SYNTHESIS OF ANTICANCER HELIANGOLIDES

这项建议涉及对综合方法的研究。 对天然存在的向日葵中的纤毛素、花青素A， 狼毒内酯A和马鞭草内酯A。 已发现化合物具有显著的抗肿瘤活性。 来源于人类鼻咽癌的细胞(KB)。全 在这些化合物中，除了马鞭草内酯A含有两个亲电的 部分，即与3(2H)-呋喃酮共轭的双键 环和能够共价的α-亚甲基内酯 与核酸和酶结合。 建议的方法包括手性化合物的烷基化。 四氢呋喃酮锂烯酸酯，可从D-甘露糖中获得， 具有含有碘代丙烯基团的手性伽马-内酯 在β-位和受保护的羟甲基反式 它在伽马位置。1，3-不对称诱导应导致 烷基化产物在C-位具有正确的立体化学。 6、C-7和C-10的天然产物。在适当之后 转化，最初的烷基化产物应该产生一个 在伽马位置上含有碘甲基的分子 内酯环和3(2H)-呋喃酮部分可转换为 线性共轭二烯酸与强子的去质子反应 基地。二烯酸酯的伽马位置上的环烷基化 应允许关闭十元碳环 以及一种产品的生产，该产品在臭氧降解的基础上 外环双键将产生一个含有 向日葵内酯环骨架。将这一系统转换为 目标天然产物应相对直截了当 尽管它涉及到几个步骤。

This proposal is concerned with the study of a synthetic approach to the naturally occurring heliangolides ciliarin, budlein A, lychnophorolide A, and eremantholide A. Some of these compounds have been found to show significant activity against cells derived from human carcinoma of the nasopharynx (KB). All of these compounds but eremantholide A contain two electrophilic moieties, i.e., a double bond in conjugation with a 3(2H)-furanone ring and an alpha-methylene lactone, that are capable of covalent binding to nucleic acids and enzymes. The proposed approach involves alkylation of a chiral tetrahydrofuranone lithium enolate, obtainable from D-mannose, with a chiral gamma-lactone containing an iodoisprepenyl group at the beta-position and a protected hydroxymethyl group trans to it at the gamma-position. 1,3-Asymmetric induction should cause the alkylation product to have the correct stereochemistry at C- 6, C-7, and C-10 of the natural products. After appropriate transformations, the initial alkylation product should yield a molecule containing an iodomethyl group at the gamma-position of the lactone ring and a 3(2H)-furanone moiety convertible into a linearly conjugated dienolate upon deprotonation with a strong base. Cycloalkylation at the gamma-position of the dienolate should allow the closure of the ten-membered carbocyclic ring and the production of a product that upon ozonolysis of an exocyclic double bond would yield a ketone containing the heliangolide ring skeleton. Conversion of this system into the target natural products should be relatively straightforward although it involves several steps.