Advanced Organic - link.springer.com3A978-3... · epothilone. The chapter concludes with a discussion of solid-phase synthesis and its application in the synthesis of polypeptides

Advanced Organic Ch • t FOURTH

effilS fY EDITION

Part B: Reactions and Synthesis

Advanced Organic Chemistry PART A: Structure and Mechanisms PART B: Reactions and Synthesis

Advanced Organic Ch • t FOURTH emlS ry EDITION

Part B: Reactions and Synthesis

FRANCIS A. CAREY and RICHARD J. SUNDBERG University of Virginia Charlottesville, Virginia

~Springer

Library of Congress Cataloging-in-Publication Data

Carey, Francis A., 1937-Advanced organic chemistry/Francis A. Carey and Richard J. Sundberg.-4th ed.

p. em. Includes bibliographical references and index. Contents: pt. B. Reactions and synthesis

I. Sundberg, Richard J., 1938- II. Title.

QD251.2 .C36 2000 547-dc21

Library of Congress Cataloging-in-Publication Data

Carey, Francis A., 1937-Advanced organic chemistry/Francis A. Carey and Richard ). Sundberg.-4th ed.

p.cm. Includes bibliographical references and index. Contents: pt. B. Reactions and synthesis

I. Sundberg, Richard)., 1938- II. Title.

QD251.2 .C36 2000 547-dc21

A C.I.P. record for this book is available from the Library of Congress

ISBN 978-3-662-38652-1 ISBN 978-3-662-39510-3 (eBook) DOI 10.1007/978-3-662-39510-3

© 2001,1990,1984,1977 Springer Science+ Business Media New York Originally published by Springer Science Business Media, Inc. in 2001

00-059652

00-059652

All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmit­ted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher. (Springer Science+Business Media, LLC). The front cover shows the key orbital interactions in the Diels-Alder reaction. The highest-occupied molecular orbital (HOMO) of 1,3-butadiene and the lowest-unoccupied molecular orbital (LUMO) of ethylene overlap in phase with one another allowing the reaction to occur in a single step.

10 9 8 7 6 5 4 3

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Preface to the Fourth Edition

Part B emphasizes the most important reactions used in organic synthesis. The material is organized by reaction type. Chapters 1 and 2 discuss the alkylation, conjugate addition and carbonyl addition/condensation reactions of enolates and other carbon nucleophiles. Chapter 3 covers the use of nucleophilic substitution, both at saturated carbon and at carbonyl groups, in functional group of interconversions. Chapter 4 discusses electrophilic additions to alkenes and alkynes, including hydroboration. Chapter 5 discusses reduction reactions, emphasizing alkene and carbonyl-group reductions. Concerted reactions, especially Diels-Alder and other cycloadditions and sigmatropic rearrangements, are considered in Chapter 6. Chapters 7, 8, and 9 cover organometallic reagents and intermediates in synthesis. The main-group elements lithium and magnesium as well as zinc are covered in Chapter 7. Chapter 8 deals with the transition metals, especially copper, palladium, and nickel. Chapter 9 discusses synthetic reactions involving boranes, silanes, and stannanes. Synthetic reactions which involve highly reactive intermediates-carboca­tions, carbenes, and radicals-are discussed in Chapter 10. Aromatic substitution by both e1ectrophilic and nucleophilic reagents is the topic of Chapter 11. Chapter 12 discusses the most important synthetic procedures for oxidizing organic compounds. In each of these chapters, the most widely used reactions are illustrated by a number of specific examples of typical procedures. Chapter 13 introduces the concept of synthetic planning, including the use of protective groups and synthetic equivalents. Multistep syntheses are illustrated with several syntheses of juvabione, longifolene, Prelog-Djerassi lactone, Taxol, and epothilone. The chapter concludes with a discussion of solid-phase synthesis and its application in the synthesis of polypeptides and oligonucleotides, as well as to combina­torial synthesis.

