Streamlining Free Radical Green Chemistry

V. Tamara Perchyonok VTPCHEM PTY LTD, Melbourne, Victoria, Australia

Ioannis Lykakis Department of Chemistry, University of Crete, Voutes-Heraklion, Greece

AI Postigo Faculty of Science, University of Belgrano, Buenos Aires, Argentina

RSC Publishing Contents

and Chapter 1 Development of Free Radical Green Chemistry Technology: Journey through Times, Solvents, Causes, Effects and Assessments

1.1 Introduction 1 1.2 The Major Use of Free Radical Green Chemistry from the Beginning 4 4 1.3 Alternative Feedstocks 5 1.3.1 Innocuous or More Innocuous 1.3.2 Renewable 5 1.3.3 Light 5 1.3.4 Solve Other Environmental Problems 6 1.3.5 Biocatalysis 6 7 1.4 Benign Reagents/Synthetic Pathways 7 1.4.1 Innocuous or More Innocuous 1.4.2 Generates Less Waste 7 1.4.3 Selective 8 1.4.4 Catalytic 8 8 1.5 Biomass: Utilization and Sustainability 9 1.6 Green Chemical Syntheses and Processes 1.7 Basic Radical Chemistry: Structure, Reactions and Rates 10 1.7.1 General Aspects of Synthesis with Radicals: Advantages and Traditions 10 1.7.2 Reactions Between Radicals 10 1.7.3 Reaction Between a Radical and a Non-radical 10 1.7.4 Reactivity and Selectivity 11 11 1.7.5 Enthalpy: In Brief 13 1.7.6 Entropy 1.7.7 Steric Effects 14 1.7.8 Stereoelectronic Effects 15

Streamlining Free Radical Green Chemistry V. Tamara Perchyonok, Ioannis Lykakis and Al Postigo 2012 © V. Tamara Perchyonok, Ioannis Lykakis and AI Postigo Published by the Royal Society of Chemistry, www.rsc.org

ix X Contents

1.7.9 Polarity 17 1.8 Solvent Effect and Free Radical Transformations: General Understanding 17 22 1.9 Why Water as a Solvent? Reasons and Advantages 1.9.1 Solubility of Organic Compounds in Water 23 1.9.2 Organic Cosolvents 23 1.9.3 Ionic Derivatization (pH Control) 24 1.9.4 Surfactants 24 1.9.5 Hydrophilic Auxiliaries 25 1.9.6 Summary 25 1.10 Classical Synthesis in Modern Solvents 25 1.10.1 Perfluorinated Solvents—a Novel Reaction Medium in Organic Chemistry: General Introduction 26 1.10.2 Benzotrifluoride and Derivatives: Useful Solvents for Organic Synthesis and Fluorous Synthesis 28 1.10.3 Reactions in Supercritical Carbon Dioxide 29 (SCCO2) as a Novel Reaction Medium 1.10.4 Solvent-free Reactions as an Alternative: General Interest for Solvent-free Processes 29 1.11 Methods of Generating Free Radicals 31 1.11.1 Thermal Cracking 31 1.11.2 Homolysis of Peroxides and Azo Compounds 32 1.11.3 Photolytic Bond Homolysis 32 1.11.4 Electron Transfer 32 1.11.5 Hydrogen and Halogen Atom Abstraction 33 1.11.6 The Configuration of Free Radicals 33 1.11.7 Elementary Reaction Steps between Radicals and Non-radicals: Reactions of Free Radicals 34 1.12 Sustainable Chemistry Metrics and Radical Chemistry: Comparative Approach 35 1.12.1 Classical Metrics of Chemical Reactions 36 1.12.2 How do Contemporary Free Radical Transformations Hold Up? Focus on Sustainability, Atom Efficiency and Advantages 38 1.13 Classics and Catalysis in Free Radical Chemistry: Reagents, Reactants and Protocols 45 1.14 Radical cascades and Free Radical Green Chemistry 46 1.15 Artificial Enzymes in Free Radical Synthetic Chemistry: the Chemist's Perspective 47 1.16 Future Challenges and Opportunities for the Chemical Profession and the Science of Chemistry 48 Streamlining Free Radical Green Chemistry xi

