Lepadiformine类生物碱的立体选择性合成方法研究

Lepadiformine-type alkaloids (Lepadiformines, Fasicularin and Cylindricines) that are generally isolated from certain ascidiaceas are classified as a series of tricyclic marine alkaloids. They possess some intriguing biological activities such as cyto-toxicity against multiple tumor cell lines, hypotensive, antiarrythmic properties and various cardiovascular effects(e. g. blocking the cardiac muscle Kir channel). The wide range of physiological activities of these alkaloids and their complex structure which contains multichiral centers, azaspirocycle and a sterically congested tricyclic system have raised the attention of many synthetic chemists. Quite a few innovative methods have already been developed for the construction of the core tricyclic system and the total synthesis of these natural products. But in all the articles about steroselective synthetic routes , chiral materials or chiral reagents were usually employed as the chiral origin and the asymmetric catalytic reaction was never reported as a key process . .In our proposed study, we plan to use the tandem asymmetric catalytic Michael addition reaction and the oxidative dearomatization as the key procedures and develop more efficient and flexible methods for the steroselective synthesis of these alkaloids and their analogues. A preliminary screening of physiological activities on the cardiovascular system of the synthetic alkaloids and their intermediates is also in the plan. This project will prove its important academic value in the field of synthetic organic chemistry, especially for the total synthesis and the bioactivity investigation of complex natural products and their analogues.

Lepadiformine类生物碱是从海洋生物海鞘中分离到的一类三环生物碱，吡咯-/吡啶[1,2-j]喹宁是此类生物碱共同的环系骨架结构。具有抗肿瘤、降血压、抗心率失常、心肌Kir通道阻滞等生理活性。此类生物碱含有多手性中心和氮杂螺环的稠密环系结构及其广泛的生理活性吸引了众多合成化学家的关注，发展了很多新颖的方法来构建此类生物碱环系骨架结构，并用于此类天然产物的全合成。已报道的不对称合成方法均采用手性原料或手性试剂引入手性源，未见手性催化反应作为关键步骤的合成路线。本项目拟分别以1.不对称催化Michael加成串联反应；2.氧化去芳化反应为关键步骤，探索和发展更高效率和更具普适性的合成方法，应用于此类生物碱及其类似物的立体选择性全合成，并对合成产物进行初步心血管系统生理活性筛选。本项目对有机合成方法学，特别是复杂天然产物及类似物的全合成及生理活性研究具有重要的学术价值。

Lepadiformine类生物碱是从海洋生物海鞘中分离到的一类三环生物碱，具有抗肿瘤、降血压、抗心率失常、心肌Kir通道阻滞等生理活性。本项目分别以1.不对称催化Michael加成串联反应；2.氧化去芳化反应为关键步骤，探索和发展更高效率和更具普适性的合成方法，应用于此类生物碱及其类似物的立体选择性全合成，并对合成产物进行初步心血管系统生理活性筛选。项目发展了不对称催化两次或三次Michael加成一瓶反应，高效立体选择性构建多取代环己烷，还发展了一类锌/醋酸/盐酸（或氢溴酸）条件下的多步一瓶环化反应，首先完成了石蒜生物碱(‒)-Zephranthine的对映选择性全合成。进而完成了Lepadiformine及Fasicularin类各一个生物碱的合成，为更多复杂生物碱提供了高效和通用的立体选择性合成方法。酚类化合物的氧化偶联反应研究中，成功建立了系列氮杂螺环的合成方法，还发现了含全碳季碳的非氮杂螺环的高效合成方法，具有显著的创新性和进行深入研究的价值。还开展了绿色化学研究，发展了一类烯丙位氧化的绿色合成方法、及无溶剂无过渡金属参与下的环氧开环反应制备β-氨基醇类化合物和药物合成方法，具有应用价值。另外，依托本项目进行药物设计与活性研究中，发现一类比对阳性照药物（PRIMA-1)活性和选择性更好的靶向P53的抗肿瘤活性先导化合物，有必要在后续工作中进行深入研究。