229), an MR antagonist, was evaluated as therapy for resistant hypertension with an effective amount of tadalafil [112, 113] (Fig. 35). For synthesis convergence, a vinyl bromide geometric isomer and chiral alaninol derivative were required building blocks. Key to the synthetic route development is a stereoselective synthesis of the E-vinyl bromide via a sequential double Heck reaction, Suzuki-Miyaura cross-coupling of the vinyl bromide, a selective nitro reduction, and a highly sensitive cyanamide hydrolysis to the urea. Improvements in yield and processing were accomplished by two sets of telescoping methods which decreased the manufacturing time and provided purity enhancements. In an effort to prepare active pharmaceutical ingredient (API) for clinical evaluation, a multikilogram synthesis was developed which was based on a cross-coupling retrosynthesis of vinyl bromide 230 and aryl bromide 231. This article describes the development of a practical means for preparing 229 on the pilot plant scale. The first-generation synthetic process was efficient such that it afforded multiple kilogram quantities of API for early animal toxicology and clinical evaluation [114–116] (Figs. 36 and 37). François-Xavier Felpin et al. have reported the findings on the use of a modified simplex algorithm using an optimization algorithm and modified Nelder-Mead

230

F

Fig. 36 First-generation synthesis route

Step 3

b) filter solution

a) 5% Pt/C (0.7 mol%), Et3N, o EtOAc, H2, 55 C, 20 h

Four steps (E-geometric isomer)

Br

O

B B

O

O N Me

Step 1

N H NH2

O O Pd2(dba)3 (1 mol%), Cy3P, KOAc, H2O, 1,4-Dioxane, 85 oC, 20 h

O

234

O

O

F

B O

O

N CN

b) MTBE, CH2Cl2 silica thiol c) MTBE, 80% Step 4

OPh a) 55 oC, 20 h

PhO

232

F

O Me

N

Step 2

NH N CN 235

N

Pd(OAc)2 (0.8 mol%) Ph3P (0.25 mol%), K2CO3, H2O, 85 oC, 20 h b) EtOAc,/ MTBE, 56%

a) Compound 231

O

O

NO2

Step 5

F

N H

233

b) EtOAc, 10 oC, 89%

a) CH2Cl2, H2O, TFA, O oC, 3h

Me

N

229

O F

Application of Organometallic Catalysts in API Synthesis 149

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D. Basu et al. F

F HO Br I 236

Br

F

O

237

K2CO3, DMF 88% Step 1

O

OEt

O Br

I 238

Br Pd(OAc)2 (3 mol%), TBAB, ο NaOAc, NMP, 60 C, 93% Step 2

239

CO2Et

Pd(OAc)2 (4 mol%), TBAB, NaOAc, NMP, 145 οC, Lab: 61% yield, 96.4 area%

Steps 2, 3 in one pot Double Heck

O Pd(OAc)2 (4 mol%), TBAB,

F

ο

a) IPA, H2O, LiOH

231

b) HoAc, NBS, 84%

NaOAc, NMP, 120 C, 57% EtO2C Lab: 77% overall step 2, 3 240 Step 3

Step 4

Fig. 37 Preparation of 231 by sequential and double Heck reactions Fig. 38 Optimization of a Heck-Matsuda reaction in a flow device

O OMe

Pump A Reactor Pump A

Cl

243

N2BF4 Cl

OH

241 HO 242

method for the optimization of a Heck-Matsuda reaction in a flow device, involving the arylation of cis-2-butene-1,4-diol with simple experimental conditions not requiring any additive including base and ligand (Fig. 38) [117]. Moreover, the modified simplex algorithm has showed great flexibility since the experimental conditions tuned according to the nature of the objective function which could be either the yield, the productivity, or the unitary cost. The Pd-catalyzed arylation of activated alkenes such as acrylates or styrenes with diazonium salts is now well mastered [118–122]. Arylation of unactivated acyclic alkenes is one of the synthetic challenges in this research line [123–126]. During these studies, the team identified arylation of acyclic alkenes requires the use of a ligand for stabilizing Pd complexes and success in batch mode while the use of flow conditions remain unknown. Therefore, the team envisioned that if the better mass, heat transfer, and efficient mixing in flow chemistry could allow Pd-catalyzed arylation of unactivated alkenes with diazonium salts without the use of any additive including base and ligand to reduce the waste associated with process, experimental simplicity and environmental concerns. With the aim of developing a more practical and sustainable procedure, they reasoned that kinetic enhancements usually observed in flow reactors over conventional batch equipment could allow to simplify drastically the experimental procedure, through the suppression of both ligand and base. In order to address this challenge, they studied a benchmark reaction involving the coupling of cis-2-butene-1,4-diol (2) with 4-chlorobenzene diazonium tetrafluoroborate (1) (Fig. 39).

Application of Organometallic Catalysts in API Synthesis Fig. 39 General scheme of the strategy

151

OH N2BF4 Cl

O

+

DMF/MeOH 241

OMe

Pd(TFA) 2

242

OH

Flow Cl Intelligent algorithm

243

N2BF4 LOOP A

241

Cl

OH

1 mL MeOH/DMF

HO

242 0.1 M in DMF/MeOH Temperatue control

O OMe

5 mL Cl 243

Reactor

MeOH/DMF

1 mL Pd(OTFA)2 DMF/MeOH

New Conditions

Intelligent algorithm

Offline GC-MS analysis

LOOP B

Fig. 40 Overview of the equipment configuration

To avoid the clogging issues due to crystallinity of diazonium salts and the rapid decomposition of Pd complexes into Pd nanoparticles depositing on the side of the tubing associated in the flow, the team screed a variety of solvents and found a mixture of DMF/MeOH (5/1) solubilizes diazonium salt 241 while stabilizing Pd(TFA)2 with no apparent formation of Pd NPs after 30 min of stirring. The experimental setup consisted in two ways equipped with 1 mL loops (Fig. 40). Loop A was loaded with a solution of 1 and 2 in DMF/MeOH with a concentration of 0.1 M, and loop B was filled with a solution of Pd(TFA)2 in DMF/MeOH with the required loading. Each way was pumped with two independent pumps and the flow streams met at a T-shaped mixer (3 μL). The resulting mixture was introduced in a PEEK reactor (5 mL) placed in an oven and finally collected into a fraction collector for offline analysis by GC-MS. The team selected the Nelder-Mead simplex method due to its simplicity, robustness, and low requirement of function evaluations (experiments) compared to other optimization methods (e.g., gradient-based methods and metaheuristics), making it particularly well suited for expensive-toevaluate optimization problems [127]. The modified Nelder-Mead algorithm was used for the optimization of three different objective function, e.g., (1) maximization of the yield, (2) maximization of the productivity expressed as mg/h, and (3) minimization of the production cost expressed as €/g of product 243. Polymer-supported catalysis plays a significant role for the currents industrial needs toward economic and environmental processes. Lie Yu et al. described palladium nanoparticles on the polyaniline (Pd@PANI) catalyst with 0.005 mol% for Sonogashira couplings of aryl iodides with phenylacetylene derivatives, and the

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D. Basu et al. PhNH2 + PdCl2

Fig. 41 Pd@PANIcatalyzed ligand-free Sonogashira coupling

Gram-Scale Preparation 85% H + RX

Fig. 42 Large-scale ligandfree Suzuki coupling in H2O

R1

Br X 244

(HO)2B

R2

245 X= C, N R1, R2= H, OCH3, NH2, CH3, C(O)CH3

Pd(OAc)2, K3PO4 H2O, 100 oC, 0.5-4 h

Pd@PANI

R

up to 96%

R1

R2 X 246

process is free of copper and ligands (Fig. 41) [128]. It is described that the catalysts are easily prepared on a gram scale through the oxidative polymerization of aniline in the presence of PdCl2 by using air as a clean oxidant and also these catalyst are found to be very stable. The coupling efficiency is optimized using different solvents, and MeCN is found to be the best choice of solvent for the reaction and also presented substrate scope of the Pd@PANI catalyst. This catalyst also could be recycled by centrifugation and reused for the next cycles. Charles L. Liotta and the team have described the heterogeneous palladiumcatalyzed Suzuki reactions in water between aryl bromides and phenylboronic acid with no added ligand at the 100 mL scale using 20–40 mmol of aryl bromide and described the optimization of key process parameters to achieve substrate-dependent quantitative yields [129] (Fig. 42). Olopatadine hydrochloride (253) is an antiallergic drug which was developed by Kyowa Hakko Kirin Co. Ltd. [130, 131]. The challenging issue associated with the process is to achieve stereospecific synthesis of the Z-isomer when producing a trisubstituted alkene like olopatadine hydrochloride. There are couple of processes for the synthesis of X that is reported which includes synthesis of 253 from the E/Z mixture of the t-Bu ester derivative of olopatadine by the preferential crystallization [132] and the other process via controlling the stereochemistry of the Z-isomer by the intramolecular cyclization of the E-alkene intermediate via Mizoroki-Heck reaction [133]. Koichiro Nishimura and Masahiko Kinugawa have described the new, more efficient, synthetic route of applying the intramolecular stereoselective cyclization from alkyne 250 using palladium catalyst and a hydride source [134– 136]. The ring cyclization precursor 250 is synthesized from the inexpensive starting material 247 via bromination and Sonogashira coupling with 3-butyn-1-ol. This process then be continued to the key ring cyclization, and the final product 253 synthesized after dimethylamination of terminal alcohol. Furthermore, the optimization of that key stereospecific reaction was examined by design of experiment (DoE) and the desired Z-isomer obtained with high yield (Fig. 43).

Application of Organometallic Catalysts in API Synthesis

153

Br Br

Br

Br O

OH

CO2Me

DMF 100% 248

Br O

OH

CO2Me

249 CO2Me

Pd(OAc)2 tri-o-tolylphosphine HCO2H Piperidine

80%

CO2Me

OH CO2Me

O 252

1) MsCl 2) Me2NH

O 251 NMe2

NMe2 CO2Me

OH PdCl2(PPh3)2 CuI, Et3N DMF 94%

MeOH 88%

MeCN 250

I

Ag2SO4

K2CO3

247

O

I2

CO2H . HCl

1) NaOH aq.MeOH 2) HCl aq. 83% (from 251)

O 253

Fig. 43 Synthetic route of olopatadine hydrochloride

With the optimized process for the synthesis of precursor 250 in the hand, performed the seven-membered ring cyclization of 250 using palladium catalyst and the Z-isomer dibenz[b,e]oxepin 251 obtained as a sole product. However the yield of 251 in the key ring cyclization was moderate since considerable amounts of some by-products – 254, 255, and 256 – were obtained (Fig. 44). To increase the yield of 251, performed screening of phosphine ligands in catalysts and solvents was investigated. As a result, the combination of P(o-tolyl)3 and DMF is found to be suitable for this reaction. To optimize the conditions of the key reaction for the seven-membered ring cyclization investigated by DoE using 25–1 fractional factorial design with a center point was experimented with using the automatic synthesis machine SK233. Five factors (phosphine ligand, formic acid, piperidine, DMF, temperature) were investigated as a candidate of critical factors by keeping the Pd(OAc)2 equivalent constant. The results were analyzed using the statistical analysis software “Design Expert,” and the role of temperature and formic acid has the influence on the selectivity. The influence of formic acid for this reaction was explained from the supposed mechanism in the Fig. 44 along with the formation of by-products. The highest yield was achieved using 1.1 equiv of formic acid. In conclusion, the seven-membered cyclization of 250 was achieved with 80% yield and from 251, olopatadine hydrochloride prepared via mesylation, dimethylamination, and hydrochloridation in high yield. The practical synthesis of glucokinase activator (R)-262A as a potential drug for treating type 2 diabetes has been reported by Yohei Yamashita and his team from Astellas Pharma Inc. [137]. Glucokinase (GK) is one of four members of the hexokinase family that catalyze the phosphorylation of glucose to generate

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D. Basu et al. 250 Pd(0)

OH

Br Pd

Br Pd

OH CO2Me

O CO2Me

O

A HCO2H -CO2

H Pd

OH

H Pd

B

HCO2H -CO2

OH CO2Me

O

- Pd(0)

251

O CO2Me C

- Pd(0) HCO2H 254

-CO2

O

HCO2H 255

OH

256

-CO2

OH

O

OH

OH CO2Me 254

CO2Me 255

CO2Me 256

Fig. 44 Reaction mechanism of producing by-products

glucose-6-phosphate [138, 139]. The key intermediate chiral α-arylpropionic acid (R)-262B was synthesized in high diastereomeric excess through the diastereomeric resolution of 260 without the need for a chiral resolving agent, and an epimerization process to obtain (R)-261 from the undesired (S)-261 was also developed. The counterpart 2-aminopyrazine derivative 266 was synthesized using a palladiumcatalyzed C-N coupling reaction, and this efficient process was demonstrated at the pilot scale (Figs. 45 and 46). The process chemistry team from Pfizer Inc. has reported the optimized process for the scale-up of a Buchwald-Hartwig amination reaction to synthesize the pharmaceutical intermediate [140]. This process showed an advantage of C-N coupling of chiral primary amine and minimized the formation of biaryl by-product. During the development of a scalable process, investigated various process related parameters including catalyst selection and stoichiometry of the chiral amine and also screed the conditions for the removal of residual palladium in the isolated products. The most promising condition found for the reaction is usage of Pd(dba)2 with BINAP and Cs2CO3 in THF. With this optimized conditions executed on 2.5 kg scale, the described conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium, and also this process has been successfully executed to produce more than 12 kg of compound (S)-272 (Fig. 47).

Application of Organometallic Catalysts in API Synthesis TMSCl, NaI NaHCO3, CH3CN H2O, 23 oC

Ph

Ph

O

O

O

O

I

258

Ph

1. 258, t-BuOK, THF N,N-dimethylpropylene urea, -9 oC 2. Cyclopropylboronic acid, Pd(OAc)2 PPh3, K3PO4 (aq), Toluene, 87 oC 3. NaOH (aq), THF, MeOH, 47 oC

O S O O

Ph

Ph

257

O

Ph O

O

EtOH OH

30% for three steps

Br

259

O

O

S O

Br 260

Ph

Ph Ph

Ph O

O

O

O

O

Recrystallisation with EtOH

S O

84%

O

HCl (aq), Acetone 50 oC

O

O O

155

O

Br (R)-261 90-91% de

95%

O

S O Br (R)-261

O O

O

S O

Br (R)-262A 99% de

99% de

Fig. 45 Scale-up route to (R)-2

N

Cl

OH

N

N

Cl

tert-butylchlorodimethylsilane, imidazole, DMF, 12 °C

264

263 Ph

N Ph

NH2OH·HCl, AcONa, MeOH, 22 °C

N OTBS

N

H2N

OTBS

266 HO2C N N

CO2H

KHCO3(aq), AcOi-Pr

OTBS

H2N

(2) suspension with AcOi-Pr, 97%

N N

OTBS

268

267 fumarate O

H2N

OH

O

N N

O S O

(1) fumaric acid, toluene, THF, 73% for four steps

N N

265

H2N

OTBS

N

benzophenone imine, Pd2(dba)3, rac-BINAP, t-BuONa, toluene, 61 °C

OTBS 3

1) HCl(aq), THF, 2 °C, 83% for two steps

POCl3, DMF, CH2Cl2, -3 °C, 2) recrystallization then compound 3, with aqueous EtOH, 95% DMAP, pyridine, Br CH2Cl2, -1 °C (R)-269 99% de O

Fig. 46 Scale-up route to (R)-1

H N O S O

O Br

N N

OH (R)-262B 99% de

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D. Basu et al.

