Piperidines from Organocatalytic Inverse-Demand Aza-Diels-Alder Reaction

Significance

Described is an inverse-electron-demand regioselective aza-Diels-Alder reaction of N-sulfonyl-1-aza-1,3-butadienes with α,β-unsaturated aldehydes under enantioselective organocatalytic conditions to afford optically pure polysubstituted piperidines. The reaction is presumed to occur via a dienamine intermediate formed from the reaction of the α,β-unsaturated aldehyde with a catalytic amount of chiral amine. The best results were obtained with the chiral amine 1 in association with benzoic acid. PCC oxidation of the product leads to the piperidone with predominant E-stereochemistry. While the E/Z stereoselectivity is moderate, the enantioselectivity for the formation of the E-isomer is excellent (÷97% ee). When using crotonaldehyde, two different regioisomers were obtained depending on the nature of the N-tosyl-1-aza-1,3-butadiene starting material.