康 · 学术 | Reaction of the Day No. 1555

（来源：康龙化成）

转自：康龙化成

Photocatalytic Oxygen-atom Transmutation of Oxetanes

Ying-Qi Zhang, Shuo-Han Li, Xinglong Zhang2* & Ming Joo Koh1*

1 Department of Chemistry, National University of Singapore, 4 Science Drive 2, Republic of Singapore, 117544. 2 Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

—Nature, 2025 .https://doi.org/10.1038/s41586-025-09723-3

Recommended byXiaoxu Wang_ MC5

KEY WORDS:photo chemistry, Ru catalysis, skeleton editing,atom swapping, late-stage functionalization (反应类型), oxetanes (原料), azetidines, thietanes, cyclobutanes (产物), Csp3-N, Csp3-S,Csp3-Csp3(成键类型)

ABSTRACT:Non-aromatic heterocycles and carbocycles form the skeleton of countless bioactive and functional molecules. Of note, four-membered saturated cyclic molecules such as azetidines, thietanes and cyclobutanes have garnered increasing attention in medicinal chemistry. These molecules often possess physicochemical properties relevant to drug discovery: potency, stability, metabolic stability and target specificity. 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.

Synthetic logic based on atomic replacement of oxygen in oxetanes.

Reaction scope of O-to-N swap (selected examples)

Extension to other O-atom transmutations(selected examples)

Conceptual design of photocatalytic O-atom transmutation and possible reaction pathways

Prof. Xinglong Zhang, Ming Joo Kohand his co-workers present a photocatalytic manifold that promotes preciseoxygen-atom replacement within oxetanes via a deletion-insertion regimeto afford a wide assortment of pharmaceutically important four-membered and five-membered C(sp3)-rich carbocyclicas well as nitrogen and sulfur heterocyclic entities under mild conditions. The transformation proceeds by in situ ring deconstruction to form an electrophilic dihalide intermediatewhich then undergoes cyclization with various nucleophiles in one pot. The reaction tolerates a wide spectrum of functionalities and is amenable to late-stage modification of bioactive compounds, significantly reducing synthetic manipulations to accelerate the preparation of drug-like targets.