Catalytic Activation of Acceptor‐Acceptor Bicyclobutanes Enabled by Lewis Base Catalysis

Owing to the advent of various state-of-the-art strategies, the utilization of donor-acceptor bicyclo[1.1.0]butanes (BCBs) as a three-atom component in (3 + X) cycloaddition reactions has emerged as a highly efficient platform for constructing saturated bicyclic scaffolds that can serve as arene bioisosteres. However, the application of Lewis base catalysis in such reactions remains underexplored, and the strategy for the cycloaddition of acceptor-acceptor BCBs remains unknown. Herein, we report the first formal (4 + 2) cycloaddition of acceptor-acceptor BCBs, which serve as a four-atom component, for the selective synthesis of pharmaceutically valuable oxa-bicyclo[3.1.1]heptanes (oxa-BCHeps) enabled by N-heterocyclic carbene (NHC) catalysis. BCBs and carbonyl compounds, such as aldehydes and ketones, with various functional groups, are well-tolerated under mild conditions, yielding oxa-BCHeps with up to 87% yield, competing with at least five side reactions. The versatility of this synthetic method is further demonstrated through derivatization of the (4 + 2) cycloadducts and late-stage functionalization of pharmaceuticals. The reaction mechanism and the origins of the chemoselectivity were investigated by means of density functional theory calculations.