Direct Amine-Catalyzed Enantioselective Synthesis of Pentacyclic Dibenzob,f1,4oxazepine/Thiazepine-Fused Isoquinuclidines along with DFT Calculations

A direct protocol for the asymmetric synthesis of dibenzoxazepine/thiazepine-fused 2.2.2 isoquinuclidines is developed. The reaction proceeds through a proline-catalyzed direct Mannich reaction followed by an intramolecular aza-Michael cascade sequence between 2-cyclohexene-1-one and various tricyclic imines, like dibenzoxazepines/thiazepines, as an overall 4 + 2 aza-Diels-Alder reaction. A series of pentacyclic isoquinuclidines have been prepared, with complete endo-selectivity, in good to high yields and excellent enantioselectivity (>99:1). Density functional theory (DFT) calculations further support the observed high stereochemical outcome of the reaction.