Table of Contents

Preface xv

List of Contributors xvii

1 Chorismate-Mutase-Catalyzed Claisen Rearrangement 1
Hong Guo and Niny Rao

1.1 Introduction 1

1.2 Experimental Studies 2

1.2.1 Substrate Binding 2

1.2.2 Substrate Structural Requirements for Catalysis 3

1.2.3 X-ray Structures of Chorismate Mutase 4

1.2.4 Effects of Mutations 6

1.2.5 Activation Parameters 8

1.3 Catalytic Mechanism of Chorismate Mutase 9

1.3.1 Stabilization of Transition State by Active Site Residues 9

1.3.2 Substrate Conformational Transition and the Role of Active Site Residues 10

1.3.3 Contribution of the Near Attack Conformers (NACs) 16

1.3.4 Strain Effects and Conformational Compression 19

1.4 Conclusion 20

References 21

2 Chiral-Metal-Complex-Catalyzed Aliphatic Claisen Rearrangement 25
Koichi Mikami and Katsuhiro Akiyama

2.1 Introduction 25

2.2 Binding Modes of Main-group and Late Transition Metals 26

2.3 Aluminum(III)-promoted Claisen Rearrangement 26

2.4 Copper(II)-catalyzed Claisen Rearrangement 32

2.5 Palladium(II)-catalyzed Claisen Rearrangement 38

References 42

3 Aliphatic and Aromatic Claisen Rearrangement 45
3.1 Aliphatic Claisen Rearrangement 45

Hayato Ichikawa and Keiji Maruoka

3.1.1 Introduction 45

3.1.2 Synthesis of Allyl Vinyl Ethers 46

3.1.2.1 Hg-Catalyzed Synthesis 46

3.1.2.2 From Ammonium Betaine 46

3.1.2.3 Acid-Catalyzed Synthesis 46

3.1.2.4 Wittig Olefination 47

3.1.2.5 Sulfoxide Elimination 47

3.1.2.6 Selenoxide Elimination 49

3.1.2.7 From Ketal 49

3.1.2.8 From Allene 50

3.1.2.9 Ir-Catalyzed Synthesis 51

3.1.2.10 Cu-Catalyzed Synthesis 51

3.1.2.11 Tebbe Reagent 52

3.1.3 Acyclic Aliphatic Claisen Rearrangement 53

3.1.3.1 Transition State of Aliphatic Claisen Rearrangement 53

3.1.3.2 Secondary Allylic Ethers 54

3.1.3.3 Substituted Vinyl Ethers 56

3.1.3.4 Allyl Allenyl Ethers 57

3.1.3.5 Disubstituted Vinyl Ether 58

3.1.3.6 Water-Promoted Claisen Rearrangement 59

3.1.3.7 Diastereoselective Rearrangement Using Chiral Sulfoxide Groups 60

3.1.4 Claisen Rearrangement of Cyclic Allyl Vinyl Ethers 62

3.1.4.1 Ring Expansion Claisen Rearrangement 62

3.1.4.2 Cyclohexene Synthesis 68

3.1.5 Cyclic Vinyl Ethers 68

3.1.6 Cyclic Allyl Ethers 70

3.1.7 Tandem Reactions Including Aliphatic Claisen Rearrangement 71

3.1.7.1 Vinylation/Claisen Rearrangement 71

3.1.7.2 Allylation/Claisen Rearrangement 73

3.1.7.3 Anionic Cyclization/Claisen Rearrangement 74

3.1.7.4 Claisen Rearrangement/Ene Reaction 75

3.1.7.5 Claisen Rearrangement/Conia-Type Oxa-Ene Reaction 77

3.1.7.6 Oxy-Cope/Ene/Claisen Rearrangement 78

3.1.8 The Carbanion-Accelerated Claisen Rearrangement 78

3.1.8.1 Sulfonyl-Stabilized Anions 78

3.1.8.2 Phosphine Oxide and Phosphonate-Stabilized Anions 80

3.1.8.3 Phosphonamide-Stabilized Anions 82

3.1.9 Conclusion 83

References 83

3.2 Aromatic Claisen Rearrangement 86
Hisanaka Ito and Takeo Taguchi

3.2.1 Introduction 86

3.2.2 Mechanism 86

3.2.2.1 Ortho and Para Rearrangement 86

3.2.2.2 Transition State 87

