Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

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 bicyclo1.1.0butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo1.1.0butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo1.1.0butanes with nitrones. In addition to the diverse bicyclo1.1.0butanes 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.