33(D-3) フグ毒テトロドトキシンの効率不斉全合成(口頭発表の部)

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Tetrodotoxin (TTX, 1), isolated as a toxic principle of puffer fish poisoning, is a potent neurotoxin as a specific voltage-gated Na^+ ion channel blocker. The structure was elucidated by Hirata-Goto, Tsuda and Woodward independently in 1964 to be a highly functionalized cage molecule which has 8 contiguous chiral center, cyclic guanidinium with hemiaminal and dioxa-adamantan structure. The remarkable biological activity and the structural complexity made it an attractive target for total synthesis. However only a total synthesis of racemic TTX was reported by Kishi-Goto in 1972 until the first asymmetric total synthesis of TTX in our laboratory in 2002. Now we wish to report here an alternative and efficient total synthesis of (-)-TTX starting from 4, an intermediate for our total synthesis of 11-deoxyTTX (2). This synthetic strategy was based on total syntheses of deoxy TTX analogs in our laboratory. Installation of hydroxyl group at allylic position of 4 with SeO_2 was followed by epoxidation and ozonolysis to give an epoxy aldehyde 10. Diastereoselective addition of magnesium acetylide to 10 and protecting group manipulation gave acetylene 12. Oxidative cleavage of the acetylene to carboxylic acid via α-keto acid and subsequent intramolecular epoxide opening gave a hydroxy lactone 16. After transformation of 1,2-diol protected as acetonide into dimethyl acetal, selective removal of acetates at C-9 and 10 hydroxyl groups gave diol 21, which was treated with TBSOTf to give an ortho ether 22. Deprotection of trichloroacetamide with DIBAL-H and following guanidinylation with di-Boc isothiourea gave a fully functionalized guanidine 24. Finally, global deprotection under acidic condition provided tetrodotoxin (1).
天然有機化合物討論会の論文
2004-10-01

33(D-3) フグ毒テトロドトキシンの効率不斉全合成(口頭発表の部)

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