Organic Reactions, Volume 99 E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Organic Reactions
- Sprache: Englisch
The 99th volume in this series for organic chemists in academia and industry presents critical discussions of widely used organic reactions or particular phases of a reaction. The material is treated from a preparative viewpoint, with emphasis on limitations, interfering influences, effects of structure and the selection of experimental techniques. The work includes tables that contain all possible examples of the reaction under consideration. Detailed procedures illustrate the significant modifications of each method.
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Veröffentlichungsjahr: 2019
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Table of Contents
Cover
Introduction to the Series Roger Adams, 1942
Introduction to the Series Scott E. Denmark, 2008
Preface to Volume 99
Leo Armand Paquette
Gary Herbert Posner
Chapter 1: Addition of Non‐Stabilized Carbon‐Based Nucleophilic Reagents to Chiral N‐sulfinyl Imines
Introduction
Mechanism and Stereochemistry
Scope and Limitations
Applications to Synthesis
Comparison With Other Methods
Experimental Conditions
Experimental Procedures
Tabular Survey
References
Supplemental References for Table 1a
Supplemental References for Table 1b
Supplemental References for Table 2a
Supplemental References for Table 3a
Supplemental References for Table 3b
Supplemental References for Table 4a
Supplemental References for Table 4b
Supplemental References for Table 5a
Supplemental References for Table 6a
Supplemental References for Table 6b
Supplemental References for Table 7a
Supplemental References for Table 7b
Chapter 2: Iridium‐Catalyzed, Enantioselective, Allylic Alkylations With Carbon Nucleophiles
Acknowledgments
Introduction
Mechanism and Stereochemistry
Scope and Limitations
Applications to Synthesis
Comparison With Other Methods
Experimental Conditions
Experimental Procedures
Tabular Survey
References
Supplemental References for Table 1A: Intermolecular Allylic Alkylations with Malonic Acid Derivatives as Pronucleophiles
Supplemental References for Table 2: Allylic Alkylations with β‐Keto Esters as Pronucleophiles
Supplemental References for Table 3: Allylic Alkylations with Iminoglycinates as Pronucleophiles
Supplemental References for Table 4: Allylic Alkylations with Azlactones and Related Pronucleophiles
Supplemental References for Table 6: Allylic Alkylations with Sulfones as Pronucleophiles
Supplemental References for Table 7: Allylic Substitutions with Aldehydes as Pronucleophiles (Dual Catalysis)
Supplemental References for Table 10: Allylic Substitutions with Silyl Enol Ethers as Pronucleophiles
Supplemental References for Table 11: Allylic Alkylations with Enamines as Pronucleophiles
Supplemental References for Table 13: Allylic Alkylations with Aromatic Compounds via Friedel–Crafts Type Reactions
Supplemental References for Table 14: Allylic Alkylations with Aromatic Compounds via Dearomatization Reactions
Supplemental References for Table 16: Allylic Alkylations with Organoboron Compounds as Nucleophiles
Supplemental References for Other Carbon Nucleophiles
Cumulative Chapter Titles by Volume
Author Index, Volumes 1-99
Chapter and Topic Index, Volumes 1–99
End User License Agreement
List of Illustrations
Chapter 1
Scheme 1
Figure 1 Conformation of
N
‐sulfinyl imines.
Scheme 2
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Scheme 4
Figure 2 Proposed transition state for additions of allyl organometallic r...
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Figure 3 Transition state proposals.
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Figure 4 Chiral auxiliaries for synthesis of
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Chapter 2
Scheme 1
Scheme 2
Scheme 3
Figure 1 Site selectivity of allylic alkylation with a dienylic and an alk...
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Scheme 5
Scheme 6 Reprinted with permission from Madrahimsov, S. T.; Li, Q.; Sharma...
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Scheme 8
Figure 2 Survey of phosphoramidite ligands used in lr‐catalyzed allylic su...
Scheme 9 Reprinted with permission from Raskatov, J. A.; Jäkel, M.; Straub...
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Scheme 11
Figure 3 Survey of lr‐complexes used as catalysts in reactions described i...
Figure 4 Structure of a representative (π-allyl)Ir complex. Reprinted with...
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Figure 5 Ligands other than phosphoramidites.
