抗肿瘤天然产物汉黄芩素的合成

Synthesis of Wogonin,a Natural Product with Anticancer Activity

汉黄芩素(wogonin,5,7-二羟基-8-甲氧基黄酮)是传统中草药黄芩的有效成分之一,其抗肿瘤活性显著,且对肿瘤细胞的杀伤作用有其独特的机制.目前报道的化学合成法大多总收率较低,反应条件苛刻或原料来源困难.笔者以2,4-二苄氧基-6-羟基苯乙酮与苯甲醛为原料,经Claisen-Schmidt缩合、氧化关环得到5,7-二苄氧基黄酮,通过对5,7-二苄氧基黄酮的8-位碘代、硼酸酯化和氧化从而高效引入8-位羟基,再经甲基化和脱苄基保护完成汉黄芩素的克级合成,总收率大于70%,且反应条件温和、无需柱层析,适合规模化生产.为该类化合物的进一步结构修饰、活性和机制研究提供了保障.

Wogonin （5,7-dihydroxy-8-methoxyflavone） is an active component isolated from the Traditional Chinese Medicine （TCM） Huang Qin, which exhibits significant anti-tumor activity via a unique mechanism. The reported chemical synthesis of wogonin suffered either from low overall yield, harsh reaction conditions or from noncommercially available starting materials. In this paper, a new synthesis of wogonin was achieved via Claisen-Schmidt condensation, cyclization, iodination at C-8 position of flavone, borylation of sterically hindered aryl iodides, oxidation of boronic esters, methylation and debenzylation reaction using 2,4-dibenzyloxy-6-hydroxy phenylacetone and benzaldehyde as the starting materials, which provided gram-scale wogonin in 〉70% overall yield. The total synthesis employs mild reaction conditions and conventional flash column chromatography is not needed for purification, which makes it suitable for large-scale production. The efficient and flexible entry should offer opportunities for further modification and chemical biology investigations.