Strain‐Enabled Radical‐Polar Crossover Annulation to Access Spiro‐, Fused‐, and Enantioenriched‐Aza/Oxa‐Bicyclo[3.1.1]Heptanes

Abstract 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 a readily accessible amino/hydroxy acid derivative under photoredox catalysis. The reaction exhibits a broad scope across a range of redox‐active esters and bicyclo[1.1.0]butanes (BCBs) and successfully provides previously inaccessible spiro‐ and fused‐hetero‐bicyclo[3.1.1]heptanes. Noteworthy, chiral amino/hydroxy acid derived redox‐active esters could be used to access enantioenriched hetero‐bicyclo[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 manipulations, thus offering opportunities to build up molecular complexity rapidly. Density functional theory calculations and experimental studies support an oxidative radical‐polar crossover (RPC) mechanism and rationalize the observed regioselectivity.