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Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols

Nature volume 532, pages 353–356 (2016)Cite this article

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An Addendum to this article was published on 23 May 2018

This article has been updated

Abstract

The chirality, or ‘handedness’, of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation1,2. Despite many advances in asymmetric synthesis, developing general and practical strategies for obtaining all possible stereoisomers of an organic compound that has multiple contiguous stereocentres remains a challenge3. Here, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, we synthesized these amino-alcohol products using sequential, copper-hydride-catalysed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino-alcohol products, which contain up to three contiguous stereocentres. We leveraged catalyst control and stereospecificity simultaneously to attain exceptional control of the product stereochemistry. Beyond the immediate utility of this protocol, our strategy could inspire the development of methods that provide complete sets of stereoisomers for other valuable synthetic targets.

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Figure 1: Varying biological activity of some different stereoisomers, and our strategy for constructing all stereoisomers of amino alcohols.
Figure 2: Asymmetric hydrosilylation/hydroamination of enals.
Figure 3: All stereoisomers of amino alcohols from enals.
Figure 4: Asymmetric hydrosilylation/hydroamination of enones.
Figure 5: All eight stereoisomers of amino alcohols synthesized from enones.

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Change history

  • 23 May 2018

    A small modification to the procedure for handling dimethoxymethylsilane (DMMS)—rather than evaporation of volatiles before workup, the excess DMMS is quenched with ammonium fluoride—is described in the Supplementary Information to the accompanying Addendum (http://doi.org/10.1038/s41586-018-0112-4).

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Acknowledgements

We thank the National Institutes of Health (grant GM-58160 to S.L.B.). The content of this paper is solely our responsibility and does not necessarily represent the official views of the National Institutes of Health. We thank Y.-M. Wang and M. T. Pirnot for help preparing the manuscript. The departmental X-ray diffraction instrumentation was purchased with the help of funding from the National Science Foundation (CHE-0946721). We thank P. Müller for X-ray crystallographic analysis of compound 5a.

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Authors and Affiliations

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

    Shi-Liang Shi, Zackary L. Wong & Stephen L. Buchwald

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  1. Shi-Liang Shi
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Contributions

S.-L.S. and S.L.B. conceived the idea and designed the research. S.-L.S. and Z.L.W. performed the experiments. S.-L.S. and S.L.B. wrote the manuscript. All authors commented on the final draft of the manuscript and contributed to the analysis and interpretation of the data.

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Correspondence to Stephen L. Buchwald.

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The authors declare no competing financial interests.

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Shi, SL., Wong, Z. & Buchwald, S. Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols. Nature 532, 353–356 (2016). https://doi.org/10.1038/nature17191

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