1.17 An Environmentally Friendly Economy from Green Chemistry 49 1.17.1 Renewable Energy Sources 49 1.17.2 Renewable Feedstocks 50 1.17.3 Pollution Reduction 50 1.17.4 Interdisciplinary Approach 50 1.18 Conclusion and Future Direction 51 References 51

in Chapter 2 Classical Synthetic Free Radical Transformations Alternative Media: Supercritical C02, Ionic Liquids and Fluorous Media

2.1 Introduction 58 2.2 Radicals in Synthetic Chemistry in the Nutshell 58 2.3 Reactions between Radicals 59 2.4 Elementary Reaction Steps between Radicals and Non-radicals 60 2.4.1 Additions 61 2.4.2 Substitution (Abstraction) Reactions 63 2.4.3 Elimination Reactions 64 2.4.4 Rearrangement Reactions 64 2.4.5 Termination/Electron Transfer Reactions 65 2.5 Reactivity and Selectivity 65 Processes: 2.6 Chain vs. Non-chain Free Radical 66 Reasons, Relevance and Outlook 2.7 Radical Reactions in Supercritical Fluids 66 2.7.1 Radical Reactions and Supercritical C02: Is 66 There a Hidden Advantage? 2.7.2 Radical Reactions in Supercritical Carbon Dioxide in Detail 68

2.7.3 Future Directions 70 2.8 Radical Reactions in Ionic Liquids 72 2.8.1 Ionic Liquids and Alternative Media: General Introduction 72 2.8.2 Radical Chain Reactions in Ionic Liquids: Triethylborane-induced Radical Reactions 72 2.8.3 Radical Additions of Thiols to Alkenes and Alkynes in Ionic Liquids 73 2.9 Radical Non-Chain Reactions in Ionic Liquids 75 2.9.1 Formation of Radicals by Oxidation with Transition Metal Salts: General Perspective 75 2.9.2 Oxidations involving Mn(in) in Ionic Liquids 75 xii Contents

2.9.3 Supported Ionic Liquids: Versatile Reaction and Separation Media—the Latest Developments 79 2.9.4 Conclusions and Future Directions 80

2.10 Fluorous Chemistry as an Alternative Reaction Medium for Free Radical Transformations 81 2.10.1 Fluorous Separation Techniques: from "Liquid-Liquid" to "Solid-Liquid" and "Light Fluorous" 81 2.10.2 Fluorous Chemistry and Radicals— Combined Efforts to the Rescue 83 2.10.3 Fluorous Radical Carbonylation Reactions: from Synthetic Approach to Practical Applications 83 2.11 Ishii Oxidation in Detail 89 2.12 From Phase-separation to Phase-vanishing Methods based on Fluorous-phase Screen: a Simple Way for the Efficient Execution of Organic Synthesis 91 2.13 Conclusions and Future Directions in Fluorous Chemistry 93 2.14 General Conclusion 93 References 94

Chapter 3 Solvent-Free Carbon-Carbon Bond Formations in Ball Mills and in the Solid State

3.1 Introduction 99 3.2 Radical Additions to Imines Mediated by Mn(m) 102 3.3 Solid-phase Homolytic Substitution in Action 102 3.4 Future Directions 104 References 104

Chapter 4 Microwaves in Synthesis: How do Microwaves Promote the Reaction in Conventional and Alternative Media?