Fig. 47 Synthesis of intermediate (S)-272

Br

H 2N

N CN

270

H N

OH (S)-271

Pd(dba)2 (2.5 mol%) BINAP (2.5 mol%) Cs2CO3 (1.6 equiv.) THF (14 vol.) 65 C, 15h

OH

N CN

(S)-272

8 Conclusion and Prospect The use of organometallic compounds to access structurally complex chemical entities in pharmaceutical, agricultural, and fine chemical industries was discussed in this chapter. The chemistry described in this chapter arose from process chemistry/ chemical development groups in those arenas. The chapter describes specific metal or reaction type to effectively forge C-C and C-X bonds to access simple to complex pharmaceutically active organics in process chemistry. Various metal-mediated transformations like asymmetric hydrogenation, direct arylation, hydroformylation, cross-coupling, and batch and continuous process with sufficient examples had been discussed. Instead of pursuing tedious and linear synthesis, much of the emphasis is now on sophisticated chemistry to produce complex organic molecules in production scale. The opportunities for creative research in organometallic chemistry and homogeneous catalysis seem greater than ever.

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Top Organomet Chem (2019) 65: 161–198 DOI: 10.1007/3418_2019_28 # Springer Nature Switzerland AG 2019 Published online: 29 September 2019

Process Economics and Atom Economy for Industrial Cross Coupling Applications via LnPd(0)-Based Catalysts Eric D. Slack, Peter D. Tancini, and Thomas J. Colacot

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 A Brief Overview of Cross Coupling Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Process Drawbacks of In Situ-Generated Palladium Catalysts and Even the Classical Preformed Pd(Ph3P)4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Process Drawbacks of Using Pd(OAc)2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Process Drawbacks of Pdydbaz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Process Benefits of Preformed Pd Complexes and Catalyst Selection . . . . . . . . . . . . . . . . . . . . . 3.1 Preformed Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 L2Pd(0) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 L1Pd(0) Pre-catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

162 162 164 168 170 171 171 172 181 191 193

Abstract Up to and beyond the 2010 Nobel Prize in Chemistry, Pd-based cross coupling has seen a boom in industrial applications and scientific research. These efforts have yielded a wealth of information on Pd-based catalyst technology that can be separated into two broad categories: pre-catalysts and in situ generated catalysts. Proper selection of the catalyst system, i.e., in situ vs pre-catalyst is although process dependent, herein we provide an in-depth look into the often overlooked benefits of the pre-catalyst technology for maximizing the process E. D. Slack (*) and P. D. Tancini Johnson Matthey, West Deptford, NJ, USA e-mail: [email protected] T. J. Colacot (*) Johnson Matthey, West Deptford, NJ, USA Affiliation at time of publication: MilliporeSigma (a division of Merck KGaA), Milwaukee, WI, USA e-mail: [email protected]

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economics. Although ligands play a crucial role in catalysis, it is not “all about ligands” alone. To improve the efficiency of the process one may need to precisely generate the active catalytic species for that particular reaction. In this chapter, we highlighted this concept by providing industrial case studies where switching from in situ generated to pre-catalyst technology yielded significant process economic benefits. We also provided process chemists with a methodology to properly evaluate catalyst technology and make recommendations on potential benefits by weighing the pros and cons of using in situ vs preformed. Keywords Atom economy · Catalyst cycle · Catalyst selection · Cross coupling · In situ catalyst generation · Industrial applications · LPd(0) · Pre-catalysts · Preformed Pd complexes · Process economics

1 Introduction 1.1

A Brief Overview of Cross Coupling Technology

Exploration of cross coupling-based organic processes has involved several stages, the first being the identification of the most suitable metal capable to do the three basic steps, namely, oxidative addition, transmetalation, and reductive elimination effectively [1]. Research in this area has been mostly dominated by palladium; however there is a major focus to identify earth-abundant, cheaper alternatives to palladium [2–5]. This was followed by identification of various nucleophilic coupling partners beyond unstable and less efficient organometallics such as organolithiums, organomagnesiums, etc. [6, 7]. However, there has been a very recent effort to reenergize the use of organolithium and organomagnesium reagents as nucleophiles as other reagents such as boronic acids are derived from them, thereby improving the overall efficiency of the process [8, 9]. A very important aspect of cross coupling has been the development of ancillary structures of the active metal center, otherwise known as ligands [10–12]. These advancements have allowed extensive commercial utilization of palladium (Pd)-based pre-catalysts to rise [13–16]. The major applications of cross coupling technology are geared towards the formation of critical intermediates and target molecules, under relatively milder conditions thereby accelerating the developments in the pharmaceutical, agrochemical, and electronics industries [16, 17]. The great utility and versatility that Pd had shown was recognized through the awarding of the 2010 Nobel Prize in Chemistry for the area, “Pd-catalyzed cross-coupling . . ..” to its founders Heck, Suzuki, and Negishi [18]. The contributions of the late pioneers such as Kharasch, Kumada/Corriu, Stille, Sonogashira, and even Grignard are equally important for this area to reach the current status [7]. As Negishi often stated in his lectures, “it all started with Grignard.” Development of modern ligands has allowed to explore the tunability of palladium for expanding the scope of substrates continuously [7, 19, 20]. Today, Pd has been dubbed as the “...king of transition-metal catalysts...” [21]. As mentioned earlier, in large part the exploration of palladium’s ability to couple simple and complex organic moieties has been driven by the need to synthesize more

Process Economics and Atom Economy for Industrial Cross Coupling. . .

PPh3 Ph3P Pd PPh3 PPh3

PPh2 Fe

Pd PPh2

Cl tBu P Pd PtBu 3 3 Cl

PtBu2 Fe

Pd PtBu2

Cl Cl

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N(H)Me Pd OTf XPhos

OTf Pd BrettPhos

Fig. 1 Pictorial representation of evolution in mobile phone technology and its analogous Pd-precatalyst counterpart [20]

complex APIs [15, 17, 22], as well as specialty compounds in material science [15, 23–26], with greater efficacy and specificity. This of course can be tweaked by knowledge-based screenings either to generate the lead compounds or their intermediates [27]. The efficiency and accuracy of catalyst screenings are therefore of utmost importance as conditions leading to results can impact the discovery and optimization program. The need to seamlessly scale up processes in an accelerated manner from bench to multi-kilo quantities for clinical trials is equally important. This has drastically increased our dependency on modern catalyst systems at the bench, which has been slowly but steadily translated into larger-scale operations [28]. Our growing dependence on mobile devices and cloud computing [20] is analogous to the evolution of coupling catalyst technology (Fig. 1), where initial needs were simplistic, solely telecommunication – just to make a call to another person. We can think of this like the early generation catalyst system such as palladium acetate with PPh3 or air-sensitive Pd-tetrakis, Pd(PPh3)4. These are still very popular catalyst systems that work to some extent for some simple and moderately challenging reactions under relatively harsh conditions and/or with higher loadings, where side reactions may occur, thereby minimizing the overall efficiency and efficacy [29]. For example, the air-sensitive Pd-tetrakis is less efficient in comparison to an air-stable, yet highly active PdCl2(dtbpf) catalyst, demonstrating the userfriendliness and efficiency of a new generation of catalyst [30, 31]. As our mobile

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needs have gone even further, personal portable computers accompanied by sophisticated applications that immediately suit our individual needs have become standard. This same modulation can be found in advanced palladium catalysts such as Organ’s PEPPSI [32, 33], Buchwald’s palladacycle [34], Hartwig’s and Johnson Matthey’s Pd(I) dimers developed by Colacot and coworkers [35–40], and the π-allyl/crotyl/cinnamyl Pd-monophosphine and biarylphosphine-based pre-catalysts developed independently by Shaughnessy group and Colacot’s group at Johnson Matthey [41, 42]. These pre-catalysts are easy to handle due to their stability at ambient conditions and exhibit differences analogous to different models of the latest smartphones with user-friendly features. It is noteworthy that these precatalysts should all produce 12-electron-based monocoordinated Pd(0) species as the active catalytic species. Some of these popular new-generation catalysts remain in the academic or R&D phase as their availabilities in bulk at affordable price are a key factor for their use in industrial processes. Catalyst technology aided by high-throughput screenings of free ligands in conjunction with Pd precursors is also equally employed for developing systems for advanced cross couplings in pharmaceutical and related fine chemical industries. The concept behind this approach is to increase the probability of identifying a suitable catalyst system quickly. In addition, the upfront catalyst cost associated with the use of a free ligand in conjunction with the Pd precursor might be cheaper than using a pre-catalyst. Although this may have case-by-case process economic advantages, the overall trend appears to be changing. It is here that the next era of cross coupling has begun, not specifically in tuning of the reaction using the firstgeneration catalyst systems but in the effective conversion of a stable pre-catalyst to the active catalyst and prevention of its deactivation through directed modification of the pre-catalysts [5, 34, 37, 41–43]. Throughout this chapter we would like to help dispel the assumption that a catalyst is a catalyst no matter how it is generated, i.e., in situ vs preformed. We would also like to add to this concept by showing some of the improvements to process economics that have been gained by using stable preformed Pd catalysts by various process development groups, mostly from industry. We aim to do this from the point of view of catalyst activation with precise control of the ligand to metal ratio (M:L). From an engineering point of view, preformed catalyst can be activated to LnPd(0) with a consistent M:L ratio for highly reproducible, consistent, and robust reactions compared to the catalysts derived from the conventional “in situ” technology.

2 Process Drawbacks of In Situ-Generated Palladium Catalysts and Even the Classical Preformed Pd(Ph3P)4 Entrance into cross coupling reactions relies on generating LnPd(0). Until the beginning of the twentieth century, palladium was used either directly as Pd(II) salts in harshly reductive environments or as air-sensitive Pd(0) {Pd-tetrakis or Pdxdbay

Process Economics and Atom Economy for Industrial Cross Coupling. . .

Oxidative Addition R X -PPh3 Pd(PPh3)4

+PPh3

R (II) LnPd X

- 1 or 2 PPh3 Pd(PPh3)3

+1 or 2 PPh3

Reductive Elimination

M R' Transmetallation (Nucleophilic Addition)

LnPd(0)

R R'

165

R Pd(II)Ln R'

M X

Scheme 1 Equilibria of Pd(PPh3)4 while in the catalytic cycle

(x ¼ 1,2; y ¼ 2,3) of questionable quality in the presence of a ligand such as PPh3}. Pd-tetrakis, while functional, this method can cause process setbacks for discovery chemists as the amount of ligand, PPh3, is in excess with respect to the active Pd complex. This causes what can be described as a “chemical soup.” Langmuir’s 18-electron rule states that all orbitals are filled when a metal complex has 18 electrons (e) and therefore behaves more like a noble gas with respect to reactivity. This gives the basic reasoning to identify the problems in using this complex to obtain a highly active and efficient catalyst. Due to both thermodynamics and kinetic concerns, the equilibria can be more prone to the more saturated 18 e based Pd-tetrakis. This should give an abundance of the more stabilized palladium species which is protected against oxidative addition (Scheme 1) [44–46]. If some of the ligands are driven away from the active center, likely through heating or dissolution, this could increase the concentration of the less ligated and more active LnPd(0) species. Modern research towards this area has led to the belief that the true active catalyst is the more active, unstable 12-electron-based L1Pd(0) or 14-electron-based L2Pd(0) where the size of the ligand also plays an important role to stabilize these species [47–50]. Control of the M:L ratio should therefore control the consistency and activity of coupling reactions to give the optimal results. Addition of exogenous ligand to an active catalyst should typically slow down a reaction, as seen in the synthesis of an intermediate 3 for CEP-32215 (Scheme 2) [51]. This is not an isolated case, and we have observed this from other preformed catalysts. Similar trends were observed for other coupling reactions such as α-arylation (Scheme 3), where the PtBu3-based L2Pd(0) shows lower activity in comparison to the preformed [P(μ-Br)PtBu3]2 catalyst which gets activated to L1Pd(0) [37]. A major motion towards full in situ activation was disclosed in the early 1990s. Two reports gave a brief introduction on how palladium complexes derived from acetates could be activated. The coordination in a great part relies on equilibria and in general requires excess ligand and water to force the formation of Pd(0) via reduction of Pd(II) in an irreversible manner (Scheme 4) [52–54].

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O O

N OtBu O

Pd(PPh3)2Cl2 (0.5 mol%) CsCO3, PPh3

B(OH)2

toluene, 2.5 h, 80 oC

29% conversion slow incomplete

O

O O

1

+ Cl

Pd(PPh3)2Cl2 (0.5 mol%) CsCO3

O 2

toluene/H2O, 1 h, 45 oC

O

O

N

O

3

OtBu 70% yield after purification and palladium removal

Scheme 2 Effects of excess ligand on palladium coupling towards CEP-32215 [51]

O +

Cl

Me

Me 4

[Pd] (2.0 mol%) [Pd] : PtBu3 1:1 NaOtBu, THF 60 °C, 3 h

5

O

Me 6

Scheme 3 Demonstration of metal to ligand ratios in the model α-arylation reaction using Pd (PtBu3)2 (1:2) vs [Pd(μ-Br)PtBu3]2 (1:1) [37]

H2 O

R X

R (II) LnPd X

M R'

+L Pd(OAc)2

-L

LnPd(OAc)2

2 HOAc,

O P R R R

LnPd(0)

R R'

Scheme 4 Catalyst activation and catalytic cycle Pd(OAc)2

R Pd(II)Ln R'

M X

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1800 1600 1400 1200 1000 800 600 400 200 0

Fig. 2 Palladium prices over the past decade according to Johnson Matthey [66]

The use of a Pd(0)-based precursor Pd2dba3 in conjunction with a ligand has also helped both academia and industry in their practice of Pd-catalyzed cross coupling, like classical mobile phone technology, to be able to incrementally innovate and eventually to be summarized by the motto “...it is all about the ligand...” [12, 55– 57]. The vast amount of ligands generated and used through this process has imbued the ability to uniquely tune palladium to an array of different substrates and reactions [5, 15, 19, 58–65]. Considering the rising cost due to growing scarcity of and the expanding use of Pd for different application, knowledge of ligand application and utilization will become increasingly important in order to maximize the efficiency of metalcatalyzed processes (Fig. 2) [66–68]. Knowledge of how to effectively pair the two and activate them in an atom economical and efficient manner will be of high value due to the rising price of ligands and palladium [69]. In addition minimizing residual metal levels in API has become a regulatory requirement in the pharmaceuticals arena [70–73]. While a vast array of methodologies have become available to generate active palladium [74, 75], only a few have found widespread applications in industry. Water-promoted phosphine oxidation has gained quite a bit of popularity due to its simple setup, ease of use with only surreptitious water, and efficiency of generating Pd(0). This method has not been altered much over the years; however boronic acids/ nucleophiles, certain amines, phosphine ligands, and bases have been shown to participate in the Pd reduction process [74]. For the most part, this method is still performed by mixing an appropriate palladium precursor (vide infra) with a base, ligand, and water to activate the catalyst often in the presence of other reagents. The ligand in this case plays a dual role, acting not only to activate the palladium but also to tune the reactivity during cross coupling. This of course can also be conducted

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with Pdxdbay in the presence of free ligand, where the precursor is already in the (0) oxidation state, hence no activation needed.

