George S. Zweifel Michael H. Nantz Peter Somfai AN INTRODUCTION. Second Edition

Transcription

1 George S. Zweifel Michael H. Nantz Peter Somfai AN INTRDUCTIN Second Edition

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3 Modern rganic Synthesis An Introduction

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5 Modern rganic Synthesis An Introduction Second Edition George S. Zweifel University of California, Davis Dept of Chemistry Davis, CA, US Michael H. Nantz University of Louisville Dept of Chemistry Louisville, KY, US Peter Somfai Lund University Ctre for Analysis & Synthesis Lund, SW

6 This edition first published John Wiley & Sons, Inc. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at The right of George S. Zweifel, Michael H. Nantz and Peter Somfai to be identified as the author(s) of this work has been asserted in accordance with law. Registered ffices John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA Editorial ffice 111 River Street, Hoboken, NJ 07030, USA For details of our global editorial offices, customer services, and more information about Wiley products visit us at Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty: The publisher and the authors make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties; including without limitation any implied warranties of fitness for a particular purpose. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for every situation. In view of on-going research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or website is referred to in this work as a citation and/or potential source of further information does not mean that the author or the publisher endorses the information the organization or website may provide or recommendations it may make. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this works was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising here from. Library of Congress Cataloging-in-Publication Data Names: Zweifel, George S. Nantz, Michael H. Somfai, Peter, 1960 Title: Modern organic synthesis : an introduction / George S. Zweifel, Michael H. Nantz, Peter Somfai. Description: Second edition. Hoboken, NJ : John Wiley & Sons, Inc., Includes bibliographical references and index. Identifiers: LCCN (print) LCCN (ebook) ISBN (pbk.) ISBN (pdf) ISBN (epub) Subjects: LCSH: rganic compounds Synthesis. Classification: LCC QD262.Z (print) LCC QD262 (ebook) DDC 547/.2 dc23 LC record available at Cover image: annuker/getty Cover design by Wiley Set in 10/12pt WarnockPro by Aptara Inc., New Delhi, India

7 v Contents About the Authors ix Preface to the Second Edition xi PrefacetotheFirstEdition xiii 1 Synthetic Design Retrosynthetic Analysis Reversal of the Carbonyl Group Polarity (Umpolung) Steps in Planning a Synthesis Choice of Synthetic Method Domino Reactions (Cascade or Tandem Reactions) Computer-Assisted Retrosynthetic Analysis 19 References 19 2 Stereochemical Considerations in Planning Syntheses Conformational Analysis Evaluation of Non-Bonded Interactions Six-Membered Heterocyclic Systems Polycyclic Ring Systems Cyclohexyl Systems with sp 2 -Hybridized Atoms Significant Energy Difference Computer-Assisted Molecular Modeling Reactivity and Product Determination as a Function of Conformation 36 References 42 3 The Concept of Protecting Functional Groups Protection of N H Groups Protection of H Groups 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 66 References 66 4 Functional Group Transformations xidation of Alcohols to Aldehydes and Ketones Reagents and Procedures for Alcohol xidation Chemoselective xidizing Agents xidation of Acyloins xidation of Tertiary Allylic Alcohols xidative Procedures to Carboxylic Acids 80

8 vi Contents 4.7 Allylic xidation of Alkenes Terminology for Reduction of Carbonyl Compounds Nucleophilic Reducing Agents Electrophilic Reducing Agents Regio- and Chemoselective Reductions Diastereoselective Reductions of Cyclic Ketones Inversion of Secondary Alcohol Stereochemistry Diastereofacial Selectivity in Acyclic Systems Enantioselective Reductions 104 References Functional Group Transformations Reactions of Carbon Carbon Double Bonds Reactions of Carbon Carbon Triple Bonds 160 References Formation of Carbon Carbon Single Bonds via Enolate Anions ,3-Dicarbonyl Compounds Direct Alkylation of Enolates Cyclization Reactions Baldwin s Rules for Ring Closure Stereochemistry of Cyclic Ketone Alkylation Imine and Hydrazone Anions Enamines The Aldol Reaction Condensation Reactions of Enols and Enolates Robinson Annulation 217 References Formation of Carbon Carbon Bonds via rganometallic Reagents rganolithium Reagents rganomagnesium Reagents rganotitanium Reagents rganocerium Reagents rganocopper Reagents rganochromium Reagents rganozinc Reagents rganoboron Reagents rganosilicon Reagents rganogold Chemistry 274 References Palladium-Catalyzed Coupling Reactions Palladium xidation State rganic Synthesis with Palladium(0) Complexes The Heck Reaction Palladium(0)-Catalyzed lefin Insertion Reactions Palladium-Catalyzed Cross-Coupling with rganometallic Reagents Cross-Coupling Reactions Involving sp-carbons The Trost Tsuji Reaction 304 References Formation of Carbon Carbon π-bonds Formation of Carbon Carbon Double Bonds 313

