24 (-)-テトロドトキシンの全合成研究(口頭発表の部)

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Tetrodotoxin (TTX, 1), isolated as a toxic principle of puffer fish poisoning, is a highly potent neurotoxin which inhibits electrical excitation of nerve and muscle cell membranes. The mechanism of its action is shown that the specific binding to voltage-gated Na^+ channel blocks depolarization. The structure was elucidated in 1964 independently by three groups (Hirata-Goto, Tsuda and Woodward) and the total synthesis of racemic TTX was accomplished in 1972 by Kishi-Goto and coworkers. The novel structure including contiguous eight stereogenic centers and multifunctional groups such as guanidine, hemilactal and six hydroxyl groups, and the characteristic biological activity still make it challenging target for the total synthesis. Herein, we report the synthesis of protected TTX 26. Carbon skeleton synthesis It was designed that the oxygenated cyclohexane derivative A containing the carbon framework of TTX was constructed by intramolecular aldol reaction as a key step. The aldol precursor 6 was prepared via Sonogashira coupling and Claisen rearrangement from the known diol 3. Hydroxylation at the C-5 and C-11 position of 6 were carried out through oxidation of enol ether to give dihydroxyketone 9. The acetylene moiety was then hydrated to provide methyl ketone 10, which was selectively protected via intramolecular acetal formation at C-6, and then converted to enol ether 11. Aldol condensation with TBAF yielded enone 12. Nitrogen introduction Attempted stereoselective introduction of nitrogen functionality at the C-8a position failed by Overman rearrangement giving an undesired product 27. It turned out that intramolecular Michael addition of carbamate 16→47 was effective for the C-N bond formation at C-8a. Epoxidation and the inversion of configuration at C-5 gave fully functionalized cyclohexane 20. α-Hydroxylactone synthesis Aldehyde 21 was converted to cyclic vinyl ether 22 through enolization with DBU. Three step oxidation-reduction sequence afforded α-hydroxylactone 23 as a single isomer, which was transformed to ortho ether 24. Guanidine synthesis Guanidine group was installed with Boc-protected isothiourea to afford 25, which was subjected to oxidative cleavage of 1,2-diol and subsequent treatment with acid to furnish protected TTX 26. Deprotection of 26 to accomplish the total synthesis of 1 is underway.
天然有機化合物討論会の論文
2002-09-01

24 (-)-テトロドトキシンの全合成研究(口頭発表の部)

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