Synthetic Studies of Liposidomycin : Studies of Stereochemistry and biological activity mechanism

脂质霉素是一种新型的含脂质核苷类抗生素家族，在灰孢子链霉菌的培养滤液和菌丝体中发现。它们是对磷酸-N-乙酰胞壁酰五肽转移酶显示高度特异性抑制的选择性抗生素，磷酸-N-乙酰胞壁酰五肽转移酶是细菌肽聚糖合成中脂质循环的初级阶段。脂质霉素B还抑制体外聚异戊二烯（焦）磷酸N-乙酰葡糖胺（糖缀合物生物合成的中间体）的形成。这些化合物的结构是根据核磁共振和质谱数据推测的，立体化学是通过X-射线晶体学分析得到的。实现了含苯基取代基的利泊多霉素二氮杂环庚酮环系的立体控制合成。在二氮杂环庚酮环上存在氨基的情况下，尿嘧啶基团的引入失败。N-糖基化顺利进行，得到在二氮杂环庚酮环上的氨基上具有吸电子硝基苯磺酰胺（Ns）和甲酰基保护的尿嘧啶化合物。对脂霉素全合成过程中的N-糖基化进行了详细的研究。

Liposidomycins are a family of novel lipid-containing nucleoside antibiotics of unusual complexity, found in the culture filtrate and mycelia of streptomyces griseosporeus. They are selective antibiotics showing highly specific inhibition toward phospho-N-acetylmuramylpentapeptide transferase that is the primary stage of a lipid cycle in bacterial peptidoglycan synthesis. Liposidomycin B also inhibits in vitro formation of polyprenyl(pyro)phosphate N-acetylglucosamine, an intermediate in glycoconjugate biosynthesis. The structures were proposed on the basis of NMR and mass spectral evidence of degradation compound but the stereochemistry was revealed by X-ray crystallography analysis of caprazamycin that is an analog of liposidomycins.We start to study the synthetic of liposidomycin degradation product. A stereocontrolled synthesis of the liposidomycin diazepanone ring system having a phenyl substituent has been achieved. In the presence of an amino group on the diazepanone ring, the introduction of a uracil group did failed. The N-glycosylation proceeded smoothly to obtain the uracil compound having electron-withdrawing nitrobenzenesulfonamide (Ns) and formyl protecting at an amino group on the diazepanone ring. The detailed examination of the N-glycosylation was accomplished for the total synthesis of liposidomycins.