Asymmetric Dearomative [2 + 2] Photocycloaddition of Quinoline and Indole Derivatives with Bicyclo[1.1.0]butanes

The dearomative photocycloaddition reactions of (hetero)arene feedstocks have emerged as an efficient platform for the construction of three-dimensional complexity, which is of increasing interest in medicinal chemistry. Nevertheless, the catalytic asymmetric version of such transformations with quinolines remains a challenging task because of regio-, diastereo-, and enantioselective control. Especially the presence of substituents with divergent electronic effects on the aromatic ring presents a regioselectivity control dilemma. Herein, we report highly regio-, diastereo-, and enantioselective dearomative [2 + 2] photocycloadditions of quinolines with bicyclo[1.1.0]butanes (BCBs) by utilizing a chiral Lewis acid-mediated strain-release approach. The regioselectivity and stereocontrol challenges were addressed by strategically designing catalysts with tailored steric bulk that modulated the chiral pocket in response to the electronic and steric characteristics of diverse substrate substituents. This strategy was compatible with isoquinoline, indole derivatives, naphthalene, and benzo[<i>b</i>]thiophene, providing highly decorated chiral heterocycle-fused bicyclo[2.1.1]hexanes (BCHs) in moderate to good yields with high regio-, diastereo-, and enantioselectivities (52 examples, up to 99% yield, >19:1 rr, >19:1 dr, 99% ee). Based on experimental studies and theoretical calculations, a catalytic cycle along with possible transition states was provided to understand the reaction mechanism.