Organic Reactions, Volume 105 E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Organic Reactions
- Sprache: Englisch
The 105th 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: 2021
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Table of Contents
Cover
Title Page
Copyright
INTRODUCTION TO THE SERIES BY ROGER ADAMS, 1942
INTRODUCTION TO THE SERIES BY SCOTT E. DENMARK, 2008
PREFACE TO VOLUME 105
Heinz W. Gschwend April 12, 1936 – June 16, 2019
Hans J. Reich May 6, 1943 – May 1, 2020
CHAPTER 1: ENANTIOSELECTIVE HALOFUNCTIONALIZATION OF ALKENES
ACKNOWLEDGMENTS
INTRODUCTION
MECHANISM AND STEREOCHEMISTRY
SCOPE AND LIMITATIONS
APPLICATIONS TO SYNTHESIS
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
Tabular Survey
REFERENCES
SUPPLEMENTAL REFERENCES
CHAPTER 2: REACTIONS OF DIBORON REAGENTS WITH UNSATURATED COMPOUNDS
ACKNOWLEDGMENTS
INTRODUCTION
MECHANISM
STEREOCHEMISTRY
SCOPE AND LIMITATIONS
APPLICATIONS TO SYNTHESIS
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
TABULAR SURVEY
REFERENCES
CHAPTER 3: THE MATTESON REACTION
ACKNOWLEDGMENTS
INTRODUCTION
MECHANISM AND STEREOCHEMISTRY
SCOPE AND LIMITATIONS
APPLICATIONS TO SYNTHESIS
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
TABULAR SURVEY
REFERENCES
CUMULATIVE CHAPTER TITLES BY VOLUME
AUTHOR INDEX, VOLUMES 1–105
CHAPTER AND TOPIC INDEX, VOLUMES 1–105
End User License Agreement
List of Illustrations
Chapter 1
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Figure 1 General tactics for ensuring association between chiral catalysts a...
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Figure 2 Completed total syntheses employing an enantioselective, vicinal di...
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Chapter 2
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Chapter 3
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Guide
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FORMER MEMBERS OF THE BOARD OF EDITORS AND DIRECTORS
JEFFREY AUBÉ
LAURA KIESSLING
JOHN E. BALDWIN
MARISA C. KOZLOWSKI
PETER BEAK
STEVEN V. LEY
DALE L. BOGER
JAMES A. MARSHALL
JIN K. CHA
MICHAEL J. MARTINELLI
ANDRÉ B. CHARETTE
STUART W. MCCOMBIE
ENGELBERT CIGANEK
SCOTT J. MILLER
DENNIS CURRAN
JOHN MONTGOMERY
SAMUEL DANISHEFSKY
LARRY E. OVERMAN
HUW M. L. DAVIES
T. V. RAJANBABU
VICTOR FARINA
JAMES H. RIGBY
PAUL FELDMAN
WILLIAM R. ROUSH
JOHN FRIED
TOMISLAV ROVIS
JACQUELYN GERVAY‐HAGUE
SCOTT D. RYCHNOVSKY
STEPHEN HANESSIAN
MARTIN SEMMELHACK
LOUIS HEGEDUS
CHARLES SIH
PAUL J. HERGENROTHER
AMOS B. SMITH, III
JEFFREY S. JOHNSON
BARRY M. TROST
ROBERT C. KELLY
PETER WIPF
FORMER MEMBERS OF THE BOARD NOW DECEASED
ROGER
ADAMS
HERBERT
O.
HOUSE
HOMER
ADKINS
JOHN
R.
JOHNSON
WERNER
E.
BACHMANN
ROBERT
M.
JOYCE
ROBERT
BITTMAN
ANDREW
S.
KENDE
A. H.
BLATT
WILLY
LEIMGRUBER
VIRGIL
BOEKELHEIDE
FRANK
C.
MC
GREW
GEORGE
A.
BOSWELL
,
JR
.
BLAINE
C.
MC
KUSICK
THEODORE
L.
CAIRNS
JERROLD
MEINWALD
ARTHUR
C.
COPE
CARL
NIEMANN
DONALD
J.
CRAM
LEO
A.
PAQUETTE
DAVID
Y.
CURTIN
GARY
H.
POSNER
WILLIAM
G.
DAUBEN
HANS
J.
REICH
LOUIS
F.
FIESER
HAROLD
R.
SNYDER
HEINZ
W.
GSCHWEND
MILÁN
USKOKOVIC
RICHARD
F.
HECK
BORIS
WEINSTEIN
RALPH
F.
HIRSCHMANN
JAMES
D.
WHITE
Organic Reactions
VOLUME 105
EDITORIAL BOARD
P. ANDREWEVANS, Editor‐in‐Chief
STEVEN M. WEINREB, Executive Editor
DAVID
B.
BERKOWITZ
JEFFREY
N.
JOHNSTON
PAUL
R.
BLAKEMORE
ALBERT
PADWA
SCOTT
E.
DENMARK
JENNIFER
M.
SCHOMAKER
REBECCA
L.
GRANGE
KEVIN
H.
SHAUGHNESSY
DENNIS
G.
HALL
CHRISTOPHER
D.
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DONNA
M.
HURYN
MARY
P.
WATSON
JEFFREY
B.
