CHAPTER 1
DIHYDROPYRANS BY CYCLOADDITIONS OF OXADIENES

ARNAUD MARTEL, ROBERT DHAL, CATHERINE GAULON, MATHIEU YVES LAURENT, AND GILLES DUJARDIN

IMMM-UMR 6283 CNRS, Faculté des Sciences Le Mans Université 72085 Le Mans Cedex 9 France

Edited by Steven M. Weinreb

1. Acknowledgments
2. Introduction
3. Mechanism And Stereochemistry
   1. Thermal Cycloadditions
   2. IODA Reactions Promoted by Hyperbaric Conditions
   3. Lewis Acid Catalyzed/Promoted Cycloadditions
   4. Facially Controlled Cycloadditions

1. Scope And Limitations
   1. Synthesis of Oxadienes
   2. Intermolecular Cycloadditions
   3. Unactivated Oxadienes: a,ß-Unsaturated Carbonyl Compounds and Derivatives
   4. Oxadienes Functionalized at C4
   5. Oxadienes Activated at C3
   6. Oxadienes Activated at C2
   7. Uncatalyzed Reactions
   8. Lewis Acid Catalyzed Reactions
   9. Chiral Lewis Acid Catalyzed and Organocatalyzed Reactions
   10. Cycloadditions of Oxadienes on Solid Support

1. Dimerization of Oxadienes
2. Intramolecular IODA Reactions
   1. Intramolecular IODA Reactions Involving Simple Enals
   2. Intramolecular IODA Reactions Involving Simple Enones
   3. Intramolecular IODA Reactions Involving Oxadienes Activated at C3
   4. Intramolecular IODA Reactions Involving Oxadienes Activated at C2

1. Domino Reactions
   1. Domino Reactions Involving Intermolecular IODA of Oxadienes
   2. Domino Reactions Involving Intramolecular IODA of Oxadienes

1. Applications to Synthesis
2. Comparison With Other Methods
3. Experimental Conditions
4. Experimental Procedures
   1. (3S*,4S*,5R*)-3,4-Epoxy-4-methyl-l,6-dioxaspiro[4,5]dec-7-ene [ZnCl2-Catalyzed Hetero-Diels-Alder Reaction of an Unactivated a,ß-Unsaturated Aldehyde].71
   2. 7-Methyl-2-phenyl-1,4-dioxaspiro[4,5]dec-7-ene [Hetero-Diels-Alder Reaction of an Unactivated a,ß-Unsaturated a´-Alkyl Ketone Under Microwave Irradiation].255
   3. (2S*,3R*,4R*)-2-Ethoxy-4-methyl-3-phenyl-6-((phenylsulfonyl)methyl)-3,4-dihydro-2H-pyran [TiCl2(Oi-Pr)2-Catalyzed Hetero-Diels-Alder Reaction of an Unactivated a,ß-Unsaturated a´-Alkyl Ketone].105
   4. (2S*,4R*)-8-Benzylidene-2-ethoxy-4-phenyl-3,4,5,6,7,8-hexahydro-2H-benzopyran [Yb(fod)3-Catalyzed Hetero-Diels-Alder Reaction of an Unactivated a,ß-Unsaturated a´-Alkyl Ketone].75
   5. (2S)-Ethoxy-(4S)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyran [Chromium(III)-Catalyzed, Asymmetric Hetero-Diels-Alder Reaction of an Oxadiene Monofunctionalized at C4].160
   6. (2S,SS)-2-(4-Methoxyphenyl)-2,6-dimethyl-5-(4-tolylsulfinyl)-3,4-dihydro-2H-pyran [Thermal Hetero-Diels-Alder Reaction of an Oxadiene Heterosubstituted at C3].171,343
   7. (4R*,4aR*,8aR*)-2-Methoxy-4-phenyl-4a,5,6,7,8,8a-hexahydro-4H-chromene-3-carbonitrile [Hyperbaric Hetero-Diels-Alder Reaction of an Oxadiene Activated at C3].367
   8. (4S*,5R*,6R*)-Ethyl 5,6-Dihydro-5-isopropyl-2-methyl-4-phenyl-6-(piperidin-1-yl)-4H-pyran-3-carboxylate [Thermal Hetero-Diels-Alder Reaction of an Oxadiene Activated at C3 with an Enamine].327
   9. Dimethyl ((2R,4R)-2-Ethoxy-4-methyl-3,4-dihydro-2H-pyran-6-yl)phosphonate [Copper(II)-Catalyzed Enantioselective Hetero-Diels-Alder Reaction of an Oxadiene Heterosubstituted at C2].81
   10. (2R,3S,4S,4´S)-3-Acetoxy-2,4-diethoxy-6-(carbonyl-4´-tert-butyloxazolidin-2´-one)-3,4-dihydro-2H-pyran [Me2AlCl-Catalyzed Hetero-Diels-Alder Reaction of an Oxadiene Activated at C2].36
   11. Methyl (4S,4aS,8aS)-8a-tert-Butyldimethylsiloxy-4-phenyl-4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate [Scandium(III)-Catalyzed, Enantioselective Hetero-Diels-Alder Reaction of an Oxadiene Heterosubstituted at C2].412
   12. (2R,3R,4S)-Methyl 2-((R)-4-Ethyl-2-oxooxazolidin-3-yl)-3-tetracosyl-4-tridecyl-3,4-dihydro-2H-pyran-6-carboxylate [Eu(fod)3-Catalyzed Hetero-Diels-Alder Reaction of an Oxadiene Activated at C2].102
   13. (4R,5S,6S)-Methyl 6-((R)-4-Ethyl-2-oxo-oxazolidin-3-yl)-5,6-dihydro-5-methyl-4-phenyl-4H-pyran-2-carboxylate (Endo ß) [SnCl4-Catalyzed Hetero-Diels-Alder Reaction of an Oxadiene Activated at C2].35
   14. (2-Ethoxy-3,4-dihydro-4-phenyl-2H-pyran-6-yl)methanol [Eu(fod)3-Catalyzed Hetero-Diels-Alder Reaction of an Oxadiene on Solid Support].55
   15. 2,5-Diethyl-3,4-dihydro-2H-pyran-2-carbaldehyde [Thermal Dimerization of an Oxadiene].453
   16. (4aS,8aS,SS)-(-)-4a,5,6,7,8,8a-Hexahydro-1,1,3,6,6-pentamethyl-4-(4-toluenesulfinyl)-1H-2-benzopyran [Et2AlCl-Catalyzed, Intramolecular Hetero-Diels-Alder Reaction of an Oxadiene].510

