Trans-fused polycyclic ethers such as ciguatoxins and brevetoxins are among the most spectacular classes of compounds isolated from marine sources (Scheme 1). [1] These molecules are made up of a single carbon chain locked into a ladderlike structure with a length of 3 nm. The striking regularity with which the oxygen atoms bridge the polycyclic framework is a remarkable feature of these molecules. The cyclic ethers, with sizes ranging from five-to nine-membered rings, all fuse in a trans/syn/trans fashion.
Ciguatoxins [2] (1, Scheme 1) and brevetoxins [3] (2 and 3) have attracted intense interest from biologists and chemists alike because of their potent neurotoxicity and their association with the catastrophic effects of food poisoning and redtide phenomena. Ciguatoxins were identified as the principle toxins in the widespread seafood poisoning known as ciguatera. [4] The toxins generated by the dinoflagellate Gambierdiscus toxicus [5] are transferred through the aquatic food chain, and ingestion of ciguateric fish by humans leads to neurological, gastrointestinal, and cardiovascular disorders. On the other hand, brevetoxins are potent ichthyotoxins, and have been isolated from the dinoflagellate Karenia breve. [6] Red tides, which are caused by blooms of Karenia breve, have killed great numbers of fish and caused intoxication in humans.
These toxins exert their toxicity by binding to the voltagesensitive sodium channels (VSSC) of excitable membranes, causing them to open, and thereby allowing influx of sodium ions. [7, 8] The specific binding site shared by ciguatoxins and brevetoxins was designated as site 5. [9-11] Interestingly, more structurally complex ciguatoxins are known to possess both a higher binding affinity to site 5 and more potent toxicities than brevetoxins. The extremely limited supply of ciguatoxins from the natural sources has prevented studies on structureactivity relationships (SARs), which would help in understanding the structural requirements necessary for this highly specific ligand-receptor interaction. [11-13] Thus, a synthetic supply of ciguatoxins is urgently needed.
Recently, we achieved the first total synthesis of three members of the ciguatoxin family, namely CTX1B, CTX3C, and 51-hydroxyCTX3C (1), based on a unified synthetic strategy. [14] These routes allowed us to prepare new fully synthetic analogues of ciguatoxins for detailed SAR studies.
Here we report the total synthesis and biological evaluation of F-ring-modified analogues of 1.
Scheme 2 illustrates the last stage of our total synthesis of 51-hydroxyCTX3C (1), [14b] one of the most toxic congeners of the ciguatoxins. The comparably complex left ABCDE and right HIJKLM wings were coupled through O,S-acetal formation. The FG ring was then constructed in a stepwise manner: radical cyclization of 5 generated the seven-membered G ring of 6, and ring-closing olefin metathesis (RCM) [15] built the nine-membered F ring (7!8). Final removal of the 2-naphthylmethyl (NAP) groups [16] from 8 afforded 1. This synthetic scheme offered a unique oppor-Scheme 1. Structures of ciguatoxin 51-hydroxyCTX3C and brevetoxins.