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Figure 6 Survey of pronucleophiles yielding stabilized carbanions.
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Figure 7 Products of allylic alkylations with various malonic acid derivat...
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Figure 8 Additional sulfone pronucleophiles.
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Figure 9 Types of silyl enol ethers used in lr‐catalyzed allylic substitut...
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Guide
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Table of Contents
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Advisory Board
John E. Baldwin
James A. Marshall
Peter Beak
Michael J. Martinelli
Dale L. Boger
Stuart W. McCombie
André B. Charette
Scott J. Miller
Engelbert Ciganek
John Montgomery
Dennis Curran
Larry E. Overman
Samuel Danishefsky
T. V. RajanBabu
Huw M. L. Davies
Hans J. Reich
John Fried
James H. Rigby
Jacquelyn Gervay-Hague
William R. Roush
Heinz W. Gschwend
Tomislav Rovis
Stephen Hanessian
Scott D. Rychnovsky
Louis Hegedus
Martin Semmelhack
Paul J. Hergenrother
Charles Sih
Jeffrey S. Johnson
Amos B. Smith, III
Robert C. Kelly
Barry M. Trost
Laura Kiessling
James D. White
Marisa C. Kozlowski
Peter Wipf
Steven V. Ley
Former Members of the Board Now Deceased
Roger Adams
Ralph F. Hirschmann
Homer Adkins
Herbert O. House
Werner E. Bachmann
John R. Johnson
A. H. Blatt
Robert M. Joyce
Robert Bittman
Andrew S. Kende
Virgil Boekelheide
Willy Leimgruber
George A. Boswell, Jr.
Frank C. McGrew
Theodore L. Cairns
Blaine C. McKusick
Arthur C. Cope
Jerrold Meinwald
Donald J. Cram
Carl Niemann
David Y. Curtin
Leo A. Paquette
William G. Dauben
Gary H. Posner
Richard F. Heck
Harold R. Snyder
Louis F. Fieser
Milán Uskokovic
Boris Weinstein
Organic Reactions
Volume 99
Editorial Board
Scott E. Denmark, Editor-in-Chief
Jeffrey Aubé
Jennifer A. Love
David B. Berkowitz
Gary A. Molander
Paul R. Blakemore
Albert Padwa
Jin K. Cha
Jennifer M. Schomaker
P. Andrew Evans
Kevin H. Shaughnessy
Dennis G. Hall
Christopher D. Vanderwal
Donna M. Huryn
Steven M. Weinreb
Jeffrey B. Johnson
Jeffery B. Press, Secretary
Press Consulting Partners, Brewster, New York
Robert M. Coates, Proof-Reading Editor
University of Illinois at Urbana-Champaign, Urbana, Illinois
Danielle Soenen, Editorial Coordinator
Dena Lindsay, Secretary and Processing Editor
Landy K. Blasdel, Processing Editor
Debra Dolliver, Processing Editor
Linda S. Press, Editorial Consultant
Engelbert Ciganek, Editorial Advisor
ASSOCIATE EDITORS
Jean-Nicolas Desrosiers Keith R. Fandrick Jolaine Savoie Chris H. Senanayake Günter Helmchen Joshua D. Sieber Melissa A. Herbage Ze-Peng Yang Maurice A. Marsini Shu-Li You Jian-Ping Qu Wei Zhang Daniel Rivalti Yongda Zhang
Copyright
Copyright © 2019 by Organic Reactions, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data:
ISBN: 978-1-119-45662-9
Introduction to the Series Roger Adams, 1942
In the course of nearly every program of research in organic chemistry, the investigator finds it necessary to use several of the better‐known synthetic reactions. To discover the optimum conditions for the application of even the most familiar one to a compound not previously subjected to the reaction often requires an extensive search of the literature; even then a series of experiments may be necessary. When the results of the investigation are published, the synthesis, which may have required months of work, is usually described without comment. The background of knowledge and experience gained in the literature search and experimentation is thus lost to those who subsequently have occasion to apply the general method. The student of preparative organic chemistry faces similar difficulties. The textbooks and laboratory manuals furnish numerous examples of the application of various syntheses, but only rarely do they convey an accurate conception of the scope and usefulness of the processes.
