Spiro Compounds

1 Cover

2 Title Page

3 Copyright Page

4 List of Contributors

5 Preface

6 1 Spiro Compounds: A Brief History 1.1 Notes on IUPAC Rules for Spiro Compounds References

7 2 Selected Applications of Spirocycles in Medicinal Chemistry 2.1 Introduction 2.2 General Features 2.3 Property Optimization in Bioactive Compounds 2.4 Four‐Membered Rings: Synthesis, Applications, and New Design Principles 2.5 Further Examples 2.6 Conclusions References

8 3 Recent Advances in the Asymmetric Synthesis of Spiro Compounds Through Cycloadditions 3.1 Introduction 3.2 Organometallic Methodologies 3.3 Organocatalytic Methodologies References

9 4 Design and Synthesis of Spirocycles via Olefin Metathesis 4.1 Introduction 4.2 Formation of Aza‐spirocycles 4.3 Formation of Oxa‐spirocycles 4.4 Miscellaneous Examples References

10 5 Spirooxindoles: Synthesis via Organocatalytic Processes 5.1 Introduction 5.2 Enamine and Iminium Catalysis 5.3 Chiral Nucleophilic Catalysis with Tertiary Phosphines or Amines 5.4 Chiral N ‐Heterocyclic Carbene Catalysis 5.5 Chiral Tertiary Amine‐H‐Bond Donor Bifunctional Catalysis 5.6 Chiral Hydrogen‐Bonding Catalysis 5.7 Chiral Phosphoric Acid Catalysis 5.8 Chiral Phase‐Transfer Catalysis 5.9 Chiral Organoiodine Catalysis 5.10 Conclusion References

11 6 Spirooxindole Synthesis by Organometallic Processes 6.1 Introduction 6.2 Direct Construction of the Spirooxindole Unit by Cyclization Methodologies 6.3 Two‐component Annulation/Cycloaddition Methodologies 6.4 Miscellaneous Methods 6.5 Conclusions Acknowledgements References

12 7 Enantioselective Synthesis of Spiro Heterocycles 7.1 Introduction 7.2 Enantioselective Synthesis of Spiro Heterocycle with One Nitrogen Atom 7.3 Enantioselective Formation of Spirocycles Containing Heterocycle with One Oxygen Atom 7.4 Enantioselective Formation of Sulfur‐containing Spirocycles 7.5 Enantioselective Formation of Spirocycles Containing Heterocycle with More Than One Heteroatom 7.6 Enantioselective Formation of Other Spiro Heterocyclic Systems 7.7 Enantioselective Formation of Bispirocycles 7.8 Conclusion Acknowledgements References

13 8 Enantioselective Synthesis of all Carbon Spiro Compounds 8.1 Enantioselective Synthesis of All‐Carbon Spiro Compounds Based on Alkylation Methods 8.2 Enantioselective Synthesis of All‐Carbon Spirocycles by Metal‐catalyzed Methods 8.3 Enantioselective Synthesis of All‐Carbon Spirocycles by Cycloaddition Strategies 8.4 Enantioselective Synthesis of All‐Carbon Spirocycles by Radical Strategies 8.5 Enantioselective Synthesis of All‐Carbon Spirocycles by Cascade Reactions 8.6 Enantioselective Synthesis of All‐Carbon Spirocycles by Rearrangement Strategies 8.7 Conclusions References

14 9 Transition‐Metal‐Catalyzed Dearomative Spiroannulation Reactions 9.1 Introduction: Discovery of Aromatic Compounds 9.2 Development of Dearomatization Reactions 9.3 Development of Dearomative Spiroannulation Reactions 9.4 Dearomative Spiroannulations of Phenols 9.5 Dearomative Spiroannulation of Indoles 9.6 Dearomative Spiroannulation of Aromatic Heterocyclic Compounds 9.7 Dearomative of Other Aromatic Compounds 9.8 Conclusion References

15 10 Carbocyclic Spiro Compounds Occupying Higher Dimensions: Benzoannelated [5.5.5.5]Fenestranes and Beyond 10.1 Introduction 10.2 Selected Synthesis Strategies 10.3 Conclusions Acknowledgements References

16 11 The Synthesis of Natural Products Containing Spirocycles 11.1 Porco’s Synthesis of (+)‐Calafianin [2] 11.2 Hayashi’s Total Synthesis of Pseurotin A[6] 11.3 Trost’s Synthesis of (−)‐Ushikulide A [12] 11.4 Castle’s and Herzon’s Syntheses of (−)Acutumine 11.5 Overman’s and Carreira’s Synthesis of Spirotryprostatin B 11.6 Conclusion References

17 Index

18 End User License Agreement

1 Chapter 2 Table 2.1 Selected examples of FDA‐ approved drugs containing spirocyclic m... Table 2.2 Physicochemical and biochemical properties of selected oxetanes, ... Table 2.3 Comparison of the properties of spirocyclic oxetanes with their m...

