George S. Zweife Michael He Nantz University of California, Davis @ %$! kg$ gg W. W. FREEMAN AND COMPANY New York The marine alkaloid norzoanthamine, whose energy-minimized structure is depicted on the front cover, exhibits interesting pharmacological properties, particularly as a promising candidate for an antiosteoporotic drug. It was isolated from the genus Zoanthus, commonly known as sea mat anemone. The alkaloid possesses a complex molecular structure; its total synthesis was accom- plished in 41 steps by Miyashita and coworkers (Science 20041, 305, 495), a brilliant intellectual achievement. [Cover image by Michael Nantz and Dean Tantillo] Publisher Senior Acquisitions Editor Marketing Manager Media Editor , Associate Editor Design Manager Cover & Text Designer Senior Project Editor Copy Editor Production Coordinator Composition Printing and Binding Library of Congress Cataloging-in Publication Data Zweifel, George S. Modern organic synthesis: an introductionIGeorge S. Zweifel, Michael H. Nantz. p. cm Includes index. ISBN 0-7 167-7266-3 1. Organic compounds - - Synthesis. I. Nantz, Michael H. 11. Title. QD262.294 2006 547'. 2 - - dc22 EAN: 97807 16772668 O 2007 by George S. Zweifel and Michael H. Nantz. All rights reserved. Printed in the United States of America First Printing W. H. Freeman and Company 4 1 Madison Avenue New York, NY 100 10 Houndmills, Basingstoke RG 21 6XS, England www. whfreeman.com We dedicate this book to our former mentors at Purdue Universily, Professor Herbert C. Brown Professor Phillip 1. Fuchs who have inspired our passion for organic chemistry George S. Zvveifel was born in Switzerland. He received his Dr. Sc. Techn. degree in 1955 from the Swiss Federal Institute of Technology (E.T.H. Zurich, Professor Hans Deuel) working in the area of carbohydrate chemistry. The award of a Swiss-British Exchange Fellowship in 1956 (University of Edinburgh, Scotland, Professor Edmund L. Hirst) and a Research Fellowship in 1957 (University of Birmingham, England, Professor Maurice Stacey) made it possible for him to study conformational problems in the carbohydrate field. In 1958, he became professor Herbert C. Brown's personal research assistant at Purdue University, undertaking research in the new area of hydroboration chemistry. He joined the faculty at the University of California, Davis, in 1963, where his research interest has been the exploration of organometallics as intermediates in organic synthesis, with emphasis on unsaturated organoboron, organoaluminum and organosilicon compounds. Michael PI[. Nantz was born in 1958 in Frankfurt, Germany. In 19'70, he moved with his family to the Appalachian Mountains of Kentucky. He spent his college years in Bowling Green, Kentucky, and earned a Bachelor of Science degree from Western Kentucky University in 198 1. His interest in natural product synthesis led him to work with Professor Philip L. hiuchs at Purdue University, where he received his Ph.D. in 1987. Over the next two years, he explored asymmetric syntheses using boron reagents (Massachusetts Institute of Technology, Professor Satoru Masamune). In 1989, he joined the faculty at the University of California, Davis, and established a research program in organic synthesis with emphasis on the development of gene delivery vectors. His novel DNA transfer agents have been commercialized and have engen- dered a start-up biotechnology company devoted to nonviral gene therapy. In 2006, he joined the Chemistry Department at the University of Louisville as Distinguished University Scholar. Preface SYNTHETIC DESIGN Retrosynthetic Analysis Reversal of- fie Carbonyl Group Polarity (Umpolwg) Steps in Planning a Synthesis Choice of Synthetic Method Domino Reactions Computer-Assisted Retrosynthetic