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BARRY B. SNIDER, Secretary
JEFFERY B. PRESS, Treasurer
DANIELLESOENEN, Editorial Coordinator
DENALINDSAY, Secretary and Processing Editor
LANDY K. BLASDEL, Processing Editor
DEBRADOLLIVER, Processing Editor
ENGELBERTCIGANEK, Editorial Advisor
ASSOCIATE EDITORS
VARINDER K. AGGARWALKUMAR D. ASHTEKARBABAKBORHANENGELBERTCIGANEKBEATRICE S. L. COLLINSANA B. CUENCAELENAFERNÁNDEZARVINDJAGANATHANDONALD S. MATTESONDANIEL C. WHITEHEAD
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Library of Congress Cataloging‐in‐Publication Data:
ISBN: 978‐1‐119‐77120‐3
INTRODUCTION TO THE SERIES BY 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 BY 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 105
Janus: The Roman god with two faces that look to the future and to the past–the god of beginnings, gates, transitions, time, duality, doorways, passages, frames, and endings.
Source: Wikipedia
The ability to look to the past and the future represents the very essence of an Organic Reactions chapter. For instance, a chapter exhaustively documents the past efforts within a specific reaction manifold, while also identifying critical knowledge gaps that present the reader with potential future research endeavors. The Roman god Janus is generally depicted as having the two identical faces in a back‐to‐back orientation, albeit in the original depiction, the faces were different (with and without a beard). Notably, the ability to discriminate between two similar faces is omnipresent in stereoselective organic synthesis, as exemplified by the ability to promote si over re face selectivity in the addition of a nucleophile to a carbonyl group in the presence of a chiral catalyst. There are many other examples of this general principle, each having its challenges defined within a specific mechanistic construct. The following triumvirate of chapters focuses on reactions that share this important ability: to differentiate similar groups, faces, and termini in molecules resulting in highly chemo‐, regio‐ and stereoselective processes. Although the reactions in each chapter are mechanistically orthogonal, they each embody and illustrate the so‐called Janus effect. For instance, the first chapter outlines the enantioselective halofunctionalization of olefins, which differentiates the two olefin faces. The second chapter details the diboration of unsaturated compounds to afford unsymmetrical geminal and vicinal diboranes. The final chapter on the Matteson reaction details the stereoselective rearrangement of tetracoordinate boronate anions.
The first chapter by Kumar D. Ashtekar, Arvind Jaganathan, Babak Borhan, and Daniel C. Whitehead provides an outstanding account of the enantioselective halofunctionalization of alkenes. The seminal work on this transformation can be traced back to Bartlett and Tarbell in the mid‐1930s and the mechanistic interpretation of the anti‐stereoselectivity to Kimball shortly thereafter. Surprisingly, the area remained relatively dormant for approximately forty years until a series of reports on stereoselective intramolecular halocyclizations, specifically iodocyclizations. Nevertheless, the challenging issue of controlling facial selectivity was primarily ignored until Ishihara's landmark work, which demonstrated that the BINOL‐derived phosphorimidate promotes a stereoselective iodo‐polyene cyclization, albeit using a stoichiometric amount of the reagent. This chapter catalogs the development of this process from a mechanistic nuance into a powerful synthetic tool to facilitate the enantioselective halofunctionalization of alkenes. The Mechanism and Stereochemistry section highlights the need to avoid molecular halogens, which are too reactive to serve as viable halenium ion sources because they promote a competing and inherently nonselective background reaction. Hence, a series of less reactive halogenating agents are used along with different catalytic activation methods, namely, Brønsted acid catalysis, Lewis acid catalysis, Lewis base catalysis, and phase‐transfer catalysis. The Scope and Limitations component is organized by the halogen (Cl, Br, and I), with various nucleophiles (carboxylic acids, alcohols, amines, carbamates, thioimidates, halogens, water, and carbon nucleophiles) in the context of inter‐ and intramolecular additions with substituted alkenes. Notably, there is also a section on the desymmetrization and kinetic resolution reactions of alkenes that may be of interest to the reader. The Applications to Synthesis illustrate applications to the synthesis of several important natural products, and the Comparison with Other Methods section provides a direct comparison with the less well‐developed sulfeno‐ and selenofunctionalizations of alkenes. The organization of the Tabular Survey mirrors the Scope and Limitations, thereby making it easy for the reader to traverse between the two and identify a specific transformation. Overall, this is an outstanding chapter on a particularly important and useful process that will be a valuable resource to the synthetic community.
The second chapter by Ana B. Cuenca and Elena Fernández provides an excellent account of the diboration of unsaturated compounds, which is a particularly useful process for constructing geminal and vicinal diboranes, including unsaturated vicinal diboranes. The first direct addition of diboron compounds to unsaturated substrates, described by H. I. Schlesinger in 1954, resulted from the uncatalyzed addition of diboron tetrachloride to ethylene. Although there were follow‐up studies, the instability of the tetra(halo)diboron reagents limited their practical value for general applications. Nevertheless, in a groundbreaking paper in 1993, Akira Suzuki reported the first syn‐selective transition‐metal‐catalyzed diboration of alkynes with a tetraalkoxydiboron reagent, which prompted an explosion of interest in the development of this process. This chapter captures the historical development and important advances with various π‐components and describes the breadth of the recent developments in this active field of research. For instance, the Mechanism and Stereochemistry section delineates both uncatalyzed and transition‐metal‐ and Lewis‐base catalyzed processes. It also nicely outlines the origin of syn‐ and anti‐addition in the context of regio‐, chemo‐, and stereoselective additions, including enantioselective reactions. The Scope and Limitations component is subdivided into geminal and vicinal diboration where the latter is organized by the type of π‐component: alkenes, alkynes, allenes, arynes, dienes, α,β‐unsaturated carbonyls compounds, including a section on aldehydes, ketones, thiocarbonyls, and imines. The Applications to Synthesis provides several examples of the synthesis of natural products and pharmaceutically relevant agents, and the Comparison with Other Methods section provides a comprehensive assessment of other methods commonly deployed to construct these structural motifs. The Tabular Survey incorporates reactions reported up to April 2020. The tables follow the organization of the Scope and Limitations (i.e., geminal and vicinal diboration), where the latter is further subdivided into the type of π‐component framework (alkene, alkyne, allene, etc.) and kind of substitution (internal, terminal) to facilitate the identification of a specific reaction combination. Overall, this is a significant and timely chapter on an important transformation that continues to attract attention.
