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Total synthesis of brevianamide A

Nature Chemistry volume 12, pages 615–619 (2020)Cite this article

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Abstract

The fungal-derived bicyclo[2.2.2]diazaoctane alkaloids are of interest to the scientific community for their potent and varied biological activities. Within this large and diverse family of natural products, the insecticidal metabolite (+)-brevianamide A is particularly noteworthy for its synthetic intractability and inexplicable biogenesis. Despite five decades of research, this alkaloid has remained an elusive target for chemical synthesis due to insurmountable issues of reactivity and selectivity associated with all previously explored strategies. We herein report the chemical synthesis of (+)-brevianamide A (seven steps, 7.2% overall yield, 750 mg scale), which involves a bioinspired cascade transformation of the linearly fused (−)-dehydrobrevianamide E into the topologically complex bridged-spiro-fused structure of (+)-brevianamide A.

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Fig. 1: Diels–Alder cycloaddition and representative examples of bicyclo[2.2.2]diazaoctane alkaloids, which are proposed to be biosynthesized via intramolecular hetero-Diels–Alder reactions.
Fig. 2: Previous biosynthetic proposals for brevianamides A and B.
Fig. 3: A modified biosynthetic proposal for brevianamides A and B.
Fig. 4: Total synthesis of brevianamides A and B.

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Data availability

All the characterization data and experimental protocols are provided in this article and its Supplementary Information. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 1918446 (compound 1). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was supported by an EPSRC First Grant (EP/N029542/1) and a Marie Curie Career Integration Grant (631132, POSIN). We thank T. Herlt for assistance and advice regarding chromatography, and acknowledge SIRCAMS at the University of Edinburgh for mass spectrometry.

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Authors and Affiliations

  1. EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK

    Robert C. Godfrey, Nicholas J. Green, Gary S. Nichol & Andrew L. Lawrence

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  1. Robert C. Godfrey
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  2. Nicholas J. Green
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Contributions

R.C.G., N.J.G. and A.L.L. conceived, designed and carried out the synthetic experiments. G.S.N. performed the crystallographic studies. All authors discussed and co-wrote the manuscript.

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Correspondence to Andrew L. Lawrence.

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Supplementary information

Supplementary Information

Overview of previous total and formal syntheses of brevianamide B, Supplementary Tables 1–3, details of the materials and methods, experimental procedures and compound characterization data (1H NMR,13C NMR, IR, HRMS, optical rotations, chiral-HPLC and X-ray).

Crystallographic data

Crystallographic data for compound 1. CCDC 1918446.

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Godfrey, R.C., Green, N.J., Nichol, G.S. et al. Total synthesis of brevianamide A. Nat. Chem. 12, 615–619 (2020). https://doi.org/10.1038/s41557-020-0442-3

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