MOLECULAR REARRANGEMENTS IN ORGANIC SYNTHESIS

MOLECULAR REARRANGEMENTS IN ORGANIC SYNTHESIS

Edited by

CHRISTIAN M. ROJAS Barnard College, New York, NY, USA Copyright © 2015 by John Wiley & Sons, Inc. All rights reserved

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Library of Congress Cataloging-in-Publication Data:

Molecular rearrangements in organic synthesis / Edited by Christian M. Rojas. pages cm Includes bibliographical references and index. ISBN 978-1-118-34796-6 (cloth) 1. Rearrangements (Chemistry) 2. Organic compounds–Synthesis. I. Rojas, Christian Miguel, editor. QD281.R35M65 2015 547′.2–dc23 2015013578

Typeset in 10/12pt Times by SPi Global, Chennai, India.

Printed in the United States of America

10987654321

1 2015 CONTENTS

LIST OF CONTRIBUTORS xvii PREFACE xxi

PART 1 1,2-MIGRATIONS 1

1 Pinacol and Semipinacol Rearrangements in Total Synthesis 3 1.1 Introduction, 3 1.2 Pinacol Reaction, 4 1.2.1 Background and Introduction, 4 1.2.2 Stereochemistry of the Pinacol Rearrangement, 6 1.2.3 Preparation of Substrates for the Pinacol Rearrangement, 7 1.2.4 Applications of the Pinacol Reaction in Complex Molecule Synthesis, 7 1.3 Semipinacol Rearrangement, 15 1.3.1 Background and Introduction, 15 1.3.2 Mechanism of the Semipinacol Rearrangement, 17 1.3.3 Selected Variants of Semipinacol Rearrangements, 17 1.3.4 Key Features of the Semipinacol Rearrangement, 18 1.3.5 Examples of Semipinacol Rearrangements in Total Synthesis, 19 1.4 Conclusion, 30 References, 32 vi CONTENTS

2 Baeyer–Villiger (BV) Oxidation/Rearrangement in Organic Synthesis 35 2.1 Introduction, 35 2.2 Mechanism, 35 2.3 Synthetic Applications, 37 2.3.1 Oxidation of Linear Ketones to Esters, 37 2.3.2 Oxidation of Aldehydes to Esters, 42 2.3.3 Oxidation of Cyclic Ketones to Lactones, 42 2.3.4 Asymmetric BV Oxidation/Rearrangement, 48 2.3.5 Oxidation of 𝛼-Diketones to Anhydrides, 53 2.4 Summary and Outlook, 55 References, 55

3 The Wolff Rearrangement: Tactics, Strategies and Recent Applications in Organic Synthesis 59 3.1 Introduction, 59 3.2 Tactics and Strategies via the Wolff Rearrangement, 60 3.2.1 Methylene Carboxylic Acid Derivatives (Arndt–Eistert Reaction), 60 3.2.2 One-Carbon Ring Contraction of Cyclic 𝛼-Diazoketones, 61 3.2.3 Reactions of Ketenes and 𝛼-Oxo-Ketenes, 61 3.3 Mechanistic Features and Selectivity Issues of the Wolff Rearrangement, 63 3.4 Preparation of 𝛼-Diazocarbonyl Compounds, 64 3.4.1 Acylation of Diazoalkanes, 65 3.4.2 Diazo-Transfer Reactions, 65 3.4.3 Alkyne Cycloaddition, 66 3.5 Recent Synthetic Applications of the Wolff Rearrangement, 67 3.5.1 Wolff Rearrangements Leading to Ketene Intermediates, 67 3.5.2 Wolff Rearrangements Leading to 𝛼-Oxo-Ketene Intermediates, 73 3.6 Conclusion and Outlook, 80 References, 81

4 Alkyl and Acyl Azide Rearrangements 85 4.1 Introduction, 85 4.2 Alkyl Azide Rearrangements, 86 4.3 Acyl Azide Rearrangements, 98 4.4 Hofmann Rearrangement, 102 4.5 Lossen Rearrangement, 104 4.6 Conclusion, 107 References, 108 CONTENTS vii

