Chapter 1
[3 + 2] Dipolar Cycloadditions of Cyclic Nitrones with Alkenes

Alberto Brandi, Francesca Cardona, Stefano Cicchi, Franca M. Cordero and Andrea Goti

Dipartimento di Chimica "Ugo Schiff", Università di Firenze, Via della Lastruccia 3-13, 50019, Sesto Fiorentino (FI), Italy

1. Acknowledgments
2. Introduction
3. Mechanism and Stereochemistry
   1. Computational Studies
   2. Regioselectivity
   3. Stereoselectivity
4. Scope and Limitations
   1. Preparation of Cyclic Nitrones
   2. Cycloaddition Reactions
      1. Intermolecular Cycloadditions
         1. The Alkene Component
         2. The Nitrone Component
            1. Four-Membered Cyclic Nitrones
            2. Five-Membered Cyclic Nitrones
            3. Six-Membered Cyclic Nitrones
            4. n-Membered Cyclic Nitrones (n > 6)
         3. Catalyzed Cycloadditions
      2. Intramolecular Cycloadditions
         1. Five-Membered Cyclic Nitrones
            1. Three-Atom Tether
            2. Four-Atom Tether
            3. Five- and Six-Atom Tethers
         2. Six-Membered Cyclic Nitrones
            1. Three-Atom Tether
            2. Four-Atom Tether
            3. Five-Atom Tether
         3. Six-Atom Tether
         4. n-Membered Cyclic Nitrones (n > 6)
5. Applications to Synthesis
   1. Overview
      1. Intermolecular Cycloadditions
         1. Batzelladines
         2. (+)-Carpetimycin A
         3. Casuarine
         4. (+)-Citrinadin B
         5. (+)-Febrifugine
         6. (+)-Lentiginosine
         7. Stemonidine and Stemospironine
      2. Intramolecular Cycloadditions
         1. (-)-Flueggin A and (+)-Virosaine B
         2. Cylindrospermopsin
         3. (+)-Euphococcinine
         4. Histrionicotoxins
         5. (-)-(19R)-Ibogamin-19-ol
         6. Lepadiformine
         7. (±)-Myrioxazine A
         8. (-)-Rosmarinecine
6. Comparison with Other Methods
7. Experimental Conditions
8. Experimental Procedures
   1. 1. (3aR-cis)-4-(1,1-Dimethylethoxy)hexahydro-2,2-diphenylpyrrolo[1,2-b]isoxazole and (3aS-trans)-4-(1,1-Dimethylethoxy)hexahydro-2,2-diphenylpyrrolo[1,2-b]isoxazole [Cycloaddition of a Chiral Five-Membered Cyclic Nitrone with a 1,1-Disubstituted Acyclic Alkene].480
      2. (2R,3´S,3´aR,5S,6R)-Tetrahydro-3´-(methoxymethyl)-4,5-dimethyl-6-phenyl-spiro[morpholine-2,2´(3´H)-pyrrolo[1,2-b]isoxazol]-3-one [Cycloaddition of a Five-Membered Cyclic Nitrone with a Trisubstituted Exocyclic Alkene Under Microwave Irradiation].481
      3. (3aS,6aS,7S,8R,10aR,10bS,10cR)-7-(Acetyloxy)-8-[(acetyloxy)methyl]octahydro-2,2-dimethyl-10H-1,3-dioxolo[3,4]pyrrolo[1,2-b]pyrano[3,4-d]isoxazol-10-one and (3aR,6aS)-3a,6a-Dihydro-2,2-dimethyl-4H-1,3-dioxolo[4,5-c]pyrrole-5-oxide [Kinetic Resolution of a Chiral Racemic Five-Membered Cyclic Nitrone Through Cycloaddition with an Endocyclic Disubstituted Alkene].482
      4. [3aR-(3aa,6ß,8aß,8ba)]-Hexahydro-6-(hydroxymethyl)furo[3,4-d]pyrrolo[1,2-b]isoxazol-1(3H)-one [Synthesis of an Enantiopure Five-Membered Cyclic Nitrone by Oxidation of a Secondary Amine and Cycloaddition with an Endocyclic Alkene].483
      5. (2S,3S,3aS,4aS,5R,8S,8aR)-5,10,10-Trimethyl-2-heptyl-5,8-methanooctahydro-2H-isoxazolo[3,2-b]benzoxazole-3-carboxylic Acid, Ethyl Ester [In Situ Synthesis of an Enantiopure Five-Membered Cyclic Nitrone Containing One Heteroatom and Its Cycloaddition with a 1,2-Disubstituted Alkene].166
      6. 2,6-Anhydro-7-deoxy-1,3,4,5-tetrakis-O-(phenylmethyl)-7-[(1S,2S,2´S,3´aS,5R)-tetrahydro-5,5´-dimethyl-2-(1-methylethyl)-4´-oxospiro[cyclohexane-1,6´(2´H)-imidazo[1,5-b]isoxazol]-2´-yl]-D-glycero-L-galactoheptitol [Cycloaddition of an Enantiopure Five-Membered Cyclic Nitrone Containing One Heteroatom with a Monosubstituted Alkene].24
      7. (2R,3aR,7S)-Hexahydro-7-methyl-2-nonyl-2H-Isoxazolo[2,3-a]pyridine [In Situ Synthesis of an Enantiopure Six-Membered Cyclic Nitrone and Cycloaddition with a Monosubstituted Alkene].149
