SYNTHESIS OF AMPHIDINOLIDE P USING RUTHENIUM CATALYSIS

本研究建议描述的实验，将扩大钌催化的烯烃加成到炔烃的范围。某些1，4-非共轭二烯的简易合成使这种基于钌的方法与众不同，为多步烯化方案提供了替代方案。 反应在极性质子溶剂（DMF/H2O混合物或甲醇）中在高温（100 ℃）下进行，与其他需要低温和无水环境的碳-碳键形成反应相反。 这些反应条件不干扰其它官能团，例如酯和醇，这简化了保护基团策略。 细胞毒性剂amphidinoprotein P提供了一个很好的机会来探索这种化学。 这种大环内酯的逆合成揭示了1，4-二烯。 这种二烯的断开揭示了烯炔或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偶联方法中使用过。 该提案的第一部分研究了功能性对钌催化过程的选择性的影响。 将探讨这种强大的碳-碳键形成反应中新底物的特性。 选择的耦合合作伙伴的功能将确定最佳的反应条件下使用的第二部分的建议，其中涉及的合成amphidinopropylene P.该建议允许一种细胞毒性剂的合成与一种新的结构，并提供了一个机会，探索一个相对较新的碳-碳键形成反应的效用。 从这项研究中获得的知识将是有用的，在以后的合成，并将导致更好地了解这种钌耦合化学。

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.