Total synthesis of brevetoxin A

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'. The compound, whose mechanism of action involves binding to and opening of sodium channels, is sufficiently toxic to kill fish at concentrations of nanograms per ml and, after accumulation in filter-feeding shellfish, to poison human consumers. The precise pathway by which nature constructs brevetoxin A is at present unknown, 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. Here we describe the successful incorporation of methods that were specifically developed for the construction of these rings 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.

Surveying approaches to the formation of carbon–carbon bonds between a pyran and an adjacent ring

“…Finely powdered 4 Å MS (400 mg), Mg turnings (120 mg, 4.94 mmol), and Cp 2 TiCl 2 (1.03 g, 4.12 mmol) were placed in a flask and dried by heating with a heat gun under reduced pressure (2)(3). During this procedure care was taken not to sublime Cp 2 TiCl 2 .…”

Developmental Biology of Neoplastic Growth

“…The structures of these natural products are extraordinarily complex and their chemical synthesis in the laboratory are considered highlights in this field (Hirama et al 2001;Nicolaou et al 1998). Their structures provide ample opportunity for flexibility, enabling the toxins to adopt many conformations facilitating their binding to protein receptors.…”

Organic synthesis: the art and science of replicating the molecules of living nature and creating others like them in the laboratory

“…Such structures were unprecedented at the time, and, as such, they provided challenge and inspiration to synthetic organic chemists whose drive to advance their science to higher levels of sophistication is often fuelled by discoveries of new structural motifs from nature. Indeed, this was our main motivation in entering the campaign of the total synthesis of brevetoxin B [32][33][34] and, later on, its related congener brevetoxin A [19,35].…”