More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered the isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. The large (3 nanometers long) and complicated molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. Our highly convergent strategic approach featuring the chemoselective ring-closing metathesis reaction as a key tactic has enabled the total synthesis of ciguatoxin CTX3C, which will provide a practical supply for further studies.

Ciguatoxins are the major causative toxins of ciguatera seafood poisoning. Limited availability of ciguatoxins has hampered the development of a reliable and specific immunoassay for detecting these toxins in contaminated fish. Monoclonal antibodies (mAbs) specific against both ends of ciguatoxin CTX3C were prepared by immunization of mice with protein conjugates of rationally designed synthetic haptens, 3 and 4, in place of the natural toxin. Haptenic groups that possess a surface area larger than 400 A(2) were required to produce mAbs that can bind strongly to CTX3C itself. A direct sandwich enzyme-linked immunosorbent assay (ELISA) using these mAbs was established to detect CTX3C at the ppb level with no cross-reactivity against other related marine toxins, including brevetoxin A, brevetoxin B, okadaic acid, or maitotoxin.

More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. Furthermore, the large (3 nm in length) and complex molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. In this article, the full details of studies leading to the total synthesis of ciguatoxin CTX3C are provided. The key elements of the first-generation approach include O,O-acetal formation from the right and left wing fragments, conversion from O,O-acetal to O,S-acetal, a radical reaction to cyclize the G ring, a ring-closing metathesis reaction to close the F ring, and final removal of the 2-naphtylmethyl protective groups. Subsequent studies provided a second-generation total synthesis, which is more concise and results in a higher yield. Second-generation synthesis was accomplished by using a direct method of constructing the key intermediate O,S-acetal from ␣-chlorosulfide and a secondary alcohol. These syntheses ensure a practical supply of ciguatoxin for biological applications.ciguatera ͉ polyether ͉ convergent strategy C iguatera is a human intoxication caused by the ingestion of certain reef fish (1). More than 20,000 people suffer annually from ciguatera, making it one of the most common forms of nonbacterial food poisoning. Ingestion of affected fish leads to neurological, gastrointestinal, and cardiovascular disorders, which may last up to a month or more. The most prominent symptom is a disorder of temperature sensation. Specifically, touching cold water can induce pain similar to that of an electric shock. Other symptoms include diarrhea, vomiting, muscle pain and itching, whereas paralysis, coma, and even death may occur in severe cases.Yasumoto et al. (2) identified an epiphytic dinoflagellate, Gambierdiscus toxicus, as the causative organism and demonstrated that dinoflagellate-derived toxins are transferred by the food chain to various fish. About 100 species of fish cause ciguatera, and ciguateric fish look, taste, and smell like normal uncontaminated fish. In addition, the occurrence of poisoning is completely unpredictable. Current difficulties in predicting, detecting, and treating ciguatera have had an adverse socioeconomic impact, in particular, in developing countries.Ciguatoxins are regarded as the principal causative toxins of ciguatera seafood poisoning (Fig. 1) (3, 4). In 1989, the Yasumoto group successfully elucidated the structures of ciguatoxin (CTX) (4) and CTX4B (3) (5, 6), which were found to be large polycyclic ethers having molecular lengths Ͼ3 nm. They subsequently isolated other congeners including CTX3C (1) (7) and 51-hydroxyCTX3C (2) (8). To date, the structures of Ͼ20 congeners of ciguatoxins have been determined (9, 10).The lethal potencies of ciguatoxins (LD 50 ϭ 0.25-4 g͞kg) by i.p. injection into mic...

[structure: see text] Ciguatoxin CTX3C is a representative congener of ciguatoxins, which are known to be the principal causative agents of ciguatera seafood poisoning. The structure of CTX3C spans more than 3 nm and is characterized by 13 ether rings. In this paper, an improved total synthesis of CTX3C is reported. Alteration of the protective group from benzyl ether to 2-naphthylmethyl (NAP) ether drastically increases the yield for final global deprotection and has provided a sufficient amount of sample for further biological studies.