Tài liệu Modern Organic Synthesis (Solutions Manual) - George Zweifel, Michael Nantz

@ George S.Zweife Michael He Nantz University of California, Davis W. W. FREEMANAND %$! kg$gg 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 accomplished 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 10010 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 1981. 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 engendered 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-HybridizedAtoms 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% 4*. I?. 414 4 35 CHAPTER 5 51 5-2 Diastereoselective Reductions of Cyclic Ketones Inversion of Secondary Alcohol Stereochemistry Diastereofacial Selectivity in Acyclic Systems Enantioselective Reductions FUNCT1IBNAL GROUP TRANSF0RMdaTlg)NS: THE CHEMISTRY OF CARBON-CARBON n-BONDS AND RELATED REACBBOMS Reactions of Carbon-Carbon Double Bonds 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 ? @ " ~ E8R 8 82 CHAPTER 9 9-; 2 925 9-4 Fpg"' p'" -* i,~Ju t~ik @ SVa FORMATION OF CARBON-CARBON n-BONDS Formation of Carbon-Carbon Double Bonds Formation of Carbon-Carbon Triple Bonds SYNTHESES OF CARBOCYCLIC SYS"BERIIS lntramolecuiar Free Radical Cyclizations Cation-n Cyclizations Pericyclic Reactions Ring-Closing Olefin Metathesis (RCM) 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 concepts 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 original 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 students 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 greatly 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. In character, in manners, in style; in all things, the supreme excellence is simplicity Henry Wadsworth Longfellow Pumiliotoxin C, a cis-decahydroquinoline from poison-dart frogs, Dendrobates pumilio. hemistry touches everyone's daily life, whether as a source of important drugs, polymers, detergents, or insecticides. Since the field of organic chemistry 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 usefulness 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 possible medicinal use, have been and still are the object of intensive investigations by synthetic 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 potential and limitations. A synthetic project of any magnitude requires not only a thorough knowledge of available synthetic methods, but also of reaction mechanisms, commercial 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 project? 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 chapter outlines strategies for the synthesis of such target molecules based on retrosynthetic analysis. E. J . Corey, who won the Nobel Prize in Chemistry in 1990, introduced and promoted 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 disconnection 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. + 1- transform ---------> u I synthetic equivalents 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 reactions. Chemical bonds can be cleaved heterolytically, lzomolytically, or through concerted transform (into two neutral, closed-shell fragments). The following discussion will focus on heterolytic and cyclic disconnections. heterolytic cleavage Donor md Acceptor Synthons3">g I C-C- I I I j-c+I :c-1 - I I or -1 -c: I + CI 1 Heterolytic retrosynthe 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 synthon. Tables 1.1 and 1.2 show some important acceptor and donor synthons and their synthetic eq~ivalents.~" 1.1 Retrosynthetic Analysis -... " 3 " Acceptor Synthons e d n d a ~ ~ ~ H ~ * ~ v a Synthon Synthetic equivalent Rf (alkyl cation = carbenium ion) RCI, RBr, RI, ROTS Arf (aryl cation) ,4rh2 X- ~ z - - ~ fl + HC-X (X = NR2, OR) HC=O (acylium ion) :: + RC=O (acylium ion) RC-x (X = CI, NR,; OR') -I- HO-C=O (acylium ion) Go2 0 II CH2=CHC-R + CH20H (oxocarbenium ion) (R = alkyl, OR') HCHO + RCH-OH (oxocarbenium ion) RCHO + R2C-OH (oxocarbenium ion) R2C=0 a Note 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 1 Synthetic Design Often, more than one disconnection is feasible, as depicted in retrosynthetic analyses A and B below. In the synthesis, a plan for the sequence of reactions is drafted according to the analysis by adding reagents and conditions. Retrosynthetic analysis A 0 FGI C-C disconnection OH OH dph 3 -ihPh + donor synthon X = Br, I wX +I Ph acceptor synthon sMgX ),, 6' SE of donor synthon H Ph SE of acceptor synthon 6- Synthesis A IP reconnection Retrosynthetic analysis B TM acceptor synthon A C u donor synthon PhLi up I Ph-Br SE of acceptor synthon SE of donor synthon Synthesis B Ph-Br 2 PhLi Alternating Polarity disconnection^^^,^ + CuBr n-BuLi THF, -78 "C THF Ph2CuLi PhLi 0 TM cuprate reagent The question of how one chooses appropriate carbon-carbon bond disconnections is related to functional group manipulations since the distribution of formal charges in the carbon skeleton is determined by the functional group(s) present. The presence