高三尖杉酯碱和三尖杉酯碱的合成研究

Synthesis of Homoharringtonine and Harringtonine

天然药物高三尖杉酯碱和三尖杉酯碱是从三尖杉植物的叶和茎中分离得到的微量生物碱,是手性化合物。结构上,二者不仅含有一个共同的母核三尖杉碱,酯基侧链的α位也均为手性叔醇。因母核三尖杉碱和酯基侧链较大的空间位阻,两个结构片段的酯化偶联具有较大的挑战性。设计合成位阻较小的侧链中间体是酯化反应发生的关键。因此,化学家们相继合成了结构多样的α-羰基羧酸侧链以及含有杂环的侧链中间体,如四元内酯杂环侧链、四氢呋喃杂环侧链、六氢吡喃杂环侧链、七元内酯杂环侧链,并成功地完成了高三尖杉酯碱、三尖杉酯碱和同属其他活性生物碱的合成。本文基于本课题组的相关研究,根据侧链片段的构建策略和方法,综述了天然药物高三尖杉酯碱、三尖杉酯碱以及其他天然产物的合成研究。不仅总结了近几年来的新进展,还对我国老一辈的科学家们在此方面作出的贡献进行了回顾。

Natural drugs homoharringtonine and harringtonine are minor alkaloids isolated from the leaves and stems of plum yew Cephalotaxus harringtonia, an evergreen tree native of the southern provinces of China. Structurally, two natural drugs are all chiral compounds and have a common skeleton cephalotaxine, and the ester side chains bear chiral tertiary alcohol at α position. Because of the formidable steric bulk of both the keleton cephalotaxine and ester side chain, the esterification of both sections is extremely challenging. A less hindered side chain intermediate is key element to success for this coupling reaction. Consequently, chemists continuously designed and synthesized structurally diverse side chain intermediates such as α-ketoacids, four-membered lactone heterocycles, tetrahydrofuran heterocycles, tetrahydropyran heterocycles, and seven-membered lactone heterocycles, enabling the completion of synthesis of homoharringtonine, harringtonine and other related natural products. Based on our studies toward the synthesis of Cephalotaxus alkaloids, this paper reviews the strategic development towards the synthesis of Cephalotaxus natural drugs and other products by the types of side chain intermediates, including not only recent strategy advances but also synthetic methods developed by respected older generation chemists.