五味子降三萜天然产物Schincalide A的全合成研究

Plants of the family schisandraceae have been a hot topic for their medicinal properties within the medicinal chemistry and drug discovery communities, the same as schinortriterpenoids for their beautiful molecule architecture within synthetic chemists of natural product. In 2016, an unprecedented schinortriterpenoid named as schincalide A was isolated by Ruan and co-workers from the stems and leaves of Schisandra incarnate, a vine plant, which is mainly distributed in Hubei province. The difficulties in total synthesis of schincalide A are mainly focused on the construction of oxygenated ABC (5,5,7) ring system and tricyclo[5.2.1.0]decane-bridged system. This project will apply converged and modular synthetic route to complete the total synthesis of schincalide A. Fistly, through reasonable design of the proper chirality source, or a cascade reaction featuring asymmetric Mukaiyama-epoxide ring opening/oxa-Michael addition was devised as key step to form the ABC ring system. Secondly, asymmetric aldol reaction was designed as initial step, so as to realize the asymmetric building of GH ring in target molecule. Afterwards, two fragments will be connected through Stille carbonylation coupling reaction. Finally, a Nazarov cyclization/double Michael addition/alkene isomerization cascade will allow the single-step assembly of tricyclo[5.2.1.0]decane-bridged system with proper configuration, and asymmetric total synthesis of schincalide A could be achieved in a short route.

2016年，我国天然产物学家阮汉利教授于湖北省五味子科植物的茎叶中分离得到一个新颖的五味子降三萜天然产物Schincalide A。对其全合成的难点，集中于较高氧化态的5/5/7 (ABC)三环体系以及独特的[5.2.1.0]十碳-桥联三环中心的构建。本申请项目拟采用汇聚式模块化的合成路线，首先通过对合适的手性原料进行合理设计或者以不对称Mukaiyama开环氧/分子内氧Michael加成串联反应作为关键步骤，实现目标分子中ABC环系的不对称合成；其次以不对称Aldol反应为起始步骤，实现目标分子GH环的不对称构建；然后经Stille羰基化偶联反应完成两个片段的连接；最后采用一锅多步串联反应(Nazarov环化反应/双Michael加成反应/烯烃异构化反应)完成[5.2.1.0]十碳-桥联三环中心的构建。最终，有望以简短的步骤完成Schincalide A的不对称全合成。

五味子三萜天然产物以其新颖独特的结构、广泛且良好的生物活性，颇受合成化学家关注。本报告主要是针对五味子降三萜天然产物Schincalide A的全合成研究，该分子由于环系复杂、手性中心众多，至今尚未完成该分子的全合成，仅仅实现了一部分骨架结构的合成，而模板反应对于复杂结构的天然产物全合成具有很强的指导意义，因此我们还开展了关键环系结构的合成方法学研究。以丙酮叉保护的赤酮酸内酯为手性起始原料，利用环氧开环/氧Michael加成串联反应为关键步骤，实现了ABC环系的合成，虽然步骤简短，但最后两步收率和立体选择性都较差；而后又以(+)-马鞭草烯酮为手性起始原料经过常规步骤实现了ABC环系的合成，但合成步骤较长，达到了18步之多，不具有步骤经济性。针对分子结构中[5.2.1.0]十碳-桥联三环体系，我们设计了模板反应并利用双Michael加成反应实现了该结构的合成；针对五味子三萜天然产物中的γ-亚乙烯基-γ-丁烯酸内酯结构（即H环），我们发展了碱性条件下TiCl4促进的偶联成环反应，一步简便操作实现了其构建，并将其运用到了诸如榄香烯型萜类、乌药烷型萜类天然产物的全合成去；还针对五味子三萜天然产物Rubriflordilactone A和Rubriflordilactone B中的多取代的芳环结构（DE环系），开发了Diels-Alder/氧化芳香化构建多取代芳环的策略，首先将其在几例伊鲁烷型倍半萜天然产物中得到了应用；总之，以上反应方法学的建立为实现五味子降三萜天然产物的合成研究。