Analysis STEBPEOCHEMBCAL CONSIDERATIONS IN PLANNBNG SYNTHESES Conformational Analysis Evaluation of Nonbonded Interactions Six-Member Heterocyclic Systems Polycyclic Ring Systems Cyclohexyl Systems with sp2-Hybridized Atoms Significant Energy Difference Computer-Assisted Molecular Modeling Reactivity and Product Determination as a Function of Conformation THE CONCEPT OF PROTECTIlNG FUNCUONAL GROUPS Protection of NH Groups Protection of OH Croups of Alcohols Protection of Diols as Acetals Protection of Carbonyl Groups in Aldehydes and Ketones Protection of the Carboxyl Group Protection of Double Bonds Protection of Triple Bonds FUNCTIONAL GROUP TRANSFORMATIONS: OXIDATION AND REDUCTION Oxidation of Alcohols to Aldehydes and Ketones Reagents and Procedures for Alcohol Oxidation Chemoselective Agents for Oxidizing Alcohols Oxidation of Acyloins Oxidation of Tertiary Allylic Alcohols Oxidative Procedures to Carboxylic Acids Allylic Oxidation of Alkenes Terminology for Reduction of Carbonyl Compounds Nucleophilic Reducing Agents Electrophilic Reducing Agents Regio- and Chemoselective Reductions viii CONTENTS 4,1% Diastereoselective Reductions of Cyclic Ketones 4 *. I?. Inversion of Secondary Alcohol Stereochemistry 414 Diastereofacial Selectivity in Acyclic Systems 4 3 5 Enantioselective Reductions CHAPTER 5 FUNCT1IBNAL GROUP TRANSF0RMdaTlg)NS: THE CHEMISTRY OF CARBON-CARBON n-BONDS AND RELATED REACBBOMS 5 1 Reactions of Carbon-Carbon Double Bonds 5-2 Reactions of Carbon-Carbon Triple Bonds FORMATION 011". CARBON-CARBON SINGLE BONDS VIA IENOLATE ANIONS 1,3-Dicarbonyl and Related Compounds Direct Alkylation of Simple Enolates Cyclization Reactions-Baldwin's Rules for Ring Closure Stereochemistry of Cyclic Ketone Alkylation lmine and Hydrazone Anions Enamines The Aldol Reaction Condensation Reactions of Enols and Enolates Robinson Annulation FORMATION OF CARBON-CARBON BONDS VIA ORGANOMETALLIC REAGENTS Organolithium Reagents Organomagnesium Reagents Organotitanium Reagents Organocerium Reagents Organocopper Reagents Organochromium Reagents Organozinc Reagents Organoboron Reagents Organosilicon Reagents Palladium-Catalyzed Coupling Reactions ~&L?@"~ER 8 FORMATION OF CARBON-CARBON n-BONDS 8 Formation of Carbon-Carbon Double Bonds 82 Formation of Carbon-Carbon Triple Bonds CHAPTER 9 SYNTHESES OF CARBOCYCLIC SYS"BERIIS 9-; lntramolecuiar Free Radical Cyclizations 2 Cation-n Cyclizations 925 Pericyclic Reactions 9-4 Ring-Closing Olefin Metathesis (RCM) Fpg"' @ p'" SVa -* i,~Ju t~ ik THE ART OF SVMTHESlS Abbreviations Answers to Select End-of-Chapter Problems Index odern Organic Synthesis: An Introduction is based on the lecture notes of a special topics course in synthesis designed for senior undergraduate and beginning graduate students who are well acquainted with the basic con- cepts of organic chemistry. Although a number of excellent textbooks covering advanced organic synthesis have been published, we saw a need for a book that would bridge the gap between these and the organic chemistry presented at the sophomore level. The goal is to provide the student with the necessary background to begin research in an academic or industrial environment. Our precept in selecting the topics for the book was to present in a concise manner the modern techniques and methods likely to be encountered in a synthetic project. Mechanisms of reactions are discussed only if they might be unfamiliar to the student. To acknowledge the scientists whose research fomed the basis for this book and to provide the student access to the origi- nal work, we have included after each chapter the relevant literature references. The book is organized into the following nine chapters and an epilogue: * Retrosynthetic analysis: strategies for designing a