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

Abstract

Abstract Molecular scaffolds with a high fraction of sp 3 ‐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.

Affiliated Institutions

• University of Bari Aldo Moro IT
• American Chemical Society US
• University of Perugia IT

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