For many years American organic chemists have discussed these problems. The plan of compiling critical discussions of the more important reactions thus was evolved. The volumes of Organic Reactions are collections of chapters each devoted to a single reaction, or a definite phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint, and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes several detailed procedures illustrating the significant modifications of the method. Most of these procedures have been found satisfactory by the author or one of the editors, but unlike those in Organic Syntheses, they have not been subjected to careful testing in two or more laboratories. Each chapter contains tables that include all the examples of the reaction under consideration that the author has been able to find. It is inevitable, however, that in the search of the literature some examples will be missed, especially when the reaction is used as one step in an extended synthesis. Nevertheless, the investigator will be able to use the tables and their accompanying bibliographies in place of most or all of the literature search so often required. Because of the systematic arrangement of the material in the chapters and the entries in the tables, users of the books will be able to find information desired by reference to the table of contents of the appropriate chapter. In the interest of economy, the entries in the indices have been kept to a minimum, and, in particular, the compounds listed in the tables are not repeated in the indices.
The success of this publication, which will appear periodically, depends upon the cooperation of organic chemists and their willingness to devote time and effort to the preparation of the chapters. They have manifested their interest already by the almost unanimous acceptance of invitations to contribute to the work. The editors will welcome their continued interest and their suggestions for improvements in Organic Reactions.
Introduction to the Series Scott E. Denmark, 2008
In the intervening years since “The Chief” wrote this introduction to the second of his publishing creations, much in the world of chemistry has changed. In particular, the last decade has witnessed a revolution in the generation, dissemination, and availability of the chemical literature with the advent of electronic publication and abstracting services. Although the exponential growth in the chemical literature was one of the motivations for the creation of Organic Reactions, Adams could never have anticipated the impact of electronic access to the literature. Yet, as often happens with visionary advances, the value of this critical resource is now even greater than at its inception.
From 1942 to the 1980's the challenge that Organic Reactions successfully addressed was the difficulty in compiling an authoritative summary of a preparatively useful organic reaction from the primary literature. Practitioners interested in executing such a reaction (or simply learning about the features, advantages, and limitations of this process) would have a valuable resource to guide their experimentation. As abstracting services, in particular Chemical Abstracts and later Beilstein, entered the electronic age, the challenge for the practitioner was no longer to locate all of the literature on the subject. However, Organic Reactions chapters are much more than a surfeit of primary references; they constitute a distillation of this avalanche of information into the knowledge needed to correctly implement a reaction. It is in this capacity, namely to provide focused, scholarly, and comprehensive overviews of a given transformation, that Organic Reactions takes on even greater significance for the practice of chemical experimentation in the 21st century.
Adams' description of the content of the intended chapters is still remarkably relevant today. The development of new chemical reactions over the past decades has greatly accelerated and has embraced more sophisticated reagents derived from elements representing all reaches of the Periodic Table. Accordingly, the successful implementation of these transformations requires more stringent adherence to important experimental details and conditions. The suitability of a given reaction for an unknown application is best judged from the informed vantage point provided by precedent and guidelines offered by a knowledgeable author.
As Adams clearly understood, the ultimate success of the enterprise depends on the willingness of organic chemists to devote their time and efforts to the preparation of chapters. The fact that, at the dawn of the 21st century, the series continues to thrive is fitting testimony to those chemists whose contributions serve as the foundation of this edifice. Chemists who are considering the preparation of a manuscript for submission to Organic Reactions are urged to contact the Editor‐in‐Chief.
Preface to Volume 99
Reagents which donate their electrons to, or share them with, a foreign atomic nucleus may be termed nucleophilic…
Reagents which acquire electrons, or a share in electrons, previously belonging to a foreign molecule or ion, may be termed electrophilic….
Christopher K. Ingold
Chem. Rev. 1934, 15, 225
In 1934, at the height of the development of the electronic theory of organic chemistry, Sir Christopher K. Ingold introduced the terms “nucleophile (nucleus‐seeking)” and “electrophile (electron‐seeking)” to describe the behavior of different reagents on the basis of their affinities. He argued that these terms better described the behavior of different compounds compared to the “anionoid” and “cationoid” adjectives suggested by Lapworth. The distinction was to identify agents not on the basis of their formal charge, but on their ability to accept or donate electrons. Ingold's assertions notwithstanding, he was effectively endorsing the broader view of reactive substances as bases or acids according to the definitions provided by G. N. Lewis a decade before.
