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Denbinobin 簡捷合成之研究

Denbinobin 簡捷合成之研究.

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Denbinobin 簡捷合成之研究

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  1. Denbinobin 簡捷合成之研究 • 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。

  2. A Concise Synthesis of Denbinobin • 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 %.

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