3.2.2.3 Abnormal Claisen Rearrangement 88

3.2.3 Substrate and Substituent Effect 89

3.2.3.1 Preparation of Substrate 89

3.2.3.2 Aryl Unit 89

3.2.3.3 Allyl and Propargyl Unit 90

3.2.4 Reaction Conditions 92

3.2.4.1 Thermal Conditions 93

3.2.4.2 Solvent Effect 93

3.2.4.3 Brønsted Acid Catalyst 94

3.2.4.4 Lewis Acid Catalyst 94

3.2.4.5 Base Catalyst 96

3.2.4.6 Transition Metal Catalyst 97

3.2.4.7 Other Conditions 97

3.2.5 Thio-, Amino-, and Related Claisen Rearrangement 99

3.2.6 Asymmetric Synthesis 102

3.2.6.1 Intramolecular Chirality Transfer 102

3.2.6.2 Enantioselective Rearrangement 104

3.2.7 Synthetic Applications 104

3.2.7.1 Consecutive Cyclization 105

3.2.7.2 Tandem Reaction 106

3.2.7.3 Functional Molecule 109

3.2.7.4 Natural Products and Biologically Active Compounds 110

References 113

4 The Ireland–Claisen Rearrangement (1972–2004) 117
Christopher M. McFarland and Matthias C. McIntosh

4.1 Introduction 117

4.2 History 118

4.3 Numbering and Nomenclature 119

4.4 Rearrangement Temperature, Substituent Effects and Catalysis 120

4.4.1 Rearrangement Temperature 120

4.4.2 Substituent Effects 122

4.4.3 Catalysis 123

4.4.3.1 Pd(II) Catalysis 123

4.4.3.2 Lewis Acid Catalysis 123

4.4.3.3 Phosphine Catalysis 124

4.5 Transition State Structure 125

4.5.1 Isotope Effect Studies 125

4.5.1.1 Deuterium Isotope Effects 125

4.5.1.2 14C Isotope Effects 126

4.5.2 Theoretical Studies 126

4.5.2.1 Calculated vs. Experimental Isotope Effects and Transition State Structure 126

4.5.2.2 Cyclohexenyl Allyl Methyl Ketene Acetals 127

4.6 Stereochemical Aspects 128

4.6.1 Simple Diastereoselection: Chair vs. Boat Transition States 128

4.6.1.1 Enolate and Silyl Ketene Acetal Geometry 128

4.6.1.2 Acyclic Allyl Silyl Ketene Acetals 129

4.6.2 Diastereoface Differentiation: Cyclic Allyl Silyl Ketene Acetals 129

4.6.3 Alkene Stereochemistry 131

4.6.4 Chirality Transfer 131

4.6.4.1 Allylic Esters Possessing One Stereocenter: Absolute Stereocontrol 131

4.6.4.2 Allylic Esters Possessing Multiple Stereocenters: Relative Stereocontrol 132

4.6.5 Influence of Remote Stereocenters 135

4.6.5.1 C1′ Stereocenters 135

4.6.5.2 C5′ Stereocenters 140

4.6.5.3 C6′ Stereocenters 141

4.6.5.4 Other Remote Stereocenters 144

4.6.6 Chiral Auxiliary Mediated Asymmetric Ireland–Claisen Rearrangements 145

4.6.6.1 Chiral Glycolates 145

4.6.6.2 Chiral Glycinates 146

4.6.6.3 Chiral Boron Ketene Acetals 147

4.7 Methods of Ketene Acetal Formation 147

4.7.1 Chemoselective Deprotonations 148

4.7.1.1 Ester vs. Ketone 148

4.7.1.2 Ester vs. Butenolide 149

4.7.1.3 Ester vs. Branched Ester 149

4.7.2 ϒ-Deprotonations of Allyl Acrylates 149

4.7.3 Silyl Triflates and Tertiary Amine Bases 150

4.7.4 N,O-Bis(trimethylsilyl)acetamide and CuOTf 151

4.7.5 1,4-Additions 152

4.7.5.1 By Alkyl Cu Reagents 152

4.7.5.2 By Alkyl Radicals 153

4.7.5.3 By Enolates 153

4.7.5.4 By Silanes 154

4.7.6 Electrochemical Reduction 154

4.7.7 Diels–Alder Cycloaddition 155