The third chapter by Donald S. Matteson, Beatrice S. L. Collins, Varinder K. Aggarwal, and Engelbert Ciganek chronicles the Matteson Reaction, which is the nucleophilic displacement of a suitable leaving group from the α‐carbon of an alkylboronic ester via a tetracoordinate boronate anion. The reaction was discovered serendipitously and became more broadly useful when it was demonstrated that the addition of (dichloromethyl)lithium to boronic esters results in an efficient 1,2‐metallate transposition to (α‐chloroalkyl)boronic esters. The chapter delineates the evolution of this reaction into one that provides the ability to generate multiple stereogenic centers with exquisite control, allowing construction of an array of challenging synthetic targets. The Mechanism and Stereochemistry section of this chapter outlines the basis for the spontaneous rearrangement of tetracoordinate boronate anions derived from boronic esters that contain an adjacent leaving group. This section outlines the two main methods that have been employed to generate enantiomerically‐enriched species, namely, a chiral boronate or a chiral carbanion. It also details the impact of matched and mismatched scenarios, the role of Lewis acids, the origin of epimerization and a discussion of other nucleophiles. The Scope and Limitations is also sub‐divided into sections on chiral auxiliary and chiral carbanion approaches, providing the opportunity to compare and contrast the merits of these approaches. Notably, the former component discusses methods for preparing (α‐haloalkyl)boronic esters, different homologation modes, and some limitations. This section is further subdivided into the types of nucleophiles that have been successfully employed (carbon, nitrogen, oxygen, etc.), including some unpublished work from the Matteson laboratory. The chiral carbanion section delineates the work with chiral (α‐chloroalkyl)lithium reagents and chiral α‐lithioalkyl carbamates and esters, which includes a discussion of their limitations. There is also a section on potential new applications and extensions, which may be appealing to some readers. The Applications to Synthesis component is a real tour de force, with examples of natural products and pharmaceuticals that range from insect pheromones to a FLAP enzyme inhibitor. A particular highlight is the ability to asymmetrically C1‐deuterate prochiral glycerol to prepare a chiral variant by adding a deuterium atom. The Comparison with Other Methods section provides an exhaustive account of the preparation methods of substrates and similar products. The Tabular Survey parallels the Scope and Limitations in the context of auxiliary and chiral carbanions, with the former divided into the number of leaving groups and the type of nucleophile. Overall, this chapter provides the reader with a critical overview of this transformation's evolution and recent developments to provide a unique treatise on an important named reaction.
I would be remiss if I did not acknowledge the entire Organic Reactions Editorial Board for their collective efforts in steering this volume through the editorial process's various stages. I would like to thank Scott E. Denmark (Chapter 1) and Dennis G. Hall (Chapter 2), who were the Responsible Editors for the first two chapters. I was responsible for marshaling Chapter 3 through the later phases of development after Jeffrey S. Johnson's early involvement. I am also deeply indebted to Dr. Danielle Soenen for her heroic efforts as the Editorial Coordinator; her knowledge of Organic Reactions is critical to maintaining consistency in the series. Dr. Dena Lindsay (Secretary to the Editorial Board) is thanked for coordinating the authors', editors', and publishers' contributions. In addition, the Organic Reactions enterprise could not maintain the quality of production without the efforts of Dr. Steven Weinreb (Executive Editor), Dr. Engelbert Ciganek (Editorial Advisor), Dr. Landy Blasdel (Processing Editor), and Dr. Debra Dolliver (Processing Editor). I would also like to acknowledge Dr. Barry R. Snider (Secretary) for keeping everyone on task and Dr. Jeffery Press (Treasurer) for making sure that we are fiscally solvent!
I am also indebted to past and present members of the Board of Editors and Board of Directors for ensuring the enduring quality of Organic Reactions. The unique format of the chapters, in conjunction with the collated tables of examples, make this series of reviews both unique and exceptionally valuable to the practicing synthetic organic chemist.
P. Andrew Evans
Kingston
Ontario, Canada
Heinz W. Gschwend
April 12, 1936 – June 16, 2019
Heinz Gschwend was a superb synthetic chemist and an extraordinary drug hunter by applying rationale, skills and experience paired with instinct and pragmatism. Despite his capabilities, he remained humble, used an inclusive style as leader, and was a great coach and mentor to many who were lucky to cross his path.
He was born in the Bernese Oberland, Switzerland, in the town of Brienz. He valued and bonded to this spectacular part of the Swiss Alps his whole life and kept connections with family and friends throughout his life. Heinz studied chemistry at the Federal Institute of Technology in Zürich (ETH) and joined the group of Albert Eschenmoser for his PhD thesis, for which ETH awarded him the coveted Silver Medal for excellence. During this time and the following postdoctoral stay at Harvard University in the group of R. B. Woodward, he instrumentally contributed to the total synthesis of vitamin B12, by many considered to be the Mount Everest of total synthesis at that time.