4.1 Introduction 106 4.2 Microwave-assisted Fluorous Synthesis 107 4.3 Nitroxide-mediated Radical Cyclization and Intramolecular Addition Reactions In Microwaves 107 4.3.1 The Persistent Radical Effect: General Introduction 107 4.4 Radical Addition to C=N bonds in the Microwave 110 4.5 Microwave-assisted Generation of Alkoxyl Radicals and their Use in Additions, P- Fragmentations and Remote Functionalization 113 Streamlining Free Radical Green Chemistry xiii

4.6 Atom-transfer Reactions as Efficient and Novel Benzannulation Reactions in the Microwave 114 4.7 Conclusions and Future Directions 115 References 115

Chapter 5 Asymmetric Free-Radical Reductions Mediated by Chiral Stannanes, Germanes, and Silanes

5.1 Introduction 117 5.2 Stoichiometric Free Radical Reductions 118 5.3 Scope and Limitations 120 5.4 Examples Relevant to the Fine Chemical Industry 121 5.5 Strategies for the Avoidance of Tin Waste 121 5.6 Immobilization of Tin Reagents 122 5.7 Catalytic Reductions in Tin 123 5.8 Reducing Agents based on Germanium and Silicon 123 5.9 Summary 125 References 125

Chapter 6 Organic Radical Reductions in Water: Water as a Hydrogen Atom Source

6.1 Introduction 127 6.2 Water-soluble Organosilanes and Synthesis 128 6.3 rrw(trimethylsilyl)silane in Water and "on Water" 129 6.4 Triethylborane-Water Complex as a Reducing Agent 134 6.5 Titanium(m)-Water as a Reducing Agent 135 6.6 Summary 136 References 137

Chapter 7 Tin-Free Radical Reactions Mediated by Organoboron Compounds

7.1 Introduction 140 7.2 Organoboranes as Radical Initiators 141 7.3 In Reductive Processes 141 7.3.1 Reduction of Halides and Related Compounds 141 7.3.2 Reductive Addition of Heteroatom-centered Radicals to Alkynes and Alkenes 143 7.3.3 In Fragmentation Processes 144 7.4 In Atom-transfer Processes 145 7.4.1 Iodine Atom Transfer 145 7.4.2 Bromine Atom Transfer 148 7.4.3 Chlorine Atom Transfer 149

7.5 Organoboron Compounds as a Source of Carbon- centered Radicals 150 7.5.1 Conjugated Additions to Enones and Enals 150 xiv Contents

7.5.2 Conjugate Addition to Activated Olefins 155 7.5.3 Addition to Imine Derivatives 158 7.5.4 C-C Bond Formation via P-Fragmentation Processes 158 7.6 Organoboranes as Chain-transfer Reagents 162 7.6.1 Via Iodine Atom Transfer 163 7.6.2 Via Hydrogen Atom Transfer 165 7.7 Organoboron Compounds as Radical-reducing Agents 166 7.7.1 Complexes with Tertiary Amines 166 7.7.2 Complexes with Water and Alcohols 166 7.8 Conclusions 167 References 169

Chapter 8 Thiols as Efficient Hydrogen Atom Donors in Free Radical Transformations in Aqueous Media

8.1 Introduction 175 8.2 The Tris(trimethylsilyl)silane (TMS3SiH)/thiol System is an Efficient Radical Hydrogen Donor "on Water" 176 8.3 Thiol/Azo Initiator System in cis-trans Isomerization of Double Bonds in Aqueous Media 177 8.4 Thiols in Peptides: Degradation in Aqueous Media 181 8.5 Thiols in C-C Bond Formation in Water 182 8.6 Thiol-Ene Coupling as a Click Process for Materials and Bioorganic Chemistry 184 8.7 Hydrogen Sulfide in Oxidation and/or Reduction of Organic Compounds 185 8.8 Thiyl Radicals and the Influence of Antioxidants/Vitamins 186 8.9 Conclusions 189 References 189

Chapter 9 Advances in the Use of Phosphorus-centered Radicals in Organic Synthesis in Conventional Flasks: Advantages, Reasons and Applications

9.1 Introduction 195 9.2 Physical Organic Aspects 196 9.3 Use of P-centered Radicals as Mediators 197 9.4 Synthetic Applications of P-centered Radical Additions 202 9.4.1 Phosphinyl Radicals 203 9.4.2 Phosphonyl Radicals 204 9.5 Radicals from Hypophosphites and Phosphinates 204 9.6 Phosphinoyl Radicals 206 Streamlining Free Radical Green Chemistry xv

