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Synthesis of chiral piperidines from pyridinium salts via rhodium-catalysed transfer hydrogenation

Nature Catalysis volume 5, pages 982–992 (2022)Cite this article

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Abstract

Chiral piperidines are widespread in natural products and drug molecules. However, effective methods for their synthesis from simple starting materials are scarce. Herein, we report a rhodium-catalysed reductive transamination reaction for the rapid preparation of a variety of chiral piperidines and fluoropiperidines from simple pyridinium salts, with excellent diastereo- and enantio-selectivities and functional group tolerance. Thus, key to this reaction is the introduction of a chiral primary amine under reducing conditions, which, in the presence of water, undergoes transamination with the pyridinium nitrogen moiety while inducing chirality on the ring. The method overcomes some notable shortcomings of asymmetric hydrogenation and traditional multistep synthesis, affording various highly valuable chiral piperidines, including those bearing reducible and coordinating functional groups, heterocycles and, importantly, fluorine. The transamination mechanism also allows for alkylated and 15N-labelled piperidines to be easily accessed. The reaction is easily scalable, with multi-hundred-gram scale demonstrated.

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Fig. 1: The importance of piperidines and their synthesis via reduction of pyridines.
Fig. 2: Transfer hydrogenation of pyridinium salts.
Fig. 3: Asymmetric reductive transamination of 2-substitued pyridiniums with (R)- or (S)-PEA.
Fig. 4: Reductive transamination of 2-substitued pyridiniums with other amines.
Fig. 5: Asymmetric reductive transamination to access fluoropiperidines.
Fig. 6: Applications of ART in organic synthesis.
Fig. 7: Examples of large-scale application of ART.
Fig. 8: Mechanistic studies of the ART reaction.

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Data availability

The data supporting the findings of this study are available within this article and its Supplementary Information or from the authors on reasonable request. Crystallographic data are available from the Cambridge Crystallographic Data Centre with the following codes: compound 1 (CCDC 2076422), compound 2 (CCDC 2076423), compound 49 (CCDC 2073098) and compound 72 (CCDC 2073099). These data can be obtained free of charge from www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

We are grateful to A. Pettman (Pfizer) and J. Leonard (AstraZeneca) for advice, C. Robertson (University of Liverpool) for X-ray structure determination and P. Colbon (Liverpool ChiroChem) for discussions and technical assistance. We thank Pfizer (J.J.W), University of Liverpool (J.J.W., Z.Y.C., J.H.B., X.F.W.) and Innovate UK Knowledge Transfer Partnership (KTP11214, R.G.) for financial support.

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Authors and Affiliations

  1. Department of Chemistry, University of Liverpool, Liverpool, UK

    Jianjun Wu, Zhenyu Chen, Jonathan H. Barnard, Ramachandran Gunasekar, Xiaofeng Wu, Shiyu Zhang & Jianliang Xiao

  2. Liverpool ChiroChem, University of Liverpool, Liverpool, UK

    Jianjun Wu, Ramachandran Gunasekar & Jiwu Ruan

  3. Liverpool ChiroChem (Taizhou), Bingjiang Industrial Park, Taizhou, China

    Jianjun Wu & Chunyang Pu

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Contributions

J.X. conceived and directed the study. J.J.W. and Z.Y.C. designed and performed the experiments with contributions from C.Y.P, X.F.W., S.Y.Z. and J.W.R. J.H.B. and R.G. performed the mechanistic studies. J.X., J.J.W., J.H.B. and Z.Y.C. wrote the manuscript. All the authors contributed to the analysis and interpretation of the data.

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Correspondence to Jianliang Xiao.

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The authors declare no competing interests. Part of the results were published in a patent (WO2015145143/US20170107208A1, J.X. and J.J.W.), which has expired.

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Nature Catalysis thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–29, Tables 1–8, methods and references.

Supplementary Data 1

Crystallographic data for compound 1.

Supplementary Data 2

Crystallographic data for compound 2.

Supplementary Data 3

Crystallographic data for compound 49.

Supplementary Data 4

Crystallographic data for compound 72.

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Wu, J., Chen, Z., Barnard, J.H. et al. Synthesis of chiral piperidines from pyridinium salts via rhodium-catalysed transfer hydrogenation. Nat Catal 5, 982–992 (2022). https://doi.org/10.1038/s41929-022-00857-5

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