Convergent Total Synthesis of Caribbean Ciguatoxin C-CTX1 and Its C3-Epimer

Caribbean ciguatoxin C-CTX1 is a highly potent ladder-shaped polycyclic ether toxin responsible for ciguatera fish poisoning and has recently been detected beyond the Caribbean Sea region. Because of its extreme structural complexity and scarcity from natural sources, its structure and biological properties have not been fully validated by chemical means. We report here the first total synthesis of C-CTX1 and its naturally occurring C3-epimer through a convergent fragment-coupling strategy joining the ABCDE- and HIJKLMN-ring units, featuring late-stage radical cyclization and ring-closing metathesis to construct the central FG-rings. The synthesis provides definitive structural confirmation and practical milligram-scale access to both epimer. Comparative biological evaluation revealed a significant difference in relative neurotoxicity.