Design and Synthesis of a Conformationally Restricted Analogue of the EFGH-Ring System of Ciguatoxin

The fused-hexahydrooxonine (F-ring) of ciguatoxin (CTX), as well as its EFGH-ring fragment, undergoes a slow conformational change between two conformers in solution.In this paper, we designed and synthesized a conformationally restricted analogue of the EFGH-ring system of ciguatoxin.Chemo-and stereoselective epoxidation of the F-ring successfully impeded the dynamic behavior without affecting the overall three-dimensional shape of the molecule.Ciguatoxin (CTX, 1, Figure 1) is one of the principal causative agents of ciguatera seafood poisoning in the Pacific. 1 , 2 Ingestion of ciguateric seafood causes human gastrointestinal, neurological, and cardiovascular disturbances. 3Pharmacological studies indicated that 1 exerts its potent toxicity by binding and activating voltage-sensitive sodium channels (VSSC) in excitable membranes. 4evetoxin-A (2), 5 which is a structurally related red-tide toxin, shares the specific binding site with 1 on VSSC. 6Both toxins possess a conformationally flexible hexahydrooxonine in the center of the molecule (F-ring of 1 and E-ring of 2).As shown in Figure 2, the F-ring of 1 is known to undergo a slow conformational change between the UP and DOWN conformers, which differ only in orientation of the olefinic bond with regards to the ring plane (Figure 2). 1,7,8It has been speculated that the flexibility of the toxins plays an important role in their biological activity. 8 evaluate the precise role of this unique equilibrium, we planned to synthesize a conformationally restricted analogue of 1 with minimum perturbation of the parent structure.