2.1

Process Drawbacks of Using Pd(OAc)2

Up until recent years, in situ generation of the active species, LnPd(0), has been perceived to be an efficient remediating solution for process engineers/chemists to balance both the high cost of palladium catalysis and improve its efficiency [76, 77]. Catalysts are a high input cost, so it would only seem logical to purchase the cheapest forms of both palladium (e.g., Pd(OAc)2, Pdxdbay, PdCl2, etc.) and ligand (e.g., Ph3P). But to quote the immortal words of science-fiction novelist Robert Heinlein, “There ain’t no such thing as a free lunch” [78]. Although price per gram of commodity Pd precursors is seductive from the perspective of the bottom line, the combination of ligand and commodity precursor may not necessarily efficiently produce the desired LnPd(0) [34, 74, 79]. Lack of efficiency can force higher loadings of both the Pd precursor and ligand depending on the mode of activation from Pd(II) and Pd(0) (vide supra) and may cause incomplete reaction and complex by-product formation of the reagents and the catalyst [43, 80]. This mode of activation has two general pitfalls that could become prohibitive at scale. The first is obvious as at least one equivalent of the ligand must be destroyed to generate the active catalyst. While ligands like PPh3 or similar simple tertiary phosphines can be wasted as they are cheap at the commercial quantity [69], the use of more advanced phosphine ligands such as the biaryl ligands or related can be costly (Fig. 3). Utilization of alkyl-based phosphine ligands is also of concern as these phosphines are pyrophoric until they are ligated to a palladium source [81, 82]. This represents a challenge from an atom economy standpoint. In some cases, large volumes of water are needed to force the equilibria to the desired catalyst, increasing working volume and limiting batch size compared to a complex that is internally activated. The second is much less obvious due to the perceived stability of Pd(OAc)2. Good catalytic activity is dependent on its purity and particle size [83]. This is well known and of high concern when using catalysts based on Pd(0) (vide infra) due to

O Ph

P Ph

Ph

P

P

PCy2 iPr

iPr

PCy2 iPr

PtBu2 Ph Ph

iPr 5.7 $/mmol PPh3

O iPr

6.7 $/mmol PCy3

12 $/mmol PtBu3

26.7 $/mmol XPhos

iPr 146 $/mmol BrettPhos

Fe Ph

Ph

Pd(OAc)2

Ph

372 $/mmol QPhos

25 $/mmol

Fig. 3 Price comparison of common ligands and Pd(OAc)2 based on Millipore-Sigma prices [69]

Process Economics and Atom Economy for Industrial Cross Coupling. . .

169

a) O O

O

O

O

O

Pd

Pd

O

O

O Pd

O

O

Pd O

O

Pd O O

Pd

O

O

O

O

Pd O

O

O

O O

O Pd

O

O

O

O Pd

Pd O

O

O

N

O

O

O

O

Pd3(OAc)6 7

b)

B(OH)2

Cl MeO

+ OMe 10

Pd3(OAc)5(NO2) 9

[Pd(OAc)2]n 8 [Pd] (2 mol %) XPhos (2 mol %) K2CO3 (2 equiv) EtOH/H2O 30 ºC, 2 h

Me

MeO

11

12

Conversion (%, 4)

100 80 60

7

40

8

20

9

0

8 at 20 oC

0

1

2

3

4

Time (hours) Fig. 4 (a) Complexes found in commercially available Pd(OAc)2. (b) Suzuki coupling comparison of Pd3(OAc)6 7, with [Pd(OAc)2]n 8 and Pd3(OAc)5(NO2) 9

their instability compared to Pd(II). We have found this especially pertinent with simple Pd(OAc)2 [84, 85]. The purity of the catalyst, until it is in solution, is dependent on stability in the solid state and has been shown to deviate based on the conditions used to prepare and store the pre-catalyst. This can range from several different polymeric states, 8, to nitrate, 9, and hydroxy-incorporated palladium acetate (Fig. 4) [86]. The state of Pd(OAc)2 becomes further complicated once it is exposed to organic solvents and can rapidly change states [86]. Two recent publications from the Colacot group at Johnson Matthey on Pd(OAc)2, a commodity Pd precursor, highlight a few of these necessities and their effects on the outcome of in situ generation [21, 84, 85]. The study identified that differences in purity and morphology of Pd(OAc)2 can cause noticeable shifts in catalytic activity that are remarkably different depending on the reaction conditions. This is depicted in Fig. 4 as form 7 along with the nitrate form 9 is far more active, while the polymeric form 8 of palladium acetate has been perceived to be far less active in the model Suzuki

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Br N (1 eq) 13

S

S

[Pd] (2.0 mol%), QPhos (4 mol%), NaHCO3 (2.4 eq)

+

7: 73% 8: 78%

o

DMF (2 mL), 120 C, 4-8 h (1.2 eq) 14

9: 48%

N 15

Scheme 5 Reactivity comparison of Pd3(OAc)6, [Pd(OAc)2]n, and Pd3(OAc)5(NO2) in a Buchwald-Hartwig amination [85]

couplings [85]. While one would hope this to be generalizable to all reactions, this appears not to be the case as each set of conditions alters the activity of these complexes (Scheme 5). Presence of variable amounts of each impurity in common supplies of Pd(OAc)2 can affect the reproducibility of the reaction while carrying out in situ catalyst generation and lead to varying reactivity and process reproducibility at scale. The use of high purity Pd(OAc)2, which is now commercially available [87], can also alleviate some of these problems, although this does not address the atom economy due to other factors [88].

2.2

Process Drawbacks of Pdydbaz

Alternative methods that use sources of Pd(0) precursor Pd2(dba)3 [89] typically carry their own process problems but are still considered to be one of the most readily used palladium sources [90]. The efficiency of these sources relies on the equilibria of the sacrificial ligand, dba, being ejected from palladium or used to stabilize an intermediate LnPd(0) species. The dba ligand’s ability to be replaced by an incoming ligand, however, is known to not be completely efficient, and there have been reports on its competition and inhibition of the formation of the desired catalyst in some cases [54, 91–94]. Even more confounding, dba can also act as a buffer for certain reactions altering the effective concentration of active Pd(0) [95]. Stability and shelf life of Pd(0) is a well-documented issue both in solution and in solid state [54, 88, 94, 96]. This can often lead to optimization of the reaction through titration of the Pd2dba3 with ligand to identify the optimum stoichiometry [95]. Even in the solid state, Pd2(dba)3 degrades slowly over time resulting in the formation of Pd nanoclusters which adds to metallic Pd already present from its production (Scheme 6) [96]. All of this can have a strong impact on the performance of the catalyst while in the process and hence requirements for purifications downstream affecting the processes economy. New conditions via process engineering can alleviate this, via further optimization, thereby spending more time on process development [54, 94, 96]. It is critical when using this method to be consistent with all materials and suppliers as minor changes can be detrimental to the outcome of the reaction while scaling up for production, especially considering the rising cost of Pd. There are no precise quality control techniques to determine the purity of Pd2dba3. It is also imperative to conduct “use tests” during each run to make sure that the catalyst has not undergone any degradation with time [96]. In the long run,

Process Economics and Atom Economy for Industrial Cross Coupling. . . Scheme 6 States of Pd2dba3 in solution with added ligand

R X Pd2dba3

+L,-dba -L,+dba

171 R LnPd(II) X

R' M

L1Pd(0)dba

? L2Pd(0) + L1Pd(0) ? Pd(nanoparticles) R R'

R Pd(II)Ln R'

X M

this represents a large investment cost especially for more challenging chemistries involving cross coupling. Since Pd(dba)2 is relatively more stable and purer than the Pd2(dba)3, typically Pd2dba3 is available in the market as a mixture (varied composition depending on the vendor) which further complicates the reproducibility during scale-up.

3 Process Benefits of Preformed Pd Complexes and Catalyst Selection 3.1

Preformed Catalysts

One of the prominent goals among process chemists/engineers is to obtain clean high-yielding process with simple work-ups without waste of reagents, solvents, and catalysts, ideally, no more than a simple precipitation or crystallization, followed by a wash procedure. Earlier versions of catalyst systems may require tedious and costly purification steps of unreacted starting materials and by-products with variable levels of heavy metals from higher Pd loadings [97, 98]. Although there is a higher upfront cost, Pd pre-catalyst may allow for lower loadings with higher activity and selectivity. This may provide greater process economic advantages for the efficient use of ligand with metal to avoid the “chemical soup” [80]. More precise control of the M:L ratio can lead to more consistent and reproducible results. This is similar to advancements in online international calling using a smartphone leading to fewer dropped calls and more consistent connectivity with minimal or no charges. A higher upfront cost is paid for the smartphone itself; however the upfront cost offers flexibility and additional features such as video chatting, sending pictures and messages, touch screen, apps to perform operations such as online banking, etc. In the rest of the chapter, we shall show that this control often yields process economic benefits at scale, beyond improved reaction efficiency and for couplings that have not been possible before [99–102]. This as well is accompanied with catalyst systems that also offer a high level of reproducibility from batch to batch supported by an atom-efficient process to generate the active catalytic species, LnPd(0), in the cycle. In the next portion of the chapter, we will review available technologies specifically for making the active

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catalyst accessible to commercial applications [1, 103]. This will be discussed from the perspective of industrial applications of these catalysts from selected examples in the literature.

3.2 3.2.1

L2Pd(0) L2PdX2 Introduction

Good atom economy can be easily achieved with syntheses of L2PdX2 complexes. L2PdX2 represents a known class of 16-electron complexes that adopt a square planar geometry that allows for a low-spin d8 configuration in accordance with the 18-electron rule [104]. Although these are coordinatively unsaturated, these are air-stable complexes that accurately control the M:L ratio (1:2). They can be activated to 14-electron L2Pd(0) via several pathways; just a few are given in Scheme 7. This gives them a balance of stability, activity, and atom economy via the required reductant and often with no waste of ligand [74, 105–107]. L2PdX2 complexes have been known since the beginning of modern cross coupling and have gained considerable attention due to their utilization in many industrial processes. The well-known Pd(PPh3)2Cl2 is one of the cheapest Pd pre-catalysts in this class on the market. Although it uses the less active PPh3 ligand, it offers many of the process economic benefits of generating L2Pd(0) directly, especially in the presence of anions [108]. Pd(PPh3)2Cl2 is akin to the flip phone (second generation); it still sees use for limited and simplistic needs. It is often unable to meet complicated chemistry demands. Other more active complexes, like (dtbpf)PdCl2 or AmPhos2PdCl2, are also available commercially as newer generations of these catalysts [109, 110]. The steric bulkiness and electron richness of the ligand not only increases its oxidative addition ability but also provides sufficient bulkiness to facilitate faster reductive elimination, thereby minimizing side reactions [55].

X-

Et3N

H L2PdX2 2 R-M

NEt2

PdL2X XEt2N β-hydride Elimination

R2PdL2 + 2 M-X

HPdL2X R-R

Reductive Elimination

Scheme 7 Representative activation of L2PdX2 to L2Pd(0)

Reductive Elimination

L2Pd0

L2Pd0

Process Economics and Atom Economy for Industrial Cross Coupling. . . 1. a)

O I

HN O

2. THF/MeOH, Charcoal

N H 16

1.

b) O I

HN O

N H

TMS PdCl2 (1.5 mol%), PPh3 (3 mol%) CuI (1.5 mol%), Et3N, EtOAc

TMS (Ph3P)2PdCl2 (0.5 mol%) CuI (0.5 mol%), Et3N, EtOAc

2. THF/MeOH, Charcoal

O

TMS

HN O

2) AcOH

N H 93% 17

HN O

O 1) aq. NaOH

O

HN O

TMS

N H 18

O 1) aq. NaOH

N H

173

2) AcOH

HN O

N H

93%

Scheme 8 GSK Sonogashira coupling en route to make eniluracil using (a) in situ use and (b) preformed pre-catalyst use with the significant reduction of catalyst loading [111]

3.2.2

L2PdX2 Applications

Cooke et al. at GlaxoSmithKline (GSK) refined a process for the development of the cancer treatment aide Eniluracil (Scheme 8) [111]. Initial use of an in situ process to generate (PPh3)2PdCl2 then L2Pd(0) by mixing PdCl2 (1.5 mol%) with PPh3 (3 mol %) in refluxing ethyl acetate precipitated black solids indicating decomposition of the catalyst. Subsequently they switched to the preformed catalyst, which allowed for lower catalyst loading and prevented high amounts of palladium contamination in the final product, i.e., better atom economy. The use of (PPh3)2PdCl2 allowed for a lower co-catalyst (CuI) loading at 0.5 mol% from 1.5 mol%. In addition, the chemistry was operated under much milder conditions (r.t. vs 75 C), saving additional energy costs. Residual heavy metal content fell from greater than 5,000 ppm of both Pd and Cu to approximately 600 ppm and 100 ppm, respectively, removing their need for an EDTA washing operation. In summary, the process economic benefits likely outweighed the higher vesting of input costs to Pd pre-catalysts. The use of the preformed PdCl2(PPh3)2 as well helped scientists at Pfizer to efficiently scale up the synthesis of an endothelin antagonist [112]. Although in situderived catalyst was found to be competent for their coupling of a sulfonamide triflate 19 with a benzodioxane boronic acid 18, they found them to be unpredictable (Scheme 9). From their description of the methodology, large quantities of palladium black were observed while using the Pd(OAc)2/PPh3 catalyst system as an in situ mixture. In some occasions this led to comparable conversions to that of the preformed PdCl2(PPh3)2; however this system also led to stalled conversion. Therefore, they decided to switch to the preformed complex to obtain over 80 kg of the intermediate, 21. The reasoning for this inconsistency was not fully clear but likely due to the inefficient formation of L2Pd(0) during the in situ process. Direct comparison of the preformed PdCl2(PPh)2 catalyst to the PdCl2/PPh3 in situ catalyst

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E. D. Slack et al. O O

OTf CO2Me S O

O

Pd, carbonate

O

THF, 65 oC

+

N

O F3C

CO2Me

B(OH)2

S O

20

19

N

O F3C 21

"Pd"

ligand

Pd mol%

base

% yield`

PdCl2(PPh3)2

2PPh3

0.3

Na2CO3

94.6

PdCl2

4PPh3

0.5

K2CO3

60

Pd(OAc)2

4PPh3

0.3

K2CO3

89

Pd2dba3

2PPh3

0.8

Na2CO3

92

Scheme 9 Efficient Suzuki coupling for CI-1034 using preformed (PPh3)2PdCl2 vs in situ [112]

showed that the Pd loading could be reduced by half with almost doubling the yield. This was far better than the monoligated species derived from Pd2dba3/PPh3 which required five times loading than that of the preformed PdCl2(PPh3P)2 for a comparable yield. Further experiments for developing methodology to 21 from the cheaper 4-fluorobenzensulfonate analogue of 19 showed similar reproducibility issues. However, interest in the antagonist was lost, and no large-scale comparison was done for the 4-fluorobenzensulfonate.

