Ciguatoxins

A highlight in the application of RCM methodology in natural product synthesis is Hirama s total synthesis of ciguatoxin CTX3C (183) [90], including the more recent improved protective group strategy, as depicted in Scheme 34 [90b]. The structure of 183 spans more than 3 nm and is characterized by 12 six- to nine-membered trans-fused cyclic ethers and a spiroannulated terminal tetra-... 

Scheme 34 Formation of the central nine-membered ring and completion of the carbon skeleton in Hirama s improved total synthesis of the marine neurotoxin ciguatoxin CTX3C (183)[90b]...

Clark s group also reported on ring-closing enyne metathesis for the preparation of six- and seven-membered cyclic enol ethers 428 n= 1,2) as potential building blocks for the synthesis of marine polyether natural compounds such as brevetoxins and ciguatoxins. Metathesis products 428 were obtained from ene-ynes 427 in 72-98% yield when the NHC-bearing catalyst C was used (Scheme 84) [179]. 

Stabilizers bind at a site separate from those of traditional activators and of ciguatoxin-brevetoxin, but they exert a synergistic action on both types of activators (J5, 42). This action potentiates the activators and generally increases their efficacy, yielding larger depolarizations at lower doses 42) it occurs uniquely with the peptide stabilizers and not with ions or oxidants that also slow the inactivation of Na current 37). 

Ciguatoxin. The toxin was isolated from moray eels and purified to crystals by Scheuer s group (1). Structural determination of the toxin by x-ray or NMR analyses was unsuccessful due to the unsuitability of the crystals and due to the extremely small amount of the sample. The toxin was presumed to have a molecular formula of C Hg NO from HRFAB-MS data (MH+, 1111.5570) and to have six hydroxyls, five methyls, and five double bonds in the molecule (2). The number of unsaturations (18 including the five double bonds) and the abundance of oxygen atoms in the molecule point to a polyether nature of the toxin. The toxin, or a closely related toxin if not identical, is believed to be the principal toxin in ciguatera. Ciguatoxin was separable on an alumina column into two interconvertible entities presumably differing only in polarity (J). 

Assays of ciguatoxin. Determination of ciguatoxin levels in fish was carried out in many laboratories by mouse assays. Enzyme immunoassay to screen inedible fish has been proposed by Hokama (9). No specific chemical assay has been developed, as information on functional groups suitable for fluorescence labeling is not available. Analyses conducted in the authors laboratory on remnant fish retrieved from patients meals indicated that ciguatoxin content as low level as 1 ppb could cause intoxication in adults. An extremely high sensitivity and a sophisticated pretreatment method will be required for designing a fluorometric determination method for the toxin. 

This chapter summarizes recent work on the molecular basis of the toxic actions of ciguatoxin and brevetoxins. It is shown (i) that the molecular target for these toxins is the voltage-dependent Na channel of excitable tissues arid (ii) that ciguatoxin and brevetoxins share a common receptor site on the Na channel. 

All these results are clear indications that CTx and PbTx have similar modes of action and that they increase the membrane permability of excitable cells to Na ions by opening voltage-dependent Na channels. This action fully accounts for the toxicity of ciguatoxin and brevetoxins. 

As this book goes to press, two events have occurred that bear mention. First, the structure of ciguatoxin has just been published in the Journal of the American Chemical Society (1989, 111, 8929-8931). Despite the determined efforts of many scientists over several years, the structure of this important marine toxin, discussed in Chapters 8,11, and 13, has resisted elucidation. Its publication marks a notable achievement, attained through the cooperation of investigators with different, complementary skills. 

Indian Bunt of Wheat Indian Licorice Seed Toxin Indian Ocean Ciguatoxin 4 Indischer Weizenbrand Infectious Abortion Infectious Ovine Encephalomyelitis Infectious Porcine Encephalomyelitis Inferno... 

The impetus for developing this technology was provided by the continuing need for methodology amenable to the preparation of polycyclic arrays that constitute the frameworks of numerous polyether natural products such as the bre-vetoxins, ciguatoxin and maitotoxin 124 (Fig. 3). 

Satake M, Ofuji K, Naoki H, James KJ, Furey A, Mcmahon T, Silke J, Yasumoto T (1998) Azaspiracid, a new marine toxin having unique spiro ring assemblies, isolated from Irish mussels, Mytilus edulis. J Am Chem Soc 120 9967-9968 Scheuer PJ, Takahashi W, Tsutsumi J, Yoshida T (1967) Ciguatoxin isolation and chemical nature. Science 155 1267-1268... 

The oxypalladation method mentioned above was introduced as a crucial step in the synthesis of several natural products. As shown in Scheme 8.51, Metz and coworkers used this strategy in an enantioselective synthesis of ricciocarpin A [122], Other impressive applications including the acetalization-RCM sequence have been employed in the synthesis of the AB ring of ciguatoxin [123] and of the Q-C fragment of laulimalide [124] (Scheme 8.52). 

---