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Branched aldehydes as linchpins for the enantioselective and stereodivergent synthesis of 1,3-aminoalcohols featuring a quaternary stereocentre

Nature Catalysis volume 1, pages 523–530 (2018)Cite this article

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Abstract

The atom-economic conversion of chemical feedstocks into biologically relevant complex molecules in a stereocontrolled fashion remains a continuous challenge to synthetic chemists. In this context, the use of simple ambiphilic starting materials as linchpins allows a bidirectional increase of molecular complexity from widely available precursors. Here, we report the use of branched aldehydes as versatile linchpins for various Zn-ProPhenol-catalysed C–C bond-forming reactions to efficiently construct enantioenriched 1,3-aminoalcohols bearing an acyclic quaternary stereogenic centre. The ability of the Zn-ProPhenol catalyst to selectively activate ambiphilic aldehydes first as nucleophiles for Mannich reactions and then as electrophiles for aldol, Henry and alkyne addition reactions allows for the one-pot synthesis of complex stereotriads from common building blocks. Moreover, this approach can be diastereodivergent by simply selecting the proper catalyst combination. Overall, this catalytic method directly transforms simple and readily available aldehydes into highly functionalized compounds and provides streamlined access to valuable 1,3-aminoalcohols relevant to the synthesis of biologically important molecules.

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Fig. 1: Background and reaction development.
Fig. 2: Enantioselective Mannich reaction between branched aldehydes and Boc- or Cbz-imines.
Fig. 3: Asymmetric sequential Mannich/aldol reactions of aldehydes.
Fig. 4: Stereodivergent synthesis of 1,3-aminoalcohols.
Fig. 5: Diastereodivergent process using other nucleophiles.
Fig. 6: Synthetic applications of enantio- and diastereoenriched 1,3-aminoalcohols.

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Acknowledgements

We thank the National Science Foundation (CHE-1360634) and National Institutes of Health (GM033049) for generous support of our programmes. We thank S. Lynch (Stanford University) for conducting nuclear Overhauser effect experiments and A. Oliver (University of Notre Dame) for X-ray crystallographic analysis. T.S. is grateful to the Swiss National Science Foundation for a postdoctoral fellowship.

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  1. These authors contributed equally: Chao-I (Joey) Hung, Tanguy Saget.

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  1. Department of Chemistry, Stanford University, Stanford, CA, USA

    Barry M. Trost, Chao-I (Joey) Hung, Tanguy Saget & Elumalai Gnanamani

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Contributions

B.M.T., C.-I.H. and T.S. conceived and designed the project. B.M.T. supervised the project. C.-I.H., T.S. and E.G. performed the experiments. B.M.T., C.-I.H. and T.S. co-wrote the manuscript.

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Correspondence to Barry M. Trost.

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Supplementary Methods, Supplementary Figures 1–70, Supplementary References

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Trost, B.M., Hung, CI.(., Saget, T. et al. Branched aldehydes as linchpins for the enantioselective and stereodivergent synthesis of 1,3-aminoalcohols featuring a quaternary stereocentre. Nat Catal 1, 523–530 (2018). https://doi.org/10.1038/s41929-018-0093-6

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