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Photocatalytic oxygen-atom transmutation of oxetanes

Nature volume 647, pages 906–912 (2025)Cite this article

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Abstract

Non-aromatic heterocycles and carbocycles form the skeleton of countless bioactive and functional molecules1,2. Of note, four-membered saturated cyclic molecules such as azetidines, thietanes and cyclobutanes have garnered increasing attention in medicinal chemistry3,4,5,6,7. These molecules often have 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-based, sulfur-based 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 multistep 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.

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Fig. 1: Synthetic logic based on atomic replacement of oxygen in oxetanes.
Fig. 2: Mechanistic hypothesis and studies.
Fig. 3: Reaction scope of O-to-N swap.
Fig. 4: Extension to other O-atom transmutations.
Fig. 5: Application to late-stage functionalization and complex molecule synthesis.

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Data availability

Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under reference nos. CCDC-2446264 (23), CCDC-2446104 (49), CCDC-2446091 (51), CCDC-2446094 (61), CCDC-2446107 (66) and CCDC-2446108 (67). All other data are available in the main text or the Supplementary information.

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Acknowledgements

This research was supported by the U.S. Air Force Office of Scientific Research: FA2386-25-1-4031 (M.J.K.), the Ministry of Education of Singapore Academic Research Fund Tier 1: A-8001693-00-00 (M.J.K.), National University of Singapore Foresight Grant: A-8002845-00-00, A-8002845-01-00, A-8002845-02-00 (M.J.K.), National Research Foundation, Prime Minister’s Office, Singapore under the NRF Investigatorship Programme: NRF-NRFI10-2024-0009 (M.J.K.), Novartis Early Career Award in Chemistry Unrestricted Grant: E-143-00-0072-01 (M.J.K.), the Chinese University of Hong Kong (CUHK) Vice-Chancellor Early Career Professorship Scheme Research Startup Fund: 4933634 (X.Z.) and Research Startup Matching Support: 5501779 (X.Z.). I. I. Roslan assisted with X-ray crystallographic measurements.

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Author notes

  1. These authors contributed equally: Ying-Qi Zhang, Shuo-Han Li

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore

    Ying-Qi Zhang, Shuo-Han Li & Ming Joo Koh

  2. Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong

    Xinglong Zhang

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Contributions

M.J.K. and Y.-Q.Z. conceived the work. Y.-Q.Z. and S.-H.L. conducted the optimization, reaction scope and mechanistic studies. X.Z. designed and performed the DFT studies. M.J.K. directed the research and wrote the manuscript, with revisions provided by the other authors.

Corresponding authors

Correspondence to Xinglong Zhang or Ming Joo Koh.

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Extended data figures and tables

Extended Data Fig. 1 DFT-computed energetics of key reaction barriers and intermediates.

Values in parentheses indicate relative free energies in kcal mol−1 referenced to intermediate I.

Extended Data Fig. 2 Further studies in O-to-N swap with complex amines.

L-Phenylalanine methyl ester, mexiletine and oseltamivir underwent reaction with 8 to give the corresponding azetidine products. Ac, acetyl.

Extended Data Fig. 3 Previously reported synthetic routes to advanced drug intermediates.

In past protocols, extensive functional group interconversions, redox manipulations and protecting group strategies were necessary to access medicinally relevant building blocks 79 and 2. Ms, mesyl.

Supplementary information

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Zhang, YQ., Li, SH., Zhang, X. et al. Photocatalytic oxygen-atom transmutation of oxetanes. Nature 647, 906–912 (2025). https://doi.org/10.1038/s41586-025-09723-3

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