Modular Synthesis of Bridge‐Disubstituted Bicyclo[3.1.1]heptanes via Stereoselective Difunctionalization of Tricyclo[4.1.0.0 2 , 7 ]heptane

Scaffolds with flexible bond exit vectors are essential in bioisosteric design, enabling adaptive molecular recognition of conformationally dynamic targets, and fine‐tuning key physicochemical properties. Despite this potential, current benzene bioisosteres based on bicyclo[n.1.1]alkanes are confined to three‐dimensional scaffolds with fixed exit vectors at their rigid bridgehead positions. As a critical piece for mimicking substituted arenes, the development of C(sp 3 )‐enriched bioisosteres bearing two flexible vectors has been thwarted by the lack of stereoselective synthetic routes. Herein, we report a photochemical nickel‐catalyzed selective 1,7‐difunctionalization of tricyclo[4.1.0.0 2,7 ]heptane using readily available organohalides. This sequential protocol generates previously elusive anti ‐stereoselective 6,7‐difunctionalized bicyclo[3.1.1]heptanes with high stereocontrol, broad coupling‐partner scope, and built‐in handles for post‐functionalization. Biological assays and computational modeling on drug analogues demonstrate the bioisosteric potential of these dual‐flexible‐vector bicyclo[3.1.1]heptane scaffolds. This methodology unlocks previously unexplored chemical space with broad implications for drug discovery and beyond.