synthetic project, including construction of the carbon skeleton and control of stereochemistry and enantioselectivity Conformational analysis and its effects on reactivity and product formation Problems for dealing with multiple functionality in synthesis, and their solutions Functional group transformations: classical and chemoselective methods for oxidation and reduction of organic substrates, and the availability and utilization of regio-, chemo-, and stereoselective agents for reducing carbonyl compounds Reactions of carbon-carbon n bonds: dissolving metal reductions, conversions to alcohols and enantiomerically pure alcohols, chemo- and enantioselective epoxidations, procedures for cleavage of carbon-carbon double bonds, and reactions of carbon-carbon triple bonds Formation of carbon-carbon single bonds via enolate anions: improvements in classical methods and modern approaches to stereoselective aldol reactions * Methods for the construction of complex carbon-carbon frameworks via organometallics: procedures involving main group organometallics, and palladium-catalyzed coupling reactions for the synthesis of stereodefined alkenes and enynes Formation of carbon-carbon n-bonds: elaboration of alkynes to stereodefined alkenes via reduction, current olefination reactions, and transposition of double bonds Synthesis of carbocyclic systems: intramolecular free-radical cyclization, the Diels-Alder reaction, and ring-closing metathesis An epilogue featuring selected natural product targets for synthesis We wish to express our gratitude to the present and former Chemistry 131 stu- dents at the University of California at Davis and to the teaching assistants of the course, especially Hasan Palandoken, for their suggestions and contributions to the development of the lecture notes. We would also like to thank our colleague Professor Dean Tantillo for his helpful advice. Professors Edwin C. Friedrich (University of California at Davis) and Craig A. Merlic (University of California at Los Angeles) read the entire manuscript; their pertinent comments and constructive critiques great- ly improved the quality of the book. We also are indebted to the following reviewers of the manuscript: Amit Basu, Brown University Stephen Bergmeier, Ohio University Michael Bucholtz, Gannon University Arthur Cammers, University of Kentucky Paul Carlier, Virginia Polytechnic Institute and State University Robert Coleman, Ohio State University Shawn Hitchcock, Illinois State University James Howell, Brooklyn College John Huffman, Clemson University Dell Jensen, Jr., Augustana College Eric Kantorowski, California Polytechnic State University Mohammad Karim, Tennessee State University Andrew Lowe, University of Southern Mississippi Philip Lukeman, New York University Robert Maleczka, Jr., Michigan State University Helena Malinakova, University of Kansas Layne Morsch, DePaul University Nasri Nesnas, Florida Institute of Technology Peter Norris, Youngstown State University Cyril Pirkinyi, Florida Atlantic University Robin Polt, University of Arizona Jon Rainier, University of Utah 0. LeRoy Salerni, Butler University Kenneth Savin, Butler University Grigoriy Sereda, University of South Dakota Suzanne Shuker, Georgia Institute of Technology L. Strekowski, Georgia State University Kenneth Williams, Francis Marion University Bruce Young, Indiana-Purdue University at Indianopolis We wish to thank Jessica Fiorillo, Georgia Lee Hadler, and Karen Taschek for their professional guidance during the final stages of writing the book. Finally, without the support and encouragement of our wives, Hanni and Jody, Modern Organic Synthesis: An Introduction would not have been written. Print Supplement Modern Organic Synthesis: Problems nnd Solutions, 0-7 1 