Synthesis of Novel Cytotoxic Marine Macrolides

新型细胞毒性海洋大环内酯类化合物的合成

• 批准号: 9974384
• 负责人: Horacio Olivo
• 金额: $ 1.8万
• 依托单位: University of Iowa
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9974384&HistoricalAwards=false
• 关键词: Synthesis; Novel; Cytotoxic; Marine; Macrolides

This Research Planning Grant is supported by the Organic and Macromolecular Chemistry Program. Prof. Horacio F. Olivo of the University of Iowa will synthesize the aglycone moiety of the natural product, callipeltoside, a natural product recently isolated from a lithistid sponge. Callipeltoside is a 14-membered macrocyclic halogenated lactone. The synthesis involves Cr(II)-mediated coupling of two key fragments, the synthesis of which involves whole-cell systems and isolated enzymes. A biocatalytic method will be used to introduce the two stereogenic centers present in the chlorocyclopropane side chain. The non-racemic synthesis of the first intermediate involve the desymmetrization of a meso-cyclopropane using an esterase. The second fragment will be prepared via a Baeyer-Villiger oxidation using an engineered Baker's yeast. During the eighteen-month grant period, the PI will prepare these two key intermediates in racemic form and investigate their chemistry. He will investigate stereo- and regio-controlled ring openings of bicyclic oxiranes derived from cyclopentadiene to provide new methods for the elaboration of substituted hemiketal oxane rings. Prof. Olivo will also explore the use of palladium and chromium coupling reactions in an effort to develop new synthetic methods. Most of the 2500 naturally occurring organohalogen compounds known have had their structure elucidated in the last decade and a half. Several cytotoxic and/or antitumor macrolides have been encountered in marine sponges. One form of callipeltoside appears promising as an anti-HIV agent and as a chemotherapeutic agent.

这项研究计划补助金由有机和高分子化学计划支持。 Horacio F.教授爱荷华州大学的奥利沃将合成天然产物- Callipeltoside是一种14元大环卤代内酯。 该合成涉及Cr（II）介导的两个关键片段的偶联，其合成涉及全细胞系统和分离的酶。 一种生物催化方法将被用来引入两个立体中心存在于氯环丙烷侧链。 第一中间体的非外消旋合成涉及使用酯酶的内消旋环丙烷的去对称化。 第二个片段将使用工程化的面包酵母通过Baeyer-Villiger氧化制备。 在18个月的资助期内，PI将制备这两种外消旋形式的关键中间体并研究其化学性质。 他将研究由环戊二烯衍生的双环环氧乙烷的立体和区域控制的开环，为取代的半缩酮氧杂环的制备提供新的方法。 Olivo教授还将探索钯和铬偶联反应的使用，以开发新的合成方法。 已知的2500种天然存在的有机卤素化合物中的大多数在过去的15年中已经阐明了它们的结构。 在海绵中发现了几种细胞毒性和/或抗肿瘤的大环内酯类。 一种形式的金盏花糖苷似乎有希望作为抗HIV剂和作为化疗剂。