19 シガトキシン9員環エーテル部分の合成と立体配座解析(口頭発表の部)

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Ciguatoxin (CTX1B, 1) and its congeners are the toxic principles of ciguatera, a widespread seafood poisoning of dinoflagellate origin, and reported to bind to the same site of voltage-sensitive sodium channels (VSSC) as brevetoxins, another class of structurally related marine toxins. The ciguatoxin molecule consists of 12 trans-fused cyclic ethers ranging from six- to nine-membered, where another five-membered oxacycle is spirally attached at one end. The most remarkable structural feature is that oxonene ring F in the central region of the molecule undergoes a rather slow conformational change in solution. Thus, ring F functions as a hinge in the conformational alternation, which is speculated to play an important role in its binding to VSSC. However, little is known about the detailed mechanism of this conformational change. From the synthetic point of view, construction of the oxonene ring system is a formidable and challenging synthetic objective because severe difficulties such as unfavorable entropy factors and transannular interactions have to be overcome. We now report the first achievement in synthesis fused oxonene ring systems 2 and 3 and their conformational analysis on the basis of the dynamic NMR studies. The present synthesis of 6-9-6 tricyclic system 2 involves as the key steps (i) Lewis acid-mediated intramolecular condensation of γ-alkoxyallylsilane-acetal to yield O-linked oxacycles and (ii) SmI_2-mediated intramolecular Reformatsky-type reaction to construct an oxonane ring. As seen for ciguatoxin, ^1H and ^<13>C NMR signals on the oxonene ring in 2 extremely broadened at room temperature. As the temperature decreased, these signals sharpened and separated into two sets of peaks, which corresponded to the two alternating conformers with a ratio of about 1: 1 in pyridine-d_5 solution. The structures of these conformers were assigned by ^3J_<H,H> data at -20℃ and appeared to closely mimic the ring F of ciguatoxin except the ratio of the two conformers. The free energy of activation for this conformational change was estimated to be approximately 14kcal/mol from the coalescence temperature (28℃). The present strategy for the construction of a fused oxonene ring was also successfully applied to the synthesis of the 6-6-9-7-6-6 hexacyclic system 3. Compound 3 also exists in an equilibrium of two conformational states of the oxonene ring as was the case with 2. In order to clarify the relationships between conformational flexibility and biological activity, further investigation toward the synthesis of decacyclic ciguatoxin model compound 29 is currently underway.
天然有機化合物討論会の論文
1997-07-20

19 シガトキシン9員環エーテル部分の合成と立体配座解析(口頭発表の部)

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