抗癌聚酮天然产物 Biselyngbyolide A 的全合成研究

Stereoselective synthesis of complicated chiral polyol and polyene fragments in polyketide has been challenging for a long time. Due to the general low efficieny of chemical total synthesis, most of the polyketide drugs are prepared through fermentation or semi-synthesis. This proposal aims to combine enzymatic kinetic resolution and chemical synthesis in the total synthesis of anticancer polyketide biselyngbyolide A via a stereoconvergent strategy. Biselyngbyolide A owns potent anticancer activity (IC50 = 12 nM for HL60 cells). Its chemical structure features a 18-membered macrolactone ring, five tertiary stereogenic centers, one 1,3,5-syn,syn –triol fragment, four E-alkenes, and one trisubstituted Z-alkene. In the current project, enzyme is proposed to realize the kinetic resolution of racemic vinylogous Mukaiyama aldol (VMAR) product in a highly enantioselective manner. The resulted two enantiomers will be utilized as the starting materials toward two key chiral fragments, respectively. Three chiral carbon centers at C10, C3, and C5 will be introduced via a Zirconium-catalyzed methylation and syn-selective iodolactonization. Iron-catalyzed stereoselective methylation of alkyne is also introduced to construct the challenging trisubstituted Z-alkene. After merging two chiral fragments through Wittig or Julia olefination, the desired 18-membered macrolactone ring will be realized by macrolactonization and subsequent removal of the protecting group will complete the enantioselective synthesis of biselyngbyolide A.

聚酮类分子复杂的多羟基手性及多烯片段的立体选择性合成长期以来是化学合成的挑战性课题。绝大多数聚酮类临床药物都是通过生物发酵或化学半合成制备，化学全合成往往效率低下。本项目拟将酶促的动力学拆分反应与化学合成相结合，采用手性汇聚策略高效完成聚酮类天然产物biselyngbyolide A的不对称全合成。Biselyngbyolide A具有良好的抗癌细胞活性 (IC50 = 12 nM, HL60细胞)。该分子结构特点包含十八元大环内酯，五个叔碳手性中心，一个1,3,5-syn,syn三羟基片段，四个反式烯烃和一个顺式烯烃。本项目计划利用酶催化实现消旋VMAR产物的高效动力学拆分，拆分所得两个产物分别作为两个复杂手性片段的起始原料。随后通过锆甲基化/Michael加成串联反应以及底物控制的碘内酯化反应引入C10、C3和C5位手性中心。顺式三取代烯烃则采用铁催化的炔烃的立体选择性甲基化得以实现。

聚酮类分子复杂的多羟基手性及多烯片段的立体选择性合成长期以来是化学合成的挑战性课题。绝大多数聚酮类临床药物都是通过生物发酵或化学半合成制备，化学全合成往往效率低下。本项目拟将酶促的动力学拆分反应与化学合成相结合，采用手性汇聚策略高效完成聚酮类天然产物biselyngbyolide A的不对称全合成。Biselyngbyolide A具有良好的抗癌细胞活性 (IC50 = 12 nM, HL60细胞)。该分子结构特点包含十八元大环内酯，五个叔碳手性中心，一个1,3,5-syn,syn三羟基片段，四个反式烯烃和一个顺式烯烃。从酶拆分所得的炔丙醇衍生物以及生物发酵大量制备得到的1,3-手性二醇出发，利用锆氢化/偶联串联反应构建1,3,5-三醇手性中心，最终利用RCM反应完成了18元大环内酯的建立，进而实现了biselyngbyolide A类似物的不对称合成。为进一步快速完成biselyngbyolide A的不对称全合成，以及建立化合物库并进行活性-结构关系研究奠定基础。