SYNTHESIS OF MEDICINALLY IMPORTANT NATURAL PRODUCTS

这项建议描述了一种新的合成方法。 几种潜在的含氢吡喃的天然产物 治疗价值：二氢压缩蛋白(一种降胆固醇药物) 和他的米贝霉素/阿维菌素家族的螺酮单位 抗生素(抗寄生虫剂)。 紧凑素的合成以底物控制的反应为特征 用于建立所需构型的大环内酯 在偏远的立体中心。将制备两种二羟基癸内酯 在这项研究中很可能是前药物的结构类型不 还没有报道。目标分子的氢化对苯二烯部分 将通过对新的串联式Michael-Aldol进行修改来制备 这个实验室最近开发出了反应序列。 提案研究中的米贝霉素-阿维菌素部分使用 试剂控制的反应(夏普莱斯环氧化和不对称反应 氢化硼)来建立远程立体中心，同时 芳环是一种潜在的β-二羰基单元。延拓 这一策略应用于四和更高级聚酮的合成， 许多重要生物分子的结构亚基将是 检查过了。

This proposal describes novel methodology for the synthesis of several hydropyran-containing natural products of potential therapeutic value: dihydrocompactin (a hypocholesterolemic agent) and he spiroketal units of the milbemycin/avermectin family of antibiotics (antiparasitic agents). The compactin synthesis features substrate-controlled reactions on a macrocyclic lactone for establishing the desired configurations at remote stereocenters. Two dihydroxy decanolides to be prepared in this study are likely to be pro-drugs of a structural type not yet reported. The hydronapthalene portion of the target molecule is to be prepared via a modification of a new tandem Michael-aldol reaction sequence recently developed in this laboratory. The milbemycin-avermectin portion of the proposal study uses reagent-controlled reactions (Sharpless epoxidation and asymmetric hydroboration) to establish remote stereogenic centers while an aromatic ring serves as a latent beta-dicarbonyl unit. Extension of this strategy to the synthesis of tetra- and higher polyketides, structural subunits of many important biomolecules, will be examined.