The control of reactivity to achieve specific syntheses is one of the overarching goals of organic chemistry. In the decade since the publication of the third edition, major advances have been made in the development of efficient new methods, particularly catalytic processes, and in means for control of reaction stereochemistry. For example, the scope and efficiency of palladium- catalyzed cross coupling have been greatly improved by optimization of catalysts by ligand modification. Among the developments in stereocontrol are catalysts for enantioselective reduction of ketones, improved methods for control of the

v

Vl

PREFACE TO THE FOURTH EDmON

stereoselectivity of Diels-Alder reactions, and improved catalysts for enantioselective hydroxylation and epoxidation of alkenes.

This volume assumes a level of familiarity with structural and mechanistic concepts comparable to that in the companion volume, Part A, Structure and Mechanisms. Together, the two volumes are intended to provide the advanced undergraduate or beginning graduate student in chemistry a sufficient foundation to comprehend and use the research literature in organic chemistry.

Contents of Part B

Chapter 1. Alkylation of Nucleophilic Carbon Intermediates .......... .

1.1. 1.2. 1.3. 1.4. 1.5. 1.6. 1.7. 1.8. 1.9.

1.10.

Generation of Carbanions by Deprotonation .................... . Regioselectivity and Stereoselectivity in Enolate Formation .......... . Other Means of Generating Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . Alkylation of Enolates .................................. . Generation and Alkylation of Dianions ....................... . Medium Effects in the Alkylation of Enolates ................... . Oxygen versus Carbon as the Site of Alkylation ................. . Alkylation of Aldehydes, Esters, Amides, and Nitriles ............. . The Nitrogen Analogs of Enols and Enolates-Enamines and Imine Anions ............................................. . Alkylation of Carbon Nucleophiles by Conjugate Addition .......... . General References ................................... . Problems

5 10 11 20 20 23 28

31 39 47 47

Chapter 2. Reaction of Carbon Nucleophiles with Carbonyl Groups . . . . . . 57

2.1. Aldol Addition and Condensation Reactions. . . . . . . . . . . . . . . . . . . . . 57 2.1.1. The General Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 2.1.2. Mixed Aldol Condensations with Aromatic Aldehydes . . . . . . . . 60 2.1.3. Control of Regiochemistry and Stereochemistry of Mixed Aldol

Reactions of Aliphatic Aldehydes and Ketones . . . . . . . . . . . . . 62 2.1.4. Intramolecular Aldol Reactions and the Robinson Annulation . . . 89

2.2. Addition Reactions of !mines and Iminium Ions . . . . . . . . . . . . . . . . . . 96 2.2.1. The Mannich Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 2.2.2. Amine-Catalyzed Condensation Reactions. . . . . . . . . . . . . . . . . 100

2.3. Acylation of Carbanions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

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CONTENTS OF PART B

2.4. The Wittig and Related Reactions of Phosphorus-Stabilized Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ill

2.5. Reactions of Carbonyl Compounds with oc-Trimethylsilylcarbanions. . . . . . 120 2.6. Sulfur Ylides and Related Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . 122 2.7. Nucleophilic Addition--Cyclization. . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

Chapter 3. Functional Group Interconversion by Nucleophilic Substitution . . 141

3.1. Conversion of Alcohols to Alkylating Agents . . . . . . . . . . . . . . . . . . . . 141 3 .1.1. Sulfonate Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

3.2.

3.3. 3.4.

3.1.2. Halides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 Introduction of Functional Groups by Nucleophilic Substitution at Saturated Carbon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. General Solvent Effects ............................. . 3.2.2. Nitrites ........................................ . 3.2.3. Azides ........................................ . 3.2.4. Oxygen Nucleophiles .............................. . 3.2.5. Nitrogen Nucleophiles .............................. . 3.2.6. Sulfur Nucleophiles ............................... . 3.2.7. Phosphorus Nucleophiles ............................ . 3.2.8. Summary of Nucleophilic Substitution at Saturated Carbon ..... . Nucleophilic Cleavage of Carbon-Oxygen Bonds in Ethers and Esters ... . Interconversion of Carboxylic Acid Derivatives .................. . 3.4.1. Preparation of Reactive Reagents for Acylation ............. . 3.4.2. Preparation of Esters .......................... : . ... . 3.4.3. Preparation of Amides .............................. . Problems

