SYNTHESIS OF AMPHIDINOLIDE P USING RUTHENIUM CATALYSIS

钌催化合成氨吡啶内酯 P

• 批准号: 6377928
• 负责人: John Daniel Chisholm
• 金额: $ 3.48万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6377928
• 关键词: alkenes; alkynes; catalyst; chemical addition; chemical synthesis; diene; drug design /synthesis /production; macrolide antibiotics; methanol; ruthenium; solvents

This research proposal describes experiments that will expand the scope of the ruthenium catalyzed addition of alkenes to alkynes. The facile synthesis of certain 1,4-unconjugated dienes distinguishes this ruthenium based methodology, providing an alternative to multistep olefination protocols. Reactions are performed in polar protic solvents (DMF/H2O mixtures or methanol) at elevated temperatures (100 degrees C), in contrast to other carbon-carbon bond forming reactions which require low temperature and an anhydrous environment. These reaction conditions do not disturb other functionality, such as esters and alcohols, which simplifies protecting group strategies. The cytotoxic agent amphidinolide P offers an excellent opportunity to explore this chemistry. Retrosynthesis of this macrolide reveals a 1,4-diene. Disconnection of this diene reveals an enyne or a 1,3-diene as substrates for the ruthenium catalyzed transformation. These two functional groups have not been previously utilized in this coupling method. The first part of the proposal studies the effect of functionality on the selectivity of the ruthenium catalyzed process. The characteristics of new substrates in this powerful carbon-carbon bond forming reaction will be explored. Choice of functionality on the coupling partners will determine the best reaction conditions to be used in the second part of the proposal, which deals with the synthesis of amphidinolide P. The proposal allows for the synthesis of a cytotoxic agent with a novel structure, and provides an opportunity to explore the utility of a relatively new carbon-carbon bond forming reaction. The knowledge gained from this study will be useful in later syntheses, and will lead to a better understanding of this ruthenium coupling chemistry.

本研究计划描述了将扩大钌催化烯烃加成成炔的范围的实验。某些1,4-非共轭二烯的简单合成区分了这种基于钌的方法，提供了多步烯烃协议的替代方案。反应在极性质子溶剂（DMF/H2O混合物或甲醇）中在高温（100摄氏度）下进行，而其他碳-碳键形成反应需要低温和无水环境。这些反应条件不干扰其他功能，如酯和醇，这简化了保护基团的策略。细胞毒性物质两萜内酯P为探索这种化学作用提供了一个极好的机会。该大环内酯的反合成得到1,4-二烯。该二烯的分离揭示了一个烯或1,3-二烯作为钌催化转化的底物。这两个官能团以前没有在这种耦合方法中使用过。第一部分研究了官能团对钌催化反应选择性的影响。在这种强大的碳-碳键形成反应中，新底物的特性将被探索。选择偶联体上的功能将决定在第二部分中使用的最佳反应条件，该部分涉及两苯环内酯p的合成。该提议允许合成具有新结构的细胞毒性剂，并为探索相对较新的碳-碳键形成反应的效用提供机会。从这项研究中获得的知识将在以后的合成中有用，并将导致更好地理解这种钌偶联化学。