Strain-Release Radical-Polar Crossover Annulation: A Unified Strategy to Access Spiro-, Fused-, and Enantioenriched-Aza/Oxa-Bicyclo[3.1.1]hepatanes

Conformationally rigid bridged bicyclic scaffolds have emerged as bioisosteric replacements for planar aromatic rings. However, bioisosteric mimetics of heteroaromatic rings have been investigated less due to the challenges of incorporating heteroatoms into bicycloalkanes. Herein, we report a unified strategy to access both aza- and oxa-bicyclo[3.1.1]heptanes in a single experimental protocol from readily accessible amino/hydroxy acids under photoredox catalysis. The method shows broad applicability across various redox-active esters and bicyclo[1.1.0]butanes and successfully provides previously inaccessible spiro- and fused-heterobicyclo[3.1.1]heptanes. Noteworthy, chiral amino/hydroxy acids derived redox-active esters could be used to access enantioenriched chiral heterobicyclo[3.1.1]heptanes. Furthermore, the strategy has been extended to access aza-bicyclo[2.1.1]hexanes, another important motif in medicinal chemistry. The functional groups introduced during the reaction serve as a synthetic handle for downstream manipulation, thus offering opportunities to build up molecular complexity rapidly. Density functional theory calculations and experimental studies support an oxidative radical-polar crossover mechanism and rationalize the observed regioselectivity.