Spiro Compounds

Ramon Rios Torres, PhD is Associate Professor in Organic Chemistry at the University of Southampton. He is the author of more than 130 papers, 18 chapters in chemical books, and a patent. Dr. Rios has edited two books with Wiley: Stereoselective Organocatalysis: Bond Formation Methodologies and Activation Modes and The Pauson-Khand Reaction: Scope, Variations and Applications.

• List of Contributors xiPreface xiii1 Spiro Compounds: A Brief History 1Marta Meazza1.1 Notes on IUPAC Rules for Spiro Compounds 6References 72 Selected Applications of Spirocycles in Medicinal Chemistry 9Matthias Baud2.1 Introduction 92.2 General Features 152.3 Property Optimization in Bioactive Compounds 172.4 Four-Membered Rings: Synthesis, Applications, and New DesignPrinciples 192.5 Further Examples 262.6 Conclusions 28References 293 Recent Advances in the Asymmetric Synthesis of Spiro Compounds Through Cycloadditions 35Alberto Vega-Peñaloza, Suva Paria, Luca Dell’Amico, and Xavier Companyó3.1 Introduction 353.2 Organometallic Methodologies 363.2.1 Organometallic [3+2] Cycloaddition Strategies to Construct Spiro Compounds 363.2.2 Organometallic [4+2] Cycloaddition Strategies to Construct Spiro Compounds 423.2.3 Organometallic Miscellaneous Strategies to Construct SpiroCompounds 443.3 Organocatalytic Methodologies 483.3.1 Organocatalytic [3+2] Cycloaddition Strategies to Construct Spiro Compounds 483.3.2 Organocatalytic [4+2] Cycloaddition Strategies to Construct Spiro Compounds 523.3.3 Organocatalytic [4+3] and [2+2] Cycloaddition and Switchable Strategies to Construct Spirocompounds 553.3.4 Organocatalytic Miscellaneous Strategies to Construct Spiro Compounds 60References 624 Design and Synthesis of Spirocycles via Olefin Metathesis 65Sambasivarao Kotha, Vikas R Aswar and Yellaiah Tangella4.1 Introduction 654.2 Formation of Aza-spirocycles 844.3 Formation of Oxa-spirocycles 874.4 Miscellaneous Examples 97References 985 Spirooxindoles: Synthesis via Organocatalytic Processes 103Peng-Wei Xu, Xiao-Yuan Cui, Jin-Sheng Yu, and Jian Zhou5.1 Introduction 1035.2 Enamine and Iminium Catalysis 1055.3 Chiral Nucleophilic Catalysis with Tertiary Phosphines or Amines 1145.4 Chiral N-Heterocyclic Carbene Catalysis 1205.5 Chiral Tertiary Amine-H-Bond Donor Bifunctional Catalysis 1275.6 Chiral Hydrogen-Bonding Catalysis 1425.7 Chiral Phosphoric Acid Catalysis 1445.8 Chiral Phase-Transfer Catalysis 1495.9 Chiral Organoiodine Catalysis 1515.10 Conclusion 153References 1536 Spirooxindole Synthesis by Organometallic Processes 161Albert Moyano6.1 Introduction 1616.2 Direct Construction of the Spirooxindole Unit by Cyclization Methodologies 1616.2.1 Intramolecular Heck Reaction and Related Cyclizations 1616.2.2 Alkylation–Cyclization of 3-Substituted Oxindoles 1676.2.3 Cyclization of 3-Substituted Indoles 1706.3 Two-component Annulation/Cycloaddition Methodologies 1716.3.1 Cyclopropyl Spirooxindoles by [2+1] Cycloaddition Reactions 1716.3.2 [2+2] Cycloaddition Reactions 1736.3.3 [3+2] Annulation/Cycloaddition Reactions 1756.3.4 [3+3] Cycloaddition Reactions 1886.3.5 [4+1] Cycloaddition Reactions 1896.3.6 [4+2] Cycloaddition/Annulation Reactions 1906.3.7 [5+2] Cycloaddition Reactions 1956.4 Miscellaneous Methods 1956.4.1 Darzens Reaction of Isatins 1956.4.2 Cyclization of 3,3-Disubstituted Oxindoles 1986.4.3 Three-component Reactions 1986.5 Conclusions 200Acknowledgements 200References 2007 Enantioselective Synthesis of Spiro Heterocycles 205Michal Urban and Jan Veselý7.1 Introduction 2057.2 Enantioselective Synthesis of Spiro Heterocycle with One Nitrogen Atom 2067.2.1 Enantioselective Formation of Spiropyrrolidines 2067.2.1.1 Organometallic Approaches 2067.2.1.2 Organocatalytic Approaches 2087.2.1.3 Cooperative-catalytic Approaches 2097.2.2 Enantioselective Formation of Spirocycles Containing Indoline and Indolenine Ring 2107.2.2.1 Organometallic Approaches 2107.2.2.2 Organocatalytic Approaches 2117.2.3 Enantioselective Formation of Spiropiperidines 2147.2.3.1 Organometallic Approaches 2147.2.3.2 Organocatalytic Approaches 2167.3 Enantioselective Formation of Spirocycles Containing Heterocycle with One Oxygen Atom 2187.3.1 Enantioselective Formation of Spirocycles Containing Dihydrofuranone and Tetrahydrofuran Ring 2187.3.1.1 Organometallic Approaches 2187.3.1.2 Organocatalytic Approaches 2217.3.2 Enantioselective Formation of Spirocycles Containing Benzofuranone