Nucleophilic additions and substitutions constitute enormous classes of carbon‐carbon bond forming reactions, the workhorses of organic synthesis. Not only are myriad pairwise combinations of nucleophile and electrophile possible, but both of these processes are capable of creating stereogenic centers. The two chapters in this volume involve reactions of carbon‐based nucleophiles, but differ significantly in the electrophilic partner and the mechanism by which new stereogenic centers are created.
The first chapter describes the nucleophilic addition of organometallic reagents to chirally‐modified imine electrophiles. This chapter, entitled “Addition of Non‐Stabilized Carbon‐Based Nucleophilic Reagents to Chiral N‐Sulfinyl Imines” by Melissa A. Herbage, Jolaine Savoie, Joshua D. Sieber, Jean‐Nicolas Desrosiers, Yongda Zhang, Maurice A. Marsini, Keith R. Fandrick, Daniel Rivalti and Chris H. Senanayake provides a comprehensive treatment of the scope and stereochemical control aspects of this nucleophilic addition. This class of azomethines pioneered by Prof. Jonathan Ellman has achieved the enviable status of a name reagent owing to the generality and predictability of the addition process. Despite the fact that the reaction is an auxiliary‐controlled process – requiring stoichiometric formation of the N‐sulfinyl imines – the ready availability of the enantiomerically‐enriched sulfinamide, the predictability of the stereochemical outcome and the ease of removal of the sulfinyl group (in enantiomerically‐enriched form, if desired) conspire to make this the gold standard for setting nitrogen‐bearing stereogenic centers. N‐Sulfinyl imines derived from both aldehydes and ketones are suitable substrates and lead to the formation of secondary and tertiary carbon centers bearing an amino group with high selectivity. The most common organometallic nucleophiles are organomagnesium reagents, though –lithium, –zinc, –copper and –indium reagents have been used as well. The Boehringer‐Ingelheim team has organized the chapter by nucleophile which encompasses (inter alia), alkyl, alkenyl, alkynyl, allyl, propargyl and aryl organometallic reagents. Moreover, they have separated the reaction of aldimines and ketimines to further illustrate the scope and limitations of the process. The comprehensive Tabular Survey is similarly organized to facilitate the discoverability of the specific transformation of interest to the reader. Because this reaction has been used extensively in academic and industrial settings, many illustrations in the context of complex‐molecule synthesis are provided along with helpful guidance for installation and removal of the chiral auxiliary. This chapter is destined to be the “go to” resource for applications of the Ellman protocol.
On the other hand, the second chapter represents a nucleophilic substitution process of allylic alcohols and esters under catalysis by chiral iridium complexes. Although the archetypal transition‐metal‐catalyzed allylic substitution involves palladium catalysis (the Tsuji‐Trost reaction), many other metals have been conscripted into useful service for this substitution. Whereas palladium complexes generally lead to linear products of allylic substitution with branched electrophiles, molybdenum and iridium complexes lead to the branched isomers and are thus ideally suited for enantioselective catalysis. Indeed, Chapter 1 in Volume 84 in this series by Christina Moberg details all aspects of the molybdenum‐catalyzed allylic substitution process. Chapter 2 in this volume entitled “Iridium‐Catalyzed, Enantioselective, Allylic Alkylations with Carbon Nucleophiles” by Jian‐Ping Qu, Günter Helmchen, Ze‐Peng Yang, Wei Zhang, and Shu‐Li You completes the set of transformations available for reliable formation of enantiomerically‐enriched, branched‐chain products. We were extremely fortunate to combine the efforts of one of the pioneers of this transformation (G. Helmchen) with one of the most active developers of the reaction (S.‐L. You) to produce a definitive treatise on the state of the art in enantioselective catalysis of carbon‐carbon bond formation. Because the scope of this reaction has expanded so rapidly in the past 10 years, the authors limited their coverage to the use of carbon‐based nucleophiles, but even so, literally dozens have been employed. The two major classes involve nucleophiles stabilized by electron‐withdrawing or conjugating groups and non‐stabilized nucleophiles such as organozinc, –boron, and –silicon reagents as well as enoxysilanes, enamines and electron‐rich arenes. In view of the many different ligands that have been developed for this reaction, the authors have provided an expertly crafted summary of the best ligands to use for each class of substrate and nucleophile. The current understanding of the origin of site and enantioselectivity are clearly presented, allowing readers to understand the unique features of the process. The comprehensive Tabular Survey is organized by nucleophile first, then allylic electrophile second, enabling an easy path to locate specific reactant combinations as guides for the experimentalist.