67-7494- 1 This manual contains all problems from the text, along with complete solutions. Pumiliotoxin C, a cis-decahydroquinoline from poison-dart frogs, Dendrobates pumilio. In character, in manners, in style; in all things, the supreme excellence is simplicity Henry Wadsworth Longfellow hemistry touches everyone's daily life, whether as a source of important drugs, polymers, detergents, or insecticides. Since the field of organic chem- istry is intimately involved with the synthesis of these compounds, there is a strong incentive to invest large resources in synthesis. Our ability to predict the use- fulness of new organic compounds before they are prepared is still rudimentary. Hence, both in academia and at many chemical companies, research directed toward the discovery of new types of organic compounds continues at an unabated pace. Also, natural products, with their enormous diversity in molecular structure and their possi- ble medicinal use, have been and still are the object of intensive investigations by syn- thetic organic chemists. Faced with the challenge to synthesize a new compound, how does the chemist approach the problem? Obviously, one has to know the tools of the trade: their poten- tial and limitations. A synthetic project of any magnitude requires not only a thorough knowledge of available synthetic methods, but also of reaction mechanisms, commer- cial starting materials, analytical tools (IR, UV, NMR, MS), and isolation techniques. The ever-changing development of new tools and refinement of old ones makes it important to keep abreast of the current chemical literature. What is an ideal or viable synthesis, and how does one approach a synthetic proj- ect? The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps) and selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). Furthermore, the experimental ease of the transformations and whether they are environmentally acceptable must be considered. Synthesis of a molecule such as pumiliotoxin C involves careful planning and strategy. How would a chemist approach the synthesis of pumiliotoxin C?' This chap- ter outlines strategies for the synthesis of such target molecules based on retrosyn- thetic analysis. E. J. Corey, who won the Nobel Prize in Chemistry in 1990, introduced and pro- moted the concept of retrosynthetic analysis, whereby a molecule is disconnected, leading to logical precursor^.^ Today, retrosynthetic analysis plays an integral and indispensable role in research. The following discussion on retrosynthetic analysis covers topics similar to those in Warren's Organic Synthesis: The Disconnection roach^' and Willis and Will's Organic Synthe~is.~g For an advanced treatment of the subject matter, see Corey and Cheng's The Logic of Chemical Basic Concepts The construction of a synthetic tree by working backward from the target molecule (TM) is called retrosynthetic analysis or antithesis. The symbol + signifies a reverse synthetic step and is called a transform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI). Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions. Structural changes in the retrosynthetic direction should lead to substrates that are more readily available than the TM. Syntlzons are fragments resulting from discon- nection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Also, reagents derived from inverting the polarity (IP) of synthons may serve as SEs. transform synthetic 1 > equivalents - u I or reagents I Synthetic design involves two distinct steps3": (1) retrosynthetic analysis and (2) subsequent translation of the analysis into a "forward direction" synthesis. In the analysis, the chemist recognizes the functional groups in a molecule and disconnects them proximally by methods corresponding