Total synthesis of ciguatoxins (Figure 1), the causative neuro￾toxins of ciguatera seafood poisoning,1–4 has been a formida￾ble challenge in organic synthesis, and is expected to have an
impact on studies of the voltage-sensitive sodium ion channel
(VSSC) and the development of an immunoassay, which have
been impeded by the extreme difficulty in isolating ciguatox￾ins. Thus, chemical synthesis has been the sole realistic solu￾tion available for obtaining sufficient quantities of ciguatoxins
for these studies. There was little prospect of success for total
synthesis of ciguatoxins when we first launched our endeavors
towards synthesizing these fascinating and gigantic molecules
in 1989.5 However, our efforts culminated in the first total syn￾thesis of ciguatoxin CTX3C (1)6 in 2001.7,8

Ciguatera is one of the largest sources of food poisoning.
It is caused by the ingestion of a variety of reef fish that have
accumulated trace amounts of ciguatoxins of dinoflagellate
origin via the food chain.1–4
Annually, more than 20,000
people suffer from ciguatera, particularly in subtropical and
tropical regions. Ingestion of affected fish leads to various dis￾orders involving the neurological, gastrointestinal, and cardio￾vascular systems. The most prominent symptom is a sensory
disorder causing a reversal in temperature perception. Such
neurological disorders may last months or longer, while in
severe cases paralysis, coma, and death may occur. The lethal
potencies of ciguatoxins (LD50 = 0.25–4mg/kg) by intraperi￾toneal injection into mice2–6 are much greater than the struc￾turally related red-tide toxins, brevetoxins.9–12 Ciguateric fish look, taste, and smell the same as uncontaminated fish. Difficulties in predicting, detecting, and treating ciguatera have a significant economic and human health impact. Pharmaco￾logical studies have indicated that ciguatoxins exert their
potent toxicities by binding to VSSC, which results in
persistent activation of the channels.13–17 The site-specificity
and selective function of these toxins may serve for investi￾gation into the activation and gating mechanisms of the
channels.

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