It is appropriate here to acknowledge the expert assistance of the entire editorial board, in particular Dennis Hall (Chapter 1) and Jin K. Cha (Chapter 2) who shepherded these chapters to completion. The contributions of the authors, editors, and publisher were expertly coordinated by the board secretary, Dr. Dena Lindsay. In addition, the Organic Reactions enterprise could not maintain the quality of production without the dedicated efforts of its editorial staff, Dr. Danielle Soenen, Dr. Linda S. Press, Dr. Engelbert Ciganek, Dr. Robert M. Coates, Dr. Landy Blasdel, and Dr. Debra Dolliver. Insofar as the essence of Organic Reactions chapters resides in the massive tables of examples, the authors' and editors' painstaking efforts are highly prized.
Scott E. Denmark
Urbana, Illinois
Leo Armand Paquette
July 15, 1934 - January 21, 2019
Leo A. Paquette was born in Worcester, Massachusetts on July 15, 1934. He attended the College of the Holy Cross in his home town and graduated with a degree in chemistry, magna cum laude, in 1956. He attended the Massachusetts Institute of Technology where he received his Ph.D. in organic chemistry in 1959 under the tutelage of Norman Nelson. After graduation, Leo was employed as a research associate at the Upjohn Company in Michigan until he joined the faculty at the Ohio State University in 1963. He was promoted to full professor in 1969, Kimberly Professor in 1981, and Distinguished University Professor in 1987. During his academic career, “Doc”, as he was affectionately called by his students, mentored approximately 150 doctoral students, 300 postdoctoral associates, and countless masters students and undergraduates.
Leo served on the editorial boards of a number of chemistry journals, including Organic Reactions from 1979‐2008, where he was the Editor‐in‐Chief from 1989–1999. During his reign at Organic Reactions, he was responsible for Volumes 38–55 and a significant expansion of the series. He was the founding Editor of the Encyclopedia of Reagents for Organic Synthesis (EROS) which is now known in electronic format as e‐EROS. Leo also served on advisory committees at the NIH and NSF and was a consultant for Eli Lilly for many years. Leo was the recipient of a number of honors and awards including an Alfred P. Sloan Fellowship (1965), a Guggenheim Fellowship (1976) and Arthur C. Cope Scholar (1987). In 1984 he was awarded the ACS Award for Creative Work in Synthetic Organic Chemistry and was elected to the National Academy of Sciences that same year.
Leo's research interests encompassed a broad range of organic chemistry: the study and synthesis of heterocycles, metal‐catalyzed strained ring chemistry, multiple syntheses of structurally‐novel hydrocarbons, the development of numerous synthetic methods, the synthesis of complex natural products, synthetic applications of anion‐assisted oxy‐Cope rearrangements, and more. Some specifics are worth highlighting.
Throughout his entire career Leo was fascinated by the interactions of conjugated π‐electron systems. In his early years this manifested itself, inter alia, in studies on azepine and oxepin. Subsequently, he studied fluxional systems, such as bullvalene, semibullvalene and their aza‐counterparts. He also made major contributions to our understanding of neutral and charged aromaticity (e.g., cyclooctatetraene dications) and homoaromaticity (e.g., elassovalene, triquinacenes and propellanes). Many of these systems presented major synthetic challenges and Leo and his coworkers often used Ramberg Backlund reactions to install olefin linkages that were hard to prepare by other means. He also used chloroisocyanate reactions (e.g., with Dewar benzene derivatives) and di‐π‐methane rearrangements as novel approaches for preparing many of the systems discussed above.