4.7.8 Brook Rearrangement 155

4.7.9 Boron Ketene Acetals 156

4.7.10 Post-Rearrangement Enolization 157

4.8 Structural Variations in Allylic Esters 158

4.8.1 Allylic Esters with a-Heteroatoms 158

4.8.1.1 Glycolates 158

4.8.1.2 Lactates 162

4.8.1.3 Mandelates 163

4.8.1.4 Other Higher Esters 163

4.8.1.5 Glycinates and Other Higher Esters 164

4.8.2 Allyl Silanes and Stannanes 165

4.8.3 Glycals 167

4.8.4 Allyl Lactones 168

4.8.4.1 Lactones with Exocyclic Allylic Alkenes 169

4.8.4.2 Lactones with Endocyclic Allylic Alkenes 171

4.8.5 Tertiary Alcohol-Derived Allylic Esters 175

4.8.6 bis-Allylic Esters 178

4.8.7 Fe-Diene Complexes 179

4.8.8 Hindered Esters 179

4.9 Applications to Natural Product Synthesis 180

4.9.1 Prostanoids 180

4.9.2 Nonactic Acid 181

4.9.3 Lasalocid A 181

4.9.4 Tirandamycic Acid 182

4.9.5 Monensin A 183

4.9.6 Sphydofuran 185

4.9.7 Calcimycin 185

4.9.8 Ceroplasteric Acid 186

4.9.9 Erythronolide A 187

4.9.10 Ebelactone A and B 187

4.9.11 25-OH Vitamin D2 Grundmann Ketone 188

4.9.12 Zincophorin 188

4.9.13 Steroid Side Chain Homologation 189

4.9.14 Pseudomonic Acid C 189

4.9.15 Pine Sawfly Pheromone 190

4.9.16 Asteltoxin 191

4.9.17 Breynolide 191

4.9.18 Methyl Ydiginate 192

4.9.19 (–)-Petasinecine 192

4.9.20 β-Elemene 193

4.9.21 (+)-Dolabellatrienone 193

4.9.22 2-Keto-3-Deoxy-Octonic Acid (KDO) 194

4.9.23 Methylenolactocin 194

4.9.24 Eupomatilones 195

4.9.25 Trichothecenes 195

4.9.26 (+-)-Widdrol 196

4.9.27 Equisetin 197

4.9.28 Muscone 197

4.9.29 Quadrone 198

4.9.30 Ingenanes 198

4.9.31 (+-)-Samin 200

4.9.32 (+)-Monomorine 200

4.9.33 Dictyols 201

4.10 Propargyl Esters 201

4.11 Conclusion 203

References 205

5 Simple and Chelate Enolate Claisen Rearrangement 211

5.1 Simple Enolate Claisen Rearrangement 211
Mukund G. Kulkarni

5.1.1 Introduction 211

5.1.2 History 212

5.1.3 Simple Enolates of Allylic Esters 214

5.1.4 Stereoselectivity in Enolate Formation 220

5.1.5 Simple Enolates of Allylic Esters of α-Hetero Acids 223

5.1.6 Simple Enolates of N-Allyl Amides 226

5.1.7 Miscellaneous Enolates 229

5.1.8 Conclusion 230

References 231

5.2 Chelate Enolate Claisen Rearrangement 233
Uli Kazmaier

5.2.1 Introduction 233

5.2.2 Claisen Rearrangements of Substrates with Chelating Substituents in the α-Position 234

5.2.2.1 Rearrangement of α-Hydroxy Substituted Allylic Esters 234

5.2.2.2 Rearrangement of α-Alkoxy-Substituted Allylic Esters 239

5.2.2.3 α-Amido Substituents 256

5.2.2.4 Rearrangement of α-Thio Substituted Allylic Esters 288

5.2.3 Claisen Rearrangements of Substrates Bearing Chelating Substituents in the β-Position 289

5.2.3.1 β-Hydroxy Substituents 289

5.2.3.2 β-Alkoxy Substitutents 291

5.2.2.3 β-Amino Substituted Substrates 291

5.2.4 Chelation Controlled Aza-Claisen Rearrangements 293

References 295

6 Claisen–Johnson Orthoester Rearrangement 301
Yves Langlois

6.1 Introduction 301

6.2 Historical Overview 301

6.3 Mechanistic Aspects 303

6.3.1 Reactivity 303

