Novel Sulfonium Reagents for the Modular Synthesis of Spiro [2.3] Hexanes and Heteroatom‐Containing Analogues: Synthesis, Application, and Evaluation as Bioisosteres

Molecular scaffolds with a high fraction of sp3-hybridized centers have attracted considerable attention in medicinal chemistry as bioisosteres for a wide range of aromatic and nonstrained heterocycles. In particular, strained spiro-heterocycles have garnered popularity for this purpose, although access to spiro[2.3]hexane analogues is underrepresented. We herein report modular access to nine different spiro[2.3]hexane analogues, including previously underdeveloped 5-oxa-1-azaspiro[2.3]hexane and 1,5-diazaspiro[2.3]hexane motifs. Our synthetic approach leverages novel cyclobutane-, oxetane-, and azetidine-substituted sulfonium salts, which can undergo Johnson–Corey–Chaykovsky type reactions with alkenes, carbonyls and imines to provide access to the desired spiro[2.3]hexanes. Here, we also report the first comprehensive computational and predictive in silico evaluation of their bioisosteric potential, with validation provided by in vitro experiments.