降碳三萜malabanone A及其天然类似物的不对称全合成研究

Terpenoids are widely distributed in nature. Among them, triterpenoids are payed more attentions by pharmaceutical and synthetic chemists due to their novel and complex skeletons together with good bioactivities. Malabanone A, an octanorterpenoid which contains a novel [6-6-6-5-3] pentacyclic fused skeleton, was isolated from the ground stem bark of ailanthus malabarica DC(a unique pharmcutical plant mainly distributed in Indian and Indo-China) in 2001 by professor Koichi Takeya and coworkers in Tokyo university. Malabanone A shows moderate cytotoxic activity on P-388 murine leukemia cells. Due to its poor availability from nature sourse(0.00013%), therefore, the total synthesis of this compound will be great significence for further study on its physiological activity and mechanism of action. We choose malabanone A and its natural analogues as our synthetic targets and intend to start from natural (R)-carvone, via several cycloaddition reactions, to complete their asymmetric total synthese. With a sufficient amount of the synthetic intermediates and natural products in hand, we will test their bioactivities and analysize the structure-activity relationships to find and confirm the crucial structure and active site of this type of triterpenoids. All these will build a solid foundation for further research and development of new drugs.

萜类化合物在自然界广泛存在，其中三萜因为大多具有新奇而复杂的骨架结构及良好的生理活性而广为药物和合成化学家所青睐。Malabanone A 是日本东京大学的分离化学家Koichi Takeya等人2001年从印度和中南半岛特有药用植物ailanthus malabarica的茎皮中分离得到的一个具有【6-6-6-5-3】五环稠和新颖骨架结构的降八碳三萜，活性实验表明其对小鼠白血病P388细胞具有中等细胞毒活性。由于植物中该类化合物含量低微（0.00013%），因此人工全合成该化合物将对进一步研究其生理活性及作用机制具有重大意义。我们拟从天然(R)-香芹酮出发，经由若干环加成反应，完成malabanone A及其类似物的不对称全合成，得到足量的合成中间体和目标天然产物，通过对它们的活性测试，分析其构效关系，从而寻找并确认该类三萜产生生理活性的必须结构和活性位点，为进一步的新药研发奠定基础。

三萜类天然产物大多具有复杂的环系骨架和良好的生理活性，其化学合成及构效关系研究是发现先导药物和开展合成方法和策略研究的平台。2015年1月-2018年12月四年间，我们研究小组在国家自然科学基金面上项目（NSFC21472079）的资助下，以降碳三萜malabanone A的全合成为主攻方向，开展了对具有良好生理活性复杂萜类天然产物的全合成及相关方法学研究。在此期间，我们合成了具有良好生理活性的20多个天然产物，其中有7个萜类天然产物，如polyrhaphin D , (-)-8-epi-chromazonarol, (-)-15-oxopuupehenol等。此外我们还开展了绿色环保的合成方法学研究，并发展了一系列高效构建中小环系的新方法。项目执行期间，我们培养了4名硕士和1名博士，并获得甘肃省2015年度自然科学一等奖和2018年度Thieme Chemistry Journal Award。