1. Tabular Survey
   1. Chart 1. Asymmetric Catalysts and Ligands Used in Tables
   2. Table 1. Cycloaddition of Unactivated a, ß-Unsaturated Aldehydes
   3. Table 2. Cycloaddition of Unactivated a, ß-Unsaturated a´-Alkyl Ketones
   4. Table 3. Cycloaddition of Unactivated a, ß-Unsaturated a´-Aryl Ketones
   5. Table 4. Cycloaddition of Unactivated a, ß-Unsaturated a´-Heteroaryl Ketones
   6. Table 5. Cycloaddition of Oxadienes Monofunctionalized at C4
   7. Table 6. Cycloaddition of Oxadienes Heterosubstituted at C3
   8. Table 7. Cycloaddition of Oxadienes Activated at C3
   9. Table 8. Cycloaddition of Oxadienes Heterosubstituted at C2
   10. Table 9. Cycloaddition of Oxadienes Activated at C2
   11. Table 10. Cycloaddition of Oxadienes on Solid Support
   12. Table 11. Dimerization of Oxadienes
   13. Table 12. Intramolecular Cycloaddition of Oxadienes
   14. Table 13. Domino Reactions Involving Intermolecular IODA of Oxadienes
   15. Table 14. Domino Reactions Involving Intramolecular IODA of Oxadienes
2. References

Acknowledgments

We are grateful to the National Center of Scientific Research (CNRS) and the French Ministry of Research for financial support of the research on heterocycloadditions performed at the Le Mans Université.

Introduction

Among the most common types of hetero-Diels-Alder reaction is the formation of dihydropyrans by a [4 + 2] process involving a carbonyl group acting either as a dienophile or as part of a heterodienic framework. These two complementary versions of the oxa-Diels-Alder reaction (ODA) have created opportunities for the regio-, diastereo-, and enantiocontrolled access to natural products and bioactive molecules, including important carbohydrate derivatives, given the presence of tetrahydropyran frameworks in such compounds.

Inverse-electron-demand oxa-Diels-Alder reactions (IODA) of a,ß-unsaturated carbonyl compounds with electron-rich dienophiles lead to 3,4-dihydro-2H-pyrans (Scheme 1). These site-selective reactions have been known for a long time and were first observed with the dimerization reactions of acrolein1 and methyl vinyl ketone.2 Initially restricted to highly electron-rich dienophiles such as enamines and enol ethers under thermal conditions, intermolecular IODA reactions have since been...