5 Beckmann Rearrangements and Fragmentations in Organic Synthesis 111 5.1 Introduction, 111 5.1.1 Beckmann Rearrangement, 112 5.1.2 Beckmann Fragmentation, 115 5.1.3 Photo-Beckmann Rearrangement, 117 5.2 Strategic Planning: A Historical Perspective, 118 5.3 Recent Applications Toward the Synthesis of Natural Products, 121 5.3.1 Toward the Total Synthesis of Pinnaic Acid and Halichlorine, 121 5.3.2 Access to the Core of Mersicarpine, 123 5.3.3 Formal Synthesis of Gephyrotoxin 287C, 124 5.3.4 First Asymmetric Total Synthesis of (+)-Sparteine, 126 5.3.5 Synthesis of the Chloropentane Core of Palau’amine, 128 5.3.6 The Total Synthesis of (−)-Elegansidiol, 128 5.4 Access to Diverse Scaffolds via the Beckmann Reaction, 129 5.4.1 Diterpene Hydrocarbons, 129 5.4.2 Monoterpene-Related Synthesis, 133 5.4.3 Furopyran Synthesis, 133 5.4.4 Synthesis of a Pyrazine Imide, 134 5.5 Formation of Heterocyclic Scaffolds, 136 5.5.1 Oxadiazoles, 136 5.5.2 Synthesis of Benzisoxazoles and Benzoxazoles, 138 5.5.3 Isatins, 138 5.5.4 N-Imidoylbenzotriazoles, 139 5.6 Synthesis of Functional Groups, 140 5.6.1 Amidines, 140 5.6.2 Thioamides, 141 5.6.3 Synthesis of DNA-Photocleaving Agents, 142 5.7 Summary and Outlook, 144 References, 145

6 Brook Rearrangement 151 6.1 Introduction, 151 6.2 Mechanism, 152 6.3 Methods for Generation of 𝛼-Silyl Alkoxides, 153 6.4 Synthetic Reactions Using Brook Rearrangements in the Reactions of Acylsilanes with Nucleophiles, 154 6.4.1 Preparation of Acylsilanes, 154 6.4.2 Reaction of Acylsilanes with Nucleophiles, Either of Which Contains an 𝛼-Leaving Group, 155 viii CONTENTS

6.4.3 Reaction of Acylsilanes with Nucleophiles, in Which Generated Carbanions Can Be Stabilized by Conjugating Groups, 157 6.4.4 Use of Ketone Enolates as Nucleophiles Containing an Electron-Accepting Moiety, 163 6.5 Synthetic Reactions Using Brook Rearrangements Triggered by Deprotonation of 𝛼-Silyl Alcohols, 166 6.6 Synthetic Reactions Using Brook Rearrangements Triggered by Addition of Silylmetallic Reagents, 169 6.7 Synthetic Reactions Using Brook Rearrangements in 𝛼-Silyl Alkoxides Generated via Regioselective 𝛽-Ring-Opening of 𝛼,𝛽-Epoxysilanes by a Nucleophile, 172 6.8 Synthetic Reactions Using Brook Rearrangements in 𝛼-Silyl Alkoxides Generated by a Base-Induced Ring-Opening of 𝛼,𝛽-Epoxysilanes, 173 6.9 Conclusion, 176 References, 178

PART II 1,2-MIGRATIONS VIA THREE-MEMBERED RINGS 183

7 The Quasi-Favorskii Rearrangement 185 7.1 Introduction, 185 7.1.1 The Favorskii Rearrangement, 185 7.1.2 The Quasi-Favorskii Rearrangement, 189 7.2 Retrons of the Quasi-Favorskii Rearrangement, 191 7.3 Mechanistic Considerations in the Quasi-Favorskii Rearrangement, 192 7.4 The Preparation of Substrates for the Quasi-Favorskii Rearrangement, 193 7.5 Applications of the Quasi-Favorskii Rearrangement in Synthesis, 199 7.5.1 Methodology, 199 7.5.2 Natural Products, 205 7.5.3 Unnatural Products, 215 7.6 Conclusions and Prospects, 220 Acknowledgments, 222 References, 222

8 The Ramberg–Bäcklund Reaction 227 8.1 Introduction, 227 8.2 Methods to Synthesize Sulfones as RBR Precursors, 229 8.3 Variations of the RBR, 231 8.4 Mechanistic Evaluation of the RBR, 233 CONTENTS ix

8.5 Strategic Considerations Relevant to the Use of the RBR in Synthesis, 234 8.6 Utility, Scope, and Limitations of the RBR, 236 8.6.1 (Sterically Crowded) Acyclic Alkenes, 236 8.6.2 Acyclic Trisubstituted Alkenes, 239 8.6.3 Polyunsaturation, 240 8.6.4 Strained Cyclic Alkenes, 242 8.7 Recent Applications of the RBR in the Synthesis of Complex Target Structures, 246 8.7.1 Fawcettidine, 246 8.7.2 Cylindrocyclophanes A and F, 247 8.7.3 Hirsutellones A–C, 249 8.7.4 Aigialomycin D, 251 8.8 Concluding Remarks, 254 Acknowledgments, 256 References, 256

9 Applications of Di-𝛑-Methane and Related Rearrangement Reactions in Chemical Synthesis 261 9.1 Introduction: The Basic Process and its Variants, 261 9.2 Mechanistic Features and Competing Reactions, 265 9.3 Structural Requirements of Substrates and Matters of Regio- and Stereochemistry, 271 9.3.1 Basic Structural Requirements, 271 9.3.2 Matters of Regioselectivity, 273 9.3.3 Matters of Stereoselectivity, 275 9.4 Synthetic Routes to Substrates and Applications in Synthesis, 277 9.5 Outlook, 284 References, 285

