Beyond <i>para</i> ‐ and <i>meta</i> ‐Substitution: Synthesis and Biological Validation of Chalcogen‐Rich Thiabicyclo[3.1.1]heptanes as Bioisosteres of Aryl Thioether Derivatives

ABSTRACT While bicyclo[3.1.1]heptanes (BCHeps) and oxa‐/aza‐BCHeps have emerged as valuable arene bioisosteres, the corresponding thia‐analogs remain underdeveloped. Notably, synthetic efforts to access aryl thioether mimetics have focused predominantly on strain‐release thiofunctionalization of [1.1.1]propellane or [3.1.1]propellane to access para ‐ and meta ‐substituted surrogates, whereas three‐dimensional analogs of ortho ‐ and 1,2,4‐trisubstituted aryl thioethers remain elusive. Herein, we report a one‐pot stepwise protocol featuring anti ‐thio(seleno)sulfonylation/annulation of bicyclo[1.1.0]butanes (BCBs) to enable scalable access to functionalized 2‐thiabicyclo[3.1.1]heptanes (thia‐BCHeps) under mild conditions. The synthetic utility is further demonstrated by diverse derivatization of these thia‐BCHeps building blocks and facile access to bioisosteres of ortho ‐, meta ‐, and 1,2,4‐trisubstituted aryl thioether derivatives (e.g., aryl sulfones and aryl sulfoximines). DFT calculations revealed that the reaction proceeded via a polar addition pathway, involving nucleophilic attack of cesium methanesulfinate with BCB. The observed diastereoselectivity originates from the stabilization of the anti ‐addition transition state by a favorable π–π stacking interaction between two phenyl rings. Crystallographic analysis revealed that these thia‐BCHeps display geometric properties almost identical to those of ortho‐ , meta‐ , and 1,2,4‐trisubstituted aryl thioethers. Physicochemical studies and biological evaluation further validated these thia‐BCHeps as a new generation of saturated bioisosteres for aryl thioethers.