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Enantioselective Total Synthesis of Miyakolide

Miyakolide的对映选择性全合成

基本信息

批准号：
7324254
负责人：
Brandon Lee Ashfeld
金额：
$ 3.43万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-06 至 2007-07-31
项目状态：
已结题

项目摘要

A strategy for the enantioselective synthesis of miyakolide, a potent anti-tumor marine natural product is proposed. Miyakolide was isolated from a marine sponge of the genus Polyfibrospongia, and shares a number of structural features similar to the potent anti-cancer bryostatins. Miyakolide is not only an intriguing target as a complex natural product, but its analysis may also provide insight in to what functional moieties are important in tumor inhibition by comparison to structurally similar, biologically active compounds. The proposed route toward miyakolide illustrates how transition metal-catalyzed coupling reactions can be used to construct complex natural products in an atom economical method. A tandem ruthenium-catalyzed alkene-alkyne coupling/palladium-catalyzed asymmetric allylic alkylation stereoselectively assembles a key intermediate. One of the more challenging hydropyran rings is constructed utilizing a unique palladium(ll)- catalyzed alkyne-alkyne coupling/cyclization cascade. A catalytic enantioselective anti-aldol reactior followed by macrolactonization completes the total synthesis of miyakolide. The convergent nature of the _roposed route allows for the synthesis of structurally related analogs. The synthesis will also provid_ significant quantities of miyakolide for its development as a novel therapeutic agent, and for biological ._omparison studies to the anti-neoplastic bryostatins.

本论文研究了一种具有抗肿瘤活性的海洋天然产物miyaklavin的对映选择性合成策略，提出了Miyakiaguli分离自Polyfibrospongia属的海绵，并与其他海绵共享一个许多结构特征类似于有效的抗癌苔藓抑素。宫崎骏不仅是一个耐人寻味的目标作为一个复杂的天然产物，但它的分析也可以提供洞察力，在什么功能部分，与结构相似的生物活性化合物相比，在肿瘤抑制中是重要的。的一条通往宫崎骏的拟议路线说明了如何使用过渡金属催化的偶联反应以原子经济的方法构建复杂的天然产物。一种串联的铼催化的烯烃-炔烃偶联/钯催化的不对称烯丙基烷基化立体选择性组装一个关键中间体更具挑战性的氢吡喃环之一是利用独特的钯（II）- 催化的炔-炔偶联/环化级联。一种催化的对映选择性反羟醛缩合反应器然后进行大环内酯化完成miyaklutone的全合成。的收敛性质，所述路线允许合成结构上相关的类似物。综合报告还将提供- 大量的miyaklantine用于其作为新的治疗剂的开发，以及用于生物学 ._对抗肿瘤苔藓抑素的研究。