9 Contents vii 9.2 Formation of Carbon Carbon Triple Bonds 343 References Syntheses of Carbocyclic Systems Intramolecular Free Radical Cyclizations Cation π Cyclizations Pericyclic Reactions Ring-Closing lefin Metathesis 375 References 378 Index 383

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11 ix About the Authors George S. Zweifel was born in Switzerland. He received his Dr. Sc. Techn. degree in 1955 from the Swiss Federal Institute of Technology (ETH Zürich, Switzerland, Professor H. Deuel), working in the area of carbohydrate chemistry. The award of a Swiss British Exchange Fellowship in 1956 (University of Edinburgh, Scotland, Professor G.. Aspinall) and a Research Fellowship in 1957 (University of Birmingham, England, Professors S. A. Barker and A. B. Forster) made it possible for him to study conformational problems in the carbohydrate field. In 1958, he became Professor H. 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 H. Nantz earned a Bachelor of Science degree from Western Kentucky University in His interest in natural product synthesis led him to work with Professor Philip L. Fuchs at Purdue University, where he received a PhD degree in ver the next 2 years, he studied asymmetric synthesis with Professor Satoru Masamune at the Massachusetts Institute of Technology. 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. In 2006, he joined the faculty at the University of Louisville as Professor of Chemistry and Distinguished University Scholar. Peter Somfai was born in Sweden and received his PhD in 1987 from the Chalmers University of Technology. After a 2-year post doc in the group of Professor S. Masamune at the Massachusetts Institute of Technology, he returned to Sweden. In 1999, he was appointed as Professor at the Royal Institute of Technology (KTH) in Stockholm. He joined the faculty at Lund University in 2012, where he is Professor in organic chemistry. He is interested in the development of new methodology for organic synthesis and its application to the synthesis of complex organic molecules.

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13 xi Preface to the Second Edition rganic synthesis is a dynamic subject under constant development. Much progress has been made since the first edition of this book was printed in ur aim for this edition was to update the many advances in the methodologies and interpretations already presented in Modern rganic Synthesis: An Introduction (MS) as well as to introduce emerging technologies. As a result, many new examples and more than 500 literature references have been included to provide students an overview of contemporary organic synthesis. The content of the book is organized using the same thematic chapters as in the previous edition with one exception. During the last decade, palladium-catalyzed coupling reactions have evolved into a powerful technique for synthesis of organic molecules. A new chapter, Chapter 8, is now devoted to this chemistry. As with the previous edition, the present one is intended to enlighten senior undergraduate and beginning graduate students. Updating MS has been stimulating and rewarding; we hope you will find this edition informative.

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15 xiii Preface to the First Edition Modern rganic 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. ur 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 formed 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. 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 (UC Davis) and Craig A. Merlic (UCLA) read the entire manuscript; their pertinent comments and constructive critiques greatly improved the quality of the book. Finally, without the support and encouragement of our wives, Hanni and Jody, Modern rganic Synthesis: An Introduction would not have been written. George S. Zweifel Michael H. Nantz ctober 27, 2005 Davis, California

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17 1 1 Synthetic Design In character, in manners, in style, in all things, the supreme excellence is simplicity. Henry Wadsworth Longfellow Chemistry 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. ur 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? bviously, 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), 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? 1 This chapter outlines strategies for the synthesis of such target molecules based on retrosynthetic analysis. E. J. Corey (Nobel Prize, 1990) introduced and promoted the concept of retrosynthetic analysis, whereby a molecule is disconnected leading to logical precursors. 2 Today, retrosynthetic analysis plays an integral and indispensable role in research. 1.1 Retrosynthetic Analysis 3 The following discussion on retrosynthetic analysis covers topics similar to those in Warren s rganic Synthesis: The Disconnection Approach 3a and Willis and Will s rganic Synthesis. 3g For an advanced treatment of the subject matter, see Corey and Cheng s TheLogicofChemicalSynthesis. 3b Modern rganic Synthesis: An Introduction, Second Edition. George S. Zweifel, Michael H. Nantz and Peter Somfai John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