9.6.1 Thiophosphonyl and Other Sulfur- containing Radicals 206 9.7 Elimination of Organophosphorous Radicals 207 9.7.1 Phosphoranyl Radicals 207 9.7.2 P-Elimination of P-centered Radicals 208 9.8 Conclusion and Perspectives 209 References 210

Chapter 10 Metal-based Homogeneous Catalysis and Free Radical Synthesis: Advantages, Developments and Scope

10.1 Introduction 212 10.2 Metal-mediated Reduction and Oxidation Reactions in Water 212 10.3 Metal-radical-mediated Carbon-Carbon Bond Formation Reactions in Water 228 10.3.1 Metal-mediated Radical Cyclizations in Water 228 10.3.2 Reformatzky Reactions in Water 238 10.3.3 Alkylation of Carbonyl Compounds, Imine Derivatives and Electron-deficient Alkenes in Water 240 10.3.4 Allylation of Carbonyl Compounds and Imine-derivatives in Water 248 10.3.5 Radical Conjugate Additions to a,|3- Unsaturated Carbonyl Compounds in Water 268 10.3.6 Synthesis of a,(3-Unsaturated Ketones 275 10.3.7 Metal-mediated Mannich-type Reactions in Water 277 10.3.8 Pinacol and Other Coupling Reactions in Water 278 10.4 Conclusion and Future Direction 286 Acknowledgments 287 References 287

Chapter 11 Radicals and Transition-metal Catalysis: a Complementary Solution to Increase Reactivity and Selectivity in Organic Chemistry

11.1 Introduction 296 11.2 Radical Cyclizations Terminated by Ir-catalyzed Hydrogen-atom Transfer 302 11.3 Conclusion 306 References 307 xvi Contents

Chapter 12 Reagent Control in Transition-metal-initiated Radical Reactions

12.1 Introduction 309 12.2 Reagent Control in Transition-metal-initiated Radical Reactions 311 12.3 Carbonyl Compounds as Radical Sources: Pinacol Couplings 312 12.3.1 Stoichiometric Reagent-controlled Couplings 312 12.3.2 From Stoichiometric to Catalytic Pinacol Couplings 316 12.4 Protonation of Metal-Oxygen Bonds in Catalytic Radical Reactions 320 12.5 Carbonyl Compounds as Radical Precursors: Additions of Ketyl Radicals to C-C and C-X Bonds 322 12.6 Epoxides as Radical Precursors 328 12.6.1 Stoichiometric Reagents 328 12.6.2 Titanocene-catalyzed Epoxide Openings 333 12.6.3 Catalytic Enantioselective Epoxide Openings 336 12.7 Conclusion and Future Direction 340 References 340

Chapter 13 Enantioselective Radical Reactions and Organocatalysis

13.1 Introduction 348 13.2 Organic Reagents and Organocatalysts in Stereoselective Radical Chemistry 349 13.2.1 Chiral Lewis Acid Activation 349 13.3 Enantioselective Hydrogen Atom Transfer 353 13.4 Aminocatalysis/Enamine Activation 355 13.5 Future Directions for Organocatalysis in Radical Chemistry 362 13.6 Conclusion 364 References 364

Chapter 14 The Sunny Side of Chemistry: Green Synthesis by Solar Light

14.1 Introduction 366 14.2 Historical Background 368 14.3 Synthesis using Non-concentrated Sunlight 370 14.4 Photocatalytic/Photomediated Processes 370 14.5 Photodimerization 372 14.6 Cycloadditions 374 14.7 Cyclizations 375 14.8 Photopinacolization (Photoreduction) 376 Streamlining Free Radical Green Chemistry xvii