He remained on the East Coast of the United States together with his wife Katharina Gschwend‐Steen and joined Ciba Pharmaceutical in Summit NJ, in 1967, where he refined his medicinal chemistry and drug discovery skills, taking positions with increasing amount of responsibilities, finally heading drug discovery at the site. It was during this time that Heinz could realize the dream of every medicinal chemist to be instrumentally involved in the discovery of novel drug molecules that will become successful therapeutics. These efforts resulted in the marketed drugs Benazepril, an ACE‐inhibitor to lower blood pressure, and Letrozole, an aromatase inhibitor to treat hormone‐responsive breast cancer.
In 1989, he moved to Basel, Switzerland, to head the Central Research Laboratories and take responsibility for the two subsidiaries in Takarazuka, Japan, and Macclesfield, UK. These institutes ran traditionally a highly diverse research portfolio, including polymer chemistry, agrochemicals, dyes, drug discovery, synthetic methodologies and material science. Heinz was tasked to reorganize this fragmented portfolio. With his leadership, the focus was reoriented to three major topics with pharmaceutical applications in mind: material sciences, carbohydrates and nucleic acids. The way he approached this difficult task was unique during these times: rather than relying on external consultants or his own opinion, he chose an inclusive approach and encouraged scientists internally to provide input and proposals, which formed the basis for the new scientific focus. The antisense oligonucleotide projects, in collaboration with ISIS Pharmaceuticals (now Ionis) and internal biology, resulted in the identification of novel chemical matter that is still used now and reflects a benchmark in the field of modified oligonucleotides.
Heinz moved back to the US and joined Arris Pharmaceuticals, an emerging Bay Area biotech company to take on multiple senior roles, including the role as Executive Vice President of Research and Preclinical Development. In 1998, he became an independent consultant and besides advising many biotech companies with his synthetic and drug discovery experience, he supported multiple Venture firms with his knowledge.
While Heinz was highly successful in drug discovery, he never lost his passion for synthetic chemistry. Over decades, he built and assembled a collection of useful and important reactions. Whenever synthetic problems were up for discussion, he would often remember the specifics for a key transformation and be able to pull it out from his formidable stack of index cards. He was the senior author of the very important Organic Reactions chapter on Heteroatom‐Facilitated Lithiations (Gschwend, H, W.; Rodriguez, H. R. Org. React. 1979, 24, 1). With close to a thousand citations, it is one of the most cited chapters in this series. This eventually led to his appointment to the Editorial Board of Organic Reactions from 1982 to 1989, a role he took very seriously and was greatly proud of. He also served as Chairman of the Gordon Research Conference on Heterocyclic Chemistry in 1988. Heinz was a humble giant in the world of chemistry.
In retirement, Heinz enjoyed the simple pleasures of tending to his fruit trees, chopping wood, playing tennis, hiking along the Sonoma Coast and enjoying the local wineries. He was a devoted father, grandfather and attentive family man. Musical aptitude was apparent for many generations in Heinz's family and he expertly played classical pieces on the piano right up to the time of his passing.
Heinz passed away on June 16, 2019 with his wife, Cynthia, at his side. He is survived by his brother Martin Gschwend, Switzerland, his wife, Cynthia Healy of Santa Rosa, California, sons Dominik of Rockledge, Florida, Daniel of Windham, New Hampshire, Gregory of New York, N.Y., Connery of Georgetown, Washington D.C. and three grandchildren, Kyle, Kaelin and Andrew.
Heinz Moser
Novartis
Hans J. Reich
May 6, 1943 – May 1, 2020
Hans J. Reich was born in Danzig, Germany, and emigrated to Canada in 1950. After earning a B.Sc. at the University of Alberta in 1964, he entered graduate school at UCLA. He received a Ph.D. with D. J. Cram in 1968. Reich met his future wife, Ieva, while they were both graduate students at UCLA. Reich spent two years doing postdoctoral work supported by a Canadian National Research Council Postdoctoral Fellowship, the first at Cal Tech with J. D. Roberts, and the second at Harvard with R. B. Woodward. In 1970, Reich joined the faculty at the University of Wisconsin at Madison. He was promoted to Associate Professor in 1976 and to full Professor in 1979. From 1975 to 1979 he held a Sloan Fellowship. Professor Reich has held visiting Professorships at the University of Marburg in Germany, the Louis Pasteur University in Strasbourg, France, and the University of Alicante, Spain.
In the Chemistry Department, Reich was Chair of the Organic Division from 1991 to 1999 and Associate Chair of the Department from 1999 to 2005. His contributions to the Department and the UW‐Madison campus more broadly were recognized by the Helfaer Professorship in Chemistry, the Professor James W. Taylor Excellence in Teaching Award (1994) and the University of Wisconsin Mid‐Career Award (1995).
Reich's scholarly achievements were recognized by the Arfvedson‐Schlenck Prize (Lithium Award) sponsored by the German Chemical Society (2007) and the James Flack Norris Award in Physical Organic Chemistry sponsored by the American Chemical Society (2012).
In his 43 years as a faculty member Reich served as research supervisor for 39 Ph.D. students, 18 M.S. students and 59 undergraduate researchers. He published more than 150 papers in refereed journals, 9 review articles and a computer program. His most cited paper, on the selenoxide elimination, received over 900 citations up to the time of his death.