to known and reliable reconnection reac- tions. Chemical bonds can be cleaved heterolytically, lzomolytically, or through con- certed transform (into two neutral, closed-shell fragments). The following discussion will focus on heterolytic and cyclic disconnections. heterolytic I I I 1- -1 +I cleavage C-C- j -c+ :c- or -c: C- I I I I I1 Donor md Acceptor Heterolytic retrosynthe Synthons3">g breaks the TM into an acceptor synthon, a carbocation, and a donor synthon, a carbanion. In a fomal sense, the reverse reaction - the formation of a C-C bond - then involves the union of an electrophilic acceptor synthon and a nucleophilic donor syn- thon. Tables 1.1 and 1.2 show some important acceptor and donor synthons and their synthetic eq~ivalents.~" [...]... that a-halo ketones also may serve as synthetic equivalents of enolate ions (e.g., the Reformatsky reaction, Section 7.7) Synthon Derived reagent Synthetic equivalent R- (alkyl, aryl anion) RMgX, RLi, R2CuLi R-X -CN (cyanide) NaCEN HCN RC-C- RC=CMgX, RC=CLi RC-CH (acetylide) A+ -/ P h3P-C R& \ 0xenolate) (ylide) ~0~(a-nitro anion) A O-M (M = Li, BR2) [P~. ~-( -HI x- / H-c-x \ R - No2 - - - - 4 - C!-iAPTER... RCH2CH 2- Br ~ - ~ - ~ ~ ~ ~ ~ - - - 4 - 4 ~ ~ z & - - - ~ ~ - ~ - 7 6 ~ ~ ~ ~ J Org Chem 1961, 26, 280; see also Hunsdiecker reaction, Org React 1957, 9, 332 c Allylic and Propargylic Bromides Allylic bromination ) alkene - NBS + free-radical initiator RCH=CHCH2Br ) i RCECCH2Br -> RCH=CHCH20H - NaBr, BF,*OE~,~ RCH=CHCH20H - NBS, IMe2sd RC?CCH20H - CBr4, Ph3P W - ~ W ~ ~ ~ W W P ~ ~ & A ~ ~ -. .. convergent synthesis is the product of yields of the longest linear sequence For the synthesis of the above TM, only three stages are involved in the convergent strategy shown below, with an overall yield of 51% (0.83 x 100) - stage 1 A+ B C+ D C-D A-B E+F G+H ' -r G-H E-F stage 2 I I stage 3 A-B-C-D E-F-G-H 1 J A-B-C-D-E-F-G-H It should be noted, however, that the simple overall yield calculation is somewhat... and Michael acceptors "" - "" t-* [ * J \- i : -2 $ - Synthetic Design OH H? - I + R'-CHO R-CI y- * R-C-C-R' I CN I CN H cy yH R-C-C-R' 4~ H I 0 OH -& - II I + R-C-C-R' I H CN(catalyst) phaPh cat NaCN mCHo 0 + 14 1,4-addition Acyl Anions Derived from Enol Ethers The a-hydrogens of en01 ethers may be deprotonated with tert-BUL~.'~ Alkylation of the resultant vinyl anions followed by acidic hydrolysis... or ~ ~ O L~AIH(O~-BU)~' RCH2COOH - thexylchloroborane RCH2COOR' - a i-Bu2AIH ,-7 8 "C; b H30+ RCH2CN - a CBu2AIH, -7 8 " C ; b H30+ 3 RCOC~ - a (CH3),CuLi, -7 8 "C; b H30+ a MeLi (2 eq); b H30+ c-3 11 RCECH R' - HgS04, H30+ FH-OH - Jones, Swern, or NaOCI, HOAc oxidation organometallic reagentsq R' - a R'Li or R'MgX; b H ~ O '' \ P' h C=O 3 benzene - RC0Cl-t AICI3 ' "Synthesis 1981,165;Org... encountered in organic synthesis are shown in Table 1.4a-k 1.3 Steps in Planning a Synthesis 19 Functional Group lnterconversions Wm-V%WZZSm PJ-/d-WA%W&W-#flSH& W& %-~ %W%,V~?"W.%WL~-XX -W~X~W~-WYA*? *&waE& a Alkyl Chlorides NO HCI is formed; high yields of 1" and 2" alkyl chlorides; Angew Chem., Int Ed, 1975, 14, 801 %.Alkyl Bromides W ~ ~ ~ ~ ~ 9 ~ RCH=CH2 - HBr + free-radical initiator RCH=CH~ - a BH3eTHF;... *qwa~"+%*?ar*5 . R2CuLi R-X -CN (cyanide) NaCEN HCN RC-C- (acetylide) RC=CMgX, RC=CLi RC-CH 0- O-M A- xenolate) A (M = Li, BR2) + -/ P h3P-C (ylide) / [P~. ~-( -HI x- H-c-x R& ~0~ (a-nitro. Cataloging-in Publication Data Zweifel, George S. Modern organic synthesis: an introductionIGeorge S. Zweifel, Michael H. Nantz. p. cm Includes index. ISBN 0-7 16 7-7 26 6-3 1. Organic compounds -. Hanni and Jody, Modern Organic Synthesis: An Introduction would not have been written. Print Supplement Modern Organic Synthesis: Problems nnd Solutions, 0-7 1 6 7-7 49 4- 1 This manual