14.9 Synthesis via Elimination of a Group 377 14.10 Arylation Reactions 379 14.11 Isomerizations 379 14.12 Halogenations 380 14.13 Synthesis of Endoperoxides 381 14.14 Oxidations/Oxygenations 382 14.15 Concentrated Sunlight 384 14.15.1 General Remarks 384 14.15.2 Photooxidations and Photooxygenations 385 14.15.3 Cycloadditions 387 14.16 Photocatalytic Reactions 387 14.17 Photoacylations 389 14.18 E/Z Isomerizations 389 14.19 Potential Industrial Applications 390 14.20 Conclusion and Future Direction 391 References 391

Chapter 15 Sonochemistry: Ultrasound Application in Radical Synthesis

15.1 Introduction 401 15.2 Energy Efficiency 403 15.3 Sonochemical Initiation of Radical Chain Reactions: Hydrostannation and Hydroxystannation of C-C Multiple Bonds 404 15.4 Homogeneous Sonochemistry of Hydrostannation in Detail 406 15.5 Sonication-induced Halogenative Decarboxylation of Thiohydroxamic Esters 411 15.6 Aerobic Conversion of Organic Halides to Alcohols: an Oxygenative Radical Cyclization 412 15.7 A New Method for Nitration of Alkenes to a,p-Unsaturated Nitroalkenes 413 15.8 Conclusion and Future Direction 413 References 414

Chapter 16 Black-light-initiated Free Radical Reactions for Synthetic Applications, Micro-reactors and Modified Nucleoside Synthesis

16.1 Introduction: Why Black Light is so Important 416 16.2 C2',3'-Cyclic Carbonates Derived from Nucleosides Why They are Important 417 16.3 C5' General Comments and History 417 16.4 Black-light induced Radical Cyclization Approach 418 to Cyclonucleosides: an Independent Approach xviii Contents

16.5 Radical Cyclization "Tin-free" Approach to C2',C3'-Cyclic Carbonates Derived from Nucleosides: an Independent Approach 422 16.6 Black-light-induced Direct Generation of C2'- Nucleosidyl Radicals in Adenosine, Thymidine and Uridine in Organic and Aqueous Media 426 16.7 Black-light-induced Radical/Ionic Hydroxymethylation of Alkyl Iodides with Atmospheric CO in the Presence of Tetrabutylammonium Borohydride 428 16.8 Towards the Synthesis ofAlkyl Alkynyl Ketones by Pd/Light-induced Three-component Coupling Reactions of Iodoalkanes, CO, and 1-Alkynes 431 16.9 Vicinal C-Functionalization of Alkenes: Pd/Light- induced Multicomponent Coupling Reactions Leading to Functionalized Esters and Lactones 433 16.10 Closing the Gap: from Single Molecule Synthesis the Conventional Way to Microreactors—the Power of Black Light 434 16.11 Synthesis in Microchemical Systems 436 16.12 Microflow Photo-radical Chlorination of Cycloalkanes 436 16.13 Continuous Microflow Chlorination of Cyclohexane with Molecular Chlorine in Detail 437 16.14 Microflow Chlorination with Sulfuryl Chloride and Black Light 438 16.15 The Barton Reaction Using a Microreactor and Black Light: Continuous-flow Synthesis of a Key Steroid Intermediate for an Endothelin Receptor Antagonist 439 16.16 Conclusion 442 References 442

Chapter 17 Photo-catalysis and Metal-Oxygen-anion Cluster Decatungstate in Organic Chemistry: a Manifold Concept for Green Chemistry

17.1 Introduction 457 17.2 C-C Bond Formation via C-H Bond Fragmentation under Anaerobic Conditions 458 17.2.1 Functionalization of Alkanes by Homolytic C-H Bond Cleavage 458 17.2.2 Functionalization of Aldehydes by Homolytic C-H Bond Cleavage 461 17.2.3 Functionalization of Amides by Homolytic C-H Bond Cleavage 462 Streamlining Free Radical Green Chemistry xix

