Ladder toxin

Most recently, we have investigated the use of iterative oxonium ylide [1,2]- or [2,31-shifts as a convenient approach to the polypyran domains often found in the marine polyether ladder toxins (Scheme 18.8) [21]. Initial studies indicated that [l,2]-shifts of O-benzyl oxonium ylides such as 19 a or 19 b were inefficient. Alternative metallocarbene processes including C-H insertion and dimerization were found to predominate in these cases, again suggesting that carbene-ylide equilibration may occur [21b]. On the rationale that concerted [2,3]-shifts of the corresponding O-allyl oxonium ylides might occur more readily, the allyl ethers 19 c, 19 d were then examined. These examples were much more effective, especially in conjunction with the optimized catalyst Cu(tfacac)2 [21a]. However, rhodium(II) triphenylacetate (Rh2(tpa)4) [22] was found to... 

When combined with reductive decomplexation methods, the Nicholas reaction has found extensive use in the synthesis of marine polyether ladder toxins, such as ciguatoxin (Scheme 7.7). ... 

Even in cases where two similar alkenes both appear to be available, conformational factors may result in valuable stereoselectivity, as in a synthesis of the AB rings 8.273 of ciguatoxin, one of the ladder toxins... 

Biological systems have evolved to exploit the reactivity of epoxides in the synthesis of a number of secondary metabolites (Fig. 4.1) [1], including ionophore antibiotics such as monensin (1) [2], terpene ethers, represented by thyrsiferol (2) [3], ladder toxins, represented by brevetoxin (3) [4], and annonaceous acetogenins, represented by murisolin (4) [5]. Chemical synthesis of cyclic ethers also frequently utilizes epoxides, often in the context of cascade cyclizations in which the hydroxyl group that is liberated... 

Nicolaou engaged in an effort to reverse the regioselec-tivity of these reactions in the context of synthesizing the ladder toxins. This study was based on the hypothesis that... 

Although no natural product synthesis has yet to be completed by a cascade in water under neutral conditions, the Jamison group has used the protocol to prepare the impressively complex tetfa-tetfahydropyran core of the ladder toxin gymnocin (188 Scheme 4.43) [78]. Triepoxide 189 was heated to 80°C in water for 9 days to yield 188 in 35% yield. The reaction rate was slower than previously observed rates because the final cyclization step was sluggish. The authors... 

Challenges still remain in this area despite the dramatic advances that have been detailed. Definitive proof of the epoxide cascade route to the marine ladder toxins has yet to be... 

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