Direct Catalytic Enantioselective Aza-Diels-Alder Reactions

Significance

While indirect, catalytic, enantioselective aza-Diels-Alder reactions have been reported, this paper describes the first direct, organocatalytic aza-Diels-Alder reaction. Three components, enone, aqueous formaldehyde, and amine, are mixed with the proline catalyst and enantioselectivities greater than 94% are produced in many cases. When the enone was β-substituted, the Mannich adduct was isolable. This indicated a stepwise mechanism where first the proline and enone form a chiral enamine, which reacts with the in situ formed imine (Mannich reaction); the anionic nitrogen then adds intramolecularly in a 1,4-fashion to the iminium ion and hydrolysis leads to the chiral aza-Diels-Alder adduct.