Photocatalytic oxygen-atom transmutation of oxetanes.

Abstract

Non-aromatic heterocycles and carbocycles form the skeleton of countless bioactive and functional molecules^1,2. Of note, four-membered saturated cyclic molecules such as azetidines, thietanes and cyclobutanes have garnered increasing attention in medicinal chemistry^3-7. These molecules often possess physicochemical properties relevant to drug discovery: potency, stability, metabolic stability and target specificity³. The replacement of oxygen atoms in readily available oxetanes would offer a direct route to a variety of these cyclic pharmacophores, yet such atom swapping has been rarely reported for non-aromatic molecules. Here we report a general photocatalytic strategy that selectively substitutes the oxygen atom of an oxetane with a nitrogen-, sulfur- or carbon-based moiety, transforming it into a diverse range of saturated cyclic building blocks in a single operation. This atom swapping method exhibits high functional group compatibility and is applicable to late-stage functionalization, substantially simplifying the synthesis of pharmaceuticals and complex drug analogues that would otherwise require multi-step routes. Mechanistic investigations unveil insights on the origin of chemoselectivity that allows the endocyclic oxygen atom to react preferentially to generate an acyclic dihalide intermediate, which then undergoes efficient ring reconstruction in the presence of a nucleophilic species.