6.3.2 Stereoselectivity 306

6.3.3 Alternatives to the Orthoester Rearrangement 310

6.4 Synthetic Applications 312

6.4.1 Terpenes, Fatty Acids, and Polyketide Derivatives 312

6.4.2 Steroids 332

6.4.2.1 Syntheses of the Tetracyclic Core of Steroids 332

6.4.2.2 Syntheses of Steroid Side Chains 335

6.4.3 Alkaloids 340

6.4.3.1 Indole Alkaloids 340

6.4.3.2 Other Alkaloids 345

6.4.4 Carbohydrates 347

6.4.5 Miscellaneous Compounds 349

6.5 Conclusion 361

References 362

7 The Meerwein–Eschenmoser–Claisen Rearrangement 367
Stefan N. Gradl and Dirk Trauner

7.1 Definition, Discovery and Scope 367

7.2 Formation of Ketene N,O-Acetals 370

7.2.1 Condensation with Amide Acetals or Ketene Acetals (Eschenmoser–Claisen Rearrangement) 370

7.2.2 Addition of Alkoxides to Amidinium Ions (Meerwein–Claisen Rearrangement) 372

7.2.3 Addition of Alcohols to Ynamines and Ynamides (Ficini–Claisen Rearrangement) 373

7.2.4 Miscellaneous Methods 374

7.3 Selectivity 376

7.3.1 Regioselectivity 376

7.3.2 Stereoselectivity 377

7.3.2.1 Cyclic Allylic Alcohols 377

7.3.2.2 Acyclic Allylic Alcohols 378

7.4 Applications in Synthesis 385

References 394

8 The Carroll Rearrangement 397
Mark A. Hatcher and Gary H. Posner

8.1 Introduction 397

8.2 Mechanism 398

8.3 Synthetic Applications 401

8.3.1 Tertiary and Quaternary Carbon Bond Formation 401

8.3.2 Natural Products 406

8.3.3 Steroidal Side-Chain Formation 412

8.3.4 Aromatic Carroll Rearrangements 415

8.4 Carroll Variants 419

8.4.1 α-Sulfonyl Carroll Rearrangement 419

8.4.2 Asymmetric Carroll Rearrangement 422

8.4.3 Metal-Catalyzed Carroll Rearrangement 426

8.5 Conclusion 429

References 429

9 Thio-Claisen Rearrangement 431
Stéphane Perrio, Vincent Reboul, Carole Alayrac, and Patrick Metzner

9.1 Introduction 431

9.1.1 Early Developments 431

9.1.1.1 Aromatic and Heteroaromatic Series 431

9.1.1.2 Aliphatic Series 433

9.1.2 Specificities of the Sulfur Version – Kinetics Versus Thermodynamics 433

9.1.3 Reviews 435

9.2 Basic Versions 435

9.2.1 Flexible Synthesis of the Substrates 435

9.2.2 Scope and Limitations, Reaction Conditions 437

9.2.2.1 Synthesis of Unsaturated Aldehydes (via Transient Thioaldehydes) 437

9.2.2.2 Thioketones 437

9.2.2.3 Dithioesters 437

9.2.2.4 Thionesters 438

9.2.2.5 Thioamides 439

9.2.2.6 Thioketenes 439

9.2.2.7 Rearrangement of Tricoordinated Sulfur Derivatives: Sulfonium Salts or Sulfoxides 440

9.2.3 Catalysis 441

9.3 Rearrangement with Stereochemical Control 441

9.3.1 Relative Control Exclusively Through Double-Bond Configurations 442

9.3.2 Control Through an Asymmetric Carbon Center 443

9.3.3 Stereogenic Sulfur Center 446

9.3.4 Cyclic Chiral Auxiliary 447

9.3.5 Axial Chirality 449

9.4 Applications in Organic Synthesis 449

9.4.1 Synthesis of Heterocycles 449

9.4.2 Synthesis of Natural Products and Construction of Building Blocks 451

9.5 Conclusion 455

References 455

10 Aza-Claisen Rearrangement 461
Udo Nubbemeyer

10.1 Introduction 461

