Abstract
Skeletal editing of heterocyclic building blocks offers an appealing way to expand the accessible chemical space by diversifying molecular scaffolds for drug discovery. Despite the recent boom in this area, catalytic strategies that directly introduce fluorine into the backbone of small-ring heterocycles remain rare owing to the challenges of strain-induced ring cleavage and defluorination. Here we describe a copper-catalysed approach for skeletal expansion of oxygen heterocycles by reaction with a difluorocarbene species generated in situ to induce carbon atom insertion. The α,α-difluoro-oxetane products are potential surrogates of oxetane, β-lactone and carbonyl pharmacophores on the basis of their computed molecular properties and electrostatic potential maps. The utility of this approach is highlighted by synthesis of various drug-like molecules and fluorinated isosteres of biologically active compounds. Experimental and computational investigations provide insight into the mechanism and the unique role of the copper catalyst in promoting both ring-opening and cyclization steps of the reaction.
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Data availability
Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under reference no. CCDC-2323644 (31). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available in the main text or the Supplementary Information.
Change history
28 February 2025
In the second paragraph of the “Mechanistic studies” section, an additional citation to ref. 23 (Zeng, X., Li, Y., Min, Q.-Q., Xue, X.-S. & Zhang, X. Copper-catalysed difluorocarbene transfer enables modular synthesis. Nat. Chem.15, 1064–1073 (2023)) has been added alongside the text “which was first described by Zhang and co-workers”. This correction has been made to the HTML and PDF versions of the article.
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Acknowledgements
This research was supported by the Ministry of Education of Singapore Academic Research Fund Tier 1: A-8001693-00-00 (M.J.K.) and the National Science Foundation (NSF): CHE-2247505 (P.L.). F.Z. acknowledges support from the postdoctoral programme of the International Training Plan for Young Talents of Guangdong Province. DFT calculations were carried out at the University of Pittsburgh Center for Research Computing and the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) program, supported by NSF award numbers: OAC-2117681, OAC-1928147 and OAC-1928224 (P.L.). G. K. Tan assisted with X-ray crystallographic measurements.
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T.-D.T. and F.Z. contributed equally to this work. M.J.K. and T.-D.T. conceived the work. T.-D.T., F.Z., Y.-Q.W. and X.L. conducted the optimization, reaction scope and mechanistic studies. K.P.Q. conducted the DFT calculations. D.Z.W.N. conducted the physicochemical property and metabolic stability studies. M.J.K., P.L. and E.C.Y.C. directed the research. M.J.K. wrote the manuscript, with revisions provided by the other authors.
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Supplementary Figs. 1–6, Tables 1–7, experimental data, synthesis and characterization data, DFT calculation data, X-ray crystallographic data, NMR spectra and references.
Supplementary Data 1
Crystallographic data for compound 31; CCDC reference 2323644.
Supplementary Data 2
Cartesian coordinates of DFT-optimized structures.
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Tan, TD., Zhou, F., Quirion, K.P. et al. Catalytic difluorocarbene insertion enables access to fluorinated oxetane isosteres. Nat. Chem. 17, 719–726 (2025). https://doi.org/10.1038/s41557-024-01730-7
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DOI: https://doi.org/10.1038/s41557-024-01730-7
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