1 Chapter 1 Figure 1.1 Growing interest in spiro compounds in chemical literature. Figure 1.2 Dye sensitizer 9,9‐spirobifluorene. Figure 1.3 Donor–acceptor spiro compounds and colors displayed by them. Figure 1.4 Examples of naturally occurring compounds containing the spiro mo... Figure 1.5 Spiro functionality in nicotinic receptor antagonists. Figure 1.6 Examples of marketed spiro compound drugs. Figure 1.7 ACC inhibitors of pharmaceutical interest. Figure 1.8 Commercial spirocyclic insecticide/acaricide products. Figure 1.9 Recently patented spiro compound of agrochemical interest. Figure 1.10 Example of numbering of spirocyclic compounds. Figure 1.11 Example of naming chiral spiro compounds.

2 Chapter 2 Figure 2.1 X‐ray crystal structure (pdb 2gfx 12) of Platensimycin ( 2, sticks ... Scheme 2.1 Key enyne cycloisomerization step in Nicolaou’s total synthesis o... Figure 2.2 Schematic comparison of substituted biaryl and spiro[3,4]octane s... Figure 2.3 Examples of saturated spirocyclic ring systems frequently encount... Figure 2.4 Examples of lead optimization employing spirocycles. Scheme 2.2 Summary of common strategies for the synthesis of common four‐mem... Figure 2.5 Comparison between carbonyl, gem‐dimethyl, and oxetane groups, hi... Figure 2.6 (a) Spiro‐oxetane as a morpholine bioisostere. (b) comparison... Figure 2.7 Replacement of morpholine by 2‐oxa‐6‐azaspiro[3.3]heptane in BTK ... Figure 2.8 Top: Structure of thalidomide 34and its oxetano analogue 35. Bot... Figure 2.9 Representative examples of spirocyclic bioactive lead molecules.... Figure 2.10 Additional examples further illustrating the breadth of ring typ... Figure 2.11 Representative examples of (a) multifunctional spiro building bl...

3 Chapter 3 Scheme 3.1 Scandium‐catalyzed enantioselective carboannulation between alkyl... Scheme 3.2 Copper‐catalyzed asymmetric [3+2] cycloaddition between alkyliden... Scheme 3.3 Copper‐catalyzed asymmetric construction of dispiropyrrolidine sk... Scheme 3.4 Magnesium‐catalyzed asymmetric [3+2] cycloaddition between methyl... Scheme 3.5 Rhodium‐catalyzed enantioselective [3+2] annulation to form spiro... Scheme 3.6 Palladium‐catalyzed stereoselective 1,6‐conjugate addition/annula... Scheme 3.7 Copper‐catalyzed asymmetric synthesis of spirocyclic β‐lactams th... Scheme 3.8 Bimetallic relay catalysis for the enantioselective synthesis of ... Scheme 3.9 Regio‐ and enantioselective aza‐Diels–Alder reactions of 3‐vinyli... Scheme 3.10 Ni‐catalyzed asymmetric Diels–Alder/[3,3]sigmatropic rearrangeme... Scheme 3.11 Scandium‐catalyzed asymmetric cycloaddition between ketenes and ... Scheme 3.12 Rhodium‐catalyzed [2+2+2] cycloadditions between alkynes and cyc... Scheme 3.13 Synergistic palladium/chiral secondary amine‐catalyzed formal ri... Scheme 3.14 Conjugate umpolung of β,β‐disubstituted enals and isatins promot... Scheme 3.15 Bifunctional squaramide‐catalyzed synthesis of enantioenriched s... Scheme 3.16 Chiral phosphoric acid‐catalyzed enantioselective 1,3‐dipolar cy... Scheme 3.17 Stereoselective synthesis of spiroindene via trienamine catalysi... Scheme 3.18 Organocatalytic [4+2] addition reactions via tetraenamine interm... Scheme 3.19 Chiral H‐bond donor‐catalyzed asymmetric Tamura [4+2]‐cycloaddit... Scheme 3.20 Enantioselective Diels–Alder cyclization for the synthesis of ca... Scheme 3.21 NHC‐catalyzed [4+3] annulation of oxotryptamines with enals to a... Scheme 3.22 Organocatalytic enamine‐activation of cyclopropanes for highly s... Scheme 3.23 Chiral primary amine‐catalyzed regiodivergent asymmetric cycload... Scheme 3.24 Organocatalytic asymmetric tandem Nazarov cyclization/semipinaco... Scheme 3.25 Chiral phosphoric acid‐catalyzed asymmetric synthesis of SPINOL ...