and Benzodihydrofuran Ring 2247.3.2.1 Organometallic Approaches 2247.3.2.2 Organocatalytic Approaches 2277.3.2.3 Cooperative-catalytic Approaches 2337.3.3 Enantioselective Formation of Spirocycles Containing Dihydrocoumarin, Dihydro- and  Tetrahydropyran Ring 2347.3.3.1 Organometallic Approaches 2347.3.3.2 Organocatalytic Approaches 2367.4 Enantioselective Formation of Sulfur-containing Spirocycles 2407.5 Enantioselective Formation of Spirocycles Containing Heterocycle with More Than One Heteroatom 2447.5.1 Enantioselective Formation of Spirocycles Containing Pyrazolone Ring 2447.5.1.1 Organometallic Approaches 2447.5.1.2 Organocatalytic Approaches 2467.5.1.3 Cooperative-catalytic Approaches 2557.5.2 Chapter 7.5.2 – Enantioselective Formation of Spirocycles Containing Barbituric Acid and Hydantoin 2567.5.3 Chapter 7.5.3 – Enantioselective Formation of Spirocycles Containing Azlactones 2597.5.3.1 Organometallic Approaches 2597.5.3.2 Organocatalytic Approaches 2597.5.3.3 Cooperative-catalytic Approaches 2597.5.4 Chapter 7.5.4 – Enantioselective Formation of Spirocycles Containing Rhodanines and Sultams 2627.5.4.1 Organometallic Approaches 2627.5.4.2 Organocatalytic Approaches 2647.5.5 Chapter 7.5.5 – Enantioselective Formation of Spiroketals (Spiroacetals) 2667.5.5.1 Organometallic Approaches 2677.5.5.2 Organocatalytic Approaches 2687.5.5.3 Cooperative-catalytic Approaches 2697.6 Enantioselective Formation of Other Spiro Heterocyclic Systems 2707.6.1 Organometallic Approaches 2707.6.1.1 Organocatalytic Approaches 2727.7 Enantioselective Formation of Bispirocycles 2737.8 Conclusion 274Acknowledgements 275References 2758 Enantioselective Synthesis of all Carbon Spiro Compounds 283Ramon Rios8.1 Enantioselective Synthesis of All-Carbon Spiro Compounds Based on Alkylation Methods 2858.2 Enantioselective Synthesis of All-Carbon Spirocycles by Metal-catalyzed Methods 2868.3 Enantioselective Synthesis of All-Carbon Spirocycles by Cycloaddition Strategies 2948.4 Enantioselective Synthesis of All-Carbon Spirocycles by Radical Strategies 3008.5 Enantioselective Synthesis of All-Carbon Spirocycles by Cascade Reactions 3018.6 Enantioselective Synthesis of All-Carbon Spirocycles by Rearrangement Strategies 3078.7 Conclusions 310References 3109 Transition-Metal-Catalyzed Dearomative Spiroannulation Reactions 313Lu Bai, Jingjing Liu and Xinjun Luan9.1 Introduction: Discovery of Aromatic Compounds 3139.2 Development of Dearomatization Reactions 3139.3 Development of Dearomative Spiroannulation Reactions 3149.4 Dearomative Spiroannulations of Phenols 3149.4.1 Dearomative Spiroannulation Without Oxidants 3159.4.1.1 Dearomative Alkylation of Phenols 3159.4.1.2 Dearomative Arylation of Phenols 3199.4.2 C–H Bond Activation/Dearomative Spiroannulation Reactions 3259.5 Dearomative Spiroannulation of Indoles 3329.5.1 Intramolecular Dearomative Allylic Alkylation 3329.5.2 Intramolecular Dearomative Arylation 3349.5.3 Intermolecular Dearomative Spiroannulation of Indoles 3389.6 Dearomative Spiroannulation of Aromatic Heterocyclic Compounds 3429.6.1 Dearomative Spiroannulation of Pyrroles 3429.6.2 Dearomative Spiroannulation of Furans 3449.6.3 Dearomative Spiroannulation of Thiophenes 3469.7 Dearomative of Other Aromatic Compounds 3499.8 Conclusion 352References 35210 Carbocyclic Spiro Compounds Occupying Higher Dimensions: Benzoannelated [5.5.5.5]Fenestranes and Beyond 357Hak-Fun Chow and Dietmar Kuck10.1 Introduction 35710.2 Selected Synthesis Strategies 36210.2.1 The Access to Benzoannelated Fenestranes 36510.2.2 Derivatives of [5.5.5.6]-Fenestranones and Fenestrindane 37110.2.3 Fenestrindanes as a Core Embedded in a Closed π-Electron Periphery 37810.2.4 Three Spiranes Merged in a Centropolycyclic Framework: Centrohexaindane and Its Derivatives 38410.3 Conclusions 392Acknowledgements 394References 39411 The Synthesis of Natural Products Containing Spirocycles 401Ramon Rios11.1 Porco’s Synthesis of (+)-Calafianin 40111.2 Hayashi’s Total Synthesis of Pseurotin A 40511.3 Trost’s Synthesis of (−)-Ushikulide A 40811.4 Castle’s and Herzon’s Syntheses of (−)Acutumine 41211.4.1 Castle’s Synthesis of (−)-acutamine 41311.4.2 Herzon’s Synthesis of (−)-Acutumine 41711.5 Overman’s and Carreira’s Synthesis of Spirotryprostatin B 42111.5.1 Overman’s Synthesis of Spirotryprostatin B 42111.5.2 Carreira’s Synthesis of (−)-Spirotryprostatin B 42311.6 Conclusion 427References 427Index 429