Limitations of L2PdX2 Pre-catalysts Several other examples not mentioned herein still exist in the literature that shows the strength of this catalyst family [110, 113, 114]. It is important to note that L2PdX2 pre-catalysts can be activated relatively easily at reasonable temperatures through the use of base, solvent, or certain substrates [31, 115–117]. Their low cost, ease of activation, and bench stability make this a family of reasonably effective pre-catalysts to generate L2Pd(0) with consistent M:L ratio. Some limitations do exist for this catalyst family as ligand choice is somewhat restricted. For example, the L2PdX2 complex of PtBu3 is unknown and cannot be made. Often complexes containing triaryl ligands limit coupling to easily activated aryl halide (Ar-I, Ar-Br, and Ar-OTf) electrophiles at lower temperatures, whereas aryl chlorides typically require better ligands (bulky electron rich) and/or higher temperatures [104]. However, some exceptions to this are available as the bulky electron-rich di-tert-butylbased ligands such as (neopentyl)di tert-butylphosphine and Amphos (tBu2P ( p-C6H4-NMe2)P) are available as the L2PdX2 complex.

Process Economics and Atom Economy for Industrial Cross Coupling. . .

NHMe

Cl

+ MeO 22

23

175 Me N

"Pd" NaOtBu, toluene rt, 40 min

OMe 24

Pd

mol %

Conv. (%)a

(QPhos)Pd(crotyl)Cl

0.5

100

Pd(dba)2/QPhos (Pd:L 1:1)

0.5

80

QPhos2Pd

0.5

9

a) Conversion determined by GC

Scheme 10 Competitive ligand effect on cross coupling

For certain chemistries, kinetics require L1Pd(0) vs L2Pd(0). While these complexes can generate L2Pd(0) from activation, it still may require heating in a solvent to access L1Pd(0) efficiently during the coupling process [86]. As in the example of Buchwald-Hartwig coupling of 22 and 23, L1Pd(0) catalyst systems quickly perform the amination, while L2Pd(0) is unable to compete at room temperature (Scheme 10).

3.2.3

A Special Class of L2Pd(0): Bidentate (L-L)PdX2

In the L2PdX2 category, there is the bis-phosphine (bidentate ligands or chelating) ligands used for many cross coupling reactions. Hayashi’s pioneering work on (dppf)PdCl2 revealed that the bite angle played a major role on the activity and selectivity. Later, van Leeuwen and Colacot also independently observed similar trends [10, 118, 119]. The pre-catalyst form appears to have similar structures as the diphosphine complex, L2PdX2, except that the bidentate ligand is often cis-coordinated, whereas the monodentate phosphine is trans-coordinated. However, during the catalytic cycle, the geometry around Pd may change. Evidence also suggests that they activate often similar to other L2PdX2 complexes via reduction, leading to (L-L) Pd(0) [120–122]. Because of their unique structure, they do not appear to retain this form after oxidative addition [123]. From isolated complexes of oxidatively added (L-L)Pd(0), there are reports that after transmetalation, only one of the phosphines is ligated to the palladium, suggesting (L-L)Pd(0) catalyst acts similar to L1Pd(0) species when bulky ligands are used [104, 119]. Chelating bisphosphines though appear to be a unique class of complexes as even those precomplexed can form the monophosphine oxide depending on the conditions used and the ligand itself [116].

Application of Bidentate (L-L)PdX2 The applications of (L-L)PdX2 have been extensively studied, and they need to be in the process chemist’s tool box; an example is the new-generation catalyst (dtbpf)

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Cl

"Pd", MeCN, 82 oC CO2Et

Cl

H N CO2Et

N3OP(O)H2

X O

25 O O Si O

CO2Et

H P OMe

26

NH2

H N

Cl

CO2Et

H

X

27

28

X

"Pd"

26

27

28

Br

Pd(OAc)2 (2 mol%)/dppp (2 mol%)

0

36

60

I Br

Pd(OAc)2 (2 mol%)/dppp (2 mol%) PdCl2dppf (2 mol%)

35 55

34 24

26 4

SO2Ph N CO2Et

Cl

H N

Cl

PdCl2dppf EtOAc, 82 oC N3OP(O)H2

Cl

SO2Ph Cl N CO2Et

Br O

29 O

O Si O

NH2

H P OMe

82% 30

H N

O

CO2Et H P OMe

2% 31

Cl

SO2Ph N CO2Et Br 5% 32

Scheme 11 Optimization of phosphination towards GSK2248761A and optimized conditions. Conversion determined by HPLC

PdCl2, whose potential as an excellent air-stable catalyst was originally identified by Colacot’s group at Johnson Matthey (Shea and Grasa) [22, 99]. The specific activity of (L-L)PdX2 depends heavily on the method of activation and the type of ligand used. This can be seen on the synthesis and scale up of GSK2248761A for a particularly difficult carbon-phosphite (C-P) coupling process (Scheme 11) [124]. Activation of Pd(OAc)2 with diphenylphosphinopropane (dppp) showed low to no conversion of 25 along with high amounts of dehalogenation product, 27. A simple switch to (dppf)PdCl2 improved the yield from 35% to 55% with lower amounts of side products with almost complete conversion of 25. Further modifications of the substrate helped to prevent unwanted dehalogenation, where the preformed (dppf)PdCl2 complex allowed for 82% conversion to the desired material 30 with fewer number of by-products. These modifications also prevented hydrolysis of the phosphonate ester with the reduction of the electrophilic halogen (Scheme 11). While activation of (L-L)PdX2 complexes often is facile, sometimes alternative methods can be used to better produce the desired Pd(0). During the catalyst screening for the synthesis of rucaparib, the Pfizer group found that (dppf) PdCl2•CH2Cl2 was the most ideal catalyst to couple their advanced indole intermediate 32 (Scheme 12) with 4-formylphenyl boronic acid [125]. However, when they attempted this as a one-pot reaction at large scale, they found undesirable by-products, low yields, and a batch-to-batch variability. Whereas by heating (dppf)PdCl2•CH2Cl2 in dimethylacetamide (DMAC) along with 32 for an hour before the addition of the 4-formylphenylboronic acid led to the isolation of pure 33 in 92% yield.

Process Economics and Atom Economy for Industrial Cross Coupling. . .

O

4-formylphenyl boronic acid PdCl2(dppf)•CH2Cl2

H N

-Poor yield -byproducts

Na2CO3, DMAc O

H N

Br

O

N H

F

177

32

F 1.PdCl2(dppf)•CH2Cl2 DMAc, 95oC, 1 h 2.4-formylphenylboronic acid Na2CO3, DMAc

N H

H 33

-92% yield -easily crystalized as pure product

Scheme 12 Comparison of “dump and stir” method of (dppf)PdCl2 activation to “pre-activation” method

3.2.4

Special Note on L2PdX2

As stated above, bidentate (L-L)PdX2 complexes carry some interesting facets that benefit from in situ activation. While in most cases activation generates a monodentate ligand that is oxidized and lost, in the case of bidentate ligands, the phosphine oxide remains close by attached to the scaffold. This as well gives access to unique ligands that often cannot be synthesized independently. The diphosphine is proposed often to act much the same as L2Pd(0); however when heated, loss of ligation by one of the phosphines to form the L1Pd(0) intermediate before reductive elimination may occur, although size of the ligand may play a big role [124]. This makes a rare case when it is advantageous specifically to screen both systems: Pd(OAc)2/water with the ligand (L-L) and (L-L)PdCl2 instead of solely using the preformed complex, as in the case of linifanib synthesis (Scheme 13, 36) [127]. There is some evidence that phosphine oxidation as well can occur using the dichloride pre-catalysts in certain case [116]. Therefore, it must be stressed out that control of ligand must be rigorously implemented especially during the in situ generation of catalysts for optimum results as highly stabilized Pd(L-L)2 complexes can be formed in this situation [30].

3.2.5

L2Pd(0) Pre-catalysts

The commercial accessibility of L2Pd(0) has played a crucial role in accelerating the development of Pd-catalyzed cross couplings in a faster pace. Nicholas explored this type of species for the carbonylative amidations during the 1980s, but much of the interest lays dormant until the end of the century [128]. Koie and Fu picked up this area independently with the use of the bulky electron-rich ligand, PtBu3, due to its superior control over the M:L ratio (1:2), which caused an explosion of cross coupling research where they showed the exceptional power of in situ-generated Pd(PtBu3)2 catalyst for the previously challenging aryl chloride substrates [129].

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O HN

F

O

N H

CH3

+ O

B

HN

Cl

H2N

F N H

CH3

Pd (3 mol%), K3PO4 (2 eq.)

N

toluene:EtOH:water (1:1:1), 50 oC

N H

O

H2N N

(1 eq) 35

N H

36

(1.1 eq) 34 Pd

time(h)

conv.

(dtbpf)PdCl2

19

81

Pd(OAc)2 + dtbpf (1:1)

4

100

Pd(dba)2 + dtbpf (1:1)

4

0

a

Pd(PtBu3)2

26

99b

a

a

Ligand and catalyst stirred in EtOH before reaction. b Conversion after 19 h at 50 oC 44 %. Heated to 77 oC after 19 h.

Scheme 13 Optimized Suzuki coupling in Abbot’s synthesis of linifanib [127]

Despite Fu’s findings [130], methods to produce L2Pd(0) remained unoptimized and highly inefficient. Small quantities of L2Pd(0) were either synthesized by using unstable or volatile precursor, such as Pd(η3-C3H5)(η5-C5H5), or by extensive recrystallization under cryogenic conditions when Pd2(dba)3 was used as the Pd source [131–135]. This resulted in prohibitively high manufacturing cost for a catalyst with poor stability to atmospheric conditions, discouraging industrial use. As a result, in many current processes, a higher loading of air-stable 16-electronbased L2PdX2 catalysts or a stable salt of the phosphine is preferred due to convenience and safety, although one cannot make L2PdX2 of the PtBu3 [136]. However, Colacot’s group at Johnson Matthey succeeded in identifying an atomeconomical process at room temperature to synthesize several L2Pd(0) complexes with PtBu3 as an example (Fig. 5) [138]. The overall process relies on the order of operation, two equivalents of NaOMe (NaOH/MeOH) followed by two equivalents of tri-alkyl- or tri-aryl-phosphine (PR3) to transform a cheap stable Pd-source (Pd(COD)X2) into a high-value catalysts in one pot at ambient temperatures, although certain ligands require higher temperatures for the last step [138]. So far this remains as one of the most economical and practical routes to make L2Pd(0) complexes [137, 138]. Unlike L2PdX2, isolated L2Pd(0) pre-catalyst complexes give process chemists the most direct and atom-economical access to Pd(0) with little to no waste of Pd or ligand. For the α-arylation of propiophenone (Scheme 14), L2Pd-based catalyst is more ideal than the respective L1Pd-based catalyst with di(t-butyl)neopentyl) phosphine as the ligand. This stability allows the species to persist (longer shelf life) along with the slow α-arylation and efficiently complete the transformation before catalyst deactivation. This example clearly demonstrates that in order to get

Process Economics and Atom Economy for Industrial Cross Coupling. . .

H 2

H

(tBu)

P

(tBu)

Np

(tBu)

P

o-tolyl

P

H 4L O°C - rt

(tBu)

Cy

o-tolyl

P

Br

2 NaOMe O°C - rt

P (tBu) Ph Fe Ph

N

Cy

Ph

(tBu) L4

Ph

Ph

(tBu) P

Cy

2 L Pd0 L

(tBu)

L3

L2

o-tolyl

2 L Pd L

(tBu) P (tBu) Ph

(tBu)

L1

OMe

Br Pd Pd Br OMe

2 NaOMe PdBr2 O°C - rt

179

L7

L6

L5

Fig. 5 Atom economical synthesis of L2Pd(0) complexes [137] O

O Cl

"Pd"

+ 37

38

NaOtBu, dioxane 100 oC

39

Pd

mol %

Conv. (%)a

Pd2dba3/dtbnp (1:1 Pd:L)

1

42

(dtbnp)Pd(allyl)Cl (1:1 Pd:L)

1

79

dtbnp2Pd

1

99

dtbnp2PdCl2

1

99

a) Conversion determined by GC

Scheme 14 Superiority of L2Pd in comparison to L1Pd catalysts in the α-arylation of propiophenone [104]

the optimum activity, one has to have the optimal catalyst although the ligand and the metal are the same.

Process Applications of L2Pd(0) Application of these catalyst complexes is vast. These catalysts and their components had often been avoided at scale, specifically in the case of PtBu3, even up to the beginning of the current decade due to fears of handling conditions and higher costs [82]. The strengths of using these types of catalyst compared to the abovementioned fears at scale have finally been overcome.

180

E. D. Slack et al.

MeO2S

40 + Br

MeO2S

B(OH)2

N

Pd(PtBu3)2 (0.25 mol%)

GSK1292263A

Et3N, EtOH/water

N

F F

41

85-90% 42

Scheme 15 Synthesis of a biaryl intermediate 42 by Pd(PtBu3)2 towards GSK1292263A

While cost and sensitivity of the catalyst is often cited as a barrier for its use, the loading of catalyst required is often far less. GSK showed that with proper handling techniques, the use of Pd(PtBu3)2 catalyst at scale was not of high concern. Pd (PtBu3)2 was used for a rapid development of a pilot plant-scale process for their GPR119 agonist GSK1292263A on multigram scale [139]. Previous attempts to use larger quantities of Pd(PPh3)4, 5 mol%, and lower quantities of Pd(dppf)Cl2, 0.4–0.5 mol%, were successful for the coupling of 2-bromo-5-chloropyrazine with methylsulphonate boronic acid, 40. While shifting to 2-bromo-5-fluoropyridine, 41, GSK found that they could consistently use Pd(PtBu3)2 at lower loading (0.25 mol%) for three batches to obtain a total output of 75 kg of their desired intermediate 42 (Scheme 15). GSK described the process as a highly robust and relatively cost-effective method for the rapid delivery of their desired targets, although the upfront cost of catalyst/gram is lot more higher than that of Pd(Ph3P)4 and dppfPdCl2. The rate at which target molecules can be delivered is one of the great assets that these active complexes offer. Relatively early on the R&D group at Pfizer took this approach when generating scalable lab synthesis of a series of PI3K inhibitors derived from a convergent iodothiophene, 43 [140]. The use of both Pd(PPh3)4 and Pd(dppf)Cl2•DCM gave varied results that required extensive optimization of solvent and base when the boronic acid was altered to produce 44. However, the use of Pd(PtBu3)2 seemed to negate much of this problem by showing good conversion (>80%) even when boronic acids were exchanged (Scheme 16). This was not the case for other catalyst systems tried, which ranged from low to high conversion and were highly dependent on the conditions used.