18 2 Modern rganic Synthesis Basic Concepts The construction of a synthetic tree by working backward from the target molecule (TM) is called retrosynthetic analysis or antithesis. Thesymbol 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 FGI. Structural changes in the retrosynthetic direction should lead to substrates that are more readily available than the TM. Synthons are fragments resulting from disconnection of carbon carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SEs). Also, reagentsderived from inverting the polarity (IP) of synthons may serve as SEs. Synthetic design involves two distinct steps 3a : (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 proximally by methods corresponding to known and reliable reconnection reactions. Chemical bonds can be cleaved heterolytically or homolytically, or through concerted transform (into two neutral, closed-shell fragments). The following discussion will focus on heterolytic and cyclic disconnections. Donor and Acceptor Synthons 3c,g Heterolytic retrosynthetic disconnection of a carbon carbon bond in a molecule breaks the TM into an acceptor synthon, a carbocation, and into a donor synthon, a carbanion. In a formal 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 equivalents. 3c ften, 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.

19 Table 1.1 Common Acceptor Synthons a Note that α-halo ketones also may serve as synthetic equivalents of enolate ions. Table 1.2 Common Donor Synthons

20 4 Modern rganic Synthesis Alternating Polarity Disconnections 3g,4 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 (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: 4a E Class: Groups conferring electrophilic character to the attached carbon (+): H, R,, NR, X (halogens) G Class: Groups conferring nucleophilic character to the attached carbon (-): Li, MgX, AlR 2, SiR 3 A Class: Functional groups that exhibit ambivalent character (+ or -): BR 2,C CR 2,C CR, N 2, N, SR, S()R, S 2 R The positive charge (+)is placed at the carbon attached to an E class functional group (e.g.,, H, 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 oftenbeachieved. Examples of choosing reasonable disconnections of functionally substituted molecules based on the concept of alternating polarity are shown below. ne Functional Group 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.

21 1 Synthetic Design 5 Two Functional Groups in a 1,3-Relationship Synthesis (path a) Synthesis (path b) The consonant charge pattern and the presence of a β-hydroxy ketone moiety in the TM suggest a retro-aldol transform. Either the hydroxy-bearing carbon or the carbonyl carbon of the TM may serve as an electrophilic site and the corresponding α-carbons as the nucleophilic sites. However, path b is preferable since it does not require a selective FGI (reduction). Two Functional Groups in a 1,4-Relationship

22 6 Modern rganic Synthesis The dissonant charge pattern for2,5-hexanedione exhibitsapositive (+) polarityat one oftheα-carbons, asindicated intheacceptorsynthonabove.thus,theα-carbon in this synthon requires an inversion of polarity (Umpolung in German) from the negative ( ) polarity normally associated with a ketone α-carbon. An appropriate substrate (SE) for the acceptor synthon is the electrophilic α-bromo ketone. It should be noted that an enolate ion might act as a base resulting in deprotonation of an α-halo ketone, a reaction that could lead to the formation of an epoxy ketone (Darzens condensation). To circumvent this problem, a weakly basic enamine is used instead of the enolate. In the case of 5-hydroxy-2-hexanone shown below, Umpolung of the polarityin the acceptorsynthon isaccomplished by using the electrophilic epoxide as the corresponding SE. The presence of a C C H 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. 1.2 Reversal of the Carbonyl Group Polarity (Umpolung) 5 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 or as an acyl cation. A reversal of the positive polarity of the carbonyl group so it acts as a formyl or as an acyl anion would be synthetically very attractive. To achieve this, the carbonyl group is converted to a derivative whose carbon atom has 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 Seebach. 5b,c Umpolung in a synthesis usually requires extra steps. Thus, one should strive to take maximum advantage of the functionality already present in a molecule.