PART III 1,3-TRANSPOSITIONS 289

10 Payne Rearrangement 291 10.1 Background on the Payne Rearrangement, 291 10.1.1 Payne Rearrangement, 291 10.1.2 Aza-Payne Rearrangement, 293 10.1.3 Thia-Payne Rearrangement, 295 10.2 Synthetic Applications of 2,3-Epoxy Alcohols, 295 10.2.1 Construction of Requisite Starting Materials for Payne Rearrangement, 295 10.2.2 Product Structures Accessible by Way of Payne Rearrangement, 297 x CONTENTS

10.3 Utilization of the Payne Rearrangement for the Preparation of Fluorine-Containing Compounds, 307 10.3.1 Payne Rearrangement for Trifluorinated Compounds, 308 10.3.2 Ring Opening of CF3-Containing Epoxy Alcohols by Nitrogen Nucleophiles, 312 10.4 Conclusion, 317 References, 318

11 Vinylcyclopropane–Cyclopentene Rearrangement 323 11.1 Introduction, 323 11.2 Thermal VCP–CP Rearrangement, 324 11.3 Acid-Mediated VCP–CP Rearrangement, 328 11.4 Mechanisms, 330 11.4.1 Mechanism of the Thermal Vinylcyclopentene Rearrangement, 330 11.4.2 Mechanism of the Acid-Mediated VCP–CP Rearrangement, 333 11.5 Heteroatom-Containing Analogues of the VCP–CP Rearrangement, 334 11.5.1 Mechanism, 335 11.6 Applications in Synthesis, 336 11.7 Photochemical VCP–CP Rearrangement, 340 11.7.1 Mechanism, 343 11.7.2 Applications in Synthesis, 344 11.8 Metal-Catalyzed VCP–CP Rearrangement, 346 11.8.1 Rh-Catalyzed VCP–Cyclopentene Rearrangement, 347 11.8.2 Mechanism, 347 11.8.3 Pd-Catalyzed VCP–Cyclopentene Rearrangement, 348 11.8.4 Mechanism, 350 11.8.5 Ni-Catalyzed VCP–Cyclopentene Rearrangement, 351 11.8.6 Mechanism, 353 11.9 Heteroatom Variants of the Metal-Catalyzed VCP–CP Rearrangement, 354 11.9.1 Mechanism, 356 11.9.2 Applications in Synthesis, 357 11.10 Summary and Outlook, 359 References, 360

12 Ferrier Carbocyclization Reaction 363 12.1 Introduction, 363 12.2 General Discussion and Mechanistic Features, 365 12.2.1 Reaction Conditions for the Ferrier Carbocyclization Reaction, 366 CONTENTS xi

12.2.2 Mechanism and Stereoselectivity of the Ferrier Carbocyclization Reaction, 370 12.3 Synthetic Strategies Based on the Ferrier Carbocyclization Reaction, 373 12.3.1 Inositol and Aminocyclitol Synthesis, 373 12.3.2 Combination of Ferrier Carbocyclization and Three-Component Coupling Reaction, 374 12.3.3 Combination of Ferrier Carbocyclization and Sigmatropic Rearrangement, 375 12.3.4 Enol-Acetate Version of the Ferrier Carbocyclization Reaction, 377 12.4 Methodologies for Assembling the Ferrier Carbocyclization Reaction Substrates, 377 12.5 Applications of the Ferrier Carbocyclization Reaction in Natural Product Synthesis, 380 12.5.1 Preparation of an Aminocyclitol: Synthesis of Hygromycin A, 380 12.5.2 Construction of a Polycyclic Alkaloid: Synthesis of Lycoricidine, 381 12.5.3 Three-Component Coupling Reaction: Synthesis of (−)- and (+)-Actinoboline, 383 12.5.4 Sigmatropic Rearrangement with Chirality Transfer (1): Synthesis of Galanthamine, 387 12.5.5 Sigmatropic Rearrangement with Chirality Transfer (2): Synthesis of Rapamycin, 388 12.5.6 Cascade Sigmatropic Rearrangement: Synthesis of Morphine, 390 12.5.7 Rearrangement of Enol Acetates (1): Synthesis of an Inositol Tetrakis(phosphate), 394 12.5.8 Rearrangement of Enol Acetates (2): Synthesis of Tetrodotoxin, 395 12.6 Conclusion, 397 References, 398

PART IV [3,3]- AND [2,3]-SIGMATROPIC REARRANGEMENTS 401

13 The Claisen Rearrangement 403 13.1 Introduction, 403 13.1.1 Fundamentals of the Claisen Rearrangement Reaction, 403 13.1.2 Functional Group Versatility: Claisen Rearrangement Reaction Variants, 405 13.1.3 Stereochemistry, 405 xii CONTENTS

