Studies toward Determination of Absolute Stereochemistry and Total Synthesis of Stereochemically Undefined Bioactive Natural Polyether Macrolides

本文从有机合成化学的角度研究了未明确生物活性的天然聚醚大环内酯类化合物的绝对立体化学性质，以期建立一种有效的测定方法。Goniodomin A是村上在1988年从平野山Alexandrium中分离得到的抗真菌药物。后来发现其独特的生物活性，如调节肌动球蛋白atp酶活性，增加人天文细胞丝状肌动蛋白含量，以及通过抑制内皮细胞肌动蛋白重组而具有抗血管生成活性。虽然报道了其详细的核磁共振数据和独特的平面结构，包括5-和6-元环醚（a -，D-和e -环部分），螺旋环缩醛（c -环部分）和6-元环半缩醛（f -环部分）的32元大内酯，但性腺结构素a的立体化学尚不清楚。Caribenolide I是由Shimizu于1995年从双鞭毛藻Amphidinium sp.S1 . More -36-5中分离得到的细胞毒性物质，对HCT116具有较强的细胞毒性，IC_<50>的浓度为1.6 nM。虽然它的平面结构是由一个26元的内酯与一个氧烷、一个6元的环半缩醛、一个环氧化物和5个羟基（包括一个半缩醛羟基）组成，但它的相对和绝对构型尚未确定。本课题完成了性腺域蛋白A的部分立体化学测定和部分合成：(1)利用Murakami报道的性腺域蛋白A的核磁共振数据预测了A-、BC-、D-、E-和f -环部分的相对构型；(2)合成了具有预测立体化学性质的A-、D-、E-和f -环；(3)天然性腺蛋白A的核磁共振数据与人工合成的A-、D-、E-和f -环段的核磁共振数据吻合较好；(4)通过比较天然性腺素A与宏观环中合成de环的核磁共振数据，确定de环部分的相对立体化学性质；(5)通过对goniodomin a的核磁共振预测结构进行综合评价，确定了bc环部分的相对立体化学性质，并设计了一些羰基内酯I的合成类似物以确定其相对立体化学性质。少

Toward development of an efficient methodology for determination of the absolute stereochemistry of undefined bioactive natural polyether macrolides, goniodomin A and caribenolide I were investigated in view of organic synthetic chemistry. Goniodomin A was isolated from dinoflagellate Alexandrium hiranoi as an antifungal agent by Murakami in 1988. Later, its particular bioactivities, such as modulation of actomyosin ATPase activities, increasing the filamentous actin content of human astronoma cells, and antiangiogenic activity via inhibition of actin reorganization in endothelial cells, were found. Although its detailed NMR data and unique planer structure featured by a 32-membered macrolactone including 5- and 6-membered cyclic ethers (the A-,D- and E-ring parts), a spirocyclic acetal (the BC-ring part), and a 6-membered cyclic hemiacetal (the F-ring part) were reported, the stereochemistry of goniodomin A was unclear. Caribenolide I was isolated from dinoflagellate Amphidinium sp.S1 … More -36-5 as a cytotoxic agent, which showed strong cytotoxicity against HCT116 with 1.6 nM of IC_<50>, by Shimizu in 1995. While its planer structure, characterized by a 26-membered macrolactone with an oxolane, a 6-membered cyclic hemiacetal, an epoxide, and 5 hydroxy groups (including a hemiacetal hydroxy group), was elucidated, its relative and absolute configurations were not determined. From this research project, determination of partial stereochemistry and partial synthesis of goniodomin A have been achieved as follows : (1)the relative configurations of the A-,BC-,D-,E-, and F-ring parts were predicted from the NMR data of goniodomin A reported by Murakami ; (2)the A-,D-,E-, and F-ring segments possessing the predicted stereochemistries were synthesized ; (3)NMR data of natural goniodomin A agreed well with those of synthetic A-,D-,E-, and F-ring segments ; (4)relative stereochemistry of the DE-ring part was determined by comparison of NMR data of natural goniodomin A with the synthetic DE-ring included in a macro ring ; (5)the proper stereochemistry of the BC-ring part was elucidated by synthetic assessment of the predicted structure from the NMR data of goniodomin A. Some synthetic analogues of caribenolide I were also designed in order to determine its relative stereochemistry. Less