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Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction

An Erratum to this article was published on 20 June 2014

This article has been updated

Abstract

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin β-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

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Figure 1: The iterative assembly of bifunctional building blocks is a versatile strategy for the preparation of small molecules.
Figure 2: Three examples of applying the standardized three-step retrosynthetic algorithm to polyene natural products not synthesized previously.
Figure 3: A general platform for making polyene motifs via iterative cross-coupling.
Figure 4
Figure 5: The total synthesis of three polyene natural products using bifunctional MIDA boronate building blocks and one set of reaction conditions in an iterative fashion.

Change history

  • 18 May 2014

    In the version of this Article originally published, the Competing Financial Interest statement provided by the authors at submission was inadvertently removed during the production process. It should read "The University of Illinois has filed patents on MIDA boronate chemistry." This has been corrected in the online versions of the Article.

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Acknowledgements

We gratefully acknowledge A. Hill for helping to complete the synthesis of physarigin A and S. O'Hara and S. Fujii for building-block synthesis, as well as the National Institutes of Health (GM080436 and GM090153) and Howard Hughes Medical Institute (HHMI) for funding. M.D.B. is an HHMI Early Career Scientist and E.M.W. was a Natural Science Foundation Predoctoral Fellow.

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E.M.W. and M.D.B. conceived the project. E.M.W., J.R. and M.D.B. designed and executed the experiments. E.M.W. and M.D.B. wrote the paper.

Corresponding author

Correspondence to Martin D. Burke.

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Competing interests

The University of Illinois has filed patents on MIDA boronate chemistry.

Supplementary information

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Supplementary information (PDF 5928 kb)

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Crystallographic data for compound BB1 (CIF 37 kb)

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Crystallographic data for compound BB2 (CIF 16 kb)

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Crystallographic data for compound BB3 (CIF 16 kb)

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Crystallographic data for compound BB4 (CIF 16 kb)

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Woerly, E., Roy, J. & Burke, M. Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nature Chem 6, 484–491 (2014). https://doi.org/10.1038/nchem.1947

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