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Iterative synthesis of 1,3-polyboronic esters with high stereocontrol and application to the synthesis of bahamaolide A

Nature Chemistry volume 15, pages 248–256 (2023)Cite this article

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Abstract

Polyketide natural products often contain common repeat motifs, for example, propionate, acetate and deoxypropionate, and so can be synthesized by iterative processes. We report here a highly efficient iterative strategy for the synthesis of polyacetates based on boronic ester homologation that does not require functional group manipulation between iterations. This process involves sequential asymmetric diboration of a terminal alkene, forming a 1,2-bis(boronic ester), followed by regio- and stereoselective homologation of the primary boronic ester with a butenyl metallated carbenoid to generate a 1,3-bis(boronic ester). Each transformation independently controls the stereochemical configuration, making the process highly versatile, and the sequence can be iterated prior to stereospecific oxidation of the 1,3-polyboronic ester to yield the 1,3-polyol. This methodology has been applied to a 14-step synthesis of the oxopolyene macrolide bahamaolide A, and the versatility of the 1,3-polyboronic esters has been demonstrated in various stereospecific transformations, leading to polyalkenes, -alkynes, -ketones and -aromatics with full stereocontrol.

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Fig. 1: Iterative approaches to the stereocontrolled synthesis of polyacetates.
Fig. 2: Iterative synthesis of all eight diastereomers of a tetraboronic ester.
Fig. 3: Retrosynthetic analysis of bahamaolide A.
Fig. 4: Preparation of octaboronic ester 21 and the enantiopure chiral carbenoid precursors for its homologation.
Fig. 5: Completion of the total synthesis of bahamaolide A from octaboronic ester 21.
Fig. 6: Synthesis and functionalization of polyboronic esters.

Data availability

The data supporting the findings of this work are provided in the Supplementary Information. The crystallographic data for the structure of boronic ester 25 reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2150709. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank H2020 ERC (no. 670668, V.K.A.) for financial support. H.-H.L. and T.B thank the Marie Skłodowska-Curie Fellowship programme for support (Horizon 2020, no. 746045 (H.-H.L.) and no. 626828 (T.B.)). We thank N. Pridmore and H. Sparkes for X-ray analysis, D. J. Blair for useful discussions and C. P. Butts for assistance with NMR analysis.

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  1. These authors contributed equally: Sheenagh G. Aiken, Joseph M. Bateman, Hsuan-Hung Liao.

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  1. School of Chemistry, University of Bristol, Bristol, UK

    Sheenagh G. Aiken, Joseph M. Bateman, Hsuan-Hung Liao, Alexander Fawcett, Teerawut Bootwicha, Paolo Vincetti, Eddie L. Myers, Adam Noble & Varinder K. Aggarwal

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Contributions

S.G.A., J.M.B. and H.-H.L. contributed equally to this work. S.G.A., J.M.B., H.-H.L, A.F. and T.B. conducted the experimental work and analysed the data. All authors contributed to the preparation of the manuscript.

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Correspondence to Varinder K. Aggarwal.

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Supplementary Information

Experimental procedures and characterization for all compounds synthesized in this work, Supplementary discussion, Supplementary Figs. 1–4, Supplementary Schemes 1–13 and Supplementary Tables 1–10.

Supplementary Data

Crystallographic data for compound 25: CCDC 2150709.

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Aiken, S.G., Bateman, J.M., Liao, HH. et al. Iterative synthesis of 1,3-polyboronic esters with high stereocontrol and application to the synthesis of bahamaolide A. Nat. Chem. 15, 248–256 (2023). https://doi.org/10.1038/s41557-022-01087-9

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