of a heteroatom in a molecule imparts a pattern of electrophilicity and nucleophilicity to the atoms of the molecule. The concept of alternating polarities or-latent polarities 1.1 Retrosynthetic Analysis 5 (imaginary charges) often enables one to identify the best positions to make a disconnection within a complex molecule. Functional groups may be classified as follows:4" E class: Groups conferring electrophilic character to the attached carbon (i-): ---NH2, -OH, -OR, =0, =NR, -X (halogens) G class: Groups conferring nucleophilic character to the attached carbon (-): -Li, -MgX, -AlR2, -SiR3 A class: Functional groups that exhibit ambivalent character (+ or -): ----BR2, C=CR2, CECR, -NO2, EN,---SIX, ----S(O)R. -S02R The positive charge (+) is placed at the carbon attached to an E class functional group (e.g., =0,-OH, -Br) and the TM is then analyzed for consonant and dissonant patterns by assigning alternating polarities to the remaining carbons. In a consonant pattern, carbon atoms with the same class of functional groups have matching polarities, whereas in a dissonant pattern, their polarities are unlike. If a consonant pattern is present in a molecule, a simple synthesis may often be achieved. Consonant patterns: Positive charges are placed at carbon atoms bonded to the E class groups. Dissonant patterns: One E class group is bonded to a carbon with a positive charge, whereas the other E class group resides on a carbon with a negative charge. Examples of choosing reasonable disconnections of functionally substituted molecules based on the concept of alternating polarity are shown below. One Functional Group ;a Analysis OH 43, 5 8 I - I TM Adonor synthon + "i + acceptor synthon -MgBr acceptor synthon donor synthon - -- 6 - -Ci-!APTZ!? M y n t h e t i c Design Synthesis (path a) In the example shown above, there are two possible ways to disconnect the TM, 2-pentanol. Disconnection close to the functional group (path a) leads to substrates (SE) that are readily available. Moreover, reconnecting these reagents leads directly to the desired TM in high yield using well-known methodologies. Disconnection via path b also leads to readily accessible substrates. However, their reconnection to furnish the TM requires more steps and involves two critical reaction attributes: quantitative formation of the enolate ion and control of its monoalkylation by ethyl bromide. Two Functional Groups in a 1,3-Relationship Analysis TM (consonant pattern) donor synthon acceptor synthon 0 FGI II XK Ph SE (X = GI, Br) acceptor synthon donor synthon Synthesis (path a) LDA = LiN(i-Pr)* 0 0 [HI /q‘/I‘~h - s k i t & - breduction? IJIPh VS. 0 OH II I -~h not the desired TM 1.1 Retrosynthetic Analysis. 7 ....,........,....... .. ... ..-.... .- Synthesis (path b) desired TM Thc consonant chargc pattern and the presence of a P-hydroxp ketolle moiety in the TM suggest a retroaldol transform. Either the hydroxy-bearing carbon or the carbony1 carbon of the TM may serve as an electrophilic site and the corresponding a-carbons as the nucleophilic sites. However, path b is preferable since it does not require a selective functional group interconversion (reduction). Two Functional Groups in a 1,4-Relationship 0 Analysis acceptor synthon donor synthon 0 TM (dissonant patterns) enolate enamine SE SE a a SE Synthesis The dissonant charge pattern for 2,5-hexanedione exhibits a positive (+) polarity at one of the a-carbons, as indicated in the acceptor synthon above. Thus, the a-carbon in this synthon requires an inversion of polarity (Umpolung in German) from the negative (-) polarity normally associated with a ketone a-carbon. An appropriate substrate (SE) for the acceptor synthon is the electrophilic a-bromo ketone. It should be noted that an enolate ion might act as a base, resulting in deprotonation of an a-halo ketone, a reaction that could lead to the formation of an epoxy ketone (Darzens condensation). To circumvent this problem, a weakly basic enarnine is used instead of the enolate. In the case of 5-hydroxy-2-hexanone shown below, Umpol~lngof the polarity in the acceptor synthon is accomplished by using the electrophilic epoxide as the corresponding SE. Analysis OH or TM (dissonant patterns) donor synthon acceptor synthon enolate A SE Synthesis The presence of a C-C-OH moiety adjacent to a potential nucleophilic site in a TM, as exemplified below, points to a reaction of an epoxide with a nucleophilic reagent in the forward synthesis. The facile, regioselective opening of epoxides by nucleophilic reagents provides for efficient two-carbon homologation reactions. CARBBNYL CROUP POLARITY .-.I(61MPOLUAIG)5 --XX^X-X--_^XI-I -,--" .