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Total synthesis of brevetoxin A

Nature volume 392, pages 264–269 (1998)Cite this article

Abstract

Brevetoxin A is the most potent neurotoxin secreted by Gymnodinium breve Davis, a marine organism often associated with harmful algal blooms known as ‘red tides’1,2,3. The compound, whose mechanism of action involves binding to and opening of sodium channels4,5,6,7, is sufficiently toxic to kill fish at concentrations of nanograms per ml (refs 3, 4) and, after accumulation in filter-feeding shellfish, to poison human consumers. The precise pathway by which nature constructs brevetoxin A is at present unknown8,9, but strategies for its total synthesis have been contemplated for some time. The synthetic challenge posed by brevetoxin A reflects the high complexity of its molecular structure: 10 oxygen atoms and a chain of 44 carbon atoms are woven into a polycyclic macromolecule that includes 10 rings (containing between 5 and 9 atoms) and 22 stereogenic centres. Particularly challenging are the 7-, 8- and 9-membered rings which allow the molecule to undergo slow conformational changes and force a 90° twist at one of its rings1,2,3,4,5,6. Here we describe the successful incorporation of methods that were specifically developed for the construction of these rings10,11 into an overall strategy for the total synthesis of brevetoxin A in its naturally occurring form. The convergent synthesis reported here renders this scarce neurotoxin synthetically available and, more importantly, allows the design and synthesis of analogues for further biochemical studies.

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Figure 1: Molecular structure (a), strategic bond disconnections (b), and retrosynthetic analysis (c) of brevetoxin A (1).
Figure 2: Construction of the BCD bis-lactone system 16.
Figure 3: Construction of the BCDE lactone 26.
Figure 4: Construction of the BCDE phosphine oxide 2.
Figure 5: Construction of the GHIJ ring system 3.
Figure 6: Total synthesis of brevetoxin A (1).

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Acknowledgements

We are indebeted to those of our collaborators whose early contributions on this project made its success possible; their names will appear in the full account of this work. We thank K.Nakanishi and Y. Shimizu for samples of natural brevetoxin A, and D. H. Huang, G. Siuzdak and R.Chadha for the NMR, mass spectroscopic and X-ray crystallographic assistance, respectively. This work was supported by the National Institutes of Health USA (GM), The Skaggs Institute for Chemical Biology, Novartis, Merck, Hoffmann-La Roche, Schering Plough, DuPont Merck, the American Chemical Society (graduate fellowship sponsored by Aldrich to J.L.G.) and the Foundation for the Promotion of Scientific Investigations (postdoctoral fellowship to P.G.). Z.Y. and G.S. contributed equally to this project.

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Authors and Affiliations

  1. Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Zhen Yang, Guo-qiang Shi, Janet L. Gunzner, Konstantinos A. Agrios & Peter Gärtner

  2. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Zhen Yang, Guo-qiang Shi, Janet L. Gunzner, Konstantinos A. Agrios & Peter Gärtner

  3. K. C. Nicolaou

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  1. K. C. Nicolaou
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Correspondence to K. C. Nicolaou.

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Nicolaou, K., Yang, Z., Shi, Gq. et al. Total synthesis of brevetoxin A. Nature 392, 264–269 (1998). https://doi.org/10.1038/32623

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