During his time at Wisconsin Reich taught a number of courses, both at the undergraduate level, where he initiated and regularly taught Chemistry 547, Advanced Organic Chemistry, and at the graduate level, where he taught Chemistry 605, Structure Determination Using Spectroscopic Methods (mainly NMR) annually from 1981 until after his retirement. This course was legendary among many generations of Wisconsin graduate students. Reich reached over 1000 chemists through an ACS continuing education short course, Frontiers of Organic Chemistry, from 1982 to 2007.
His research program was supported continuously by the National Science Foundation from 1972 to 2010, and sporadically by the National Institutes of Health (National Institute for Arthritis, Digestive Diseases and Kidneys, National Institute for Environmental Health Sciences), by grants from private funds and industrial sources. The program explored the synthetic and mechanistic aspects of organoselenium, organosilicon, and organolithium compounds. His efforts included smaller forays into organotellurium, organotin, organoantimony, organosulfur and organoiodine compounds.
Reich's work in organoselenium chemistry was aimed at developing methods for performing previously difficult or impossible chemical transformations of organic molecules using the special properties of this element. One of the methods developed (the selenoxide elimination to form α,β‐unsaturated carbonyl compounds and other alkenes) has become a standard procedure adopted by chemists throughout the world; this chemistry is covered in many undergraduate textbooks. His work with selenium compounds also contributed to understanding the chemical aspects of the role this essential trace element plays in metabolism.
Work in the synthetic area was always supported and enhanced by clarifiying mechanistic studies, especially when an unexpected chemical event jeopardized the synthetic utility of the reactions being developed. When he became seriously interested in organolithium chemistry in the mid 1980's his work took a decidedly stronger mechanistic organometallic turn. This experimentation, which made heavy use of NMR spectroscopic investigations, contributed substantially to our understanding of the chemical behavior of these widely used, highly reactive and structurally complicated reagents. He firmly established the presence of multiple aggregation states and identified changes in structure and reactivity that occurred under different conditions. His students developed a Rapid‐Inject NMR apparatus capable of operation down to –140 °C, and the group used this device to perform the first accurate measurements of the reactivity of specific oligomers, such as the dimer and tetramer of n‐butyllithium, the monomer, dimer and tetramer of several enolates, and of oligomers of aryllithium reagents.
Reich had an extraordinary commitment to the assembly of data that would be broadly useful to organic chemists, and to making this information available to other scholars and students. The Division of Organic Chemistry of the American Chemical Society recently launched an Organic Chemistry Data website (https://organicchemistrydata.org/) that is largely based on resources that Reich developed over many years. He also served for many years on the Board of Editors for Organic Reactions.
Reich had an unusual and appealing personality. He was deeply insightful, and he was direct in his communications. As one colleague observed, he could explain to you why your favorite hypothesis could not possibly be correct in a way that did not leave you feeling bad. For this reason, he was widely sought among colleagues and students for advice and guidance. Hans Reich is deeply missed by his wife, fellow chemist Dr. Ieva Reich, his former students, his colleagues at UW‐Madison and by friends and fellow scholars around the world.
Samuel H. Gellman,
University of Wisconsin–Madison
CHAPTER 1ENANTIOSELECTIVE HALOFUNCTIONALIZATION OF ALKENES
KUMAR D. ASHTEKAR
Yale School of Medicine, Pharmacology Department, Cancer Biology Institute, Yale West Campus, West Haven, CT, 06516, USA
ARVIND JAGANATHAN
Corteva Agriscience, Indianapolis, IN, 46268, USA
BABAK BORHAN
Department of Chemistry, Michigan State University, East Lansing, MI, 49924, USA
DANIEL C. WHITEHEAD
Department of Chemistry, Clemson University, Clemson, SC, 29634, USA
Edited by SCOTT E. DENMARK
CONTENTS
ACKNOWLEDGMENTS
INTRODUCTION
Evolution of Enantioselective Alkene Halofunctionalization
Chapter Organization
MECHANISM AND STEREOCHEMISTRY
SCOPE AND LIMITATIONS
Enantioselective Chlorofunctionalization of Alkenes
Carboxylic Acid Nucleophiles: Enantioselective Chlorolactonization
Carboxylic Acid Nucleophiles: Enantioselective Chloroesterification
Alcohol Nucleophiles: Enantioselective Intramolecular Chloroetherification