17.2.4 Functionalization of Toluenes, Anisoles and Thioanisole by Homolytic C-H Bond Cleavage 463 17.3 Homogeneous Oxidation of Organic Compounds by Decatungstate 463 17.3.1 Oxidation of Aliphatic Alcohols and Alkanes 464 17.3.2 Oxidation of Aromatic Alcohols and Alkanes 465 17.3.3 Oxidation of Aliphatic and Aromatic Alkenes 466 17.4 Heterogeneous Oxidation of Organic Compounds by Decatungstate 467 17.4.1 Immobilization on a Solid Support 468 17.4.2 Immobilization inside the Silica or Zirconia Network 472

17.4.3 Immobilization on Silica containing Ammonium Cations 472 17.4.4 Immobilization onto Organic Ion-exchange Resins 473 17.4.5 Immobilization with Organic Sensitizers 475 17.4.6 Immobilization in Polymeric Membranes 476 17.5 Degradation of Organic Pollutants by Decatungstate 478 17.6 Conclusion and Future Directions 483 References 483

Chapter 18 Radical Domino Reactions: Intermolecular Telescopic Reactions

18.1 Introduction: Advantages and Limits 486 18.2 Radical/Radical Domino Processes in Synthesis 490 18.3 Conclusion and Future Direction 508 References 509

Chapter 19 Telescopic Reactions and Free Radical Synthesis: Focus on Radical and Radical-Ionic Multicomponent Processes

19.1 General Introduction: Advantages and Limitations 513 19.2 Mnemonic Classification 514 19.3 Three-component Radical Reactions 516 19.3.1 3-CR-ADA 516 19.3.2 3-CR-DAD 519 19.3.3 3-CR-DAA 521 19.3.4 3-CR-DDA 522 19.4 Four- and Five-Component Radical Reactions 524 19.4.1 4-CR-DAAD 524 19.4.2 4-CR-ADAA 525 19.4.3 4-CR-AADA 525 19.5 Multicomponent Radical-Ionic Reactions 527 XX Contents

19.5.1 Multicomponent Radical-Anionic Reactions 527 19.5.2 Multicomponent Radical-Cationic Reactions 529 19.5.3 Sequential Multicomponent Radical-Polar Crossover Reactions 531 19.6 Conclusion and Future Direction 532 References 532

Chapter 20 Radical-Radical-Radical Telescopic Reactions: from Rules through Reasons to Applications

20.1 Introduction 537 20.2 The "Round Trip" Strategy in Action 537 20.3 Conclusion and Future Direction 550 References 551

Chapter 21 Applications of Conventional Free Radicals and Advances in Total Synthesis: from the Bench to the Future through the Vinyl Radical

21.1 The Vinyl Radical, a Precious Tool for Radical Cascades in 5-exo-dig Cyclizations 553 21.2 Linear Triquinanes from Acyclic Precursors 555 21.3 First Total Synthesis of Natural Protoilludane, epz-Illudol 556 21.4 Asymmetric Intramolecular Radical Vinylation using Enantiopure Sulfoxides as Temporary Chiral Auxiliaries 559 21.5 Conclusion and Summary 561 References 561

Chapter 22 Streamlining Organic Free Radical Synthesis through Modem Molecular Technology: from Polymer-supported Synthesis to Microreactors and Beyond

22.1 Free Radicals: a Brief Introduction and Why they are Important 563 22.2 Polymer-supported Reagents and Free Radical Synthesis: a Few Initial Remarks and Approaches 564 22.2.1 PEG-bound Reagents and Free Radical Transformations to Date: the Journey Has Begun 564 22.2.2 Solid-state Radical Reactions 565 22.3 Ultraporous Materials as Possible Microreactors and Free Radical Synthesis 567 22.3.1 A Few Words About Polarity Reversal Catalysis and its Advantages in Free Radical Transformations in PolyHIPEs 569 Streamlining Free Radical Green Chemistry

