Chiral Lithium Phosphate-Catalyzed Photoredox-Neutral [2σ + 2σ] Cycloaddition of Cyclopropylamines with Bicyclo[1.1.0]butanes

Abstract Enantioenriched bicyclo[3.1.1]heptanes (BCHeps) are attractive three-dimensional bioisosteres of meta-substituted arenes, yet catalytic asymmetric methods for their preparation remain limited. Here, we report an enantioselective, photoredox-neutral [2σ + 2σ] cycloaddition of N-(quinolin-8-yl)cyclopropylamines with bicyclo[1.1.0]butanes (BCBs) enabled by the cooperative action of di(pyridin-2-yl)methanone (DPM) and a chiral lithium phosphate. Under blue-light irradiation, a broad range of ester- and ketone-substituted bicyclobutanes undergo cycloaddition to furnish 1,5-disubstituted BCHep-derived amines in up to 90% yield and 99% ee. The protocol accommodates a broad range of structurally diverse and biologically relevant substituents, and its synthetic versatility is further demonstrated by downstream derivatizations and the synthesis of an enantioenriched BCHep-based bioisostere of the fungicide boscalid. Mechanistic studies support initial single-electron oxidation of the cyclopropylamine by photoexcited DPM, followed by radical addition to the bicyclobutane and enantioselective intramolecular cyclization. Cooperative hydrogen bonding and Lewis acid–base coordination organizes the radical-cation intermediate within the chiral catalyst environment, thereby promoting both reactivity and stereocontrol. This azaaryl-assisted recognition strategy provides a general platform for controlling challenging asymmetric photoreactions.