--,---s--,w,--- In organic synthesis, the carbonyl group is intimately involved in many reactions that create new carbon-carbon bonds. The carbonyl group is electrophilic at the carbon atom and hence is susceptible to attack by nucleophilic reagents. Thus, the carbonyl group reacts as a formyl cation or as an acyl cation. A reversal of the positive polarity of the carbonyl group so it acts as a forrnyl or acyl anion would be synthetically very attractive. To achieve this, the carbonyl group is converted to a derivative whose carbon atom has the negative polarity. After its reaction with an electrophilic reagent, the carbonyl is regenerated. Reversal of polarity of a carbonyl group has been explored and systematized by S e e b a ~ h . ~ ~ , " Urnyolung in a synthesis usually requires extra steps. Thus, one should strive to take maximum advantage of the functionality already present in a molecule. 1.2 Reversal of t h e Carbonyl Group Polarity (Umpolung)-- 9 "traditional" approach q6- ' 9- R$Y\ Nu Nu- Umpolung approach (E' = electrophile) 0 II /c\ E formyl anion when R = H acyl anion when R = alkyl The following example illustrates the normal disconnection pattern of a carboxylic acid with a Grignard reagent and carbon dioxide as SEs (path a) and a disconnection leading to a carboxyl synthon with an "unnatural" negative charge (path b). Cyanide ion can act as an SE of a negatively charged carboxyl synthon. Its reaction with R-Br furnishes the corresponding nitrile, which on hydrolysis produces the desired TM. approach Since formyl and acyl anions are not accessible, one has to use synthetic equivalents of these anions. Several reagents are synthetically equivalent to formyl or acyl anions, permitting the Umpolung of carbonyl reactivity. Foamyl and A q l Anions The most utilized Umpolung strategy is based on formyl and acyl anion equivalents derived from 2-lithio- 1,3-dithiane species. These are readily generated from 1,31.3-Dithiane~~~~'~' dithianes (thioacetals) because the hydrogens at C(2) are relatively acidic (pK, -3 I ) . ~ In this connection it should be noted that thiols (EtSH, pK, 11) are stronger acids compared to alcohols (EtOH, pK, 16). Also, the lower ionization potential and the greater polarizability of the valence electrons of sulfur compared to oxygen make the divalent sulfur compounds more nucleophilic in S,2 reactions. The polarizability factor may also be responsible for the stabilization of carbanions cc to s ~ l f u r . ~ Derived from H (e.g., TsOH) 1,3-dioxane (an acetal) pKa- 40 1,3-dithiane (a thioacetal) pKa = 31 -. 10 ". CkiAPTER '! Synthetic Design The anions derived from dithianes react with alkyl halides to give the corresponding alkylated dithianes. Their treatment with HgC1,-HgO regenerates aldehydes or ketones, respectively, as depicted below. formyl anion SE R-X (1" or 2") aldehydes acyl anion SE R'-X (1") ketones Dithiane-derived carbanions can be hydroxyalkylated or acylated to produce, after removal of the propylenedithiol appendage, a variety of difunctional compounds, as shown below. In the presence of HMPA (hexamethylphosphoramide, [(Me,N),P=O]), dithiane-derived carbanions may serve as Michael donor^.^ However, in the absence of HMPA, 1,2-addition to the carbonyl group prevails. 1. R'X R'CHO H H 1.2 Reversal of the Carbonyl Group Polarity (Umpolung) 'i1 An instructive example of using a dithiane Urnyolung approach to synthesize a complex natural product is the one-pot preparation of the multifunctional intermediate shown below, which ultimately was elaborated to the antibiotic verrni~ulin.~ TMEDA = N,N,N1,N'-tetramethylethylenediamine (Me2NCH2CH2NMe2);used to sequester Li+ and disrupt n-BuI1 aggregates. d. 0 II HCNMe2 -78" to 10°C vermiculin workup A q l Anions Derived from Nitroalkanes9 steps The a-hydrogens of nitroalkanes are appreciably acidic due to resonance stabilization of the anion [CH3N02,pK, 10.2; CH3CH2N02,pK, 8.51. The anions derived from nitroalkanes give typical nucleophilic addition reactions with aldehydes (the Henry-Nef tandem reaction). Note that the nitro group can be changed directly to a carbonyl group via the Nef reaction (acidic conditions). Under basic conditions, salts of secondary nitro compounds are converted into ketones by the pyridine-HMPA complex of molybdenum (VI) peroxide.9bNitronates from primary nitro compounds yield carboxylic acids since the initially formed aldehyde is rapidly oxidized under the reaction conditions. R' CHO Henry reaction 0acyl anion SE or H2S04, H20 Nef-type reactions OH mixture of diastereomers I OH nitronate anion - HN02 An example of an a-nitro anion Umpolung in the synthesis of jasrnone (TM) is depicted next.ga -- 12 ""- CHAPTER i Synthetic Design Analysis II FGI \ 11 (dissonant) Synthesis workup 1,2-addition 83% (two-phase system) Nef reaction 5a. EtOH, NaOH reflux rc.- jasmone 5b. H 20workup intramolecular aldol, dehydration Acy! Anions Derived from CyanohydrinsLo 0-Protected cyanohydrins contain a masked carbonyl group with inverted polarity. The a-carbon of an 0-protected cyanohydrin is sufficiently activated by the nitrile moiety [CH,CH,CN, pK, 30.91" so that addition of a strong base such as LDA