147 147 150 150 152 155 158 158 159 159 164 166 172 172 180

Chapter 4. Electrophilic Additions to Carbon-Carbon Multiple Bonds . . . . . 191

4.1. Addition of Hydrogen Halides.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 4.2. Hydration and Other Acid-Catalyzed Additions of Oxygen Nucleophiles . . 195 4.3. Oxymercuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 4.4. Addition of Halogens to Alkenes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 4.5. Electrophilic Sulfur and Selenium Reagents. . . . . . . . . . . . . . . . . . . . . . 209 4.6. Addition of Other Electrophilic Reagents . . . . . . . . . . . . . . . . . . . . . . . 216 4.7. Electrophilic Substitution Alpha to Carbonyl Groups. . . . . . . . . . . . . . . . 216 4.8. Additions to Allenes and Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 4.9. Addition at Double Bonds via Organoborane Intermediates . . . . . . . . . . . 226

4.9.1. Hydroboration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 4.9.2. Reactions of Organoboranes. . . . . . . . . . . . . . . . . . . . . . . . . . . 232 4.9.3. Enantioselective Hydroboration. . . . . . . . . . . . . . . . . . . . . . . . . 236 4.9.4. Hydroboration of Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Problems .......................................... . 241

Chapter 5. Reduction of Carbonyl and Other Functional Groups ....... . 249

5.1. Addition of Hydrogen .................................. . 249 5 .1.1. Catalytic Hydrogenation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 5 .1.2. Other Hydrogen-Transfer Reagents .................... . 262

5.2. Group III Hydride-Donor Reagents .......................... . 262 5.2.1. Reduction of Carbonyl Compounds .................... . 262 5.2.2. Stereoselectivity of Hydride Reduction .................. . 273 5.2.3. Reduction of Other Functional Groups by Hydride Donors .... . 280

5.3. Group IV Hydride Donors ................................ . 286 5.4. Hydrogen-Atom Donors ................................. . 288 5.5. Dissolving-Metal Reductions .............................. . 290

5.5 .1. Addition of Hydrogen ............................. . 292 5.5.2. Reductive Removal of Functional Groups ................ . 296 5.5.3. Reductive Carbon-Carbon Bond Formation ............... . 299

5.6. Reductive Deoxygenation of Carbonyl Groups .................. . 307 5.7. Reductive Elimination and Fragmentation ..................... . 310

General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Problems 316

Chapter 6. Cycloadditions, Unimolecular Rearrangements, and Thermal Eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331

6.1. Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 6.1.1. The Diels-Alder Reaction: General Features . . . . . . . . . . . . . . . 332 6.1.2. The Diels-Alder Reaction: Dienophiles . . . . . . . . . . . . . . . . . . 339 6.1.3. The Diels-Alder Reaction: Dienes. . . . . . . . . . . . . . . . . . . . . . 345 6.1.4. Asymmetric Diels-Alder Reactions . . . . . . . . . . . . . . . . . . . . . 349 6.1.5. Intramolecular Diels-Alder Reactions. . . . . . . . . . . . . . . . . . . . 353

6.2. Dipolar Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 6.3. [2 + 2] Cycloadditions and Other Reactions Leading to Cyclobutanes . . . 367 6.4. Photochemical Cycloaddition Reactions. . . . . . . . . . . . . . . . . . . . . . . . 370 6.5. [3,3] Sigmatropic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

6.5.1. Cope Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376 6.5.2. Claisen Rearrangements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

6.6. [2,3] Sigmatropic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 6.7. Ene Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 6.8. Unimolecular Thermal Elimination Reactions. . . . . . . . . . . . . . . . . . . . 403

6.8.1. Cheletropic Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 6.8.2. Decomposition of Cyclic Azo Compounds . . . . . . . . . . . . . . . . 405 6.8.3. fi Eliminations Involving Cyclic Transition States. . . . . . . . . . . . 408 General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 Problems 414

IX

CONTENTS OF PART B

X

CONTENTS OF PART B

Chapter 7. Organometallic Compounds of the Group I, II, and III Metals . . 433

7.1. Preparation and Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 7 .2. Reactions of Organomagnesium and Organolithium Compounds. . . . . . . . 445