Alcohol Nucleophiles: Enantioselective Intermolecular Chloroetherification
Amide Nucleophiles: Enantioselective Chlorocyclization of Amides
Carbamate Nucleophiles: Enantioselective
O
‐Nucleophile Carbamate Chlorocyclization
Carbamate Nucleophiles: Enantioselective
N
‐Nucleophile Carbamate Chlorocyclization
Thioimidate Nucleophiles: Enantioselective Chlorocyclization of Thioimidates
Amine Nucleophiles: Enantioselective Intramolecular Chloroaminocyclization
Amine Nucleophiles: Enantioselective Intermolecular Chloroamination
Halogen Nucleophiles: Enantioselective Vicinal Dichlorination
Water as a Nucleophile: Enantioselective Chlorohydrin Formation
Carbon Nucleophiles: Enantioselective Chlorenium‐Ion‐Induced Rearrangements
Enantioselective Bromofunctionalization of Alkenes
Carboxylic Acid Nucleophiles: Enantioselective Bromolactonization
Monosubstituted Alkenes: γ‐Bromolactones
1,1‐Disubstituted Alkenes: γ‐Bromolactones
1,1‐Disubstituted Alkenes: δ‐Bromolactones
1,2‐Disubstituted Alkenes: γ‐ and δ‐Bromolactones
1,1,2‐Trisubstituted Alkenes: γ‐ and δ‐Bromolactones
1,1,2,2‐Tetrasubstituted Alkenes: γ‐ and δ‐Bromolactones
Benzoic Acid Nucleophiles: Preparation of Benzolactones by Bromocyclization
Enantioselective Bromolactonization of Enyne Substrates
Enantioselective Bromolactonization of Allenic Substrates
Carboxylic Acid Nucleophiles: Enantioselective Bromoesterification
Alcohol Nucleophiles: Enantioselective Intramolecular Bromoetherification
Alcohol Nucleophiles: Enantioselective Intermolecular Bromoetherification
Amide Nucleophiles: Enantioselective Bromocyclization of Amides
O
‐
Cyclization
N
‐
Cyclization
Carbamate Nucleophiles: Enantioselective
N
‐Nucleophile Carbamate Bromocyclization
Amine Nucleophiles: Enantioselective Intramolecular Bromoaminocyclization
Amine Nucleophiles: Enantioselective Intermolecular Bromoamination
Halogen Nucleophiles: Enantioselective Vicinal Dibromination/Bromochlorination
Water as a Nucleophile: Enantioselective Bromohydrin Formation
Carbon Nucleophiles: Enantioselective Bromenium‐Ion‐Induced Cyclization/ Rearrangement
Bromenium‐Ion‐Induced Cyclization
Bromenium‐Ion‐Induced Enantioselective Rearrangement
Addition of
CX
4
Reagents: Enantioselective Kharasch Reaction
Miscellaneous Bromenium‐Ion‐Promoted Reactions
Miscellaneous Enantioselective Bromocyclizations
An Enantioselective Hydrobromination
Enantioselective Iodofunctionalization of Alkenes
Carboxylic Acid Nucleophiles: Enantioselective Iodolactonization
Alcohol Nucleophiles: Enantioselective Intramolecular Iodoetherification
Amide Nucleophiles: Enantioselective Iodocyclization of Amides
Amine Nucleophiles: Enantioselective Iodoaminocyclization
Amine Nucleophiles: Enantioselective Intermolecular Iodoamination
Carbon Nucleophiles: Enantioselective Iodocyclization and Rearrangement
Miscellaneous Nucleophiles: Miscellaneous Enantioselective Iodocyclizations
Enantioselective Iodocyclization of Oximes and Hydrazones
Enantioselective Iodocyclization of Acetimidates
Enantioselective Iodocyclization of Phosphoramidates
Enantioselective Iodocyclization of Carbonates
Desymmetrization and Kinetic Resolution via Alkene Halofunctionalization
Bromenium‐Ion‐Induced Desymmetrization
Desymmetrization by Enantioselective Bromolactonization
Desymmetrization by Enantioselective Cycloetherification
Desymmetrization by Enantioselective Amide Cyclization
Iodenium‐Ion‐Induced Desymmetrization
Chlorenium‐Ion‐Induced Kinetic Resolution
Bromenium‐Ion‐Induced Kinetic Resolution
Iodenium‐Ion‐Induced Kinetic Resolution
APPLICATIONS TO SYNTHESIS
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
(
R
)‐5‐(Chloromethyl)‐5‐(4‐fluorophenyl)dihydrofuran‐2(3
H
)‐one [Enantioselective Chlorolactonization].
(
R
)‐2‐Chloro‐1‐(2‐methoxyphenyl)‐2‐[(
R
)‐tetrahydro‐2
H
‐pyran‐2‐yl]ethan‐1‐one [Enantioselective Chloroetherification].
(2
R
,3
R
)‐2,3‐Dichloroundecan‐1‐ol [Enantioselective Vicinal Dichlorination].
(
S
)‐5‐[(
S
)‐1‐Bromo‐2‐methylpropyl]dihydrofuran‐2(
3
H
)‐one [Enantioselective Bromolactonization].
(
R
)‐5‐(Bromomethyl)‐2,5‐diphenyl‐4,5‐dihydrooxazole [Enantioselective Bromocyclization of an Allylic Amide].
(2
R
,4a
R
,10a
S
)‐2‐Bromo‐1,1,4a‐trimethyl‐1,2,3,4,4a,9,10,10a‐octahydrophenanthrene [Enantioselective Bromocyclization of Homogeranylbenzene].
(1
S
,2
R
)‐2‐Bromo‐1‐phenylcyclohexyl(phenyl)methanone [ Enantioselective Bromination/Semi‐Pinacol Rearrangement].
(
R
)‐6‐Iodomethyl‐6‐(3‐tolyl)tetrahydro‐2
H
‐pyran‐2‐one [ Enantioselective Iodolactonization].
tert
‐Butyl (3a
R
,7
S
,7a
S
)‐7‐Bromo‐2‐oxo‐2,3,7,7a‐tetrahydrobenzofuran‐3a(
6
H
)‐carboxylate [Desymmetrization by Enantioselective Bromolactonization].
(4
R
,6
R
)‐6‐Bromomethyl‐4,6‐diphenyltetrahydro‐
2
H
‐pyran‐2‐one and (
S
)‐3,5‐Diphenylhex‐5‐enoic Acid [Kinetic Resolution by Enantioselective Bromolactonization].
