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Intramolecular hydroamidation of alkenes enabling asymmetric synthesis of β-lactams via transposed NiH catalysis

Nature Catalysis volume 6, pages 784–795 (2023)Cite this article

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A preprint version of the article is available at arXiv.

Abstract

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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Fig. 1: Intramolecular umpolung hydroamination of alkenes harnessing TMH.
Fig. 2: Reaction development and preliminary mechanistic investigations.
Fig. 3: Experimental investigations towards the feasibility of stepwise mechanism.
Fig. 4: Mechanistic considerations of the concerted insertion mode.
Fig. 5: Reaction scope of the NiH-catalysed intramolecular hydroamidation.
Fig. 6: NiH-catalysed enantioselective hydroamidation of alkenyl dioxazolones.
Fig. 7: Synthetic applications of the NiH-catalysed enantioselective hydroamidation.

Data availability

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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Acknowledgements

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.

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Authors and Affiliations

  1. Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, Republic of Korea

    Xiang Lyu, Changhyeon Seo, Hoimin Jung, Dongwook Kim, Sangwon Seo & Sukbok Chang

  2. Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Xiang Lyu, Changhyeon Seo, Hoimin Jung, Dongwook Kim & Sukbok Chang

  3. Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Münster, Germany

    Teresa Faber

  4. Department of Physics and Chemistry, DGIST, Daegu, Republic of Korea

    Sangwon Seo

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  1. Xiang Lyu
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Contributions

S.S. and S.C. conceived and designed the project. X.L. optimized the reaction conditions for asymmetric hydroamination, and performed and analysed the experiments for the reaction scope and mechanistic investigations. X.L. and C.S. carried out experiments for the synthetic applications. T.F. contributed to the initial findings and reaction optimization of the standard hydroamidation reaction. D.K. performed the X-ray crystallographic analysis. H.J. carried out the DFT calculations. S.S and S.C. organized the research and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Sangwon Seo or Sukbok Chang.

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Nature Catalysis thanks Cristina Trujillo and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, Tables 1–15, Figs. 1–22 and references.

Supplementary Data 1

Crystallographic data for compound 2.

Supplementary Data 2

Crystallographic data for compound 15.

Supplementary Data 3

Crystallographic data for compound 17.

Supplementary Data 4

Crystallographic data for compound (R)-22.

Supplementary Data 5

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

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