Total synthesis of brevetoxin A

K. C. Nicolaou (), Zhen Yang, Guo-qiang Shi, Janet L. Gunzner, Konstantinos A. Agrios and Peter Gärtner
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Zhen Yang: The Scripps Research Institute
Guo-qiang Shi: The Scripps Research Institute
Janet L. Gunzner: The Scripps Research Institute
Konstantinos A. Agrios: The Scripps Research Institute
Peter Gärtner: The Scripps Research Institute

Nature, 1998, vol. 392, issue 6673, 264-269

Abstract: 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.

Date: 1998
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DOI: 10.1038/32623

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