Limitations of L2Pd(0) While L2Pd(0) is one of the quickest and most atom economical ways to introduce Pd(0) into a reaction, it still suffers some from limitations. Unlike the L2Pd(II) species, L2Pd(0) lacks tolerance to air causing oxidation and catalyst deactivation, hence considered to be one of the major concerns, as shown in Fig. 6, although the complexes alleviate the pyrophoric nature of the ligands. Hence these catalysts still must be handled and stored with care under inert atmosphere, preferably under mild refrigeration. The reactors must be purged of

Process Economics and Atom Economy for Industrial Cross Coupling. . . O N

N

N

S

N

43

I

O ArB(OH)2 CO2Et Pd(PtBu ) , CsF 3 2 toluene/dioxane, Δ

ArB(OH)2 Cl

(HO)2B

N

S

N

44

CO2Et

181

O

N N

Ar

S N H

N

Ar N

Pd mol%

yield (%)

yield (g)

5

70%

11

5

100

19

1.5

90

200

Cl Cl

(HO)2B MeO

CN

(HO)2B F

Scheme 16 Rapid diversification based on Pd(PtBu3)2 [140]

Fig. 6 Degradation of Pd(PtBu3)2 when exposed to air

air, with a nitrogen blanket prior to the reaction. However, its handling is very similar to the well-known Pd(Ph3P)4. Problems from the oxidation often manifest itself as irreproducibility of different lots of catalyst depending on who supplies (vendor) the catalyst, as in the case of Pd2(dba)3. In their synthesis of a renin inhibitor, Sumitomo Dainippon Pharma found this to be true [141]. Their original synthesis used the preformed L2Pd(0) which was highly effective but inconsistent among different lots of the product. Instead, they went forward with large-scale production of their intermediate using in situ-derived Pd(PtBu3)2 from Pd(OAc)2 and PtBu3.

3.3

L1Pd(0) Pre-catalysts

Although L2Pd(0) can be isolated as crystalline solids for bulk applications, its thermodynamically unstable counterpart, L1Pd(0), has neither been isolated nor fully characterized directly. However, there is indirect evidence for its existence.

182

E. D. Slack et al. L1Pd(0)

+

L1Pd(0)

L2Pd(0)

+

Pd(0) "Black/DeadCatalyst"

Scheme 17 Disproportionation of L1Pd(0) to L2Pd(0) and dead palladium

Mass spectrometry has detected the discrete species generated from Buchwald’s palladacycles (vide infra) [142]. Several examples of the tricoordinate oxidative addition complex have also been isolated and studied by several groups using various ligands [35, 143, 144]. Precisely controlling the M:L ratio can be very difficult both at microscale and at plant scale when generating catalyst in situ. Minor amounts of extra ligand during in situ formation of L1Pd(0) can have drastic effects on the equilibria [145]. The opposite logically should be true, as the liberated palladium is highly electron deficient and can interact with multiple electron donors to form more stable L2Pd(0) species, even to the point of disproportionation of a ligand when no other groups are around for stabilization (Scheme 17) [88]. Thus, an efficient synthesis to L1Pd(0) needs special attention with regard to the “chemical soup” conundrum as it falls adjacent to the energy well of L2Pd(0). Because L2Pd(0) is thermodynamically favored, controls must be in place to prevent its formation. Low concentrations and slow releases of the catalyst into high concentration of aryl halides are among the easiest ways to prevent disproportionation. Thus it follows with previous sections that the presumed best method to generate L1Pd(0) is through the use of preformed palladium complexes [10]. With a preponderance of literature to support the idea of a highly active 12-electron monoligated palladium complex, several groups sought methodology to directly generate the coveted complex efficiently [145]. As mentioned many times earlier, there are significant difficulties in controlling the M:L ratio using both Pdxdbay and Pd(OAc)2 (vide supra) especially at scale. This led various groups to try alternative methods to form monoligated palladium species. The advantages of preformed complexes became obvious towards this goal (vide infra) with their consistent control of M:L ratio, making them the primary method to generate L1Pd(0) at this time. Some of the examples of this approach are Buchwald’s palladacycles [146], Organ’s PEPPSI catalysts [32, 33], Johnson Matthey’s π-allylPd(II) complexes developed by the Colacot group [147], and Pd(I) dimers developed and commercialized by Johnson Matthey team led by Colacot as well as by the academic groups of Hartwig and Shoenebeck [35–40, 148]. Many of these complexes have made to general use beyond academia, likely due to their larger scope of well-known incorporated ligands into their scaffold. These different versions of pre-catalysts to L1Pd(0) are in analogy with the different closely related to newer features of the smartphones.

3.3.1

Development of L1Pd(0) Buchwald Palladacycle Pre-catalysts

While not historically the first entry into monoligated precomplexes, palladacycle scaffold like those that now bear Buchwald’s name dates back to the late 1990s and

Process Economics and Atom Economy for Industrial Cross Coupling. . . L H2N Pd Cl

L H2N Pd Cl

L H2N Pd OMs

183 H L Ph/Me N Pd OMs

G1

G2

G3

G4

Limited Ligand Scope

Improved Ligand Scope

Full Ligand Scope

No carbazole inhibition

Fig. 7 Evolution of Buchwald’s palladacycle

early 2000s [149, 150]. However, Buchwald has highly refined this idea into more practical systems. Four generations of these pre-catalyst palladacycle complexes now do exist. The most advanced complexes being the fourth generation, G4, while the most commonly used ones are the G3 (Fig. 7) [151]. Like previous catalysts, activation is achieved through reduction of air-stable L1Pd(II) pre-catalyst to L1Pd(0). Unique to these complexes, the catalytic cycle has already been started leading to the oxidative addition state relatively easily. Their ease of activation comes from the initial nucleophilic partner which is attached internally as an amino group on the biphenyl, which releases carbazole and the L1Pd(0) as the active 12-electron species (Scheme 18). The advantage being disproportionation becomes far less likely as only a small amount of the L1Pd(0) exists in relationship to the aryl halide at any given time. This prevents much of the catalyst from forming L2Pd(0) or other intermediate species until high amounts of conversion are achieved.

Application of Buchwald Palladacycles These complexes have found extensive use in the field of palladium cross coupling from both academic and process groups trying to obtain lower cost lead molecules in an accelerated rate through process improvements. The Buchwald palladacycle has become a consistent companion for medicinal/discovery chemist and development groups looking to generate libraries of compounds quickly for screening as they are easily handled and distributed to carry out reactions in microplates as well as solids [27, 152]. It is difficult to find a recent discovery patent that does not include one of these pre-catalysts lurking somewhere in the disclosure. Although these catalysts were introduced as an emerging technology almost less than a decade [146], their applications are still rising. We shall provide a few examples below where these preformed relatively expensive catalysts were critical to improve process economics. Among the disclosures found in patent literature is the synthesis of lead compounds for P13K/mTOR inhibitors from PIQUR Therapeutics. A direct comparison of in situ-derived SPhos “chemical soup” with Pd(OAc)2 yielded only 52% of the desired product, while the use of the preformed XPhos G2 palladacycle yielded 92% (Scheme 19) [153]. The use of preformed catalyst turned a reaction that was likely

184

E. D. Slack et al. R M OR

L

NH2

Pd(II)

R X

H2N (II) L Pd X

X

L1Pd(II) X

M R'

L1Pd(0) R Pd(II)L1 R'

R R' HN

M X

carbazole

Scheme 18 Activation of Buchwald’s palladacycle to L1Pd(0)

Pd(OAc)2 (6 mol%), SPhos (12 mol%)

O

O

O B

H

CF3

N

N

NH2

N

N

52% yield

N

O 45

K3PO4, DMF, 100 C

N

+

O H

o

Cl

XPhos Pd G2 (5 mol%)

N N O

N

dioxane:H2O (2:1), 95 oC 46

92% yield

CF3

N NH2

47

Scheme 19 Comparative synthesis of advanced intermediate from PIQUR Therapeutics towards P13K and mTOR inhibitors

not scalable to one that could be plausible. This of course does not encompass the breadth of process advantages obtained from this type of preformed palladium catalyst; however it gives the best picture of the improved atom economy and ease of deployment. Development of methods towards GDC-0084 [154], another lead compound for P13K/mTOR inhibition as a treatment for glioblastomas [155], gives a more in-depth analysis of how preformed palladacycles can improve the process economics due to the efficient formation of L1Pd(0). Initial screening of the coupling towards the desired intermediate showed “poor conversion” for in situ generation using Pd(OAc)2 and SPhos and other milder preformed catalysts. They however found that the purine core, 48, using 8 mol% (dppf)PdCl2 under microwave conditions could couple with 49 for 27% yield in an unoptimized processes (Scheme 20). Lower catalyst loadings, 2 mol%, could be used when a mixture of THF/water was used for improving the yield to 98% thereby alleviating some of the previously observed Pd leaching. Adoption of Buchwald Generation 2 XPhos palladacycle (XPhos Pd G2) allowed for further lowering of the loading, 0.5 mol%, with comparable yields. To the credit of the catalyst, addition of exogenous XPhos did not seem to slow the catalyst activity in this case. Further process economic benefits

Process Economics and Atom Economy for Industrial Cross Coupling. . .

185

O

O

N N O

N

N pinB

N

N

+ N

N

Cl

48

N

Conditions NH2

N

O

49

N N

N

50

N

NH2

GDC-0084 Process Generation

cat.

solv. (total vol.)

temp. ( oC)

conv. (yield%)

0

SPhos/Pd(OAc)2 8 mol%

dioxane/H2O(-)

140, μW

poor

0

PdCl2(dppf) CH2Cl2 8 mol%

dioxane/H2O(-)

140, μW

- (27)

1

PdCl2(dppf) CH2Cl2 5 mol%

dioxane/H2O(-)

140, μW

- (70)

2

PdCl2(dppf) CH2Cl2 2 mol%

THF/H2O (386 L)

80

98 (80)

3

XPhos Pd G2 0.5 mol%

THF/H2O (113 L)

65

100 (94)

Scheme 20 Cross coupling optimization of GDC-0084 [154, 156]

beyond lowered upfront cost gained by using less catalyst; purification needs to get below the 10 ppm Pd threshold was far less with only 10 wt% of a thiol resin instead of 20 wt%. The changes also allowed for lower overall solvent usage of the multistep sequence and helped decrease the process mass intensity (PMI) from 140 down to 70. Direct cross couplings to obtain biaryls have not been the only methodology that has been improved via preformed L1Pd(0) pre-catalyst. Generation of boroncontaining coupling partners as well has found process improvement from introduction of the preformed L1Pd(0) catalysts. Methods to generate boronic acid are inhibited at scale as they tend to be harsh and labor intensive, require lowered temperatures (often cryogenic), and are atom inefficient besides the usage of pyrophoric reagents. Formation of the pinacol ester can be done through a milder palladium-catalyzed coupling but comes at the cost of a more stable and less reactive intermediate pinacol borane (Bpin) [157]. Processes to access more desired boronic acid from the pinacol esters often require extensive testing and process work to efficiently hydrolyze the boronic ester to the acid (Scheme 21) [158]. While this is often possible, it is not a forgone conclusion, as many of the boronic acids automatically deborylate and form the boroxines under hydrolysis conditions [158]. Reports towards avoiding the boron ester, similar to that developed by Molander [159], were reported for AMPK activators from Pfizer [160]. The use of this tactic

186

E. D. Slack et al. 1.Mg or Li or alkyl lithium 2.B(OR)3 3.H+ R

R X

R B(OH)2

1.PdLn, B2pin2

B O

O

(Bpin ester)

2.H+

Scheme 21 Traditional route to boronic acids vs cross coupling

B2(OH)2, XPhos Pd G2 XPhos, NaOtBu, o KOAc, EtOH, 80 C

OH

51

Br

65% OH

OH

B(OH)2

52

O

Cl

1.PdCl2(dppf), KOAc, THF, 60 oC 2.HN(CH2CH2OH)2, iPrOH 3.3 M HCl

53 55%

OH

N H

PF-06409577

Scheme 22 Comparison of boronic acid synthesis towards Pfizer’s PF-06409577

with Pd-XPhos G2 allowed for quick and efficient generation of three different structures in route to their desired lead compounds. The main thrust of this was to avoid a three-step protocol to hydrolyze the pinacol boron to form the boronic acid (Scheme 22). Although this methodology was not adopted for the final synthesis, not due to the inefficiency of the preformed catalyst but presumably due to the difficulty in obtaining large quantities of Buchwald-type palladacycle-based pre-catalysts and possible toxicity of tetrahydroxydiboron impurities [161]. Researchers at Albany Molecular Research, Takeda Pharmaceutical, and Carbogen developed large-scale methodology towards this end by using tetrahydroxydiboron (bis-boronic acid, BBA) as the Suzuki-Miyaura reagent for TAK-117. From initial attempts towards Suzuki-Miyaura borylation of 54, they found poor conversions with in situ-derived catalysts from Pd(OAc)2 with several ligands (Scheme 23) [162]. Most preformed catalysts could be used with varying degrees of success, however required higher catalyst loadings (>1 mol%), with the exception of Pd(PtBu3)2 and Buchwald G2 of the same type. Through optimization of other parameters, the merits of the L1Pd(0) catalyst were realized in comparison to Fu’s catalyst, Pd(PtBu3)2. Even at elevated temperatures that would presumably diminish the possible competitive ligation of PtBu3, Buchwald’s palladacycle proved to be exceptionally active even at extremely low loadings, 0.05 mol%, compared to Pd(PtBu3)2 giving double the conversion to 55 and diminishing the by-products, 56 and 57.

Process Economics and Atom Economy for Industrial Cross Coupling. . .

187

H

N NH2

Br

N NH2 O

cat., (HO)2BB(OH) 2

(HO)2B

O

N

solvent, 90 oC

O

56

NH2

O H 2N

N

N

55

54

NH2 57

Cat.

mol%

solvent

conv. (%)

Pd(OAc) 2 + ligand (1:2)

2

sBuOH

poor

Pd(PtBu3)2

0.5

sBuOH

99

PtBu3 Pd G2

0.5

sBuOH

99

Pd(PtBu3)2

0.05

MeOH

45

PtBu3 Pd G2

0.05

MeOH

96

O

Scheme 23 Partial optimization of direct synthesis of boronic acid towards TAK-117

Br

N NH2 O

BBA, Pd G3 PtBu3

(HO)B

KOAc, (CH2OH)2 MeOH

Less Expensive Batch Process

Br

N NH2 O

1.n-BuLi 2. B(OiPr)3 3. HCl

N O

NHBo c

More Expensive - Flow Process

Scheme 24 Takeda Pharmaceutical’s comparison of flow and batch process to TAK-117 intermediate

This was accompanied with further modifications that allowed development of methodology at kilo scale that offered a 47% saving compared to the original process requiring hydrolysis of the pinacol borane ester. In an almost unprecedented follow-up study, they as well compared this method with inflow lithiation and found that the use of the palladacycle was cheaper overall (Scheme 24) [163]. The major cost came from other materials required under lithiation conditions, such as tert-butyloxycarbonyl (Boc) protecting group. Lithiation did have one benefit in avoiding the BBA, which is believed to a mutagen [161]. In no way are these the only methods that have been improved through efficient synthesis of L1Pd(0). Scientists at Merck found alleviation of poor catalyst formation of the L1Pd(0) species from Pd(OAc)2 with PCy3 when synthesizing anacetrapib, a new generation of cholesterol drug. Attempts to form a key intermediate of their synthesis, 60, were described as capricious when mixing Pd(OAc)2 (2 mol%) with PCy3 (4 mol%) prior to coupling to give yields ranging from 45 to 80%. The use of PCy3 Pd G2 at 0.5 mol% loading was found to reliably give 98% yield, with an order of magnitude cost less than the (dtbpf)PdCl2 catalyst, which also gave reasonable reliable yields at the same loading (Scheme 25) [152].