By the 1980s, Leo's interests had turned to the synthesis of natural products. Among his favorite targets were triquinane natural products. His early achievements included pentalene, pentalenolactone and modhephene in the early 1980s and progressed to coriolin and hypnophilin in 2002 with many other successes in between. He used an anion‐assisted oxy‐Cope rearrangement, followed by a dihydroxylation/pinacol rearrangement to prepare the complex taxane ring structure (e.g., taxusin). He also employed the anion‐assisted oxy‐Cope rearrangements as the key steps in his synthesis of vulgarolide and cerorubenic acid. Ultimately the Paquette research group completed well over 50 total syntheses.
Leo is best known for his synthesis of the Platonic solid dodecahedrane in 1982, which was completed after a decade of research. Although the original rationale for preparing this exotic molecule was inspired by the use of an adamantylamine (e.g., memantine) as an NMDA calcium channel blocker for treating Alzheimer's disease, it ultimately became his personal quest to prepare a beautifully symmetric target molecule for much the same reason that many adventurers attempted to climb Mount Everest – because it's there. This work is generally recognized as a significant achievement in organic synthesis and is illustrative of his persitence, creativity, and devotion to science.
Leo was very demanding of his students and post‐doctoral associates but he personally set the standard when it came to devotion and hard work. He authored over 1300 peer‐reviewed papers, 38 book chapters, and 17 books. He also lectured at various institutions both domestically and internationally, and was noted for his excellent seminars. An added benefit of Leo's travels was that he brought home exotic beers from the places he visited, and offered them to his students at his annual Christmas party. His son, Ron, would add them to his beer can collection that totaled over 2000 different cans from around the world!
I (MW) knew Leo for over 50 years. I showed up in his lab for the first time as an NSF visiting summer student in 1968 and learned how to do recrystallizations for elemental analysis from the master himself. When my academic career was interrupted for military service, Leo kept in touch with me during those two years by sending me preprints of various publications he had underway. My years at Ohio State working with “Doc” are filled with only good memories.
In my case (DL), Leo did more to shape my professional development than any other single individual. While there was no doubt that he was demanding, the work ethic that he instilled in all of us who worked in his research group has served us well in our careers.
Leo's competitive side also showed up outside of the lab. He was an overly enthusiastic participant on our softball and basketball teams! Leo was a big fan of the Ohio State football program. Gameday was one of the few legitimate reasons for not being in the lab!
Leo passed away on January 21, 2019 after a long battle with Parkinson's Disease. He was married for 61 years to Estelle, a wonderful woman, and they have five children, Ron, Donna, Susan, Linda and Lisa. They also have 13 grandchildren and 5 great‐grandchildren.
Leo Paquette was an excellent mentor and a good friend over the years. May he rest in peace.
Matthew Wyvratt (Ph.D., 1976),
Dennis Liotta
(Postdoc, 1974–1976)
Gary Herbert Posner
June 2, 1943-February 26, 2018
Gary H. Posner, Jean and Normal Scowe and Research Professor of Chemistry, Johns Hopkins University. Left, as a graduate student in E. J. Corey's group, Harvard, ca. 1967. Right, on the occasion of receiving the Cope Senior Scholar Award of the American Chemical Society, 2004.
Gary Posner was born and raised in New York City in a deeply religious Jewish tradition, which guided his principles throughout his life. He earned an undergraduate degree in chemistry from Brandeis (1964) and Masters (1965) and Doctoral (1968) degrees in organic chemistry from Harvard (with E. J. Corey). After his postdoc with Dauben at Berkeley, he joined the Department of Chemistry at Johns Hopkins where he remained for 47 years until his retirement in 2016. He also had a long‐term affiliation with the Malaria Research Institute at the Johns Hopkins Bloomberg School of Public Health. At Hopkins, he supervised more than 60 Ph.D. students and almost as many postdoctoral fellows. Posner was a member of Organic Reactions' Editorial Board from 1977–1988 and a member of its Advisory Board from 1989 until his death in 2018, altogether over 40 years of continuous service. He also authored two chapters in that series on organocopper chemistry. Gary served as executive editor of Tetrahedron Reports (1996–2005) and on the Editorial Board of Steroids from 1996 until his death.
Posner's more than 375 scientific publications and patents cover a wide range of new synthetic methods, natural product total syntheses and medicinal chemistry. His earliest research involved the development of organocopper reagents, which led to publications, review articles and a textbook,An Introduction to Synthesis Using Organocopper Reagents. The Corey‐House‐Posner‐Whitesides reaction involves the addition of a lithium diorganocuprate to an organic halide.
