SYNTHESIS OF OLIVOMYCIN A & POLYHYDROXYLATED COMPOUNDS

Olivomycin A是一个成员的金酸组的 抗肿瘤抗生素 该组织的某些成员被用来 临床上用于治疗睾丸肿瘤，但有毒副作用 这些作用限制了这些化合物的有用性。 我们建议 开发橄榄霉素A的会聚的立体选择性合成， 从而定义一种可能有助于合成 具有非天然寡糖残基的类似物和改进的 治疗指标 在前一个赠款期间，我们完成了 糖苷配基、橄榄石和AB二糖的合成。 在 新的赠款期间，我们将集中精力解决最后一个 一个化学问题，即发展 合成β-2-脱氧糖苷键的有效方法。 这种新的方法将被用于综合 在AB和CDE单元与CDE三糖的偶联中， 糖苷配基 我们还建议探索外异头效应作为一个新的 立体化学控制策略的对映体和 多羟基和氨基的非对映选择性合成 取代的分子 将努力发展高效的 手性γ-烷氧基烯丙基金属试剂和手性乙醇酸酯， 甘氨酸烯醇化物当量。 如果开发成功，这些新的 试剂将用于栗精胺的合成， 苦马豆素是两种多羟基生物碱， 作为糖苷酶抑制剂。

Olivomycin A is one member of the aureolic acid group of antitumor antibiotics. Certain members of the group are used clinically for treatment of testicular tumors, but toxic side effects limit the usefulness of these compounds. We propose to develop a convergent, stereoselective synthesis of olivomycin A, and thereby define a strategy that may be useful for synthesis of analogues with unnatural oligosaccharide residues and improved therapeutic indices. In the preceding grant period we completed syntheses of the aglycone, olivin, and the AB disaccharide. In the new grant period we will focus our efforts on solving the last remaining chemical problem, namely the development of an efficient method for synthesis of beta-2-deoxyglycosidic linkages. This new methodology will then be used in the synthesis of the CDE trisaccharide and in the coupling of the AB and CDE units to the aglycone. We also propose to explore the exo-anomeric effect as a new strategy for stereochemical control in the enantio- and diastereoselective synthesis of polyhydroxylated and amino substituted molecules. Efforts will be made to develop efficient chiral gamma-alkoxyallylmetal reagents and chiral glycolate and glycine enolate equivalents. If successfully developed, these new reagents will be applied to the synthesis of castanospermine and swainsonine, two polyhydroxylated alkaloids that are of intense interest as glycosidase inhibitors.