SYNTHESIS OF OLIVOMYCIN A & POLYHYDROXYLATED COMPOUNDS

Olivomycin A是抗肿瘤的金酸类药物， 抗生素 该组的三个成员（橄榄霉素A、色霉素A3和 光神霉素）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质中起着关键作用。 金酸转化为DNA 我们建议完成一个高度立体选择性 橄榄霉素A的合成，从而确定了可能有用的策略 用于合成具有非天然寡糖的类似物，并改进 治疗指标 糖苷配基、橄榄石和AB的合成 二糖已经完成，和高度立体选择性的方法， 已经开发了芳基β-2-脱氧糖苷的合成， AB二糖与糖苷配基的偶联。 最后剩下的 问题是建立一种有效的方法，用于合成 CDE中出现的三个2-脱氧-β-糖苷键 三糖 虽然CD二糖41和44是在合成中合成的， 在授权期之前，β-糖苷的选择性较小 由于未预料到的亲核试剂依赖性， 2 α-苯硒基糖基乙酸酯的构型不稳定性 37和38的糖基供体。 未来的努力 资助年度将集中于2 α-苯硫基糖苷供体102-106 由于初步结果表明，2alpha-PhS取代 糖苷没有通过可逆表锍离子差向异构化倾向 中间体的 展望了这项综合工作将在 下一个阶段是非常好的。 外消旋异头效应作为不对称立体控制因素的研究 和无环非对映选择性合成将继续进行。 在 在此之前，我们发现手性（Z）-γ- 含有甘露糖基助剂的烷氧基烯丙基锡烷64表现出优异的 在BF 3催化的与手性醛的反应中的非对映体控制。 合成顺式二醇124的该方法的一般性将是： 充分探索。 改进的助剂（例如，137)如有需要， 以最大化立体选择性。 这一战略将扩大到 手性（E）-γ-甘露糖基烯丙基铬试剂142的开发 反二醇的对映选择性合成125. 这个“阿尔法- 羟基烯丙基化”方法在合成 碳水化合物和其他多羟基化天然产物。 两个目标 直接感兴趣是栗精胺（150）和苦马豆素（151）。 我们实验室以前开发的合成方法将 应用于霉酰胺A和B的高立体选择性全合成， 一组有效的抗病毒和抗肿瘤剂。

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.