13.2 Strategic Planning for the Claisen Rearrangement Reaction, 407 13.2.1 Identification of Structural Elements, 408 13.3 Mechanistic Features of the Claisen Rearrangement Reaction, 409 13.3.1 Diastereoselectivity: Acyclic Substrates, 409 13.3.2 Diastereoselectivity: Cyclic Substrates, 412 13.3.3 Reactivity: Effect of Substrate Substitution, 414 13.3.4 Reactivity: Choice of Claisen Variant, 417 13.4 Methodologies for Synthesis of Claisen Rearrangement Substrates, 417 13.4.1 Substrates Possessing Vinylic Ethers, 417 13.4.2 Substrates Possessing Ketene Acetals and Ketene Aminals, 420 13.5 Applications of the Claisen Rearrangement Reaction in Target-Oriented Synthesis, 421 13.5.1 Cananodine, 421 13.5.2 Basiliolides, 422 13.5.3 Ene–Diynes in Bergman Cyclization Reactions, 424 13.5.4 Azadirachtin, 424 13.6 Conclusions, 426 References, 427

14 [3,3]-Sigmatropic Rearrangements with Heteroatom–Heteroatom Bonds 431 14.1 Introduction, 431 14.2 [3,3]-Sigmatropic Rearrangements of N–O Bonds, 434 14.2.1 Synthesis of Benzofurans from O-Aryloxime Ethers, 434 14.2.2 Rearrangements of O-Vinyl Oximes to Pyrroles, 436 14.2.3 Rearrangements of O-Vinyl-N-Arylhydroxylamines to Indoles, 2-Amino-2′-Hydroxy-1,1′Biaryls, and 𝛼-Arylated Carbonyl Compounds, 437 14.2.4 𝛼-Oxygenation Using [3,3]-Rearrangements of O-Protected Oximes and O-Vinyl Hydroxamates, 441 14.3 [3,3]-Sigmatropic Rearrangements of N–N Bonds, 445 14.3.1 Piloty–Robinson Pyrrole Synthesis, 445 14.3.2 The Use of Hydrazones for Enolate Coupling, 448 14.3.3 Benzidine Rearrangement, 449 14.4 [3,3]-Rearrangements of N–N Bond Fragments that Eliminate N2, 451 14.4.1 Oxidant-Promoted N-Allylic Hydrazone Rearrangements, 452 14.4.2 Acid-Promoted N-Allylic Hydrazone Rearrangements, 452 14.5 Summary, 454 References, 455 CONTENTS xiii

15 [2,3]-Rearrangements of Ammonium Zwitterions 459 15.1 Introduction, 459 15.2 [2,3]-Meisenheimer Rearrangement of Amine N-Oxides, 460 15.2.1 General Discussion of [2,3]-Meisenheimer Rearrangement, 460 15.2.2 Synthesis Strategies Based on [2,3]-Meisenheimer Rearrangement, 461 15.2.3 Methodologies for Assembling Amine N-Oxide Substrates, 461 15.2.4 Applications of [2,3]-Meisenheimer Rearrangements in Synthesis, 462 15.2.5 Mechanistic Features Crucial for Synthetic Utility: Stereoselectivity, 467 15.3 [2,3]-Stevens Rearrangement of Ammonium Ylides, 479 15.3.1 General Discussion of [2,3]-Stevens Rearrangement, 479 15.3.2 Synthesis Strategies Based on [2,3]-Stevens Rearrangement, 479 15.3.3 Methodologies for Assembling the Ammonium Ylide Substrates, 480 15.3.4 Applications of [2,3]-Stevens Rearrangements in Synthesis, 483 15.3.5 Mechanistic Features Crucial for Synthetic Utility: Stereoselectivity, 485 15.4 Conclusion and Outlook, 492 References, 493

16 Oxonium Ylide Rearrangements in Synthesis 497 16.1 Introduction, 497 16.1.1 Oxonium Ylides: Generation and Rearrangement Reactions, 497 16.1.2 Strategic Planning, 499 16.1.3 Selectivity Aspects, 499 16.1.4 Substrate Preparation, 506 16.2 Applications in Synthesis: Oxonium Ylide [2,3]-Sigmatropic Rearrangements, 507 16.2.1 Tetrahydrofuran-Containing Targets, 507 16.2.2 Benzofuranone-Containing Targets, 514 16.2.3 Tetrahydropyran-Containing Targets, 516 16.2.4 Reaction via Bicyclic Oxonium Ylides, 521 16.3 Applications in Synthesis: Oxonium Ylide [1,2]-Stevens Rearrangements, 528 16.3.1 Dactylol, 532 16.3.2 Tigliane/Daphnane Skeleton, 534 xiv CONTENTS

