基于铑催化串联环化策略的生物碱Mersinine A的对映选择性全合成研究

Mersinine A是2001年在Kopsia singapurensis树叶中分离出来的一类结构新颖的单萜变种吲哚生物碱。这类生物碱有着非常密集的稠和五环结构以及5个连续的手性中心（两个全碳季碳），此类天然产物也是人们首次分离发现的含有四氢喹啉结构单元的蕊木属生物碱。相应的生物学测试表明这类生物碱能够有效地逆转肿瘤细胞（KB/VJ300）对Vincristine的抗药性。然而该家族分子迄今未见有合成报道。本课题拟采用高度汇聚的路线，从廉价易得的手性原料出发，通过铑催化分子内N-磺酰基1,2,3-三唑裂解/分子内3+2偶极环化串联关键反应来实现生物碱Mersinine A的多环骨架的对映选择性构建并进一步完成其全合成。通过本课题研究有可能发展出该家族生物碱的高效通用的合成路线，确定该家族天然产物的绝对构型，并提供后续的生物学测试、需求更加广泛的生物学用途所需要足量的样品。

Mersinine A, one of the Mersinine alkaloids, was initially isolated in 2001 form the leaf extract of Kopsia singapurensis. This family of natural products is characterized by a novel pentacyclic skeleton containing five contiguous carbogenic stereocenters (two of which are all carbon-chiral ones). And the unique quinolinic chromophore distinguished these compounds from all other Kopsia alkaloids so far known. A relative biological testing shown Mersinine A was able to reverse drug-resistance in drug-resistant KB (KB/VJ300) cells. To date, no synthetic efforts for this class of compounds can be found in the literature. The present project targets at a concise and enantioselective total synthesis of mersinine A from steadily available L-prolinol featuring a rhodium catalyzed tandem cyclization process. This total synthesis will not only confirm the absolute configuration of mersinine A, but also provide a general synthetic solution to this family of natural products. The ample amounts of samples for the natural Mersinine A and its analogues acquired through synthesis may also facilitate the related biomedical studies.