Synthetic methods for constructing enantioenriched β-lactams are highly valuable given their ubiquity in bioactive compounds, most notably in antibiotics such as penicillins and carbapenems. Intramolecular hydroamidation of β,γ-unsaturated amides would provide a convenient means to reach this alluring chemical space, yet it remains limited due to the regioselectivity issue arising from the difficulty associated with the formation of strained four-membered rings. Here we describe a NiH-catalysed strategy that addresses this challenge through the use of readily accessible alkenyl dioxazolone derivatives. The reaction transcends the conventional NiH operation mode via a transposed mechanism initiated by N-activation, thus allowing for proximal C–N bond formation with excellent regioselectivity, regardless of the electronic properties of substituents. This mechanistic platform is also highly effective for the enantioselective intramolecular hydroamidation of alkenes to enable a convenient access to enantioenriched β-lactams.
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The X-ray crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC2236294 (2), CCDC2236394 (15), CCDC2236312 (17) and CCDC2236313 ((R)-22). These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. All other data are available from the authors upon reasonable request.
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This research was supported by the Institute for Basic Science (IBS-R010-Y2 (S.S.) and IBS-R010-D1 (S.C.)) in South Korea. S.S. also acknowledges support from the DGIST Start-up Fund Program of the Ministry of Science and ICT (2023040012). Computational works for this research were performed on the High Performance Computing Resources in the IBS Research Solution Center.
The authors declare no competing interests.
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Supplementary Methods, Tables 1–15, Figs. 1–22 and references.
Crystallographic data for compound 2.
Crystallographic data for compound 15.
Crystallographic data for compound 17.
Crystallographic data for compound (R)-22.
Cartesian coordinates of DFT-optimized structures.
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Lyu, X., Seo, C., Jung, H. et al. Intramolecular hydroamidation of alkenes enabling asymmetric synthesis of β-lactams via transposed NiH catalysis. Nat Catal 6, 784–795 (2023). https://doi.org/10.1038/s41929-023-01014-2