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

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.