Enantioselective Synthesis of 2-Oxabicyclo[2.1.1]hexanes and Bicyclo[2.1.1]hexanes via Catalytic Asymmetric Intramolecular Photocycloadditions.

Due to the ubiquitous presence of ortho-disubstituted benzenes in pharmaceuticals and agrochemicals, the exploration of their bioisosteres incorporating three-dimensional bridged cyclic scaffolds has attracted significant interest among chemists in recent years. As a result, 4,5-disubstituted 2-oxabicyclo[2.1.1]hexanes have recently emerged as promising candidates owing to their enhanced pharmacological potency, improved metabolic stability, and, importantly, superior aqueous solubility. Herein, we report our recent progress on enantioselective synthesis of such compounds via an intramolecular [2 + 2] photocycloaddition enabled by cooperative photoinduced energy transfer (EnT) and chiral Brønsted acid catalysis. A broad range of valuable pyridine-functionalized 2-oxabicyclo[2.1.1]hexane derivatives have been obtained in high yields with good to excellent enantioselectivity and diastereoselectivity. In addition, this transition metal-free approach offers an efficient and modular route to pyridine-based bicyclo[2.1.1]hexanes, which contain a significant yet challenging structural motif-pyridine rings directly attached to the bridgehead carbon atoms. Mechanistic studies demonstrate that the photosensitizer and low reaction temperature are crucial for rendering the chiral catalyst indispensable in facilitating substrate activation to the triplet state, thereby enabling enantiocontrol in this highly reactive transformation.