Enantioselective formal 4π+2σ cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

Abstract The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclon.1.1alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of BCB using a chiral Lewis acid catalyst and a bidentate chelating BCB substrate, as exemplified by the current enantioselective formal 4π+2σ cycloaddition of BCBs with nitrones. In addition to the diverse BCB incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo3.1.1heptane product with up to 99% yield and >99% ee.