13 海洋動物タツナミガイから得られた細胞毒性環状デプシペプチド、ドリキュライドの立体構造と全合成(口頭発表の部)

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Doliculide (1), a cytotoxic 16-membered cyclodepsipeptide has been isolated from the Japanese sea hare Dolabella auricularia. This compound exhibited remarkable cytotoxicity against HeLa-S_3 cells with an IC_<50> of 0.0054μg/mL. The gross structure was elucidated by using primarily 2D NMR technique. The absolute stereostructure was deduced by extensive NOE experiments of doliculide (1) and the chiral HPLC analysis of N-methyltyrosine that was obtained by acidic hydrolysis of doliculide (1). The proposed structure of doliculide (1) was unambiguously confirmed by the efficient enantioselective total synthesis. The polyketide unit (12) was synthesized with almost complete stereocontrol by application of the Evans aldol reaction followed by the Barton deoxygenation reaction. Coupling of the polyketide unit (12) with glycine tert-butyl ester and subsequently with the tyrosine derivative (18) gave the linear depsipeptide (19). Finally, 16-membered ring formation was accomplished successfully by macrolactamization. The yield of the synthesis, based on the longest linear sequence, was 11%. Artificial analogues (21-25) of doliculide (1) were synthesized and the structure-activity relationship was examined. The results revealed the importance of the 3-iodo-N-methyl-D-tyrosine moiety with respect to cytotoxicity.
天然有機化合物討論会の論文
1994-09-20