Modular Synthesis of Bridge-Disubstituted Bicyclo[3.1.1]heptanes via Stereoselective Difunctionalization of Tricyclo[4.1.0.02 , 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(sp3)-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[4.1.0.02,7]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.