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

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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