Synthetic Studies of the Marine Alkaloids, Madangamines with Anti Tumor Activities

Madangamine A是Andersen于1994年从海绵Xestospongia ingens中分离得到的五环生物碱。不久之后，这种生物碱类型的新成分madangamines B-E从同一种生物中分离出来。Madangamine A对P388、A549、U373和MCF-7肿瘤细胞系具有细胞毒活性。在本研究项目中，我完成了madangamines的ABC和ACE环骨架的构建。酮基-氨基苯酚的N，O-缩醛化允许快速构建在C4具有季碳中心的2-氮杂双环[3.3.1]壬烷骨架。这种策略使立体选择性的建设的中央diazatricyclic核心（ABC环）的madangamine生物碱。在我们研究的下一阶段中，通过11.2.2.0<4.14>环己酮衍生物的N，O-缩醛化、几何保留交叉偶联反应和分子内还原胺化构建2-氮杂双环[3.3.1]壬烷骨架，已经完成了madangamine三环、4-氮杂三环[ www.example.com ^ ]十七碳-12-烯（包括11元大环（ACE-环））的有效构建。基于以上结果，我今后的研究工作将集中在15元大环（D环）的构建上，以用于madangamines的全合成。

Madangamine A is a pentacyclic alkaloids that was isolated from the marine sponge Xestospongia ingens by Andersen in 1994. Soon after, new constituents of this alkaloid type, madangamines B-E, were isolated from the same organism. Madangamine A exhibits cytotoxic activities against P388, A549, U373, and MCF-7 tumor cell lines. In this research project, I have accomplished the construction of the ABC and ACE-ring frameworks of madangamines. N, O-Acetalization of the keto-aminophenol allows rapid construction of the 2-azabicyclo[3.3.1]nonane skeleton with a quaternary carbon center at C4. This strategy enabled the stereoselective construction of the central diazatricyclic core (ABC-ring) of the madangamine alkaloids. In the next stage of our investigation, an efficient construction of the madangamine tricyclic ring, 4-azatricyclo[11.2.2.0^<4.14>]heptadec-12-ene, including an 11-membered macrocycle (ACE-ring) has been accomplished via construction of the 2-azabicyclo[3.3.1]nonane skeleton by N, O-acetalization of a cyclohexanone derivative, geometry-retained cross-coupling reaction, and intramolecular reductive amination. From the results obtained above, my future studies will be focused on the construction of a 15-membered macrocycle (D-ring) for the total synthesis of madangamines.