Organocatalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes

The bioisosteric replacement of 2D aromatic scaffolds with sp³-rich surrogates has become an important design element in modern medicinal chemistry. Within the sp³-rich world, the azabicyclo[2.1.1]hexane (aza-BCH) scaffold stands out as a pyrrolidine replacement and a useful building block. However, despite recent advancements in the field, a modular enantioselective synthesis of aza-BCHs remains challenging. In this study, we introduce an asymmetric organocatalytic approach relying on a confined imidodiphosphorimidate (IDPi) Brønsted acid that catalyzes the formal cycloaddition reaction of bicyclo[1.1.0]butanes (BCBs) with <i>N</i>-aryl imines under mild conditions, generating chiral aza-BCHs with high enantioselectivity (up to 99:1 er). Notably, the reaction proceeds effectively with a range of BCBs featuring ester, ketone, and amide functionalities. Experimental studies suggest that the reaction proceeds via a stepwise mechanism.