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)bicyclo[n.1.1]alkanes 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-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.