16.3.3 Zaragozic Acid Core, 534 16.4 Concluding Remarks, 535 References, 536

17 The [2,3]-Wittig Rearrangement 539 17.1 Introduction, 539 17.2 [2,3]-Wittig Rearrangement of Allyl Propargyl Ethers, 541 17.3 Factors Determining [2,3]-Wittig Versus [1,2]-Wittig Rearrangement, 544 17.4 Acyclic [2,3]-Wittig Rearrangement of Propargyl-Allyl Ethers, 547 17.5 [2,3]-Wittig–Still Rearrangement, 552 17.6 Asymmetric [2,3]-Wittig Rearrangement, 554 17.7 Aza-[2,3]-Wittig Rearrangement, 555 17.8 Other Wittig Rearrangements and Miscellaneous, 560 17.9 Conclusion, 565 References, 565

18 The Mislow–Evans Rearrangement 569 18.1 Introduction, 569

Part 1 Mechanistic Aspects and the [2,3] Nature of the Rearrangement, 571 18.2 Configurational Lability of Allylic Sulfoxides, 571 18.2.1 Racemization of S-Chiral Sulfoxides, 571 18.2.2 Opportunities for Dynamic Kinetic Resolution, 572 18.3 Deuterium Labeling to Track [2,3] Pathway, 573 18.4 Transition State Features, 573 18.4.1 Transition State Structure, 573 18.4.2 Antibody Catalysis, 575 18.5 Equilibrium Between Sulfoxide and Sulfenate, 576 18.5.1 Position of Equilibrium, 576 18.5.2 Conversion of Allylic Alcohols to Allylic Sulfoxides, 578 18.5.3 Thiophilic Capture of the Sulfenate Ester, 578 18.6 Chirality Transfer, 579 18.6.1 Carbon to Sulfur, 579 18.6.2 Sulfur to Carbon, 579

Part 2 Synthetic Considerations and Applications, 580 18.7 Alkene Stereoselectivity, 580 18.8 Diastereoface Selectivity in the Rearrangement, 583 18.8.1 Diastereoselective Applications, 583 CONTENTS xv

18.8.2 Chemoselective Oxidation of Allylic Sulfides to Sulfoxides, 585 18.8.3 Influence of Sulfoxide Stereochemistry at Sulfur, 586 18.8.4 Additional Diastereoselective Examples, 590 18.9 Epimerizations via Mislow–Evans Rearrangement Sequences, 591 18.10 Vinyl Anion Synthons Accessible via Mislow–Evans Rearrangement, 593 18.10.1 Vinyl Anion Equivalents, 593 18.10.2 Dienal Vinyl Anion Synthon in a Double Mislow–Evans Process, 595 18.11 Sequential Processes Incorporating the Mislow–Evans Rearrangement, 598 18.11.1 Diels–Alder/Mislow–Evans, 598 18.11.2 Attempted 1,3-Dipolar Cycloaddition/Mislow–Evans, 601 18.11.3 Double Overman Rearrangement/Mislow–Evans, 602 18.11.4 Claisen Rearrangement/Mislow–Evans, 603 18.11.5 Aldol/Ireland–Claisen/Mislow–Evans, 606 18.11.6 Knoevenagel Condensation/Vinyl Sulfoxide Isomerization/Mislow–Evans, 607 18.11.7 Sulfenate-to-Sulfoxide Conversion and Olefination, 612 18.11.8 Generation of Sulfenate Anions for Pd-Mediated Cross-Coupling, 613 18.12 Heteroatom [2,3]-Rearrangement Variants, 614 18.12.1 Allylic Selenoxide [2,3]-Rearrangements, 614 18.12.2 Allylic Sulfimide Rearrangements, 616 18.12.3 Rearrangement of Allylic Nitro Compounds, 618 18.12.4 Allylic Halogen Oxide [2,3]-Rearrangements, 619 18.13 [2,3]-Rearrangements of Propargyl and Allenyl Sulfenates and Sulfoxides, 620 18.14 Conclusion, 622 References, 622

PART V IPSO REARRANGEMENTS 627

19 Smiles Rearrangements 629 19.1 Introduction, 629 19.2 Scope and Mechanistic Features, 632 19.2.1 Nature and Substitution of the Aryl Ring, 632 19.2.2 Properties of the Nucleophile and Leaving Group, 633 19.2.3 Chain Length of the Tether, 634 19.3 Application of Smiles Rearrangements, 635 19.3.1 Synthesis of Fused Heterocycles through Cascades Involving Smiles Rearrangements, 635 xvi CONTENTS

19.3.2 Julia–Kocienski and Related Reactions, 639 19.3.3 Ugi–Smiles Couplings, 646 19.3.4 Miscellaneous Use of the Smiles Rearrangement in Synthesis, 656 19.4 Conclusion, 657 References, 658

20 Pummerer-Type Reactions as Powerful Tools in Organic Synthesis 661 20.1 Introduction, 661 20.2 Classical Pummerer Reaction, 662 20.2.1 Mechanistic Considerations, 662 20.2.2 Substrates, 663 20.2.3 Applications of Classical Pummerer Rearrangement, 665 20.3 Vinylogous Pummerer Reaction, 674 20.4 Interrupted and Additive Pummerer Reactions, 680 20.5 Connective Pummerer Reaction, 687 20.6 Pummerer Rearrangement in Multiple-Reaction Processes, 693 20.7 Other Pummerer Rearrangements, 696 20.8 Summary and Outlook, 700 References, 700

