STRATEGIES FOR THE SYNTHESIS OF BIOACTIVE TARGETS

描述：本文概述的研究计划针对的是 用于合成的新型通用策略的设计和开发 具有显著生物性的天然和非天然产品 活动。在这些调查过程中，调查的范围和 所选反应和过程的限制将在 复杂分子全合成的背景和新方法 对于碳-碳键的形成和官能团的操纵是 等着被发现。 需要指出的是，具体综合目标包括完成 几种重要生物天然产物的全合成 包括抗真菌抗生素Ambrticin和大环内酯类 抗生素红霉素B合成的基本策略 这些化合物中的每一个都是收敛的，并涉及到立体选择性 呋喃及其衍生的氢化吡喃的精制。新方法和新方法 不对称合成1，2，3-三取代的催化剂 环丙烷及其对三取代物立体选择性的构筑 烯烃将得到开发和应用。据报道， 红霉素B的方法是独一无二的，涉及大内酯化 一种糖基化的第二酸衍生物。首席调查员 表明红霉素的简单类似物具有 简化的分子框架上的关键碳水化合物残基将 被设计和制备以努力阐明红霉素 药效团，并最终确定新的口服活性 抗生素。他进一步指出，有几种新的生物活性 目标已经选定，将作为论坛 新化学的发明，并表明总的例子是 抗肿瘤相关候选药物FR900482的合成 将进行临床活性丝裂霉素试验。他说，关键是 他合成这种耐人寻味的生物碱的策略的要素 需要烯烃歧化反应来构建高度的 官能化氮杂环。据报道，一份简明的 一种新的角鲨烯合成酶抑制剂Zaragozic酸A的研究 以乙烯类的羟醛反应为特征来组装 构成双环核心结构的碳。 值得注意的是，天然产品和精选的数量 同类者将准备提交给C.P.斯塔克斯公司，ELI 礼来公司、默克、雅培实验室和葛兰素史克 评估为潜在的抗生素和抗真菌药物， 降胆固醇和抗癌药物。

DESCRIPTION: The research program outlined herein is directed toward the design and development of novel general strategies for the syntheses of natural and unnatural products that possess significant biological activity. During the course of these investigations, the scope and limitations of selected reactions and processes are to be explored in the context of the total synthesis of complex molecules, and new methods for carbon-carbon bond formation and functional group manipulation are to be discovered. It is noted that the specific synthetic objectives include completion of the total syntheses of several biologically important natural products including the antifungal antibiotic ambruticin and the macrolide antibiotic erythromycin B. The basic strategies for the syntheses of each of these compounds are convergent and involve the stereoselective elaboration of furans and hydropyrans derived therefrom. New methods and catalysts for the asymmetric synthesis of 1,2,3-trisubstituted cyclopropanes and for the stereoselective construction of trisubstituted olefins are to be developed and applied. It is reported that the approach to erythromycin B is unique and involves the macrolactonization of a glycosylated seco-acid derivative. The principal investigator indicates that simple analogues of the erythromycins that bear the critical carbohydrate residues on a simplified molecular framework will be designed and prepared in an effort to elucidate the erythromycin pharmacophore and ultimately to identify novel, orally-active antibiotics. He further notes that several new biologically active targets have been selected that will serve as the forum for the invention of new chemistry and indicates that example that the total synthesis of FR900482, a potent anticancer candidate related to the clinically active mitomycins will be undertaken. He states that the key element of his strategy for the synthesis of this intriguing alkaloid entails an olefin metathesis reaction to construct a highly functionalized nitrogen heterocycle. It is reported that a concise approach to zaragozic acid A, a novel squalene synthase inhibitor, has been devised that features a vinylogous aldol reaction to assemble the carbons constituting the bicyclic core structure. It is noted that quantities of the natural products and selected congeners will be prepared for submission to C.P. Starks, Inc., Eli Lilly Company, Merck, Abbott Laboratories, and Glaxo for biological evaluation as potential antibiotics and as antifungal, hypocholesterolemic and anticancer agents.