"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."
Non-aromatic four-membered saturated rings such as azetidines, thietanes, and cyclobutanes serve as important scaffolds with desirable potency, stability, metabolic stability, and target specificity. A general photocatalytic strategy selectively substitutes the endocyclic oxygen in oxetanes with nitrogen-, sulfur-, or carbon-based moieties to generate diverse saturated cyclic building blocks in a single operation. The atom-swapping method shows high functional-group compatibility and enables late-stage functionalization, streamlining access to pharmaceuticals and complex analogues that otherwise require multistep syntheses. Mechanistic studies indicate chemoselectivity arises from preferential reaction at the endocyclic oxygen to form an acyclic dihalide intermediate, which undergoes nucleophile-driven ring reconstruction.
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