188

E. D. Slack et al. OH

Cl

B(OH)2 OMe

OH

F3C

Anacetrapib

3 M K2CO3 iPrAc/iPrOH/H2O

+ CF3 58

OMe

Pd PCy3 G2 (0.5 mol%)

F 59

F 60 98%

Scheme 25 Pd PCy3 G2 synthesis of the biaryl core of anacetrapib

H N H Pd L

base

NH

L1Pd(0)

NMe/Ph

L1Pd(0)

Ar X base

N Pd Ar

X G1-G3

Me/Ph N H Pd L

base

Ar X

X Pd Ar

X G4

Scheme 26 Evolution of Buchwald’s G4 palladacycle for carbazole inhibition

Process Drawbacks of Buchwald Palladacycles Buchwald’s catalysts are a major achievement and have had a major impact on cross couplings and palladium-catalyzed reactions. However, they do have their drawbacks, mainly the generation of carbazole by-products (Scheme 26). While this can present a major problem through competitive insertion that can lower activity of the catalyst and consume starting material, this does allow for predictable by-products [151]. Recently this has been mostly alleviated with the fourth generation of Buchwald pre-catalysts incorporating different groups onto the amino nitrogen of the 20 -biphenyl amine. Further, there are some concerns as how carbazole can be effectively and safely removed from the process. As shown previously, the carbazole does not always present a threat to coupling.

3.3.2

Development of L1Pd(0) π-Allyl Pre-catalysts

Nolan’s group identified that several of their coupling reactions were conducted using the [Pd(allyl)Cl]2 to perform in situ generation and activation of Pd NHCs

Process Economics and Atom Economy for Industrial Cross Coupling. . . t-BuBrettPhos THF or toluene

Cl Pd Pd Cl

no Product rt, 1 h

AgOTf THF, rt, 0.5 h

t-BuBrettPhos [(π-allyl)Pd(t-BuBrettPhos)]OTf rt, 2h 84 %

"(allyl)PdOTf" (not isolated)

Ligands:

Me OMe

MeO i-Pr

189

PCy2 i-Pr

i-Pr BrettPhos

OMe MeO i-Pr

P(t-Bu)2 i-Pr

i-Pr t-BuBrettPhos

OMe MeO i-Pr

PAd 2 i-Pr

i-Pr AdBrettPhos

OMe Me i-Pr

P(t-Bu)2 i-Pr

i-Pr RockPhos

i-Pr

P(t-Bu)2 i-Pr

i-Pr t-BuXPhos

Me

Me

Me i-Pr

P(t-Bu)2 i-Pr

i-Pr Me4t-BuXPhos

N N

P(t-Bu)2 Ph

Ph

N N Ph

BippyPhos

Scheme 27 Versatility of π-allyl catalysts using various Buchwald ligands

[164]. Subsequently a few reports on making π-allyl catalyst based on Organ’s N-heterocyclic carbene were also reported [165–167]. Both Shaughnessy and Colacot together and independently identified pi-allyl/ crotyl/cinnamyl technology with monophosphines early on [101]. The Colacot group at Johnson Matthey further carried this technology to create a new line of products that could incorporate Buchwald-type ligands. The cationic technology has allowed for many of the known and sought-after ligands like t-butylBrettPhos and t-butylXPhos to be accessed very efficiently (Scheme 27) [147]. These catalysts are activated to L1Pd(0) very effectively. Nucleophilic addition to the allyl group, β-hydride elimination, and base addition to allyl group are all possible and have been suggested as routes to activation [166, 168–170]. Through comparative studies similar or improved reactivity to Buchwald palladacycles has been observed likely due to lack of inhibition from carbazole (Scheme 28). However, for other transformation such as Suzuki coupling, no carbazole inhibition was observed with Buchwald’s pre-catalyst.

Process Applications of L1Pd(0) Allyl/Crotyl Pd While Colacot’s group at Johnson Matthey has not reached far beyond small lab-scale application of these catalysts, we have started to observe how other production labs/pharmaceuticals have used these catalysts in comparison to other methodologies. Among them was optimization of the synthesis of GDC-0994 for clinical trials [171, 172]. Synthesis of the core biaryl was found to be difficult as inorganic impurities hampered direct use of the material synthesized from stoichiometric organometallic methods. Tedious days of Soxhlet extraction was then required to obtain material that could be used for further modification to the desired pyridinone. Further complicating process methodology for a Pd-catalyzed cross coupling was the short life span of the pyridyl organometallic coupling partner that degraded quickly above room temperature and was only accelerated when exposed to palladium catalysts in solution. To ensure that a competent method would be obtained, they attempted to optimize a plug flow reactor to outcompete the degradation of the organometallic coupling partner along with a batch reactor that could perform the coupling at lower temperatures. They found through

190

E. D. Slack et al.

Scheme 28 Comparison of π-allyl catalysts and Buchwald palladacycles for Buchwald-Hartwig amination [147]

I

F N

1.iPrMgCl•LiCl, -5 oC

N

(12 min residence) 2. PEPPSI-IPr (1 mol%) N S

N

S

N F

N N

Cl

O

N

S N N

Cl

N BsOH

F OH

60 oC (14 min residence)

GDC-0994

Scheme 29 Plug flow synthesis of biaryl intermediate towards GDC-0994 with the use of PEPPSI-IPr

extensive catalyst screening of both in situ catalysts and preformed catalyst that PEPPSI-IPr at 1 mol% in a plug flow reactor could couple the two portions efficiently at elevated temperatures, 60–65 C, for 82% yield and 79% purity by HPLC (Scheme 28). As a complement to the flow reactor, they found that both XantPhos Pd-G4 and XantPhos(π-allyl)Cl could obtain similar levels of success, 82% yield and 75% purity, at lower loadings, 0.5 mol%, and within 1 h batch cycle at 25 C. This was in contrast to XantPhos Pd-G2, which required 1 mol% loading for 58% conversion (Scheme 29). The carbazole inhibition was assumed the likely culprit of the low yields as the G4 alternative worked comparably as well as the π-allyl. Overcoming Process Drawbacks of π-Allyl Pre-catalysts Similar to L2PdX2 complexes for catalysis, π-allyl systems do not have a fully defined method of activation with several routes possible. The most simplistic of

Process Economics and Atom Economy for Industrial Cross Coupling. . . I

F N

N

1.iPrMgCl•LiCl S

2. cat.

F

N N

N S cat.

191

N

Cl conv.%

HPLC yield%

1

20

99

61

XantPhos Pd G2

0.5

1

58

XantPhos Pd G4

0.5

1

98

78

1

1

99

82

Pd(π-cinnamyl)Cl XantPhos

Pd(π-allyl)Cl XantPhos

mol% time (h)

Scheme 30 Batch synthesis of biaryl intermediate towards GDC-0994

these has been outlined by Hazari showing that the use of allyl and other unsaturated systems can rely on alcoholic solvent interactions to transfer a hydride and generate an alkene very similar to the synthesis of L2Pd(0) [75, 138]. This can lead to a situation unlike Buchwald’s palladacycles where an activated L1Pd(0) can coordinate with an unactivated pre-catalyst and form a less reactive bridged palladium dimer. To a great extent, this problem has been solved through the use of crotyl and cinnamyl ligands to prevent their formation (Scheme 29). In addition, changing the chloride with a non-coordinating OTf also circumvents the problem (Scheme 30). As expected as well, larger ligands also help to prevent the formation of the less active Pd dimer [147]. Colacot’s group at Johnson Matthey has done a detailed study to prove how one can alleviate the dimer formation, thereby improving the efficiency of the system via catalyst engineering (Schemes 31 and 32) [147].

4 Conclusion The manufacturing processes of pharmaceutical and fine chemicals are becoming more complex day by day. Drug molecules are becoming more specialized requiring extensive cross coupling screening of multiple steps followed by time-consuming optimization that has to span several variables including base, solvent, temperature, and concentration after lead discovery. Even further than the synthetic process getting more complex, regulatory concerns over impurities are becoming more and more cumbersome. Process engineers and chemists are being forced to come up with solutions that can meet these requirements with a decreasing timeline and improved profit margins. In situ formation of active catalysts requires precise engineering from lab to production. It also tends to have problems with respect to consistency from batch to batch leading to a roll of the dice on outcomes. Preformed catalyst offers two solutions to process chemists/engineers. With a preformed catalyst, especially later generations like palladacycles and π-allyls, there are fewer variables to control. Impure palladium sources do not tip the scales, and the

192

E. D. Slack et al.

L Pd Cl L Pd Cl

base

L

L

Pd

Pd Pd L Cl

"dead catalyst"

Sphos Pd Cl

Sphos Pd Cl

NaOtAmyl (1.05 equiv) PhBr (10 equiv)

Ph Sphos Pd

toluene-d8 rt, 10 min

Sphos Pd Pd Sphos Cl

Br 11%

NaOtAmyl (1.05 equiv) PhBr (10 equiv)

44%

Ph Sphos Pd

toluene-d8 rt, 10 min

Br

Sphos Pd Pd Sphos Cl

74%

0%

Scheme 31 Prevention of off-cycle nonproductive dimer of π-allyl pre-catalysts Br

O HN

Pd cat (2 mol% Pd) NaOtBu

O N

THF, 40 °C, 1h

entry

catalyst

GC Conversion

1

(μ-allyl)(μ-Cl)Pd2(SPhos)2

8%

2

SPhos Pd(allyl)Cl

48%

3

SPhos Pd(allyl)OTf

100%

4

SPhos Pd(crotyl)Cl

100%

5

SPhos Pd(crotyl)OTf

100%

Scheme 32 Catalyst engineering to prevent the formation of the dimer [147]

formation of the active catalyst is not a balancing act of forming the ligated complex, followed by activation and then perpetuation of the catalytic cycle. Leads can be identified faster and can be applied to scale operations with less concern of batch-tobatch variability. The other benefits are summed up by the saying, “garbage in, garbage out.” It is hard to think of palladium or any precious metal as garbage, but if it is not activated properly or if it is catalytically inert, that is what it becomes. Preformed catalysts allow for a highly efficient generation of the active catalyst in a defined state. Because of this, less energy is often needed for the reaction, and lower catalyst loadings are often found. Since less material is inputted into the reaction, less material is outputted, and therefore less waste is likely in the mixture. This decreases the number of steps required to purify the material as seen with many of the example given, specifically with respect to minimal amount of palladium (vide supra).

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With these benefits we have observed from the patent literature that many discovery chemists have started to use PdL2X2. The use of which is likely due to the known reactivity, stability, and lower upfront cost. Having said that many still use the standard Pd2dba3 or Pd(OAc)2 with free ligand to form the active catalyst for various couplings just as the use of flip phone usage persist even today. This trend is beginning to change as the benefits of preformed catalysts are being disclosed more often. Catalysis itself is still a puzzle, and preformed catalysts alone do not solve the problem of screening and optimization. It is very difficult to predict which ligand, base, and solvent will work well together for a specific coupling with non-model substrates, such as a pharmaceutical molecule; however a knowledge-based highthroughput screening can help to alleviate many of these issues. We have shown that with the same ligand and same metal (Pd), the activities can be very different depending on the pre-catalyst employed. An appropriate preformed catalyst can indeed help to increase the efficiency of atom economy with the reduction of process cost. Technologies such as the use of non-precious metal catalysts, photocatalysis, continuous flow process, etc. to further accelerate the process development involving organometallics are also emerging in a faster pace. Having made a strong case for pre-catalysts, we leave the decision to the process chemists and engineers to decide whether or not they go with in situ or pre-catalyst just as their process need in analogy with the different generations of the phone available in the market. If it is for just making a call older generation phones are still fine. The same is true for selecting a catalyst. Abbreviations BINAP 2,20 -Bis(diphenylphosphino)-1,10 -binaphthalene BISBI 2,20 -Bis[(diphenylphosphino)methyl]-1,10 -biphenyl DPEphos (Oxydi-2,1-phenylene)bis(diphenylphosphine) dppb 1,4-Bis(diphenylphosphino)butane dppe 1,2-Bis(diphenylphosphino)ethane dppf 1,10 -Bis(diphenylphosphino)ferrocene dppm 1,1-Bis(diphenylphosphino)methane dppp 1,3-Bis(diphenylphosphino)propane dtbpf 1,10 -Bis(di-tert-butylphosphino)ferrocene Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethyl-xanthene [55]

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Top Organomet Chem (2019) 65: 199–216 DOI: 10.1007/3418_2018_17 # Springer Nature Switzerland AG 2018 Published online: 9 September 2018

Organometallic Processes in Water Fabrice Gallou and Bruce H. Lipshutz

Contents 1 Organometallic Processes in Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Development of Tailor-Made Catalysts for Surfactant Chemistry and Their Applications to Reductions and Cross-Coupling Transformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Applications to Multistep and Telescoped Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract During our search for sustainable alternatives for reprotoxic polar aprotic solvents, the high-impact and long-term potential of surfactant technology was identified. Based on aqueous micellar catalysis, various synthetic methodologies have been developed and implemented on scale that rely on a variety of transitionmetal-catalyzed transformations, as well as other reaction types that are also amenable to this chemistry in water. Implementation typically results in significant benefits across our entire portfolio; that is, in addition to the environmental benefits, from the economic and productivity perspectives, there are also advances to be realized. Representative benefits include reduction in organic solvent consumption, water use, and cycle time, milder reaction conditions, and improved yields and selectivities, which all contribute to improved process performance and lower manufacturing costs. These surfactant-enabled reactions can be upscaled in the already existing multipurpose facilities of pharmaceutical or other chemical organizations, using a catalytic amount of a combination of a nonionic designer surfactant (e.g., TPGS750-M) in water and a well-chosen organic cosolvent, instead of traditional and undesirable organic solvents.

