STRATEGIES FOR THE SYNTHESIS OF BIOACTIVE TARGETS

本文概述的研究计划是针对设计 天然和非天然含氧化合物合成的一般策略 具有显著生物活性的产品。上 方法学前沿，偶极环加成的进一步应用 腈氧化物将被开发，我们的战略的延伸 利用呋喃和氢吡喃作为不对称合成的关键中间体， 天然产物和选定的骨架亚基的合成将 广泛延伸。将介绍新的氢吡喃官能化方法 研究了我们还将探索一些独特的策略， 大环内酯的糖基化开环酸衍生物的大环内酯化 抗生素本文介绍了不对称合成的各种新技术， 环丙烷和用于立体选择性构建三取代的 还将探索双键。 合成目标包括：（1）完成全合成 红霉素A和B的新策略，其特征在于 糖基化开环酸衍生物的大环内酯化;（2）设计和 红霉素A和B类似物的制备方法 含有天然抗生素的基本药效团， 与大环内酯骨架无关的分子骨架， 努力制备新的口服活性抗生素;（3）完成 Breynogenin的全合成，Breynins A和B的糖苷配基， 不寻常的含硫糖苷， 降胆固醇活性;（4）多羟基化 生物碱栗精胺，α-糖苷酶I的有效抑制剂， 采用可以容易地修改以访问所选择的策略， 作为治疗艾滋病的潜在候选药物的相关衍生物; (5)设计和开发了一种统一的合成方法来合成甜菜碱酸 A和密切相关的埃佐霉素A1和A2，它们表现出抗真菌和 抗真菌抗生素的全合成 安布霉素采用利用有用扩展的收敛策略 以及新技术的开发 用于1，2，3-三取代环丙烷的不对称合成 至于三取代烯烃的立体选择性合成。 将对目标化合物和选定的同系物进行分类， 准备提交给C. P.斯塔克斯公司，礼来公司，杜邦公司， Merck和Abbott Laboratories进行生物学评价。

The research program outlined herein is directed toward the design of general strategies for the syntheses of oxygenated natural and unnatural products that possess significant biological activity. On the methodological front, further applications of the dipolar cycloadditions of nitrile oxides will be developed, and extensions of our strategy exploiting furans and hydropyrans as key intermediates for the asymmetric syntheses of natural products and selected skeletal subunits will be broadly extended. New methods for functionalization of hydropyrans will be investigated. We will also explore some unique strategies for effecting macrolactonizations of glycosylated, seco-acid derivatives of macrolide antibiotics. A variety of novel techniques for the asymmetric syntheses of cyclopropanes and for the stereoselective construction of trisubstituted double bonds will also be explored. The synthetic objectives include the: (1) completion of the total syntheses of the erythromycins A and B by a novel strategy that features macrolactonization of a glycosylated seco-acid derivative; (2) design and preparation of analogues of erythromycins A and B, including substances that contain the essential pharmacophore of the natural antibiotics on a molecular framework unrelated to that of the macrolide backbone, in an effort to prepare novel, orally-active antibiotics; (3) completion of the total synthesis of breynogenin, the aglycone of breynins A and B, which are unusual sulfur containing glycosides that exhibit significant hypocholesterolemic activity; (4) total synthesis of the polyhydroxylated alkaloid castanospermine, a potent inhibitor of alpha-glycosidase I, employing a strategy that may be readily modified to access selected related derivatives as potential drug candidates for the treatment of AIDS; (5) design and development of a unified synthetic approach to octosyl acid A and the closely related ezomycins A1 and A2, which exhibit antifungal and antibiotic activity; and (6) total synthesis of the antifungal antibiotic ambruticin employing a convergent strategy that exploits useful extensions of the furan methodology together with the development of novel techniques for the asymmetric synthesis of 1,2,3-trisubstituted cyclopropanes as well as for the stereoselective synthesis of trisubstituted olefins. Quantities of the targeted compounds and selected congeners will be prepared for submission to C.P. Starks, Inc., Eli Lilly Company, DuPont, Merck, and Abbott Laboratories for biological evaluation.