Organocatalytic Asymmetric Synthesis of Azabicyclo2.1.1hexanes

High Resolution Image Download MS PowerPoint Slide The bioisosteric replacement of 2D aromatic scaffolds with sp 3 -rich surrogates has become an important design element in modern medicinal chemistry. Within the sp 3 -rich world, the azabicyclo2.1.1hexane (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 bicyclo1.1.0butanes (BCBs) with N -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.