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Heteronuclear dual-atom insertion into oxetanes via frustrated Lewis pair activation

Nature Synthesis (2026)Cite this article

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Abstract

1,3-Oxazinanes are prized motifs found in bioactive heterocycles, but their synthesis is challenging owing to the lack of reliable methodologies. An unorthodox yet elegant approach to access 1,3-oxazinanes is to design a transformation that selectively inserts a carbon and nitrogen into readily available oxetane building blocks. However, despite progress in two-component skeletal expansions, the corresponding multicomponent reactions utilizing two distinct inserting entities remain elusive. Here we report that dual-atom insertion into oxetanes using various nitrogen and carbon sources can be achieved with a boron catalyst. The method streamlines the preparation of bioactive 1,3-oxazinanes and is amenable to late-stage editing to create multiheteroatom cyclic molecules. Mechanistic studies reveal a cascade pathway in which an in situ-generated frustrated Lewis pair enables ring deconstruction and reconstruction.

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Fig. 1: Structural diversification of oxetanes via multicomponent editing.
Fig. 2: Reaction development.
Fig. 3: Mechanistic investigations.
Fig. 4: Substrate scope for dual-atom insertion editing of oxetanes and azetidines.
Fig. 5: Substrate scope of inserters.
Fig. 6: Synthetic applications.

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Data availability

Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre under reference nos. CCDC 2386484 (65), 2386485 (83) and 2386486 (21-(S)). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available within the article and its Supplementary Information.

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Acknowledgements

This research was supported by the Ministry of Education of Singapore Academic Research Fund Tier 1 (grant no. A-8001693-00-00) and National Research Foundation, Prime Minister’s Office, Singapore under the NRF Investigatorship programme (grant no. NRF-NRFI10-2024-0009 to M.J.K.). I. I. Roslan (National University of Singapore) assisted with X-ray crystallographic measurements.

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Authors and Affiliations

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

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

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  1. Ying-Qi Zhang
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  2. Shuo-Han Li
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Contributions

M.J.K. and Y.-Q.Z. conceived of the work. Y.-Q.Z. and S.-H.L. conducted the optimization, reaction scope and mechanistic studies. M.J.K. directed the research. All authors contributed to the writing of the paper.

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Correspondence to Ming Joo Koh.

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Nature Synthesis thanks Melissa Ramirez and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information (download PDF )

Supplementary Figs. 1–12 and Tables 1–6 and experimental details.

Supplementary Data 1

Single-crystal X-ray diffraction data for compound 21-(S) (CCDC 2386486).

Supplementary Data 2

Single-crystal X-ray diffraction data for compound 65 (CCDC 2386484).

Supplementary Data 3

Single-crystal X-ray diffraction data for compound 83 (CCDC 2386485).

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Zhang, YQ., Li, SH. & Koh, M.J. Heteronuclear dual-atom insertion into oxetanes via frustrated Lewis pair activation. Nat. Synth (2026). https://doi.org/10.1038/s44160-026-01031-6

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