104(P-42) チューブリン重合阻害剤(+)-オッテリオンAおよび(-)-オッテリオンBの全合成(ポスター発表の部)

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概要

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• Otteliones A (1) and B (2), which include a unique 4-methylene-2-cyclohexenone skeleton, were isolated by Hoye et al. in 1998 from the freshwater plant Ottelia alismoides collected in the Nile Delta, Egypt. These natural products show remarkable in vitro cytotoxicity at nM-pM levels against various cancer cell lines and powerful tubuline polymerization inhibitory activity (1: IC_<50> = 1.2μM). Its remarkable biological properties make otteliones an exceptionally intriguing and timely target for total synthesis, however, their stereostructures had been obscure. Thus, we embarked on the project directed toward the enantioselective synthesis of otteliones to determine their absolute configurations. We initially pursued the synthesis of 3-epi-ottelione A (3), which was considered as a most likely stereostructure for ottelione A. Our synthesis begun with the preparation of hemiacetal 13, which was then converted to hydroxy aldehyde 18 through the coupling reaction of 14 with aryllithium and base-induced lactol-opening/epimerization reaction of 17 as key steps. The sensitive dienone moiety was constructed by Corey-Winter procedure (20→21→22), which led to the synthesis of (+)-3-epi-ottelione A (3). Unfortunately, ^1H NMR of 3 was not accorded with that of natural ottelione A. Next, we investigated the synthesis of 1 and 2. The introduction of aromatic part to 13, followed by C1-epimerization reaction gave dihydroxy aldehyde 27. Then, after several steps including two-fold Wittig reaction and Corey-Winter reductive olefination, the synthesis of (+)-ottelione A (1) was successfully achieved. Epimerization at C3a position in 1 was allowed to provide (-)-ottelione B (2). The synthesized (+)-1 and (-)-2 were identical with natural samples in all respects (^1H and ^<13>C NMR, HRMS, and [α]_D) which proved that the absolute configurations of 1 and 2 are (1S, 3S, 3aR, 7aS) and (1S, 3S, 3aS, 7aS), respectively.

• 天然有機化合物討論会の論文
• 2004-10-01

著者

• 荒木 宏史

  東北薬科大学

• 加藤 正

  東北薬科大学

• 荒木 宏史

  東工大院総理工

• 井上 宗宣

  相模中研

• 加藤 正

  東工大院総理工

• 井上 宗宣

  東北薬科大学

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