131(P-78) 抗腫瘍活性アセトゲニンMosin Bの不斉合成研究(ポスター発表の部)

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概要

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• Mosin B (1) is a mono-THF acetogenin isolated by McLaughlin's group from Annona squarnosa. It has showed selective cytotoxic activity against the human pancreatic tumor cell line, PACA-2, with potency 100 times that of Adriamycin. However, the absolute configuration around THF moiety has been unknown. We assumed that the more probable structure of mosin B is a candidate (I) rather than II, since the absolute configuration of C15 and C16 positions is usually R in Annaceous acetogenins. Thus, we planned a synthesis of I to determine the stereochemistry of mosin B (1). Our synthetic strategy involves asymmetric desymmetrization of σ-symmetric diol 5 and Nozaki-Hiyama-Kishi reaction of γ-lactone segment 6 to THF core segment 2 as key steps. The THF core moiety was stereoselectively constructed by iodoetherification of E-allyl alcohol 3, which was prepared from optically pure alcohol 4. On the other hand, the γ-lactone segment 6 was synthesized by allcylation of lactone 8 with Inflate 26. Cyclohexene-1,2-diol was transformed into the chiral alcohol 4 by asymmetric desymmetrization using C_2-symmetric bis-sulfoxide 11. The alcohol 4 was converted into triol 16 by sequential reaction: (1) dihydroxylation of olefin; (2) oxidative cleavage of the 1,2-diol; (3) Wittig reaction; (4) reduction with NaBH4; (5) hydrogenation of the double bond accompanied by debenzylation. After the 1,2-diol was selectively protected as an acetonide, iodination of primary alcohol was canied out via tosylation, giving the iodide 18. The coupling reaction of 18 and acetylide generated from propargyl alcohol TBS ether using n-BuLi afforded the alkyne 19, which was converted into the E-allyl alcohol 3 by deprotection of TBS ether followed by LiAlH_4 reduction of the triple bond. Upon treatment of 3 with I(coll)_2ClO_4, iodoetherification proceeded highly stereoselectively to give the epoxide 21 after subsequent base treatment. The resulting epoxide 21 was subjected to the Grignard reaction using 6-hexenylmagnesium bromide to give diol 22, which was converted into the aldehyde 2 by silylation, dihydroxylation of olefin, and oxidative cleavage of 1,2-diol. Aldehyde 9 prepared from D-glutamic acid was converted into diol 25 by Takai's olefination and deacetonization. One-pot selective triflation and TBS protection of 25 afforded the triflate 26. Synthesis of the γ-lactone segment 6 was completed by coupling reaction of 26 with the lactone 8 followed by oxidation of sulfide to the sulfoxide and thermal elimination. Nozaki-Hiyama-Kishi reaction of 2 and 6 mediated by CrCl_2/NiCl_2 afforded alcohol 28 in good yield. Oxidation of 28 to enone 29 followed by reduction with Wilkinson catalyst provided tri-TBS ether (30). Finally, desilylation of 30 gave the candidate of mosin B (I), whose spectral data (^1H-NMR, ^<13>C-NMR, IR, MS) were nicely consistent with the reported data of natural product, and showed higher specific rotation ([α]_D=+19.4, lit. +115). Further investigation including a synthesis of another candidate (II) is in due course.

• 天然有機化合物討論会の論文
• 2000-10-01

著者

• 小島 直人

  阪大院薬

• 岩田 宙造

  阪大院薬

• 前崎 直容

  阪大院薬

• 田中 徹明

  阪大院薬

• Tanaka T

  Kvushu Univ. Fukuoka Jpn

• 坂本 篤信

  阪大院薬

• 浅井 幹登

  阪大院薬

• Tanaka T

  Osaka Univ. Osaka Jpn

• 田中 恒雄

  Department Of Pharmacy Hyogo College Of Medicine

• Tanaka Tetsuaki

  Faculty Of Pharmaceutical Sciences Osaka University

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