F. Gallou (*) Novartis Pharma AG, Chemical and Analytical Development, Basel, Switzerland e-mail: [email protected] B. H. Lipshutz Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA, USA

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Further mechanistic insight gained in the course of our efforts in the field led us to the development of new and always more effective catalytic systems, of both a homogeneous and heterogeneous nature, specifically tailor-made for the medium. The potential of even more appealing synergistic effects has been clearly demonstrated. Taken together, these advances pave the way for an overall transformational, and yet environmentally responsible, approach to catalysis. Keywords Catalysis · Chemistry in water · Scale-up · Sustainability · Synergistic effects · TPGS-750-M surfactant

1 Organometallic Processes in Water Over the past couple of decades, various neoteric solvents [1–7] have emerged as part of a sustainable response to the efforts by regulatory agencies (e.g., EPA, REACH) to discourage use of reprotoxic polar aprotic solvents [8]. While development of alternatives requires fundamental changes in common practice, these should not conceptually change the way chemistry is conducted, as it oftentimes consists in nothing more than substituting one reaction medium for another, thus leading to a more desirable outcome. Nonetheless, chemistry in water, performed under mild conditions and made possible by tailor-made surfactants [9–14], has emerged as a radical and disruptive way to not just conduct chemistry but to advance the field of synthesis. This account provides an update on our journey in the field of aqueous micellar catalysis. First intrigued by the original reports from the Lipshutz group in 2008 [15–17], Novartis started our experimental investigations in 2010, most specifically for applications to the frequently encountered transition-metal-catalyzed Suzuki-Miyaura cross couplings and related strategies [18]. At first, the interest was particularly in the use of a versatile and benign nonionic vitamin E-derived surfactant. This amphiphile, indeed, enabled several important cross-coupling reactions, such as Heck, Suzuki-Miyaura, and Stille couplings, in a very efficient and selective manner. We were particularly enthusiastic that we had for once a truly nontoxic and harmless chemical entity at our disposal to address a critical challenge. Excited by the potential of the technology, we rapidly became conscious of the disruptive impact it would have in the way to conduct chemistry, especially at industrial scale. We indeed saw in it the potential to dramatically gain in selectivity, as well as to enhance productivity, with opportunities for streamlining sequences of reactions. An important breakthrough was realized early in our evaluation when we identified the benefits of adding an organic cosolvent [19, 20]. Although counterintuitive to the fundamentals of micellar catalysis, this appeared to be a viable and general option to facilitate the transport of poorly soluble organic components into micellar inner cores and to soften a crystal lattice oftentimes encountered among our many reaction partners (Fig. 1). It indeed enabled us to work on practically any scale, ranging from small (100 kg). The cosolvent, typically a watermiscible organic solvent, when used in suitable amounts (usually 1–20% by volume

Organometallic Processes in Water Cl H N

Cl N

N

+ N

Cl

201 K3PO4 (1.2 eq) rt 5h

N

Cl N N

2% TPGS-750-M / water with or without co-solvent

N Cl

water used as the medium

THF (15%) / water used as the medium

Average micelle size

39.8 nm

109.3 nm

Isolated yield

76%

80%

Fig. 1 Effect of cosolvent

compared to that of water), was found to serve in several capacities. Not only does it help to solubilize and channel organic components to the micellar environment, but also it impacts the physical properties of the micelles. Dynamic light scattering (DLS) experiments conducted on a variety of reaction mixtures showed that micellar size increased by a factor of approximately two relative to their state in a purely aqueous medium. In addition, computational studies indicate that the dynamics of the micelles are altered significantly in the presence of a cosolvent, accelerating the rate of exchange between micelles and enhancing reactivity [21]. In the specific example in Fig. 1, a smooth nucleophilic aromatic substitution reaction occurs with high selectivity in 5 h at room temperature (rt), in similar yield with or without cosolvent. However, aggregation was observed in the absence of cosolvent, which resulted in a slightly lower yield and challenges upon scale-up. In this example and other ones within this chapter, rt. will refer to temperature of 20–25
C. With this technique in hand, we aimed at building a toolbox of chemistry to tackle the most important transformations encountered within a standard pharmaceutical portfolio [18]. Most of the initial attention was focused on organometallic chemistry and, most notably, cross-coupling events such as Suzuki-Miyaura, Negishi, or Sonogashira cross couplings. Here, the potential for reduction of precious metal consumption was immediately obvious, along with improved selectivity and yield for inherently challenging transformations, as well as the likelihood of a significantly reduced environmental footprint. In addition, we expanded our toolbox with other bond-forming reactions, such as amide bond constructions [22, 23] and nucleophilic aromatic substitutions [24, 25], as well as effective manipulation of several important functionalities, such as the reduction of nitro groups to amines, thereby gaining especially important access to key building blocks in bulk. In this chapter, we focus on organometallic chemistry, including our early development of heterogeneous and homogeneous catalysts and their applications to both reductions of important functional groups and to cross-coupling methodologies. We conclude with some case studies run on scale and, lastly, with prospects for future development.

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2 Development of Tailor-Made Catalysts for Surfactant Chemistry and Their Applications to Reductions and Cross-Coupling Transformations At the onset we envisioned tailoring heterogeneous catalysts for use in an aqueousbased medium, taking advantage of known micellar effects. If a nano-catalyst is partitioned preferentially within or around a micelle, given the high substrate concentrations, it should lead to enhanced reactivity relative to that found in standard catalytic systems in classical organic solvents. That is, by virtue of the considerably increased surface area of nanoparticles (NPs) and the compression effect associated with the micellar environment, this should result in very efficient catalysis. An additional expectation that went beyond increasing significantly the catalytic activity of such system was that reduced levels of precious transition-metal catalyst might be possible, as well as using more sustainable metals. An early breakthrough came from the use of iron salts en route to NP formation. Iron is reputedly known to contain traces of other metals, including precious metals, in its native form, and therefore constituted our starting point. The first task consisted of preparing the nanoparticles out of a source of iron, in this case, FeCl3, contaminated with varying amounts of palladium. Extensive optimization led to a robust protocol where, starting from reagent grade iron chloride and upon reduction with methyl Grignard in THF, iron nanoparticles contaminated with ppm levels of metals, such as Co and Ni and, most importantly, Pd, could be generated and shown to be highly useful in multiple reaction types [26]. To increase reliability in the preparation of the catalytic nanoparticles, iron chloride is now routinely doped with 80 ppm palladium acetate for reduction applications or 320 ppm and a suitable ligand for cross-coupling applications (Scheme 1 and Fig. 2). These nanoparticles prepared in their ligand-free state proved effective at reducing nitroaryl compounds into the corresponding arylamines, albeit with modest efficiency. Further attempts at doping and characterizing the nanoparticles, along with control experiments, showed that only a few tens of ppm of Pd, Ni, and Co were sufficient for such an output. A better suited strategy for the highly regulated pharmaceutical industry consisted in doping with incremental amounts of Pd, our

Scheme 1 Formation of palladium-doped-iron nanoparticles (NPs) for in situ utilization or storage

Organometallic Processes in Water

203

Fig. 2 Cryo-TEM images of Fe–Pd nanoparticules in aqueous TPGS-750-M

metal of choice for selectivity reasons, until a proper reaction outcome was obtained. We decided to avoid metals such as Co because of its potential reprotoxic properties [27]. With as little as 80 ppm of Pd added in the form of Pd(OAc)2, the nitro group reduction mediated by NPs containing in situ-generated palladium hydride was demonstrated to function extremely well, utilizing sodium borohydride as the stoichiometric source of hydride (Fig. 3). This finding came as a much improved process compared to the preliminary Zn-mediated reductions, as will be discussed shortly. The main interest of this novel method lies in its remarkable efficiency and selectivity associated with the mild reaction conditions involved and the flexibility in its handling. Indeed, while there are numerous other good methods relying on the use of compressed hydrogen gas [28–32], this approach allows the chemistry to take place in any standard, non-pressurized vessel, a huge benefit for organizations with limited access to high-pressure facilities. The power of this synthetic methodology was demonstrated on scale using a challenging substrate that otherwise required elevated gas pressure (20 bar of hydrogen) and had led to only moderate selectivity. Using the Pd-doped iron NPs, in an addition-controlled process (slow dosing of the starting nitroaryl), the reaction proceeded in excellent yield and selectivity (>99% selectivity and >96% yield), without generation of pressure. The operational simplicity and the absence of special requirements make it amenable to any vessel. This gain in manufacturing flexibility can appear as marginal, but in the context of a dense portfolio of projects and fast changeover, where speed is the number one priority, it is an additional significant benefit to have such technology readily available. This is relevant whether in medicinal chemistry, where reductions need be carried out in the absence of hydrogenation vessels, or in a production environment, where processes can thus be run in any multipurpose plant. During these investigations, we discovered an interesting kinetic effect where moderate rate acceleration was observed when switching from sodium to potassium

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NO2 Cl

NaBH4 KCl NP

NH2 Cl

2% TPGS-750-M / water THF rt

Fig. 3 Standard nitroaryl reduction using Pd-doped iron NPs and critical operations

borohydride (ca. 20% gain). This effect can simply be generated by addition of KCl salts to the sodium borohydride. We were intrigued by this salt effect, but the explanation behind the role of the gegenion has yet to be elucidated; hence, additional synthetic benefits have yet to be gained. Nonetheless, we went back to the original design and concept behind the nanoparticles and took advantage of the

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205

initially observed (by ICP-MS) presence of multiple metals. The preliminary findings had indeed shown that traces of several other metals such as Ni and Co were present during the catalysis. We were fortunate to rapidly demonstrate the synergy between Pd and Ni (Fig. 4) [33]. Doubly doped nanoparticles with both Pd (at 80 ppm) and Ni (ideally at 1,600 ppm) enabled reactions that had taken hours to proceed in minutes while still tolerating a variety of functional groups. In addition, for the first time, this rendered the technology feasible in flow. This technical advance translating this finding into practical processes will be reported shortly (unpublished results).

Catalyst

Reaction time yield

FeNP (Pd)

2h

ca. 80 ppm Pd

90% FeNP (Ni)

12 h

ca. 1600 ppm Ni

79% FeNP (Pd-Ni)

15 min

ca. 800 ppm Pd, and 1600 ppm Ni

92%

Catalyst

Reaction time

Comments

yield FeNP (Pd)

14 h

ca. 80 ppm Pd

95% chemical yield 90% isolated yield

FeNP (Pd-Ni)

45 min

ca. 800 ppm Pd, and 1600 ppm Ni

98% chemical yield 90% isolated yield

Fig. 4 Synergistic effect of Pd- + Ni-doped NPs in nitro group reductions

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For cross-coupling transformations, the same approach was followed, albeit with the iron NPs now containing a ligand as part of its fundamental core (Schemes 2 and 3) [26]. We have added to our toolbox, therefore, ligand-modified nanoparticles that effectively catalyze both Suzuki-Miyaura and Sonogashira cross couplings, utilizing very low loadings (1,000 ppm) of precious metal. In our first-generation toolbox,

Conditions

catalyst

base

Solvent

Temperature

yield

1

Pd(Cl2)dppf (5 mol%)

K2CO3

dioxane, H2O

rt

no reaction

2

Pd(Cl2)dppf

K2CO3

dioxane, H2O

80 oC

44%

K3PO4

2 wt % TPGS-750-M / H2O

45 oC

74%

K3PO4

H2O

45 oC

< 50%

K3PO4

2 wt % TPGS-750-M / H2O /

45 oC

90%

(5 mol%) 3

FeNp (Pd-SPhos) (1 mol%)

4

FeNP (Pd-SPhos) (320 ppm)

5

FeNP (Pd-SPhos) (320 ppm)

acetone

conditions

Conditions

catalyst

base

Solvent

Temperature

Yield

Atropisomeric

1

PdCl2(dbpf) (5

K3PO4

DMF

100 oC, 1 h

12%

5%-7%

Na2CO3

dioxane/DMF

100 oC, 16 h

47%

18%-29%

Et3N

2 wt % TPGS-750-

20 oC, 20 h

47%

16%-31%

45 oC, 16 h

65%

26%-39%

ratio

mol%) 2

RuPhos Pd G1 (5 mol%)

3

Pd(OAc)2, SPhos (1 mol%)

4

Fe NP (Pd-Sphos, ca. 300 ppm Pd)

M/H2O/toluene (5%) K3PO4

2 wt % TPGS-750M/H2O/THF (5%)

Scheme 2 Some examples of NP-catalyzed Suzuki-Miyaura cross couplings

Organometallic Processes in Water

O NHboc +

207

O

NO2 Fe NP

N H

I

Br

NO2

N H Br

2% TPGS-750M in water rt

NHboc 86%

N N

CF3

O

NO2

N H

N

CF3

N

NHboc 90%

Fe NP = FeCl3 (5 mol%), XPhos (2 mol%), MeMgCl (10 mol%)

XPhos

PCy iPr

iPr

iPr

Scheme 3 Examples of heterogeneous micellar catalysis for Sonogashira cross couplings (iron source here contaminated with ca. 300 ppm Pd and used as such)

such ligands as SPhos or XPhos were demonstrated to catalyze Suzuki-Miyaura and Sonogashira reactions, respectively, when utilized at the ca. 300 ppm level of Pd loading, and still promote the transformations with excellent yield and selectivity due to very mild conditions (reactions run between room temperature and 45
C). A double nano-effect between nanoparticles (i.e., “nano to nano”), coupling partners, and nanomicelles makes it all feasible with such productivity and selectivity. Insofar as homogeneous catalysis is concerned, we could only take advantage of the inherent benefits associated with the micellar catalysis effect (e.g., much higher reaction concentrations, milder reaction conditions, little, if any, organic solvents, etc.); thus, the process as illustrated in Scheme 4 required higher catalyst and ligand loadings, typically in the 1–5 mol% range. The outcome, however, usually remains the same with very high yields and selectivities being observed. Therefore, we endeavored to find new ligands that, as their Pd complexes, would offer features similar to those of nanoparticles, namely, high affinity for the micellar phase, while still promoting transformations under mild conditions. The first breakthrough came with the new ligand, HandaPhos (Fig. 5), that, together with palladium (1:1), formed a novel catalyst designed specifically for the medium [28]. Such a complex can promote transformations with very high efficiency and selectivity, following essentially the same pathway that consists in closely associating the reaction components in the micelles with the catalyst and increasing their residence time. Other ligands such as EvanPhos have also been made since then and shown to promote, with great efficiencies, important cross-coupling transformations

208

Conditions

F. Gallou and B. H. Lipshutz

catalyst

base

Solvent

Temperature

yield

Selectivity (mono:di)

1

Pd(PPh3)4

o

K2CO3

Acetonitrile (25 vol)

120 C, 1 h

60%

4:1

DIPEA

2% TPGS-750-M/H2O (7.5

30 oC, 16 h

83%

19:1

(8 mol %) 2

PdCl2(dtbpf) (5 mol %)

vol) / acetonitrile (7.5 vol)

99% purity by content). The latter could be used as such after simple filtration and washing with a minimum amount of water to displace residual salts. The high concentration of the reaction still made it very efficient in terms of water usage. The distilled THF could be easily reused, and the aqueous phase recycled at least two additional times in the same process. The subsequent key Suzuki-Miyaura cross coupling could then be run in the same medium; no effort was required for drying. Measurement of the amount of aryl bromide via quantitative HPLC was necessary to set the cross coupling with the proper stoichiometry of 1.0 equivalent of boronate ester and 2 mol% of the catalyst. The lipophilic ferrocene ligand (dtbpf) had previously been shown to be optimal, presumably due to its increased lipophilicity and, hence, its greater binding constant within the micelles. Slow dosing of the boronate ester was also required to minimize the amount required, by allowing less time in the pot for its decomposition, and to maximize overall productivity (minimal volume required). This transformation proceeded very smoothly with almost no impurity (only traces of protodeboronation). Upon completion, some methanol was added as a cosolvent for processability purposes, and the pH was adjusted to 14. Complete hydrolysis of the resulting methyl ester was observed after 2 h of stirring at rt. Distillation resulted again in a precipitate that was directly filtered. The cake was rinsed with water to remove salts. The isolated solid was sufficiently pure (>98% purity by content) to be used as such in the next step, again without drying. The ultimate amide bondforming step was again carried out in water using TPGS-750-M as the surfactant of choice and some PEG-200 as the preferred additive. Careful optimization had revealed it was the favored cosolvent. Indeed, extensive screening of cosolvents had shown that it resulted in one of the best kinetic profiles and selectivity and, importantly, that it afforded a stable emulsion or suspension throughout the process. Other cosolvents that performed even better chemistry-wise led to oiling out or thick precipitate formation, a root cause for lack of robustness and a risk for increased and/or new impurities. The product then precipitated as the reaction progressed, allowing for its simple isolation upon filtration. The selectivity of the transformation was much higher than for any of the previously screened and optimized conditions (ca. 1.2% of the main over-acylated impurity compared to 12% at best), which could be further depleted to below 1.0% in the precipitation process. A yield of >90% for the isolated product of purity >98.5% was finally observed, after the cake had been washed with water to remove remaining salts, remaining surfactant, and residual PEG-200. This second-generation process turned out to require 48% less solvents and 8% less water and showed an overall yield increase from 42 to 48%. It was also 186% more productive compared to the optimized process run in organic solvents as the benchmark. The reasons for such differences are for the most part the inherent selectivity and high efficiency of micellar catalysis conditions. With such an outcome, the standard extensive work-up conditions can be shortened or even omitted, when directly isolating the product as products 1, 3, and 4 in the SNAr, after the cross coupling and amide bond formation steps. Multiple extractions and washings were indeed fully bypassed here, along with classical intermediate purifications. Since the

