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Ruthenium-catalysed multicomponent synthesis of the 1,3-dienyl-6-oxy polyketide motif

Nature Chemistry volume 12, pages 629–637 (2020)Cite this article

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Abstract

Polyketide natural products are an important class of biologically active compounds. Although substantial progress has been made on the synthesis of repetitive polyketide motifs through the iterative application of a single reaction type, synthetic access to more diverse motifs that require more than one type of carbon–carbon bond connection remains a challenge. Here we describe a catalytic, multicomponent method for the synthesis of the privileged polyketide 1,3-dienyl-6-oxy motif. The method allows for the formation of two new carbon–carbon bonds and two stereodefined olefins. It generates products that contain up to three contiguous sp3 stereocentres with a high stereoselectivity in a single operation and can be used to generate chiral products. The successful development of this methodology relies on the remarkable efficiency of the ruthenium-catalysed alkene–alkyne coupling reaction between readily available vinyl boronic acids and alkynes to provide unsymmetrical 3-boryl-1,4-diene reagents. In the presence of carbonyl compounds, these reagents undergo highly diastereoselective allylations to afford the desired 1,3-dienyl-6-oxy motif and enable complex polyketide synthesis in a rapid and asymmetric fashion.

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Fig. 1: Importance of 1,3-dineyl-6-oxy motif as well as general introduction to the ruthenium-catalysed multicomponent coupling reaction.
Fig. 2: The alkene–alkyne coupling of 1,2-disubstituted vinyl boronates.
Fig. 3: NMR studies of the alkene–alkyne coupling of 1,2-disubstituted vinyl boronates and boronic acids.
Fig. 4: Alkene–alkyne coupling followed by allylation with aldehydes and ketones.
Fig. 5: One-pot methodology for the synthesis of 1,3-dienyl-6-oxy motifs with general structures A1, A2, B1 or B2.
Fig. 6: Ruthenium-catalysed multicomponent coupling for the formation of polyenes, chiral products and efomycine M.
Fig. 7: Overlay of products synthesized using this method with bioactive polyketide natural products.

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Data availability

The data supporting the finding of this study are available in this article and Supplementary information.

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Acknowledgements

We thank the Tamaki Foundation and Chugai Pharmaceuticals for their generous, partial funding of our programme.

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Authors and Affiliations

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

    Barry M. Trost, James J. Cregg, Christoph Hohn, Wen-Ju Bai, Guoting Zhang & Jacob S. Tracy

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  1. Barry M. Trost
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Contributions

J.J.C. and B.M.T. conceived the work. J.J.C., C.H., W.-J.B., J.S.T. and B.M.T. designed the experiments and analysed the data. J.J.C., C.H., W.-J.B., G.Z. and J.S.T. performed the experiments. J.J.C., W.-J.B., J.S.T. and B.M.T. wrote the manuscript.

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Correspondence to Barry M. Trost.

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Supplementary Information

Supplementary Figs. 1–5, materials, methods, text, experiments, references and NMR spectra.

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Trost, B.M., Cregg, J.J., Hohn, C. et al. Ruthenium-catalysed multicomponent synthesis of the 1,3-dienyl-6-oxy polyketide motif. Nat. Chem. 12, 629–637 (2020). https://doi.org/10.1038/s41557-020-0464-x

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