Total Synthesis of the Anticancer Agent Haterumalide NA

描述（由申请人提供）：Haterumalide NA是最近从冲绳海绵Ircinia sp中分离到的大环内酯类药物。研究发现它对P388白血病细胞具有很强的细胞毒性。本研究项目的目标是开发一种简洁、模块化、高效的对映选择性合成haterumalide NA。为了实现这一合成，将开发新的方法立体选择性形成三取代和四取代烯烃。这个新工艺将是一个由丙炔醇合成取代环烯基硅氧烷的两步序列，然后是金属介导的与有机卤化物的偶联。该合成方法的发展将为进一步探索其生物活性创造足够数量的haterumalide NA。此外，提出的新方法和灵活的合成方案将允许直接获得haterumalide NA的类似物，这可能导致结构活性谱和新的抗癌药物的发现。

DESCRIPTION (provided by applicant): Haterumalide NA is a recently isolated macrolide from an Okinawan sponge Ircinia sp. It was found to exhibit strong cytotoxicity against P388 leukemia cells. The goal of this research project is to develop a concise, modular, and efficient enantioselective synthesis of haterumalide NA. To achieve this synthesis, new methodology will be developed for the stereosetective formation of tri- and tetrasubstituted olefins. This novel process will be a two-step sequence consisting of the synthesis of substituted cycloalkenylsiloxanes from propargyl alcohols followed by metal-mediated coupling with an organohalide. The development of this synthesis will create sufficient quantities of haterumalide NA for further exploration of its biological activity. Furthermore, the novel methodology proposed and the flexible synthetic scheme will permit straightforward access to analogs of haterumalide NA that may lead to a structure activity profile and the discovery of new anticancer drugs.