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selectivity of the various transformations is much better than that observed under standard conditions, direct use of the product, therefore, was feasible. The far greater reaction concentration characteristic of micellar catalysis common to all transformations further contributed to high productivity. An even simpler and more productive strategy consists of sequentially carrying out a series of transformations in the same vessel. This strategy requires proper control to guarantee that incomplete conversion does not lead to carry-over of the original starting materials into subsequent undesirable side products as impurities. Nevertheless, it offers an opportunity to dramatically improve cycle time as well as overall mass consumption. Scheme 6 is a classic example of a telescoped sequence using the surfactant technology. In this sequence, a p-bromonitrobenzene was selectively reduced with Pd-doped iron nanoparticles/sodium borohydride, as described earlier herein. The resulting aniline was acylated using COMU after the pH was adjusted to neutrality. To the reaction the mixture was then added Pd-doped iron nanoparticles containing SPhos, along with triethylamine, and the mixture was heated to 45
C. A 2-pyridyl MIDA boronate was then slowly dosed in THF. The desired coupling product formed smoothly and was isolated after 16 h. Isolation involved an extractive work-up that started with the removal of the water-miscible cosolvent, THF, with the desired product ultimately being crystallized from ethyl acetate and methylcyclohexane [22]. This sequential strategy is a critical aspect of scale-up for multiple reasons. First, it is an obvious contributor to improved economics, as reduction in solvent and

Fe/Pd NH2

NO2

Ph

NaBH4

2% TPGS-750-M/H2O rt 16 h

Br

COOH NHboc

pH 7

Br

COMU 2,6-lutidine

Fe/Pd

F

N

O

BMIDA Ph

NEt3 45 oC 16 h

COOEt

NC O N

O

N

F

N H NHboc

OH

N N N

OH PF6

O

O COMU

MIDA

Scheme 6 Telescoped sequence using the surfactant technology

O Ph

N H NHboc

Br

Organometallic Processes in Water

213

precious metal consumption translates into immediate savings. Second, it represents an inherent simplification of post-reaction/downstream operations and treatment that can be minimized or even fully avoided in telescoped transformations. In this last example, we were able to take advantage of the readily available nitroaromatic system so as to functionalize it directly (Scheme 7). Such nitroaryl/ heteroaryl functionality offers many advantages for derivatization, utilizing the strong activation of the electron-withdrawing nature of a nitro group that directs an SNAr, or indirectly, after reduction to the corresponding amine, cross couplings with amines, or amide bond formation in overall highly efficient sequences. We also established at an early stage the feasibility of benzyl reduction and, by extension, carboxybenzyl (Cbz) removal. This process is catalyzed by the same nanoparticles, but silanes are used as the stoichiometric source of hydride. We are only now discovering the details of this process and will report shortly our findings (unpublished results). The full power of this technology is only unleashed once the various individual chemistries start to be put together. This technology accommodates not only catalytic transformations but also some of the most commonly encountered transformations within the pharmaceutical industry, such as SNAr reactions and other nucleophilic substitutions and amide formation. Very recent results in the biocatalysis field obtained in our laboratories are also further increasing our expectations, as we have demonstrated dramatic improvement of a variety of biocatalyzed transformations by using our surfactant of choice TPGS-750-M; results will be reported shortly. This creates for the first time the opportunity to run on a routine basis complex sequences of transformations with a unified solvent system. We have by H N

X

NO2

NH2

X

X

R

X

H N X

Nu

O R

H N

X = halide R = Alkyl, Aryl, Heteroaryl NO2

NH2

Nu

Nu

R

Nu

H N

O

R Nu

Scheme 7 Select manifold of reactivity suitable for homogeneous and heterogeneous micellar catalysis

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now demonstrated this in multiple examples. A key for success, however, is to keep the big picture in mind, integrating all aspects of the chemistry and processes, and not just individual steps and/or yields. On occasion, we observe that the surfactant chemistry can slightly underperform and lead to slightly lower yields. But when one makes the comparisons with existing alternatives in traditional organic solvents, the overall sequence, the specific processes involved, the number of operations, the mass balance, the potential for various recyclings (solvents, water phases, catalyst), and the analytical and regulatory strategies, chemistry in water ends up being, by far, superior in almost all cases. Another aspect that we believe will be transformational is the chemistry surrounding nanoparticles in their native forms. We sense, based on successes in hand to date, that they open up opportunities for truly sustainable chemistry not only by way of the drastic reduction in precious metal consumption to be realized but also the minimization or even avoidance of the preparation of the catalysts themselves. Our first successes with nanoparticles indeed occurred when they were prepared from an essentially raw source of iron trichloride, which contained traces of various metals, precious or otherwise available to enable valuable catalysis. The synergistic effect has since been demonstrated to be critical and also renders the catalysis feasible with minute amounts of suitable precious metals. Loadings as low as a few tens to hundreds of ppm of palladium, for example, were sufficient to enable challenging Suzuki-Miyaura cross couplings that normally require at least 1 mol% of palladium in organic solvents under standard conditions. This real opportunity remains as yet entirely untapped. It is, in our opinion, a real breakthrough for sustainability, as it indeed allows for bypassing multiple costly and environmentally very intense operations currently utilized to prepare the catalysts on which we rely today, rather than using metals in their practically native form. This is but one vivid example highlighting the change in mindset required by chemists, to learn how to utilize not fully characterized and well-defined species but rather gifts from nature that already exist in the biological or physical world. The regulatory environment will certainly have to evolve significantly to allow for such radical thinking. But, in the final analysis, we may have no other choice given the pace at which we are consuming and processing resources along traditional lines. We, as chemists, must come to grips with the overall picture of our impact on the world and that includes our environmental footprint. Fortunately, we now have some powerful tools in the toolbox, with many more coming, which offer a “win-win” situation: even better chemistry and with minimal environmental impact. Acknowledgments First and foremost, we would like to express our sincere thank you to the many dedicated and brilliant students involved in this journey, both at UCSB and at Novartis. To name just a few, Dr. Nick Isley, Dr. Chris Gabriel, Professor Sachin Handa (now University of Louisville), and our close collaborator Professor Martin Andersson (University of Copenhagen) along with the many chemists who enabled the implementation of this disruptive technology within the industry, including Dr. Larry Hamann, Dr. Michael Parmentier, Dr. Pengfei Guo, Dr. Jianguang Zhou, and Mr. Vincent Bordas. The industrialization of the technology would also not have been feasible without Novartis management’s precious trust and support. Thank you to Dr. Heiko Potgeter, Dr. Daniel Kaufmann, Dr. Thomas Heinz, and Dr. Andreas Knell. We also warmly acknowledge Novartis and the NSF (GOALISusChEM 1566212) for financial support.

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Top Organomet Chem (2019) 65: 217–252 DOI: 10.1007/3418_2018_12 # Springer International Publishing AG, part of Springer Nature 2018 Published online: 13 July 2018

Meeting Metal Limits in Pharmaceutical Processes Laura C. Forfar and Paul M. Murray

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Understanding and Optimising the Metal-Catalysed Process . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Heterogeneous Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Methods of Removal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Extraction and Precipitation Treatments and Associated Problems . . . . . . . . . . . . . . . . . . 2.2 Adsorption and Filtration Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Applying Metal Scavengers at the Pilot Plant Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Batch Versus Fixed-Bed Removal: A Cost Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Replacing Carbon with a Metal Scavenger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Use of a Metal Scavenger in Acidic Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Processes Which Require Multiple Metal Removal Techniques . . . . . . . . . . . . . . . . . . . . . 4.6 Ruthenium Removal Using a Metal Scavenger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7 Removing Multiple Metals with One Scavenger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8 Adsorbent Screening for Removal of Coloured Impurities . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Metal-catalysed transformations are essential for the synthesis of the increasingly complex structures required in the pharmaceutical industry and allow chemists to be more inventive and efficient with their synthetic routes. More than 90% of chemicals involve the use of metal catalysts in their manufacture, yet the perceived challenge of metal removal can still be a deterrent to their use in the pharmaceutical industry. Any remaining metal can interfere with subsequent steps and, importantly, should never reach the patient. To ensure this, strict regulations are in place. The technologies available for the separation of transition metals from APIs have improved greatly in recent years, allowing the efficient removal of the catalyst, recovery of the

L. C. Forfar (*) and P. M. Murray (*) PhosphonicS Ltd, Compton, UK e-mail: [email protected]; [email protected]

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metal and further improvement of the sustainability of catalytic processes. This chapter will provide an overview, with examples, of the methods for effective metal removal. The scale-up of metal removal processes including a consideration of the environmental impact and the cost of metal removal steps at scale is presented. Keywords Adsorption · API purification · Catalysis · Immobilisation · Meeting metal limits · Metal removal · Palladium · Sustainability

1 Introduction Metal-catalysed cross-coupling reactions have become a permanent fixture in the toolkit of the organic chemist, replacing multistep syntheses by stitching complex fragments together to yield highly functionalised compounds under relatively mild conditions. However, as the use of transition metals in the development of pharmaceutical products increases, so too does the need for simple and efficient methods for the removal of residual metals from the resulting products. Stringent guidelines are in place for the presence of elemental impurities in pharmaceuticals for human use, with palladium and the other platinum group metals being controlled to demanding limits of 10 μg/g in drug products, drug substances and excipients [1]. These guidelines, combined with the unwanted interference of residual metals with downstream chemistry, drive the development of new metal removal technologies. Additionally, the successful commercialisation of processes containing metal-catalysed steps is dependent on economic feasibility and environmental sustainability which can be heavily affected by the metal removal step. While there are a range of techniques available for metal removal, the paths to finding the correct method and its efficient implementation are not always straightforward. It is often difficult to sequester metals from active pharmaceutical ingredients (APIs) since they are highly functionalised and contain groups that bind strongly with metals. Choosing the correct metal removal method is more difficult when the form or oxidation state of the metal to be removed is unknown. Unfortunately, what remains in solution following the completion of a catalytic reaction is often different from the catalyst or pre-catalyst that was originally used. The speciation of the metal in a reaction mixture is complicated and can even differ from batch to batch due to minor changes in process conditions. Loss of ligands through oxidation, thermal decomposition or the general processes and reaction conditions can occur, resulting in underligated metals. The resulting metal species could be in any oxidation state, elemental or in clusters [2]. The ideal metal removal process will effectively handle metal species in a variety of oxidation states without loss of product. This chapter will provide a summary of the currently available methods for effective metal removal, describing traditional methods and newer technologies. It will also feature the scale-up of metal removal processes including a consideration of the environmental impact and cost of a metal removal step at scale. Several techniques, such as the use of advanced metal scavengers, are currently seen as expensive, yet with the correct optimisation, these can be highly economical, particularly after the employment of precious metal catalysts when recovery of the precious metal value is possible.

Meeting Metal Limits in Pharmaceutical Processes

1.1

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Understanding and Optimising the Metal-Catalysed Process

Investing time in optimising a catalytic process to reduce catalyst loading will assist in meeting metal limits. To this end, the rate-determining step should be identified and improved as much as possible. High-throughput screening [3], design of experiments (DoE) [4–7] or advanced DoE with principal component analysis (PCA) [8–10] can be employed to screen metals, solvents and ligands. DoE can also be used to identify the optimum conditions to maximise yield while using minimal metal catalyst. As a cautionary note, it is unwise to lower the catalyst loading to as low as possible until the quality of the input materials is fixed; otherwise, the process will be susceptible to variation with every new lot of starting materials. In terms of metal removal, it is preferable to keep the catalyst as pure as possible for easier removal. For example, we have seen many examples where catalyst poisoning by impurities in the starting material has changed the effective catalyst loading, resulting in a diminished amount of active catalyst. The use of higher purity starting materials prevented decomposition of the catalyst, resulting in lower catalyst loadings and therefore less catalyst to remove upon completion of the reaction. Impurities and uncontrolled factors such as peroxides or dissolved oxygen in solvents can also poison or kill catalysts leading to deactivation and resulting in a higher overall loading of the catalyst to counteract the deactivation. In a rhodium-catalysed 1,4-addition reaction, the catalyst was found to have an extremely high affinity for O2, 100 times that of Pd. The ligand and halide groups on Rh affected the catalyst behaviour, increasing the rate of oxidation. In this case, thorough purging of the system with N2 was required, rather than just a N2 blanket, to ensure the sensitive catalyst was not oxidised. Metal scavenging can be implemented at any stage in a synthetic sequence, but a fully optimised and cost-effective scavenging process is best developed when the rest of the process is finalised.

1.2

Heterogeneous Catalysis

An alternative solution to removing the metal left behind by a homogeneous catalyst is to use a heterogeneous catalyst. In bulk chemicals, where the molecules are quite simple, this is conceivable, allowing reactivity and then easy separation of the product from the catalyst, but the ability to tune the catalyst is limited, and the development of a supported catalyst is expensive and time-consuming. The supported catalysts that have been reported to date do not have the ability or stability to be commercially viable in the development of fine chemicals and APIs, which require more elaborate functionalisation. Additionally, supported catalysts are often less active than their homogeneous counterparts due to the steric hindrance of their polymeric support [2]. Heterogeneous catalysts, such as Pd/C and Pd on other solid supports, have been in use for a long time but are mainly used for hydrogenation reactions [11]. It is also possible to run Suzuki-Miyaura or Heck cross-coupling reactions using Pd/C by

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P

Molecular catalyst Rh

P

P P

Heteropolyacid anchor

Rh

X

Metal oxide support

Fig. 1 Molecular structure of chiral rhodium catalyst and the catalyst immobilised on phosphotungstic acid [15]

adding a ligand to help with activity, but this process does not work for deactivated systems [12]. Although a heterogeneous catalyst can be easily removed by filtration following completion of the reaction, metal is often leached from the catalyst into solution. It has been suggested that heterogeneous catalysts work by the metal desorbing to allow reactivity and then adsorbing back onto the solid, which may be a source of this instability. Employing supported ligands for heterogeneous crosscoupling has been useful for academic purposes but has had limited application in industry. The high cost of materials and ease of destruction of the ligand on the support, which leads to greater leaching, have been a deterrent [2]. A heterogenised molecular catalyst was recently applied in the formation of an API on the kilogramme scale [13]. The commercially available chiral catalyst Rh-(S,S)EthylDuphos (Fig. 1) was used successfully in batch, but efforts to minimise the cost and environmental footprint of the process led the team to develop an in-flow process. The same catalyst was immobilised (Fig. 1) on phosphotungstic acid (PTA) and aluminium oxide using the Augustine immobilisation technique [14] whereby heteropolyacids are dispersed on a metal oxide surface to act as anchors for cationic organometallic complexes. The catalyst was shown to be stable with very minimal leaching, and conversion was high, yielding the desired product in high purity (>98%) and enantiomeric excess (ee ¼ >99%) with low Rh contamination (