Tabular Survey
Chart A. 1,2-Diamine-Based Catalysts Used in the Tables
Chart B. 1,1'-Binaphthyl-Based Catalysts Used in the Tables
Chart C. Cinchona-Alkaloid-Based Catalysts Used in the Tables
Chart D. 1,3-Dioxolane-Based Catalysts Used in the Tables
Chart E. C3-Symmetric Catalysts Used in the Tables
Chart F. Miscellaneous Catalysts Used in the Tables
Chart H. Substituted 1,4-Diazabicyclo[2.2.2]octane-Based Halenium Sources Used in the Tables
Chart L. Chiral Ligands for Organometallic Catalysts Used in the Tables.
Chart O. Organometallic Complexes as Catalysts Used in the Tables.
Table 1. Catalytic Enantioselective Chlorocyclization of Alkenes
A. Carboxylic Acid Nucleophiles (Chlorolactonization)
B. Alcohol Nucleophiles (Chloroetherification)
C. Amide O-Nucleophiles
D. Amide O-Nucleophiles. Kinetic Resolution
E. Carbon Nucleophiles .
F. Other Nucleophiles .
Table 2. Catalytic Enantioselective Intermolecular Chlorofunctionalization of Alkenes
A. Carboxylic Acid Nucleophiles (Chloroesterification)
B. Water Nucleophile (Chlorohydrin Synthesis)
C. Alcohol Nucleophiles (Chloroetherification)
D. Amide and Imide N-Nucleophiles
E. Halogen Nucleophiles. Vicinal Dichlorination
Table 3. Catalytic Enantioselective Bromocyclization of Alkenes
A. Carboxylic Acid Nucleophiles (Bromolactonization)
B. Alcohol Nucleophiles (Bromoetherification)
C. Amide O-Nucleophiles
D. Other Oxygen Nucleophiles
E. Sulfonamide N-Nucleophiles
F. Carbamate N-Nucleophiles
G. Other Nitrogen Nucleophiles
H. Carbon Nucleophiles .
Table 4. Catalytic Enantioselective Intermolecular Bromofunctionalization of Alkenes
A. Carboxylic Acid Nucleophiles (Bromoesterification)
B. Water or Hydrogen Peroxide Nucleophile (Bromohydrin Synthesis).
C. Alcohol Nucleophiles (Bromoether Synthesis)
D. Hydrobromination
E. Vicinal Dihalogenation
F. Amide and Imide N-Nucleophiles
G. Carbon Nucleophiles
Table 5. Catalytic Enantioselective Iodocyclization of Alkenes
A. Carboxylic Acid Nucleophiles (Iodolactonization)
B. Alcohol Nucleophiles (Iodoetherification).
C. Amide O-Nucleophiles
D. Oxime O-Nucleophiles (Dihydrooxazole and Dihydrooxazine Formation)
E. Sulfonamide N-Nucleophiles
F. Hydrazone N-Nucleophiles (Dihydropyrazole Formation)
G. Carbon Nucleophiles
H. Other Nucleophiles
Table 6. Enantioselective Intermolecular Iodofunctionalization of Alkenes
REFERENCES
SUPPLEMENTAL REFERENCES
ACKNOWLEDGMENTS
The authors are deeply indebted to Professor Scott Denmark and Dr. Engelbert Ciganek for their thorough review and helpful suggestions during the preparation of this chapter and Dr. Danielle Soenen for administrative help. The authors thank Dr. Saeedeh Torabi Kohlbouni for organizing the review of the tables in the chapter. We gratefully acknowledge the NIH (GM110525) and the NSF (CHE‐1362812) for funding. K. D. A. is grateful for the support by the Arnold and Mabel Beckman Foundation.
INTRODUCTION
Electrophilic additions to alkenes provide a robust method for early‐ and late‐stage synthetic modifications, expediting access to a wide range of intermediates. Stereoselective transformations, such as epoxidations, hydroxylations, hydroaminations, selenations, sulfenylations, oxymercurations, and hydrometalations, form a fundamental class of reactions that serve as essential tools in organic synthesis. The development and scope of one such transformation—enantioselective halofunctionalization of alkenes—is the focus of this chapter.
Evolution of Enantioselective Alkene Halofunctionalization
The first reports by Bartlett and Tarbell1,2 in 1936 and 1937 and the intriguing interpretation by Kimball3 of the intrinsic anti stereoselectivity in the halogenation of alkenes lay the foundation for the exploration of the scope and mechanism of halofunctionalizations (Scheme 1a). Nevertheless, it was not until forty years later that the early reports by Bartlett,19,20 Fuji,21 Taguchi,22 and others paved the way for substrate‐controlled, diastereo‐ and enantioselective, intramolecular halocyclizations, specifically iodocyclizations (Schemes 1b and 1c). The stereoselectivity is controlled by taking advantage of the biased electronic properties of the alkene and the cyclization. Although immensely beneficial, these substrate‐controlled, diastereoselective reactions avoid a challenging aspect of halofunctionalization of alkenes: the need for controlling the absolute facial selectivity of the alkene for the approaching electrophilic halenium atom.