7.2.1. Reactions with Alkylating Agents. . . . . . . . . . . . . . . . . . . . . . . 445 7.2.2. Reactions with Carbonyl Compounds . . . . . . . . . . . . . . . . . . . . 446

7.3. Organic Derivatives of Group liB and Group IIIB Metals . . . . . . . . . . . . 458 7.3.1. Organozinc Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 7.3.2. Organocadmium Compounds .......................... 463 7.3.3. Organomercury Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . 464 7.3.4. Organoindium Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465

7.4. Organolanthanide Reagents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467 General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468

Chapter 8. Reactions Involving the Transition Metals . . . . . . . . . . . . . . . . . 477

8.1. Organocopper Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477 8.1.1. Preparation and Structure of Organocopper Reagents . . . . . . . . . 477 8.1.2. Reactions Involving Organocopper Reagents and Intermediates . . . 481

8.2. Reactions Involving Organopalladium Intermediates . . . . . . . . . . . . . . . . 499 8.2.1. Palladium-Catalyzed Nucleophilic Substitution and Alkylation. . . . 501 8.2.2. The Heck Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503 8.2.3. Palladium-Catalyzed Cross Coupling. . . . . . . . . . . . . . . . . . . . . 507 8.2.4. Carbonylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521

8.3. Reactions Involving Organonickel Compounds. . . . . . . . . . . . . . . . . . . . 525 8.4. Reactions Involving Rhodium and Cobalt . . . . . . . . . . . . . . . . . . . . . . . 529 8.5. Organometallic Compounds with 1t Bonding . . . . . . . . . . . . . . . . . . . . . 531

General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536

Chapter 9. Carbon-Carbon Bond-Forming Reactions of Compounds of Boron, Silicon, and Tin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547

9 .I. Organoboron Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 7 9 .1.1. Synthesis of Organoboranes . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 7 9.1.2. Carbon-Carbon Bond-Forming Reactions of Organoboranes . . . . . 549

9.2. Organosilicon Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 9.2.1. Synthesis of Organosilanes . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 9.2.2. Carbon-Carbon Bond-Forming Reactions. . . . . . . . . . . . . . . . . . 567

9.3. Organotin Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576 9.3.1. Synthesis ofOrganostannanes .......................... 576 9.3.2. Carbon-Carbon Bond-Forming Reactions. . . . . . . . . . . . . . . . . . 579 General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586

Chapter 10. Reactions Involving Carbocations, Carbenes, and Radicals as Reactive Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10.1. Reactions Involving Carbocation Intermediates .................. . 1 0.1.1. Carbon-Carbon Bond Formation Involving Carbocations ..... . 10.1.2. Rearrangement of Carbocations ...................... : 10.1.3. Related Rearrangements ........................... . 10.1.4. Fragmentation Reactions ........................... .

10.2. Reactions Involving Carbenes and Nitrenes .................... . 1 0.2.1. Structure and Reactivity of Carbenes .................. . 10.2.2. Generation of Carbenes ........................... . 10.2.3. Addition Reactions .............................. . 10.2.4. Insertion Reactions .............................. . 10.2.5. Generation and Reactions of Ylides by Carbenoid Decomposition 10.2.6. Rearrangement Reactions .......................... . 10.2.7. Related Reactions ............................... . 10.2.8. Nitrenes and Related Intermediates .................... . 10.2.9. Rearrangements to Electron-Deficient Nitrogen ........... .

10.3. Reactions Involving Free-Radical Intermediates ................. . 10.3.1. Sources of Radical Intermediates ..................... . 10.3.2. Introduction of Functionality by Radical Reactions ......... . 10.3.3. Addition Reactions of Radicals to Substituted Alkenes ...... . 10.3.4. Cyclization of Free-Radical Intermediates ............... . 10.3.5. Fragmentation and Rearrangement Reactions ............. . General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems

Chapter 11. Aromatic Substitution Reactions ..................... .

11.1. Electrophilic Aromatic Substitution .......................... . 11.1.1. Nitration ..................................... . 11.1.2. Halogenation .................................. . 11.1.3. Friedel-Crafts Alkylations and Acylations ............... . 11.1.4. Electrophilic Metalation ........................... .

