Total synthesis of brevetoxin A

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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' *RF 1-3*. The compound, whose mechanism of action involves binding to and opening of sodium channels [4-7], is sufficiently toxic to kill fish at concentrations of nanograms per ml [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 unknown [8,9], 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 degrees twist at one of its rings [1-6]. Here we describe the successful incorporation of methods that were specifically developed for the construction of these rings [10,11] 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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