10.2 Aromatic Simple Aza-Claisen Rearrangements 461

10.3 Aliphatic Simple Aza-Claisen Rearrangements 471

10.4 Amide Acetal and Amide Enolate Claisen Rearrangements 483

10.5 Zwitterionic Aza-Claisen Rearrangements 490

10.5.1 Alkyne Carbonester Aza-Claisen Rearrangements 491

10.5.2 Ketene Aza-Claisen Rearrangements 494

10.5.3 Allene Carbonester Aza-Claisen Rearrangements 511

10.6 Alkyne Aza-Claisen Rearrangements 512

10.7 Iminoketene Claisen Rearrangements 515

References 519

11 Mechanistic Aspects of the Aliphatic Claisen Rearrangement 525
Julia Rehbein and Martin Hiersemann

References 556

Subject Index 559

About the Author

Martin Hiersemann was born 1966 in Berlin, Germany. He received his Ph.D. in 1995 under the guidance of Johann Mulzer at the Freie Universitat Berlin. After postdoctoral stay with Gary A. Molander at the University of Colorado, he started his independent research at the Dresden University of Technology in the fall of 1997. He was a visiting scientist at the University of Tsukuba in the group of Akira Hosomi in 2002, at Harvard University in the group of David A. Evans in 2003 and at the Montana State University with Paul A. Grieco in 2004. His research activities are concerned with the catalysis of sigmatropic rearrangements as well as natural product synthesis.

Udo Nubbemeyer received his Diploma and PhD in the group of Prof. Dr. E. Winterfeldt (University of Hannover) and spent a postdoctoral spell at the Ciba-Geigy Laboratory at the University of Fribourg (Switzerland) with Prof. D. Bellus and Dr. B. Ernst (1989/1990). From 1991 to 1996, he worked on his 'Habilitation' in the group of Prof. Dr. J. Mulzer (Freie Universitat Berlin). Then, he passed an assistant lecturer period in Berlin and a temporary professorship at the TU Dresden (1999/2001). Actually, he works as an associate professor at the Johannes Gutenberg-Universitat of Mainz. His major topics of interest are olefin synthesis, aza Claisen rearrangements, radical cyclizations, medium-sized rings, total synthesis of natural and pharmaceutically important products, alkaloids, eicosanoids, steroids, and amino acids.

Reviews

"...The book commends itselfs by its lucid arrangement of the material and the wealth of material that is covered. It gives a broad overview of methodologies of this old reaction and their application in modern synthetic chemistry and is recommended in particular to PhD students, but of course also to all other chemists in academy and industry."
Advanced Synthesis & Catalysis, 07/2007

"...Insgesamt lässt sich The Claisen Rearrangementallen Wissenschaftlern an der Hochschule oder aus der Industrie empfehlen, die sich im weitesten Sinne mit (3,3)-sigmatropen Umlagerungen befassen. Einige Teilkapitel sind auch bestens zur Prüfungsvorbereitung geeignet. Nach fast einem Jahrhundert seit der Entdeckung der Claisen-Umlagerung bietet dieses Buch somit eine gelungene Abhandlung einer bedeitsamen Reaktionsklasse der organischen Chemie."
Angewandte Chemie, 10/2007