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 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.