22.4 Microreactor-controlled Selectivity in Organic Photochemical Reactions: Molecular Sieve Zeolites

to the Rescue 22.4.1 Photochemistry of Phenyl Phenylacetates Included Within Zeolites and Nafion Membranes

22.4.2 Zeolites and LDPE Films as Hosts for the Preparation of Large Ring Compounds: Intramolecular Photocycloaddition of Diaryl Compounds 22.4.3 Summary 22.5 Microflow Systems for Practical Free Radical Synthesis and Polymerization 22.6 Free Radical Polymerization in Microreactors: New Advantages and Extra Control 22.7 Conclusion References

Chapter 23 Radical Reactions and fl-Cyclodexrrin as a Molecular Ferrari: Is There a Hidden Advantage of Speed, Power and Class? From Fundamental Reactions to Potential Applications

23.1 Introduction 23.2 The Cyclodextrin Reaction Media 23.3 P-Cyclodextrin-based Molecular Reactors for Free Radical Chemistry in Aqueous Media and Chain Reactions

23.4 On the Use of P-Cyclodextrins as Molecular Reactors for the Radical Cyclizations under Tin- free Conditions: Chain and Non-chain Reactions 23.5 Radical Cyclizations in P-Cyclodextrins in Aqueous Media under Photolytic Conditions 23.6 Mn(OAc)3 Radical Cyclizations in P-Cyclodextrin 23.7 Cu(OAc)2 Radical Cyclizations in P-Cyclodextrins 23.8 On the Scope of P-Cyclodextrin-Ionic Liquid-based Molecular Reactors for Free Radical Chemistry in Bio-compatible and Alternative Media 23.9 P-Cyclodextrin-Ionic Liquids and Conventional Free Radical Reactions: Hydrogen Atom Transfer Reactions 23.10 P-Cyclodextrin-Ionic Liquid (MIM-P-CDOTs) and Conventional Free Radical Reactions: Radical Additions, Atom Transfer, Hydrosilylation and Hydrostannylation Reactions in Aqueous Media xxii Contents

23.11 Potential Practical Application: Towards the Development of Novel Drug Delivery Prototype Devices for Targeted-Delivery Drug Therapy at the Molecular Level in Aqueous Media 605 23.11.1 Path A in Detail: P-Cyclodextrin-Pro- drug as an Efficient Prototype Molecular Carrier in Water Aimed at Transporting Radical-affording Species (RAS) in Aqueous Media 607 23.11.2 Path B in Detail: Investigation of Free Radical-quenching Species (RQS) from a p-Cyclodextrin-Phenol "Molecular Antioxidant Prototype" in Water as Antioxidant Delivery to the Radical Reaction Mixture 608 23.12 Towards Streamlining Conventional Radical Reactions through the Development of |3-Cyclodextrin-based Batch, Flow-through and "Teabag" Prototype Molecular Reactors 609 23.12.1 P-Cyclodextrins as Molecular Batch Reactors610 23.12.2 p-Cyclodextrin Molecular Flow-through Reactor for Streamlining Organic Synthesis in a Continuous and Reusable Fashion 611 23.12.3 "Teabag" Methodology and Radical Reactions: Screening the Scope and Flexibility 612 23.13 Conclusion and Future Direction 613 References 614

Chapter 24 Artificial Enzymes and Free Radicals: the Chemist's Perspective

24.1 Introduction 625

24.2 Transition State Theory: a Brief Introduction 626 24.3 The "Design Approach" 629 24.3.1 Cyclodextrins as Enzyme Mimics 629 24.3.2 Vitamin B12 Functions: Enzymatic Reactions 630 24.3.3 Model Reactions with Apoenzyme Functions 632 24.4 The "Transition State Analogue Selection" Approach 633 24.4.1 The Transition State Analogue Selection Approach: General Introduction 633 24.4.2 Molecular-imprinted Polymers as a Method in the Transition State Analogue Selection Approach 634 24.4.3 Imprinting an Artificial Proteinase 636 Streamlining Free Radical Green Chemistry xxiii

