具有重要抗癌活性的三烯安莎霉素Trierixin和Mycotrienin II的高效合成研究

The triene-containing C17-benzene ansamycins (or ansatrienins) represents an important subclass of ansamycins with significant bioactivities along with intriguing structural features. Development of efficient and green strategy remains a challenging task in the synthetic community. In this proposal, two anticancer ansatrienins (trierixin and mycotrienin II, IC50 10ng/ml and 58 ng/ml, respectively) are chosen as synthetic targets for the primary interest. The current approach features: (a) enzymatic kinetic resolution of allenic alcohol developed to provide a sufficient amount of starting material bearing the C13 secondary alcohol;(b) a highly stereoselective oxonia-Cope rearrangement established for the constrcution of the 2-ene-1,5-diol motif; (c) the sensitive triene structure is constructed through a Trost-Lu isomerization of alkynone and subsequent elimination of C9-OH; (d) the stereoselective reduction of C3-ketone is realized via a macrocyclic control after the macrolactam formation; (e) a biomimetic methylthiolation of electron-rich arene is proposed to understand the strctural relationship between mycotrienin II and trierixin. The synthetic route in this proposal is efficient and highly stereoselective and also abandons the usage of precious metals as frequently chosen in previous syntheses. The corresponding SAR studies and chemical biology of such important natural products are planned.

三烯安莎霉素是一类结构独特的具有重要生理活性的天然产物，发展高效绿色的合成策略依然是开展全合成研究的核心问题。本项目以具有强抗癌活性的trierixin (IC50 10 ng/ml) 和mycotrienin II (IC50 58ng/ml) 为目标分子开展全合成研究。基于我们前期拓展的酶催化动力学拆分制备高光学纯的联烯醇结构片段，以及所发展的氧杂Cope重排反应高立体选择性地构建2-烯-1,5-二醇的合成方法，设计运用Trost-Lu炔酮异构化和串联的消除反应，采用大环构象控制的策略引入C3的手性中心，以便高效地完成mycotrienin II 的全合成。同时设计富电子芳香环的亲电甲硫基化反应，研究从 mycotrienin II 到 trierixin的仿生转化。该合成路线避免了贵金属的使用，同时发展高立体选择性的手性构建方法，为我们后续开展构效关系和化学生物学研究打下基础。

苯基安沙霉素是一类具有重要生理活性的抗生素。项目支持期间，针对C17-苯基安沙霉素目标分子中的连续手性中心和顺式三取代烯烃的结构特点，发展了高立体选择性的联烯硼氢化-烯丙基化和硼氢化-氧化反应，相继应用于聚酮类天然产物的重要结构片段。由于研究课题竞争激烈，课题进展一年多时国外同行就发表了高效合成，我们转而将建立的合成方法学应用于另一复杂聚酮天然产物lasonolide A 的全合成，我们完成的路线高效简洁，容易放大，有利于我们后续开展构效关系研究。目前我们仍然继续开展安沙霉素类抗生素的高效全合成工作，基于这些新方法的合成设计有望提高文献已有合成路线的低效高成本等问题。