23 1 Synthetic Design 7 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. Since formyl and acyl anions are not accessible, one has to use synthetic equivalents of these anions. There are several reagents that are synthetically equivalent to formyl or acyl anions, permitting the Umpolung of carbonyl reactivity. Formyl and Acyl Anions Derived from 1,3-Dithianes 5b,c,f The most utilized Umpolung strategyisbased on formyl andacyl anion equivalentsderivedfrom 2-lithio-1,3-dithiane species. These are readily generated from 1,3-dithianes (thioacetals) because the hydrogens at C(2) are relatively acidic (pka 31). 6 In this connection it should be noted that thiols (EtSH, pka 11) are stronger acids compared to alcohols (EtH, pka 16). Also, the lower ionization potential and the greater polarizability of the valence electrons in sulfur as compared to oxygen makes the divalent sulfur compounds more nucleophilic in S N 2 reactions. The polarizability factor may also be responsible for the stabilization of carbanions α to sulfur. 6 The anions derived from dithianes react with alkyl halides to give the corresponding alkylated dithianes. Their treatment with HgCl 2 Hg regenerates aldehydes or ketones, respectively, as depicted below. In addition to

24 8 Modern rganic Synthesis Hg(II)-mediated methods for dithiane deprotection, other methods, 7 such as oxidative 7b,c and photoremoval 7d approaches, have been developed to unmask the carbonyl group. 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 2 N) 3 P ]), dithiane-derived carbanions may serve as Michael donors. 8 However, in the absence of HMPA, 1,2-addition to the carbonyl group prevails. An instructive example of using a dithiane Umpolung approach to synthesize a complex natural product is the onepot preparation of the multifunctional intermediate shown below, which ultimately was elaborated to prepare the antibiotic vermiculin. 9 TMEDA = tetramethylethylenediamine (Me 2 NCH 2 CH 2 NMe 2 ); used to sequester Li + and disrupt n-buli aggregates

25 1 Synthetic Design 9 Acyl Anions Derived from Nitroalkanes 10 The α-hydrogens of nitroalkanes are appreciably acidic due to resonance stabilization of the anion [CH 3 N 2,pKa 10.2; CH 3 CH 2 N 2,pKa 8.5]. The anions derived from nitroalkanes give typical nucleophilic addition reactions with aldehydes (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. 9b Nitronates from primary nitro compounds yield carboxylic acids since the initially formed aldehyde is rapidly oxidized under the reaction conditions. An example of an α-nitro anion Umpolung in the synthesis of jasmone (TM) is depicted below. 9a

26 10 Modern rganic Synthesis Acyl Anions Derived from Cyanohydrins 11 -Protected cyanohydrins contain a masked carbonyl group with inverted polarity. The α-carbon of an -protected cyanohydrin is sufficiently activated by the nitrile moiety [CH 3 CH 2 CN, pka 30.9] 12 so that addition of a strong base such as LDA generates the corresponding anion. Its alkylation, followed by hydrolysis of the resultant alkylated cyanohydrin, furnishes the ketone. The overall reaction represents alkylation of an acyl anion equivalent, as exemplified for the synthesis of methyl cyclopentyl ketone. 11a An attractive alternative to the above protocol is the nucleophilic acylation of alkylating agents with aromatic and heteroaromatic aldehydes via trimethylsilyl-protected cyanohydrins. 11b Acyl anion synthons derived from cyanohydrins may be generated catalytically by cyanide ion via the Stetter reaction. 11c e However, further reaction with electrophiles is confined to carbonyl compounds and Michael acceptors.