INDEX 703 LIST OF CONTRIBUTORS

Laura L. Anderson, Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA Martin G. Banwell, Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, Australia Hongli Bao, Key Laboratory of Coal to Ethylene Glycol and Its Related Technol- ogy, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, China David J.-Y. D. Bon, Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, Australia Noritaka Chida, Department of Applied Chemistry, Keio University, Kohoku-ku, Yokohama, Japan Yoann Coquerel, Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, Marseille, France Donald Craig, Department of Chemistry, Imperial College London, South Kensington Campus, London, UK Laurent El Kaim, Laboratoire de Synthèse Organique, CNRS, Ecole Polytech- nique, ENSTA ParisTech – UMR 7652, Universtité Paris-Saclay, Palaiseau, France Xiaoming Feng, Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, P.R. China xviii LIST OF CONTRIBUTORS

Diego Gamba-Sánchez, Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry Department, Universidad de los Andes, Bogotá, Colombia Alison Xiang Gao, Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA Fabián Garzón-Posse, Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry Department, Universidad de los Andes, Bogotá, Colombia Gunda I. Georg, University of Minnesota, Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, Minneapolis, MN, USA Nicolas Gigant, Institut de Chimie Organique et Analytique, UMR 7311 CNRS, Université d’Orléans, rue de Chartres, Orléans Cedex 2, France Isabelle Gillaizeau, Institut de Chimie Organique et Analytique, UMR 7311 CNRS, Université d’Orléans, rue de Chartres, Orléans Cedex 2, France Laurence Grimaud, Département de Chimie, Ecole Normale Supérieure-PSL Research University, Paris, France; CNRS, UMR 8640, PASTEUR, Sorbonne Universités, UPMC Univ Paris 06, Paris, France Michael Harmata, Department of Chemistry, University of Missouri-Columbia, Columbia, MO, USA Joanne E. Harvey, School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand Trinh A. D. Holth, University of Minnesota, Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, Minneapolis, MN, USA Oliver E. Hutt, CSIRO, Industrial Chemistry and Biotechnology, Clayton South, Australia Minoru Isobe, Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, ROC Lili Lin, Key Laboratory of Green Chemistry and Technology, Ministry of Educa- tion, College of Chemistry, Sichuan University, Chengdu, P.R. China Xiaohua Liu, Key Laboratory of Green Chemistry and Technology,Ministry of Edu- cation, College of Chemistry, Sichuan University, Chengdu, P.R. China Janis Louie, Department of Chemistry, University of Utah, Salt Lake City, UT, USA Graham K. Murphy, Department of Chemistry, University of Waterloo, Waterloo, ON, Canada Chatchawan Ploysuk, Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, ROC LIST OF CONTRIBUTORS xix

Jean Rodriguez, Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, Marseille, France Christian M. Rojas, Department of Chemistry, Barnard College, New York, NY, USA Michiko Sasaki, Department of Synthetic Organic Chemistry, Institute of Biomed- ical and Health Sciences, Hiroshima University, Hiroshima, Japan Scott A. Snyder, Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA; Department of Chemistry, Columbia University, New York, NY, USA Kei Takeda, Department of Synthetic Organic Chemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan Uttam K. Tambar, Department of Biochemistry, The University of Texas South- western Medical Center at Dallas, Dallas, TX, USA Ashish Thakur, Department of Chemistry, University of Utah, Salt Lake City, UT, USA Stephen B. Thomas, Department of Chemistry, Columbia University, New York, NY, USA F. G. West, Department of Chemistry, University of Alberta, E3-43 Gunning- Lemieux Chemistry Centre, Edmonton, AB, Canada Takashi Yamazaki, Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan Lin Zhou, Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, P.R. China