His synthetic eye focused on other aspects of organocopper chemistry, the Diels‐Alder reaction, conjugate addition and domino cascades, materials and surface chemistry, and natural products research. In 2011, over 40 years after his first publication on organocopper reagents, he published a paper on the use of organocuprates to convert carboxylic acids directly to ketones.
In the area of medicinal chemistry, he and his research group studied isothiocyanates related to constituents of broccoli for their anticancer properties, vitamin D analogues for the treatment of skin disorders, cancer and neurodegenerative disorders, endoperoxides and artemisinin‐like compounds as antimalarials and antiparasitic agents, novel opthalmic materials, and artemisinin‐derived dimers as antileukemic drugs. As evidence of his growth from organic to medicinal chemist, some of the journals in which he published include Oncotarget, Bioorganic Medicinal Chemistry, Journal of Medicinal Chemistry, Antimicrobial Agents and Chemotherapy, Journal of Steroid Biochemistry and Molecular Biology, Carcinogenesis, Journal of Endocrinological Investigations among others.
Posner was the recipient of numerous awards and honors. In 1964, he was elected to Phi Beta Kappa honor society at Brandeis. In 1987, he was named Maryland Chemist of the Year by the Maryland Section of the American Chemical Society. In 2004, he received the Arthur C. Cope Senior Scholar Award from the American Chemical Society. Also, in 2004 he received the Brown University Award for Excellence in Vitamin D Research. In 2015, he was inducted into the National Academy of Inventors. He was invited to lecture around the world and was a plenary lecturer at over 70 scientific meetings. He received several teaching awards at Johns Hopkins including two via student nominations.
Gary was a planner. I remember his planning and carrying out preliminary experiments, as a postdoc in the laboratory of William G. Dauben at Berkeley (with Dauben's permission), so that his first projects as an assistant professor would succeed. He was always methodical and realistic in his plans, estimating his resources and strategizing his activities. The one thing he could not anticipate or plan for was the slow and horribly debilitating effects of Parkinson's disease that would rob him of his retirement. He hoped to spend time with his sons and grandchildren, who he adored, and to pursue his photographic ambitions (he was a talented photographer with a superb eye).
Oxbow Bend in the Snake River, Grand Tetons, Wyoming, September 2002. Photograph by and courtesy of Gary H. Posner. Gary selected this photograph to be published with an essay about him for a special issue of Tetrahedron. See below for the reference.
Gary was immensely proud of his sons, two from his first marriage: Michael (a statistics professor at Villanova) and Joseph (a software developer), and two he “inherited” upon his second marriage: Mike Nachshen (a former Major in the U.S. Air Force and now a PR professional in the aerospace industry) and Saul Nachshen (a video producer). Gary also leaves his second wife, Judith Stamberg, his grandchildren, Yael, Jonah and Ari Smith Posner, and many other family members, friends, students and colleagues.
Scott Denmark, Editor in Chief of Organic Reactions asked me to write this memorial. Gary was a dear friend of mine for 50 years, and I am greatly saddened by his death. Yet Scott's request brings some measure of satisfaction, as I am sure it does for Gary's friends and colleagues and for the archives of chemistry, to reflect on his many achievements and his life.
Gary was a solid professional. He cared for others, extended himself to the utmost. He was a responsive collaborator and inspiring teacher. He could be counted upon, and asked to be counted upon. He spoke softly, yet acted with confidence. He was analytical in his thinking, yet deeply religious in his beliefs. He was short in stature, yet tall in life.
I want to share some of the adjectives provided by his sons, his colleagues, and from my own experiences. Gary was a gentle soul, kind, humble, modest, generous, patient, supportive, and compassionate. He was thoughtful, optimistic, unflappable, and adaptive. He was wise, meticulous, thorough, rational, resourceful, and attentive. He was a mensch.
Jeffrey I. Seeman
Department of Chemistry
University of Richmond
Westhampton Way
Richmond, Virginia 23173
For several other reviews of Gary Posner's professional life, see:
1 W. A. Maio and D. T. Genna, “From Organocopper to Medicinal Chemistry: A Symposium‐in‐Print to Honor Professor Gary H. Posner,”
Tetrahedron
, 2016,
72
, 5949.
