安卓奎諾爾及其類似物之合成研究

Abstract

安卓奎諾爾(antroquinonol)屬於泛醌類(ubiquinone)的化合物，從牛樟芝的發酵菌絲體所分離得到，被發現具有抑制癌細胞及抗發炎作用。從牛樟芝取得安卓奎諾爾化合物產量很少，因此化學家們希望可藉由化學合成方式來直接獲得，同時驗證其立體化學及絕對組態。 安卓奎諾爾的結構骨架為2,3-二甲氧基環己-2-烯酮，並且由甲基、 菌綠烯醇基(farnesyl)及羥基建構三個立體中心。本論文第一階段以2,3,4-三甲氧基苯甲醛為起始物，經由拜耳–維立格氧化反應(Baeyer–Villiger oxidation)、苯酚氧化反應、麥克爾加成反應 (Michael addition)、烷基化反應、還原反應、水解反應及立體異構化簡短的7步驟，獲得(±)-安卓奎諾爾及其七個同類物。此麥克爾加成反應為第一個使用在具有四個甲氧基的多電子環己二烯酮的系統。 第二階段，發展針對多取代基環己二烯酮的系統進行不對稱催化麥克爾加成反應，可得到高效能鏡像選擇性的結果。接著將此方法，應用第一階段的天然物合成策略，可以獲得(+)-antroquinonol及(+)-antroquinonol D。

Antroquinonol, isolated in low quantity from an endemic mushroom Antrodia cinnamomea, is under clinical evaluation in patients with non-small cell lung cancer. An efficient synthesis of antroquinonol is desired to meet the medicinal need. Antroquinonol has an unusual core structure of 2,3-dimethoxycyclohex-2-enone with methyl, farnesyl and hydroxyl substituents at three contiguous stereocenters. First, starting from 2,3,4-trimethoxybenzaldehyde, a concise synthesis of (±)-antroquinonol and its seven analogues was accomplished in 7 steps comprising Baeyer–Villiger oxidation, phenol oxidation, Michael reaction, alkylation, reduction, hydrolysis and epimerization. This study demonstrates the first example for Michael reaction in a highly electron-rich cyclohexadienone system carrying four electron-donating methoxy substituents. The asymmetry catalytic conjugate additions to substituted- 4,4-dimethoxycyclohexadienones were then achieved in high enantioselective manner, and applied to the syntheses of (+)-antroquinonol and (+)-antroquinonol D in a concise manner.