The red algae dinoflagellate, Karenia brevis, converts a chain of epoxide rings into compounds with a repeating ladder-like design using water as a promoter.

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Ladder polyethers are organic chemicals with repeating units joined together by bonds that form a ladder-like configuration. They are difficult to artificially synthesize in quantity because the epoxide opening reactions that theoretically produce them tend to favor the formation of small, five-membered rings rather than the desired six-membered rings. To overcome this problem, chemists bond "directing-groups" to each and every epoxide unit which then must be removed by later reactions in many cases. This process creates low yields of ladder polyethers, generates relatively large amounts of chemical waste, and requires toxic solvents and chemicals. The dinoflagellate Karenia brevis produce large quantities of ladder polyethers called brevetoxins which produce the notorius marine die-offs associated with red tide blooms. It does so using water-based cascade reactions. It is likely that K. brevisfirst synthesizes template epoxy alchohols which then direct the formation of the desired six-member ring constituents of the ladder. An epoxide opening cascade reaction results, in which more six-member rings are added to the nascent ladder; the rate of the reaction is not affected by the number of rings already bound in the ladder. Moreover, these reactions proceed most favorably in water at a near-netural pH.


Ladder polyether synthesis. Artist: V8rik; Wikipedia.

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"We report that neutral water acts as an optimal promoter for the requisite ring-opening selectivity, once a single templating THP is appended to a chain of epoxides. This strategy offers a high-yielding route to the naturally occurring ladder core and highlights the likely importance of aqueous-medium effects in underpinning certain noteworthy enzymatic selectivities...Although they are among the most complex secondary metabolites ever characterized, all ladder polyethers possess a structural pattern and stereochemical regularity that confer upon them a certain degree of simplicity. A backbone of repeating oxygen–carbon–carbon (O–C–C) units extends from one end of the polyether network to the other...The 'ladder' topography is the consequence of consistently trans stereochemistry across the carbon-carbon bonds of the ring junctions, coupled with the relative syn configuration of adjacent junctions..[most] epoxide-opening reactions...favor the smaller heterocycle [THF], not the larger [desired] one [THP]. Most of the approaches to promote the desired outcome use 'directing groups' that must be covalently attached to the epoxides...all existing THP-selective cascades that open more than one epoxide have required a directing group at every epoxide...[with our method] the selectivity for the desired THP product increases substantially as the pH of the reaction environment approaches neutrality, even exceeding 10:1 THP:THF selectivity near pH 7." (Vilotijevic and Jamieson 2007:1189)

"Furthermore, both increased THP:THF selectivity and increased conversion...correlate with increased water content in the reaction milieu." (Vilotijevic and Jamieson 2007:1190)

"These THP-selective, epoxide-opening cascades are far higher-yielding than those that rely upon covalently attached directing groups...They are high yielding and highly THP-selective...require no directing groups on any of the epoxides, and are most effectively promoted by H2O...per-epoxide yields...do not change as a function of the number of epoxides or the number of THP rings preceding a given epoxide." (Vilotijevic and Jamieson 2007:1191)

"[T]emplated, water-promoted, THP-selective epoxide-opening cascades provide a straightforward means for efficient and rapid assembly of ladder polyethers, enabling investigations directed toward understanding the mode of action of these extraordinary natural products." (Vilotijevic and Jamieson 2007:1192)

Journal article
Epoxide-Opening Cascades Promoted by WaterScienceAugust 30, 2007
I. Vilotijevic, T. F. Jamison

Journal article
Ladder Polyether Synthesis via Epoxide-Opening Cascades Using a Disappearing Directing GroupJ. Am. Chem. Soc.January 25, 2006
Graham L. Simpson, Timothy P. Heffron, Estíbaliz Merino, Timothy F. Jamison

Journal article
Zippier synthesis in water

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