2 D. T. Genna and W. A. Maio, “There and Back Again: The Synthetic Travels of Gary H. Posner,”
Tetrahedron
, 2016,
72
, 5956.
3 J. I. Seeman, “Gary H. Posner: Professor, Scientist, Colleague, Role Model, and Friend,”
Tetrahedron
, 2016,
72
, 5950.
Chapter 1Addition of Non‐Stabilized Carbon‐Based Nucleophilic Reagents to Chiral N‐sulfinyl Imines
Melissa A. Herbage Jolaine Savoie Joshua D. Sieber Jean‐Nicolas Desrosiers Yongda Zhang Maurice A. Marsini Keith R. Fandrick Daniel Rivalti and Chris H. Senanayake
Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, United States
Contents
Introduction
Mechanism and Stereochemistry
Computational and Experimental Studies
Stereochemical Models
Effect of the Organometallic Reagent
Effect of the Solvent
Effects of Additives
Effect of Coordinating Substituents at the α‐Position
Effect of a Stereogenic α‐Carbon
Scope and Limitations
Preparation of
N
‐Sulfinyl Imines
Preparation of
N
‐Sulfinyl Aldimines
Preparation of
N
‐Sulfinyl Ketimines
Additions of Alkyl Nucleophiles to
N
‐Sulfinyl Imines
Additions of Alkyl Nucleophiles to
N
‐Sulfinyl Aldimines
Additions of Alkyl Nucleophiles to
N
‐Sulfinyl Ketimines
Additions of Alkenyl Nucleophiles to
N
‐Sulfinyl Imines
Additions of Alkenyl Nucleophiles to
N
‐Sulfinyl Aldimines
Addition of Alkenyl Nucleophiles to
N
‐Sulfinyl Ketimines
Additions of Aryl Nucleophiles to
N
‐Sulfinyl Imines
Additions of Aryl Nucleophiles to
N
‐Sulfinyl Aldimines
Additions of Aryl Nucleophiles to
N
‐Sulfinyl Ketimines
Additions of Allylic Nucleophiles to
N
‐Sulfinyl Imines
Additions of Allylic Nucleophiles to
N
‐Sulfinyl Aldimines
Additions of Allylic Nucleophiles to
N
‐Sulfinyl Ketimines
Additions of Propargylic Nucleophiles to
N
‐Sulfinyl Imines
Additions of Propargylic Nucleophiles to
N
‐Sulfinyl Aldimines
Additions of Propargylic Nucleophiles to
N
‐Sulfinyl Ketimines
Additions of Alkynyl Nucleophiles to
N
‐Sulfinyl Imines
Additions of Alkynyl Nucleophiles to
N
‐Sulfinyl Aldimines
Additions of Alkynyl Nucleophiles to
N
‐Sulfinyl Ketimines
Nucleophilic Additions of Cyanide to
N
‐Sulfinyl Imines
Nucleophilic Additions of Cyanide to
N
‐Sulfinyl Aldimines
Nucleophilic Additions of Cyanide to
N
‐Sulfinyl Ketimines
Removal and Recovery of the
N
‐Sulfinyl Auxiliary
Applications to Synthesis
Synthesis of Amino Acids
Synthesis of Active Pharmaceutical Ingredients
Bradykinin B1 Antagonists
β‐Secretase‐1 (BACE) Inhibitors
Plasmodium Dipeptidyl Aminopeptidase (DPAP) Inhibitors
Cholesteryl Ester Transfer Protein (CETP) Inhibitors
Kinase Inhibitors
Melanocortin Type 4 Receptor (MC4R)
Cetirizine
Synthesis of Natural Products
Tubulysins
Polyoxins
Syomycin A
(–)‐3‐Demethoxyerythratidinone
Comparison With Other Methods
Chiral Auxiliaries
Catalytic Enantioselective Methods
Hydrogenation of Imines and Enamides
Experimental Conditions
General Considerations on Safety
Handling Pyrophoric Reagents
Handling Cyanide Reagents
Experimental Procedures
(
R
)‐2‐Methyl‐
N
‐((
S
)