24.4.4 Bioimprinting 24.5 The "Catalytic Activity Selection Approach": General Introduction

24.5.1 Combinatorial Polymers as Enzyme Mimics 24.5.2 Directed Evolution of Enzymes 24.5.3 Catalysis with Imprinted Silicas and Zeolites 24.5.4 Catalytic Antibodies and a Few Examples of Radical Transformations 24.6 Conclusion References

Chapter 25 Applications of Conventional Free Radicals and Advances in Total Synthesis: from the Bench to Nature through Sml2 Radicals as an Efficient Trigger for Radical Cascades, a Journey from Orsay to the 21st Century

25.1 Mechanisms of Sml2-mediated Reactions: the Basics 658 25.2 Radicals and Anions from Organohalides 659 25.3 Sml2-mediated Cyclizations in Natural Product Synthesis 663 25.4 Four-membered Ring Formation Using Sml2 663 25.4.1 A Synthesis of Paeoniflorin 663 25.4.2 An Approach to the Pestalotiopsin and Taedolidol Skeletons 664 25.5 Five-membered Ring Formation Using Sml2: the Synthesis of (-)-Hypnophilin and the Formal Synthesis of (-)-Coriolin 664 25.5.1 A Synthesis of Grayanotoxin HI 664 25.5.2 A Synthesis and Structural Revision of (-)- Laurentristich-4-ol 667 25.5.3 An Approach to (-)-Welwitindolinone A Isonitrile 667

25.6 Six-membered Ring Formation Using Sml2: an Approach to Marine Polycyclic Ethers 667 25.6.1 A Synthesis of Pradimicinone 669 25.6.2 A Synthesis of (+)-Microcladallene B 669 25.6.3 A Synthesis of Botcinins C, D and F 670 25.7 Seven-membered Ring Formation Using Sml2: Syntheses of (-)-Balanol 671 25.8 Eight-membered Ring Formation Using Sml2: A Synthesis of Paclitaxel (Taxol) 673 25.8.1 A Synthesis of (+)-Isoschizandrin 673 25.9 Nine-membered Ring Formation Using Sml2: An Approach to Ciguatoxin 674 25.10 Forming Larger Rings Using Sml2: A Synthesis of Diazonamide A 674 xxiv Contents

25.10.1 A Synthesis of (3-Araneosene 674 25.10.2 A Synthesis of Kendomycin 675 25.11 Modifying Biomolecules Using Sml2 676 25.11.1 Introduction 676 25.11.2 Modifying Carbohydrates Using Sml2 678 25.11.3 Modifying Amino Acids and Peptides Using Sml2 683 25.12 Summary 685 References 685

Chapter 26 Innovative Reactions Mediated by Zirconocene: Advantages and Scope

26.1 Background of Zirconium in Organic Synthesis 689 26.2 Triethylborane-induced Radical Reaction with Schwartz Reagent 690 26.3 Radical Cyclization Reactions with a Zirconocene(alkene) Complex as an Efficient Single Electron Transfer Agent 694 26.4 Triethylborane-induced Radical Allylation Reaction with a Zirconocene(alkene) Complex 695 26.5 Conclusion 696 References 697

Chapter 27 Applications of Conventional Free Radicals and Advances in Total Synthesis: Radical Cascades in Bio-inspired Terpene Synthesis

27.1 Introduction 700 27.2 Antecedents 701 27.3 Recent Developments 703 27.3.1 Acyclic Terpenes 703 27.3.2 Radical Polyprene Cyclizations 704 27.3.3 Photo-induced Electron Transfer (PET) Reactions as Initiation 704 27.3.4 Acylselenium Derivatives as Substrates 707 27.4 Transition-metal-mediated Transformations 709 27.4.1 Manganese(m)-mediated Cyclizations 709 27.4.2 Ti(m)-mediated Epoxypolyprene Cyclizations 712 27.5 SOMO Organocatalysis and Terpenes 721 27.6 Conclusions 722 References 722

Subject Index 726