SYNTHESIS OF AMPHIDINOLIDE P USING RUTHENIUM CATALYSIS

这项研究提案描述了将扩大Ru催化的烯烃加成到炔烃的范围的实验。某些1，4-非共轭双烯的简便合成使这种基于Ru的方法与众不同，为多步烯化提供了一种替代方案。与其他需要低温和无水环境的碳-碳键形成反应不同，反应在极性质子溶剂(DMF/H2O混合物或甲醇)中高温(100摄氏度)进行。这些反应条件不会干扰其他官能团，如酯和醇，从而简化了保护基团的策略。细胞毒剂两性内酯P为探索这种化学提供了一个极好的机会。该大环内酯的逆合成产物为1，4-二烯。这种二烯的断开显示了一个烯炔或一个1，3-二烯作为Ru催化转化的底物。这两个官能团以前没有在该偶联方法中使用过。该提案的第一部分研究了官能团对Ru催化过程的选择性的影响。在这个强大的碳-碳键形成反应中，我们将探索新底物的特性。偶联伙伴上官能团的选择将决定本提案第二部分将使用的最佳反应条件，该提案涉及两性内酯P的合成。该提案允许合成具有新结构的细胞毒剂，并为探索相对较新的碳-碳键形成反应的用途提供了机会。从这项研究中获得的知识将在以后的合成中有用，并将导致对这种Ru偶联化学的更好的理解。

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.