SYNTHESIS OF OLIVOMYCIN A AND POLYHYDROXYLATED COMPOUNDS

橄榄霉素A是抗肿瘤金黄色酸基的一员 抗生素。该组的三个成员(橄榄霉素A、色霉素A3和 米特拉霉素)已在临床上用于治疗各种肿瘤， 但毒性限制了它们的用途。各种研究表明， 寡糖在识别和结合蛋白的过程中起着关键作用。 金棕榈酸转化成DNA。我们建议完成一个高度立体选择的 合成橄榄霉素A，从而确定一种可能有用的策略 非天然低聚糖类似物的合成及改进 治疗指标。苷元、橄榄素和AB的合成 二糖都已完成，并建立了一种高度立体选择性的方法 芳基β-2-脱氧糖苷的合成已被开发用于 AB二糖与苷元的偶联。最后剩下的 问题是建立一种有效的合成方法 CDE中的三个2-脱氧-β-糖苷键 三糖。而Cd双糖41和44是在 在之前的授权期内，β-糖苷的选择性较低 由于意想不到的亲核依赖， 2α-苯基硒基糖基乙酸酯的构型不稳定性 37和38作为糖基供体。未来的努力 赠款年度将集中在2α-苯硫苷捐赠者102-106 由于初步结果表明，2α-PHS取代 糖苷类化合物没有通过可逆表硫酸根离子异构化的趋势 中间体。这一合成将于年内完成的前景 下一批资助期都很好。 外异常态效应作为立体控制因素在不对称中的研究 非环非对映选择性合成将继续进行。在 在之前的授权期内，我们发现手性(Z)-伽马- 含有甘露醇助剂的烷氧基烯丙基锡烷表现出优异的性能 BF3催化的手性醛反应中的非对映界面控制。 此合成二元醇124的工艺的一般性将为 充分探索。如果需要，将开发改进的辅助剂(例如137个) 以最大限度地提高立体选择性。这一战略将扩展到 手性(E)-伽马-甘露糖基烯丙基铬试剂142的研制 抗二醇125的对映选择性合成。这个“阿尔法- 羟烯丙基化“方法学应该被证明在合成 碳水化合物和其他多羟基天然产物。两个目标 目前感兴趣的是蓖麻素(150)和苦马豆素(151)。 我们实验室以前开发的合成方法学将是 应用于高立体选择性的杨梅酰胺A和B的全合成， 一组有效的抗病毒和抗肿瘤药物。

Olivomycin A is a member of the aureolic acid group of antitumor antibiotics. Three members of this group (olivomycin A, chromomycin A3 and mithramycin) have been used clinically for the treatment of various tumors, but toxicity limits their usefulness. Various studies establish that the oligosaccharides play key roles in the recognition and binding of the aureolic acids to DNA. We propose to complete a highly stereoselective synthesis of olivomycin A, thereby defining a strategy that may be useful for the synthesis of analogues with unnatural oligosaccharides and improved therapeutic indices. Syntheses of the aglycone, olivin, and the AB disaccharide have been completed, and a highly stereoselective method for the synthesis of aryl Beta-2-deoxyglycosides has been developed for use in coupling of the AB disaccharide to the aglycone. The last remaining problem is the establishment of an efficient method for the synthesis of the three 2-deoxy-Beta-glycosidic linkages that occur in the CDE trisaccharide. While CD disaccharides 41 and 44 were synthesized in the preceding grant period, the selectivity for the Beta-glycosides was less than desired owing to the unanticipated nucleophile dependent, configurational instability of the 2alpha-phenylselenyl glycosyl acetates 37 and 38 that were used as the glycosyl donors. Efforts in the coming grant year will focus on the 2alpha-phenylthio glycoside donors 102-106 since preliminary results indicate that the 2alpha-PhS substituted glycosides show no tendency to epimerize via reversible episulfonium ion intermediates. The prospects that this synthesis will be completed in the next grant period are very good. Studies of the exo-anomeric effect as a stereocontrol element in asymmetric and acyclic diastereoselective synthesis will be continued. In the preceding grant period we discovered that the chiral (Z)-gamma- alkoxyallylstannane 64 containing a mannosyl auxiliary exhibits excellent diastereofacial control in BF3 catalyzed reactions with chiral aldehydes. The generality of this process for the synthesis of syn diols 124 will be fully explored. Improved auxiliaries (e.g., 137) will develop if required to maximize stereoselectivity. This strategy will be extended to the development of a chiral (E)-gamma-mannosylallylchromium reagent 142 for the enantioselective synthesis of anti diols 125. This "alpha- hydroxyallylation" methodology should prove very useful in the synthesis of carbohydrates and other polyhydroxylated natural products. Two targets of immediate interest are castanospermine (150) and swainsonine (151). Synthetic methodology previously developed in our laboratory will be applied in highly stereoselective total syntheses of mycalamides A and B, a group of potent antiviral and antitumor agents.