PREFACE

There is an aesthetically pleasing quality – a Kekuléan snake-seizing-its-tail appeal – to molecular rearrangements. A chemist using the arrow-pushing formalism to outline a rearrangement reaction feels a certain tactile satisfaction in charting the electron flow, an aspect that makes these reactions fun for instructors to teachor for students to work through at the blackboard. Rearrangements often have perfect atom economy, satisfying the frugal: bonds reorganized and nothing wasted. In some cases, a small molecule or other appropriate leaving group is extruded, initiating the rearrangement; sometimes, a catalyst is involved. Whatever the details, molecular rearrangements possess an inherent elegance that makes them especially appealing to students and practitioners of organic chemistry. But molecular rearrangements do not just satisfy the intellect; they are irre- placeable tools in getting the work of organic chemical synthesis done. Different types of rearrangements enable synthetically useful operations, including ring expansions as in certain Beckmann rearrangements, ring-contracting reactions (e.g., the quasi-Favorskii and Ramberg–Bäcklund rearrangements), and functional group transpositions as occur in Payne and Mislow–Evans rearrangements. Another synthetically essential hallmark of many rearrangements is their stereospecificity, providing, as in the Claisen rearrangement, a means to parlay more readily estab- lished stereochemical features of the starting material into product stereochemistry that might otherwise be difficult to access. How to group different molecular rearrangements? There is an understandable desire to classify and categorize, to find common themes, but there are many possible points of comparison. One could focus on functionality within the starting mate- rial, the type of product accessible via the rearrangement, or the reaction mecha- nism. To a certain extent, however, any categorization scheme is idiosyncratic and xxii PREFACE imperfect. For example, mechanistic categorization can be difficult for certain reac- tions, such as the vinylcyclopropane–cyclopentene rearrangement, which may have mechanistic variants, including radical, ionic, or metal-catalyzed versions. In this book, rearrangements are sorted mainly by changes in connectivity during the reac- tion: 1,2-migrations, 1,3-transpositions, or ipso rearrangements. However, sigmat- ropic rearrangements of differing order, [3,3] versus [2,3], are grouped together as a mechanistic category so as to hew to tradition and not confound the reader. The purpose of this book is to provide readers with a clear and interesting point of departure for thought and further investigation. There is a clear focus on synthetic utility, analyzing how rearrangement reactions can meet challenges in the synthesis of complex molecular structures, including biologically active natural products. Impor- tantly, the chapters are not intended as comprehensive reviews, and each is rendered in a distinctive voice. Some chapters take a broad outlook, while others concentrate on the authors’ own contributions. Some chapters are more limited to the recent liter- ature, while others provide historical context and discuss seminal studies in addition to current examples. By highlighting key examples and describing recent progress in the field, this book aims to help stimulate creative rearrangement-mediated solutions to contemporary challenges in synthetic organic chemistry. In the realization of this volume, I am indebted foremost to the chapter authors for their willingness to participate in the project and their insightful, thorough treatment of the rearrangement topics. I am also grateful to Jonathan Rose, my editor at Wiley, for his patient guidance in completion of the book. Finally, I thank Ms. Jenny Lam for her invaluable assistance in compiling the manuscript components.

Christian M. Rojas Barnard College New York, NY March 2015 PART I

1,2-MIGRATIONS

1 PINACOL AND SEMIPINACOL REARRANGEMENTS IN TOTAL SYNTHESIS

Alison Xiang Gao Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA Stephen B. Thomas Department of Chemistry, Columbia University, NY, USA Scott A. Snyder Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA; Department of Chemistry, Columbia University, NY, USA

1.1 INTRODUCTION

Among the array of reactions available to alter molecular complexity, pinacol and semipinacol rearrangements have a particularly long history, constituting among the very first (if not the first) rearrangement reactions discovered by synthetic chemists.1 However, despite being known for over a century and a half, their use in complex natu- ral product synthesis has only recently come of age. Indeed, with a clearer understand- ing of the factors governingtheir regio- and stereoselectivity, as well as more powerful variants (including asymmetric) that can induce the rearrangement under mild con- ditions, these processes have a number of specific, but highly valuable, applications whose wealth is beginning to be tapped with ever greater frequency. This chapter seeks to provide a sense of the current state of the art of both pinacol and semipinacol processes, discussing each separately under the rubric of recent applications.

Molecular Rearrangements in Organic Synthesis, First Edition. Edited by Christian M. Rojas. © 2016 John Wiley & Sons, Inc. Published 2016 by John Wiley & Sons, Inc. 4 PINACOL AND SEMIPINACOL REARRANGEMENTS IN TOTAL SYNTHESIS