Building upon the early work by Rousseau,27 Taguchi,28 Sudalai,29 and others, Ishihara reported a landmark study on reagent‐controlled, enantioselective halofunctionalization. By using the BINOL‐derived phosphorimidate 1 in stoichiometric quantities, a highly stereoselective iodo‐polyene cyclization is achieved (Scheme 2).33 Notably, this seminal contribution prompted the development of a flurry of related protocols for the catalytic enantioselective halofunctionalization of alkenes. Consequently, a number of excellent reviews on the state‐of‐the‐art are now available.34–43
Chapter Organization
This chapter provides a detailed catalog of the impressive breadth of transformations that are now available to the synthetic chemist to facilitate the enantioselective halofunctionalization of alkenes. The chapter is organized by halogen type and further subdivided by nucleophile class, with a particular focus on catalytic, enantioselective processes. In some cases, specific protocols are summarized in general, whereas specific illustrative examples are depicted for others. Catalytic, enantioselective fluorinations of alkenes are not covered, as this topic is addressed in a chapter in a previous volume. Applications of enantioselective halogenations in the context of desymmetrizations, kinetic resolutions, and total synthesis of natural products are also discussed.
Scheme 1
MECHANISM AND STEREOCHEMISTRY
Attaining exquisite stereocontrol in halofunctionalization reactions is exceedingly challenging as several factors contribute to the complexity associated with the specificity and selectivity of these reactions. The ionic addition of dihalogens to unactivated alkenes almost exclusively proceeds by means of an anti addition. Historically, the addition of chlorine and bromine to alkenes is the most commonly studied reaction to probe the origins of stereoselectivity and stereospecificity. In contrast, the conceptually related di‐iodination of alkenes cannot be accomplished as the process is kinetically precluded by steric encumbrance, which favors the prevailing attack of solvent molecules or exogenous or intramolecular nucleophiles to trap the putative iodiranium ion to afford the anti adduct. Another important aspect that contributes to the stereochemical complexity of dihalogenations and related nucleophile‐capture paradigms is the inherent difficulty in controlling the regioselectivity of the nucleophilic attack on the concomitant haliranium ion as discussed later (Scheme 5b).
Scheme 2
Activated alkenes, on the other hand, owing to their biased electronic properties, often afford a mixture of syn and anti adducts wherein the observed product distribution depends on the specific reagents and reaction conditions employed. For instance, Scheme 3 depicts the divergent stereoselectivity resulting from the dichlorination of acenaphthalene under different conditions.44 The dihalogenation of other activated substrates such as stilbene and phenanthrene display similarly divergent reactivities based on the specific reaction conditions. Recently, the catalytic syn‐selective dichlorination of alkenes has been reduced to practice.45 Despite these challenges, a number of landmark studies, outlined briefly below, shed considerable light on the mechanistic drivers governing the formation and stability of the haliranium ion as well as its subsequent reactivity.
Scheme 3
The observation of exclusive anti stereoselectivity in the halogenation of unactivated alkenes led Kimball to first propose the haliranium ion as a putative transient intermediate.3 As with most addition reactions to alkenes, halofunctionalizations are thought to proceed by an electrophilic attack on the alkene functionality at some stage during the reaction. The classical perception invokes a stepwise reaction, beginning with the capture of an electrophile to form a cationic adduct. This adduct is then intercepted by a nucleophile to furnish the addition product. Mechanistic studies demonstrate that the reactivity of alkenes in halofunctionalization reactions actually displays a continuum of possible pathways, ranging from AdE1‐type stepwise additions to an AdE3‐type concerted pathway (Scheme 4).5,6,8,9,12–14,17,46–50 The AdE1‐type mechanism (Scheme 4a) is typically the preferred process for activated alkenes that are capable of forming β‐halo carbenium ions, whereas unactivated alkenes typically require the presence of counterions such as trifluoromethylsulfonate, tetrafluoroborate, or antimony (VI) halides to form a haliranium ion. On the other hand, prototypical halofunctionalization reactions involving unactivated alkenes and common halenium atom donors, such as succinimidate, substituted hydantoins, halides, etc., require the assistance of the incoming nucleophile to sufficiently raise the HOMO of an alkene for favorable reactivity. Specifically, this scenario facilitates an AdE3‐type concerted addition by means of nucleophile‐assisted alkene activation (NAAA) (Scheme 4b).48 Note that the intramolecular transformations depicted in Scheme 4b are formally designated as AdE2 processes since these particular examples bear an intramolecularly appended nucleophile. Nevertheless, it is prudent to conceptualize the molecularity of the transition state of the alkene halofunctionalization as termolecular since the nucleophile, alkene, and halenium ion source must interact simultaneously for a productive reaction, whether or not the halofunctionalization event occurs via an inter‐ or intramolecular process. Thus, where a particular halofunctionalization transformation falls on the reactivity continuum depicted in Scheme 4 depends on three key factors: (1) the nucleophilic strength of the unperturbed alkene, (2) the leaving‐group ability of the counter ion resulting from the reaction of the halenium atom donor and, (3) the strength of the incoming nucleophile which may necessarily be involved in perturbing the HOMO of the alkene to increase the reactivity sufficiently to intercept the halenium ion.48 For a given combination of alkene substrate and the halenium ion source, their relative halenium affinities (HalA values) can be used as a reliable scale to predict the possible intermediates and the overall mechanistic outcome.51
Scheme 4
Noteworthy contributions by Olah,10,11 Brown,15,16 Braddock,52 and Denmark46 have enhanced our understanding of the behavior of haliranium ions. Understanding the configurational stability of the key haliranium intermediate is particularly relevant for potential enantioselective processes. The configurational stability of bromiranium ions generated from enantiopure bromohydrins or β‐bromotosylates has been conclusively demonstrated in the absence of additional alkene (Scheme 5a).52
Scheme 5a