27 1 Synthetic Design 11 Acyl Anions Derived from Enol Ethers The α-hydrogens of enol ethers may be deprotonated with tert-buli. 13 Alkylation of the resultant vinyl anion followed by acidic hydrolysis provides an efficient route for the preparation of methyl ketones. Acyl Anions Derived from Lithium Acetylide Treatment of lithium acetylide with a primary alkyl halide (bromide or iodide) or with aldehydes or ketones produces the corresponding monosubstituted acetylenes or propargylic alcohols. Mercuric ion-catalyzed hydration of these furnishes methyl ketones and methyl α-hydroxy ketones, respectively. The sensitivity of some propargylic alcohols toward acid conditions has led to the development of milder, acid-free conditions using gold catalysis for hydration of the derived propargylic acetates, as illustrated below Steps in Planning a Synthesis In planning an organic synthesis, the following key interrelated factors may be involved: Construction of the carbon skeleton Control of relative stereochemistry Functional group interconversions Control of enantioselectivity Construction of the Carbon Skeleton Reactions that result in formation of new carbon carbon bonds are of paramount importance in organic chemistry because they allow the construction of complex structures from smaller starting materials. Important carbon carbon bond-forming reactions encountered in organic syntheses are summarized in Table 1.3 and include: Reactions of organolithium and Grignard reagents, such as RLi, RC CLi, RMgX, and RC CMgX, with aldehydes, ketones, esters, epoxides, acid halides, and nitriles Reactions of 1 alkyl halides with NaCN (or KCN) to extend the carbon chain by one carbon Alkylations of enolate ions to introduce alkyl groups to carbons adjacent to a carbonyl group (e.g., acetoacetic ester synthesis, malonic ester synthesis) Condensations such as aldol (intermolecular, intramolecular), Claisen, and Dieckmann

28 12 Modern rganic Synthesis Table 1.3 Summary of Important Disconnections 3c TM Synthons SE (substrates) Reaction + + HCH 1,2-addition H H MgX H + H + 1,3-addition MgX CN + + CN NaCN S N 2 Br H H H + + H H H Aldol condensation R + + R R R 1,2-addition (Claisen condensation) C 2 R C 2 R + + C 2 R 1,4-addition (Michael addition) H H C 2 R H C 2 R CH + + Ph 3 P Ph 3 P C 2 R Br Wittig reaction C 2 R C 2 R + H H C 2 R C 2 R Diels Alder cycloaddition Ring-closing metathesis Michael additions, organocuprate additions (1,4-additions) Friedel Crafts alkylation and acylation reactions of aromatic substrates Wittig reactions, Horner Wadsworth Emmons olefination Diels Alder reactions to access to cyclohexenes and 1,4-cyclohexadienes Ring-closing olefin metathesis Below are summarized some important guidelines for choosing disconnections of bonds. At the initial stage of the retrosynthetic analysis, key fragments must be recognized that can be recombined in the forward synthetic step in an efficient way. 3 Disconnections of bonds should be carried out only if the resultant fragments can be reconnected by known and reliable reactions.

29 1 Synthetic Design 13 Disconnection via path a leads to synthons whose SEs can be reconnected by a nucleophilic attack of the phenoxide on the propyl bromide to furnish the desired TM. n the other hand, disconnection via path b would require either attack of n-pr on bromobenzene to reconstruct the TM, a reaction that is not feasible, or displacement of a benzenediazonium salt by n-pr M +. Aim for the fewest number of disconnections. Adding large fragments in a single reaction is more productive than adding several smaller fragments sequentially. Choose disconnections in which functional groups are close to the C C bonds to be formed since the presence of functional groups often facilitates bond-making by a substitution reaction. It is often advantageous to disconnect at a branching point since this may lead to linear fragments that are generally more readily accessible, either by synthesis or from a commercial source. A preferred disconnection of cyclic esters (lactones) or amides (lactams) produces hydroxy-carboxylic acids or amino-carboxylic acids as targets. Many macrocyclic natural products contain these functional groups and their syntheses often include a macrocyclization reaction. Functional groups in the TM may be obtained by FGI. Symmetry in the TM simplifies the overall synthesis by decreasing the number of steps required for obtaining the TM.

30 14 Modern rganic Synthesis Introduction of an activating (auxiliary) functional group may facilitate carbon carbon bond formation. This strategy works well for the synthesis of compounds exhibiting a dissonant charge pattern. After accomplishing its role, the auxiliary group is removed. There is no simple way to disconnect the TM shown below (dissonant charge pattern). However, the presence of a 1,6-dioxygenated compound suggests a ring opening of a six-membered ring. A variety of cyclohexene precursors are readily available via condensation and Diels Alder reactions or via Birch reductions of aromatic compounds. Disconnection of an internal (E)- or (Z)-double bond, or a side chain of an alkene, suggests a Wittig-type reaction or an alkylation of a vinylcuprate, for example, respectively. The presence of a six-membered ring, especially a cyclohexene derivative, implies a Diels Alder reaction.