1.2 PINACOL REACTION

1.2.1 Background and Introduction We begin with the pinacol rearrangement, a reaction process whose name derives from the starting material used in the earliest known example of the transformation. That event, the exposure of pinacol (1, 2,3-dimethylbutane-2,3-diol; Scheme 1.1) to sulfuric acid, produced pinacolone (2, 3,3-dimethylbutane-2-one). Although this reaction was first performed by Fittig in 1860,2 it was not until the early 1870s that the actual structure of the product was confirmed by Butlerov3; this lapse not only reflects the challenges of determining structure in that era but also the fact that rear- rangements were effectively unknown. In fact, a contemporary publication by Kekulé (his seminal paper on representing organic structures) included rules which suggested that carbon skeletal rearrangements could not occur.4 Inanyevent,bytheendofthe 19th century, the overall process depicted for the conversion of 1 to 2 was clear in terms of starting material and product. As additional substrates proved amenable to the process, the term pinacol rearrangement has since been used more broadly to define the conversion of any acyclic or cyclic vicinal diol into an aldehyde or ketone under acidic (proton or Lewis) conditions.5 Critically, as with many other skeletal rearrangements, there are subtleties that define both its mechanism as well as the products that can be generated from agiven substrate under a specific set of reaction conditions. One early clue to that com- plexity derived from the observation by Danilov in 1917 that a single diol substrate (4) could yield different carbonyl-containing products (3 or 5) based solely on the strength of the acid deployed (Scheme 1.1b).6 Although these outcomes reflect kinetic control, that analysis, in and of itself, is insufficient given that separate study has shown that both 4 and 5 can interconvert, suggesting the prospect of reversibility as part of the pinacol rearrangement process itself. Indeed, that concept was beauti- fully illustrated by Fry in a subsequent series of elegant 14C-labeling studies which showed the transposition of carbon atoms of an array of pinacol “products” exposed to strongly acidic conditions (Scheme 1.1d).7 A second critical observation resides in the fact that a number of pinacol rearrangements produce epoxides in addition to the standard carbonyl-containing adduct. In some cases, these materials can be induced to rearrange to standard pinacol products, while in others, they are inert to the reaction conditions. Finally, there is a wide range of contexts, employing both protic acids and Lewis acids under varying reaction conditions, that can induce the rearrangement to occur for most individual substrates (with expected variations in yield). Collectively, these findings indicate that very few mechanistic conclusions can be drawn in general terms for all diols under all conditions. However, what is reasonable to presume, and/or consider, is participation of a substrate along the generalized mechanistic process shown in Scheme 1.1 while concurrently taking into account what is reasonable to occur under a given set of conditions. For instance, in strongly acidic aqueous media, diol substrate 6 is likely in equilibrium with epoxide 8, with the more stabilized cation (7) being both the connecting intermediate and the active species for rearrangement (Scheme 1.1c). In this mechanistic paradigm, either 6 or (a) Original discovery [Fittig, 1860] (c) Key mechanistic consideration: diol/epoxide equilibrium

HO OH O OH O H2SO4 R R R R R R R R 1 2 7 8

(b) Controlling product distribution [Danilov, 1917] protic acid or Lewis acid O conc. HO OH 40% O O H SO H SO HO OH Ph 2 4 2 4 Ph R Ph Ph Ph H R Ph H Ph R R R Ph Ph R R R 3 4 5 6 9

(d) Radiolabelling studies (e) Stereochemistry studies OH OH O OH aq. O strong O HClO acid OH 4 * O * (93%) (7%) O strong O OH aq. O OH HClO Ph acid Ph 4 * Ph * Ph OH Ph Ph OH Ph Ph O (97%) (3%) Scheme 1.1 The pinacol rearrangement: discovery and key considerations.

5 6 PINACOL AND SEMIPINACOL REARRANGEMENTS IN TOTAL SYNTHESIS

8 could be viewed as a reasonable starting material for the pinacol rearrangement, with the two substrates being effectively equivalent from a product-determining per- spective. Under milder conditions, particularly as promoted by Lewis acids and/or when a good nucleophile is present, alternate pathways may proceed from 6, 7, and/or 8 to afford isolable intermediates and/or side products in addition to the desired pina- col adduct. To put these thoughts, and the dozens of successful examples of the process, in more specific terms, the following generalizations can be made about pinacol rear- rangements: • Virtually any cyclic or acyclic vicinal diol can undergo the rearrangement, with aldehydes or ketones formed based solely on the substitution pattern of the diol. • The reaction occurs in an exclusively intramolecular fashion. As such, symmet- rical diols will yield a single product, while unsymmetrical diols may lead to product mixtures. • The product is formed via the more stable carbocation intermediate, with the final product determined by the migratory aptitude of the substituents at the neighboring alcohol-bearing carbon. What the pinacol rearrangement provides from a strategic perspective is the abil- ity to generate carbonyl compounds with a high degree of substitution at the alpha position (particularly tertiary and quaternary systems), as well as to effect ring con- traction and/or expansion with a high degree of regiocontrol in appropriate systems. Few other, if any, methods provide access to such products as readily. Equally important is the following additional observation:

• The reaction can proceed with a high degree of stereoselectivity with appropri- ate substrates, especially cyclic diols.

1.2.2 Stereochemistry of the Pinacol Rearrangement The alignment of orbitals as part of the bond migration itself ensures that stereo- chemical information encoded in the starting material can be expressed with high fidelity in the rearrangement if the substrate is designed appropriately. Again, however, it is critical to note that substrate-specific subtleties can also play a role. One representative example along these lines rounds out the presentation in Scheme 1.1. In this work by Bunton and Carr, exposure of two different diastere- ∘ omers of 1,2-dimethyl-1,2-cyclohexanediol to aqueous HClO4 at 60 C afforded nearly indistinguishable distributions of two products, favoring the expected ring-contracted adduct (Scheme 1.1e).8 This outcome suggests the intermediacy of the same carbocation intermediate. However, because the final product distributions are not exactly identical, there must be a slight stereochemical memory effect that contributes to (but clearly does not dominate) the reaction process. Intriguingly, even larger differences are found with analogous five-membered systems. This key component of effecting stereocontrol will be a critical point of discussion in the case studies that follow in later sections.