Synthesis of Chiral Diazabicycloalkanes via Organocatalytic aza-Michael/Aldol Reaction

Abstract

We introduce a strategy for the one-step synthesis of chiral diazabicycloalkanes that delivers the annulated ring system in a single reaction step. The method entails a direct aza-Michael/aldol reaction of enals in conjunction with modified oxopropanamides and establishes the chiral center via iminium-enamine tandem catalysis. For this purpose, we developed simple diphenylethylendiamine frameworks as dual activation organocatalyst, effectively engaging both the substrate and reagent, thus leading to yields of 31–86% and enantioselectivities in the range of 80–98%. The final product features not only the diazabicycloalkane moiety but includes also additional functionalities, such as aldehyde motives that can be modified in situ without loss of enantioselectivity, and an sp2-bearing methyl group. Our approach accommodates a wide array of enals with high functional group tolerance. Additionally, we demonstrated the adjustability of enantioselectivity and yield by modulating the acid cocatalyst‘s quantity, thus offering multiple optimization possibilities.