SYNTHESIS OF OLIVOMYCIN A & POLYHYDROXYLATED COMPOUNDS

橄榄霉素A是金黄色酸基中的一员 抗肿瘤抗生素。该组的某些成员被使用 临床用于治疗睾丸肿瘤，但毒副作用大 影响限制了这些化合物的用途。我们建议 开发一种收敛的、立体选择性的橄榄霉素A的合成方法， 并由此定义一种策略，该策略可用于合成 含有非天然低聚糖残留物的类似物及其改进 治疗指标。在之前的授权期内，我们完成了 苷元、橄榄素和AB二糖的合成。在 新的资助期我们将集中精力解决最后一个问题 剩余的化学问题，即一种 合成β-2-脱氧糖苷键的有效方法。 然后，这种新的方法将被用于合成 CDE三糖和AB和CDE单元的偶联 苷元。 我们还建议将外异常态效应作为一种新的 对映体和对映体的立体化学控制策略 多羟基和氨基的非对映选择性合成 取代的分子。着力发展高效率 手性伽马-烷氧基烯丙基金属试剂和手性乙醇酸盐 甘氨酸烯醇型等价物。如果开发成功，这些新的 试剂将应用于蓖麻黄碱的合成和 苦马豆素，两种多羟基生物碱，具有强烈的 作为糖苷酶抑制剂的兴趣。

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.