      8. [2S-(2a,3aß,4a,5ß,6a,7ß)]-4,5-bis[[(1,1-Dimethylethyl)dimethylsilyl]oxy]hexahydro-6-hydroxy-7-(hydroxymethyl)-2H-isoxazolo[2,3-a]pyridine-2-acetic Acid, Methyl Ester [Cycloaddition under High Pressure of an Enantiopure Six-Membered Cyclic Nitrone with a Monosubstituted Alkene].484
      9. (3R,5S)-2-Methyl-1,5,6,10b-tetrahydro-2H-isoxazolo[3,2a]isoquinoline-2-carboxaldehyde [Enantioselective Cycloaddition of a Six-Membered Cyclic Nitrone with a 1,1-Disubstituted Alkene Catalyzed by an Enantiopure Iron Complex].82
      10. (8aRS,11aSR,11bRS)-5,6,11a,11b-Tetrahydro-10-methyl-5-methylene-pyrrolo[3´,3´:4,5]isoxazolo[3,2-a]isoquinoline-9,11(8aH,10H)-dione [In Situ Synthesis of a Six-Membered Nitrone and Cycloaddition with an Endocyclic Alkene].237
      11. (3aS,6S,7S,9S,10aR,10bR)-Octahydro-7-hydroxy-2,6,11,11-tetramethyl-6,9-methano-1H-pyrrolo[3´,3´:4,5]isoxazolo[2,3-a]azepine-1,3(2H)-dione [In Situ Synthesis of an Enantiopure Seven-Membered Cyclic Nitrone and Cycloaddition with an Endocyclic Alkene].485
      12. (2R,3S,3aS,6R,7S)-Hexahydro-3-(methoxycarbonyl)-7-methyl-2,6-methanopyrrolo[1,2-b]isoxazolium Methanesulfonate [In Situ Synthesis of an Enantiopure Five-Membered Cyclic Nitrone and Intramolecular Cycloaddition Followed by Alkylation of the Cycloadduct].129
      13. (2aR,3S,6aR,6bR)-Hexahydro-2-oxo-2H-1,4-dioxa-4a-azacyclopenta[cd]pentalene-3-carboxylic Acid, Methyl Ester [In Situ Synthesis of an Enantiopure Five-Membered Nitrone via Retrocycloaddition and Intramolecular Cycloaddition].220
      14. (2aSR,4aSR,7bRS)-Octahydro-1-oxa-7a-azacyclopenta[cd]indene [In Situ Synthesis of a Six-Membered Nitrone and Intramolecular Cycloaddition].378
      15. (2S,5aR,9S,11R)-9-[[[(1,1-Dimethylethyl)diphenylsilyl]oxy]methyl]octahydro-2,5a-methano-5aH-pyrido[1,2-b][1,2]oxazepine-11-carbonitrile [In Situ Synthesis of an Enantiopure Six-Membered Nitrone via Retrocycloaddition and Intramolecular Cycloaddition].430
      16. 3,11-bis[(4-Methylphenyl)sulfonyl]-13-oxa-3,7,11-triazatricyclo[5.5.1.11,6]tetradecane [In Situ Synthesis of a 12-Membered Cyclic Nitrone and Intramolecular Cycloaddition].486
9. Tabular Survey
   1. Chart 1. Cycloaddition Catalysts and Additives
   2. Table 1. Intermolecular Cycloadditions of 4-Membered Cyclic Nitrones
   3. Table 2A. Intermolecular Cycloadditions of 5-Membered Cyclic Nitrones with Acyclic Alkenes
   4. Table 2B. Intermolecular Cycloadditions of 5-Membered Cyclic Nitrones with Exocyclic Alkenes
   5. Table 2C. Intermolecular Cycloadditions of 5-Membered Cyclic Nitrones with Endocyclic Alkenes
   6. Table 3. Intermolecular Cycloadditions of 5-Membered Cyclic Nitrones with a Heteroatom in the Ring
   7. Table 4A. Intermolecular Cycloadditions of 6-Membered Cyclic Nitrones with Acyclic Alkenes
   8. Table 4B. Intermolecular Cycloadditions of 6-Membered Cyclic Nitrones with Exocyclic Alkenes
   9. Table 4C. Intermolecular Cycloadditions of 6-Membered Cyclic Nitrones with Endocyclic Alkenes
   10. Table 5. Intermolecular Cycloadditions of 6-Membered Nitrones with a Heteroatom in the Ring
   11. Table 6. Intermolecular Cycloadditions of n-Membered Cyclic Nitrones (n>6)
   12. Table 7. Intramolecular Cycloadditions of 5-Membered Cyclic Nitrones
   13. Table 8. Intramolecular Cycloadditions of 6-Membered Cyclic Nitrones
   14. Table 9. Intramolecular Cycloadditions of n-Membered Cyclic Nitrones (n>6)
10. References

Acknowledgments

We are grateful for the excellent guidance, careful reading, and editing provided by Prof. Steven M. Weinreb, for the thoughtful advice of Prof. Scott E. Denmark, and for the assistance of Dr. Linda S. Press and Dr. Jeffery B. Press. We are also grateful to Dr. Landy Blasdel and Dr. Danielle Soenen for the helpful collaboration.

Introduction

This review covers [3 + 2] dipolar cycloadditions of endocyclic nitrones with alkenes, including conjugated polyenes and cumulenes, from 1985 to 2014, thereby updating the survey published by Confalone and Huie1 in their pioneering Organic Reactions review (Scheme 1).

Scheme 1

For the sake of conciseness, this contribution is limited to cyclic nitrones and alkenes. Although the earlier chapter included acyclic...