A Concise Route to Two Distinct E-Ring Structures of Ciguatoxins

Abstract

Ciguatoxins, the causative toxins of ciguatera seafood poisoning, are large ladder-like polycyclic ethers, and known to have more than 20 structurally distinct congeners.In this paper, we describe a new concise synthesis of the two E-ring structures, of different ring sizes, found in ciguatoxins.From the common oxepane intermediate, the seven-membered E-ring was prepared in three steps, and the eight-membered E-ring was synthesized in seven steps using ring expansion and olefin isomerization as key reactions.The scarcity of ciguatoxins [e.g.CTX1B 1 (1), CTX3C 2 (2) and 51-hydroxyCTX3C 3 (3), Figure 1], their extraordinary ladder-shaped architecture, their potent neurotoxicity, and association with ciguatera seafood poisoning render these marine natural products formidable targets for a synthesis-driven investigation at the chemistry/biology interface. 4To date, more than 20 congeners of ciguatoxins have been structurally determined. 5While all the congeners share the common FGHIJ-ring structures, the ring sizes and the functional group patterns of the other parts of the congeners are diverse.For instance, 2 and 3 not only lack the additional side chain of 1, but have an eight-membered E-ring instead of the seven-membered ring found in 1.In earlier work, we reported the total syntheses of 1-3 by applying unified synthetic strategies; AB-, E-, HI-, and LM-ring fragments were assembled with construction of the CD-, FG-, and JK-ring systems to