Denbinobin 簡捷合成之研究
A Concise Synthesis of Denbinobin
中文摘要
Denbinobin(1)，為一種 phenanthrene quinone 結構的天然物，其最早被發現於 Dndrobium nobile 的成分之中。而最近有報導指出 denbinobin(1)具有抗氧化、抗 血小板凝聚、抗發炎以及抗惡性腫瘤方面的活性，為提供本化合物對其藥理作用 機轉之探討，並進一步製備並研究其衍生物及類似物。本研究係先行設計一種化
學全合成的簡捷方式以取得此天然物。在化學合成上，我們選擇以市售的2-
bromoisovanillin(22)為起始物，進行七步反應以得到 denbinobin(1)。首先，我們 先將起始物2-bromoisovanillin(22)的 OH 基接上 TBDMS 保護基，並另將 3,5- dimethoxybenzyl bromide(17)接上 triphenyl- posphine 形成 phosphonium ylide 18，
然後兩者以Wittig 反應結合，得到 olefins trans-24 及 cis-25。接著對 cis-25 以 Bu3SnH/AIBN 進行自由基環化反應形成化合物 26，再以 TBAF 摘除先前的保護 基得到化合物27，並以 Fremy`s salt 作氧化劑形成 quinone 11，最後進行 TMSI 選擇性的去甲基反應而得到denbinobin(1)，總產率為 15 %。其中，以 AIBN 作催 化劑而使用Bu3SnH 進行自由基環化反應，與以 Fremy`s salt 氧化形成 quinone 結構為此一denbinobin(1)合成之重要關鍵化學反應。
英文摘要
Denbinobin(1) containing an phenanthrene quinone skeleton is a minor constituent isolated from Dendrobium nobile. Previous studies indicated that denbinobin(1) exhibited anti-inflammatory activity, anti-oxidant, anti-platelet aggregation and anti- tumor activity in vitro and in vivo. In order to prepare denbinobin analogs for structure -activity relationship and action mechanism studies, a concise synthesis of denbinobin(1) is developed in this research. Denbinobin(1) is prepared in 7 steps from two commercial available starting materials, 2-bromoisovanillin (22) and 3,5-
dimethoxybenzyl bromide (17). The hydroxyl group of 22 was protected by treating with TBDMSCl to yield the protected 23. 3,5-Dimethoxybenzyl bromide (17) was reacted with triphenylposphine to form phosphonium ylide 18. By using Witting reaction, Compound 23 was reacted with 18 in thepresence of n-butyllithium to produce a mixture of olefins ,trans-24 and cis-25. The cis-25 isomer was treated with Bu3SnH/AIBN to form the desired phenanthrene 26. The TBDMS-protecting group of 26 was removed by tetra-n-butylammonium fluoride (TBAF) to yield 27, which was then oxidized to the phenanthrene- quinone 11 by Fremy`s salt. Finally, Compound 11 was selective demethyled with trimethylsilyl iodide (TMSI) to form denbinobin(1). The total yield of denbinobin(1) synthesis in the present study was 15
%.
