Enantioselective Synthesis of Cyclobutane‐fused Heterocycles via Lewis Acid‐Catalyzed Dearomative [2+2] Photocycloaddition of Indoles, Benzofurans, and Benzothiophenes with Alkenes

Abstract Cyclobutane‐fused heterocycles are important motifs in biologically active molecules, yet their enantioselective synthesis remains a significant challenge. We report a broadly applicable and modular strategy for constructing these strained architectures through a visible‐light‐mediated, Lewis acid‐catalyzed dearomative [2+2] photocycloaddition of indoles, benzofurans, and benzothiophenes with alkenes. The method employs a simple catalytic system based on commercially available rare‐earth Lewis acids and chiral pyridine‐2,6‐bis(oxazoline) (PyBox) ligands. A wide array of heteroarenes and styrenes bearing diverse functional groups participate efficiently, delivering cyclobutane‐fused products in up to 96% yield, >20:1 dr, and >99% ee. The synthetic utility is further demonstrated by gram‐scale synthesis and facile removal of the directing group to access functionalized amino acid derivatives. Mechanistic investigations, including ultraviolet‐visible (UV–vis) spectroscopy, nonlinear effect studies, kinetic isotope effects, and density functional theory (DFT) calculations, reveal that a triplet‐state heteroarene engages in regio‐ and enantio‐selective C─C bond formation under mild photochemical conditions. This study highlights the potential of excited‐state Lewis acid catalysis in unlocking enantioselective dearomatization pathways for complex molecular architectures.