11.2. Nucleophilic Aromatic Substitution .......................... . 11.2.1. Aryl Diazonium Ions as Synthetic Intermediates ........... . 11.2.2. Substitution by the Addition-Elimination Mechanism ....... . 11.2.3. Substitution by the Elimination-Addition Mechanism ....... . 11.2.4. Transition-Metal-Catalyzed Substitution Reactions ......... .

11.3. Aromatic Radical Substitution Reactions ...................... . 11.4. Substitution by the SRN 1 Mechanism ........................ .

General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems .......................................... .

Chapter 12. Oxidations ..................................... .

12.1. Oxidation of Alcohols to Aldehydes, Ketones, or Carboxylic Acids .... . 12.1.1. Transition-Metal Oxidants .......................... . 12.1.2. Other Oxidants ................................. .

Xl 595

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595 596 602 609 612 614 617 620 625 634 637 639 641 642 646 651 652 654 657 660 674 679 680

693

693 693 695 699 711 714 714 722 724 728 731 734 736 736

747

747 747 752

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CONTENTS OF PART B

12.2. Addition of Oxygen at Carbon-Carbon Double Bonds . . . . . . . . . . . . . . 757 12.2.1. Transition-Metal Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . 757 12.2.2. Epoxides from Alkenes and Peroxidic Reagents. . . . . . . . . . . . . 767 12.2.3. Transformations of Epoxides . . . . . . . . . . . . . . . . . . . . . . . . . 772 12.2.4. Reaction of Alkenes with Singlet Oxygen. . . . . . . . . . . . . . . . . 782

12.3. Cleavage of Carbon-Carbon Double Bonds. . . . . . . . . . . . . . . . . . . . . . 786 12.3.1. Transition-Metal Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . 786 12.3.2. Ozonolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788

12.4. Selective Oxidative Cleavages at Other Functional Groups. . . . . . . . . . . . 790 12.4.1. Cleavage of Glycols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790 12.4.2. Oxidative Decarboxylation. . . . . . . . . . . . . . . . . . . . . . . . . . . 792

12.5. Oxidation of Ketones and Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . 794 12.5.1. Transition-Metal Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . 794 12.5.2. Oxidation of Ketones and Aldehydes by Oxygen and

Peroxidic Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798 12.5.3. Oxidation with Other Reagents. . . . . . . . . . . . . . . . . . . . . . . . 802

12.6. Allylic Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803 12.6.1. Transition-Metal Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . 803 12.6.2. Other Oxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805

12.7. Oxidations at Unfunctionalized Carbon. . . . . . . . . . . . . . . . . . . . . . . . . 807 General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809

Chapter 13. Planning and Execution of Multistep Syntheses . . . . . . . . . . . . 821

13.1. Protective Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822 13.1.1. Hydroxyl-Protecting Groups .......................... 822 13.1.2. Amino-Protecting Groups. . . . . . . . . . . . . . . . . . . . . . . . . . . . 831 13.1.3. Carbonyl-Protecting Groups. . . . . . . . . . . . . . . . . . . . . . . . . . 835 13.1.4. Carboxylic Acid-Protecting Groups. . . . . . . . . . . . . . . . . . . . . 837

13.2. Synthetic Equivalent Groups. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839 13.3. Synthetic Analysis and Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845 13.4. Control of Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846 13.5. Illustrative Syntheses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848

13.5.1. Juvabione . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848 13.5.2. Longifolene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859 13.5.3. Prelog-Djerassi Lactone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869 13.5.4. Taxol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881 13.5.5. Epothilone A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890

13.6. Solid-Phase Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897 13.6.1. Solid-Phase Synthesis ofPolypeptides . . . . . . . . . . . . . . . . . . . 897 13.6.2. Solid-Phase Synthesis of Oligonucleotides.. . . . . . . . . . . . . . . . 900

13.7. Combinatorial Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903 General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910

References for Problems 923

Index 947

Advanced Organic Ch • t FOURTH emts ry EDITION

Part B: Reactions and Synthesis