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A direct approach to amines with remote stereocentres by enantioselective CuH-catalysed reductive relay hydroamination

Nature Chemistry volume 8, pages 144–150 (2016)Cite this article

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Abstract

Amines with remote stereocentres (stereocentres that are three or more bonds away from the C–N bond) are important structural elements in many pharmaceutical agents and natural products. However, previously reported methods to prepare these compounds in an enantioselective manner are indirect and require multistep synthesis. Here, we report a copper-hydride-catalysed, enantioselective synthesis of γ- or δ-chiral amines from readily available allylic alcohols, esters and ethers using a reductive relay hydroamination strategy (a net reductive process in which an amino group is installed at a site remote from the original carbon–carbon double bond). The protocol was suitable for substrates containing a wide range of functional groups and provided remote chiral amine products with high levels of regio- and enantioselectivity. Sequential amination of substrates containing several carbon–carbon double bonds could be achieved, demonstrating the high chemoselectivity of this process.

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Figure 1: Design of a CuH-catalysed relay hydroamination reaction.
Figure 2: Synthetic applications of CuH-catalysed reductive relay hydroamination.

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Acknowledgements

This paper is dedicated to P. Knochel on the occasion of his 60th birthday. Research reported in this publication was supported by the National Institutes of Health under award no. GM58160. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank P. Müller (MIT) for X-ray analysis of 3g and Y.-M. Wang, M.T. Pirnot and C. Nguyen for their advice on the preparation of this manuscript.

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Author notes

  1. Shaolin Zhu

    Present address: Present address: School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China,

Authors and Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Shaolin Zhu, Nootaree Niljianskul & Stephen L. Buchwald

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  1. Shaolin Zhu
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  2. Nootaree Niljianskul
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Contributions

S.Z. and S.L.B designed the project. S.Z., N.N. and S.L.B. co-wrote the manuscript, analysed the data, discussed the results and commented on the manuscript. S.Z. and N.N. performed the experiments.

Corresponding author

Correspondence to Stephen L. Buchwald.

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The authors declare no competing financial interests.

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Crystallographic data for compound 3g. (CIF 1225 kb)

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Zhu, S., Niljianskul, N. & Buchwald, S. A direct approach to amines with remote stereocentres by enantioselective CuH-catalysed reductive relay hydroamination. Nature Chem 8, 144–150 (2016). https://doi.org/10.1038/nchem.2418

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