Enantioselective Total Synthesis of Miyakolide

一种有效的海洋抗肿瘤天然产物米亚科利特的对映选择性合成策略 建议。Miyakolide是从聚纤维海绵属的海绵中分离出来的，具有 许多结构特征类似于有效抗癌的苔藓抑素。米亚科莱德不仅是一位耐人寻味的 靶标是一种复杂的天然产物，但它的分析也可能提供对哪些功能部分的洞察 与结构相似、具有生物活性的化合物相比，它们在抑制肿瘤方面很重要。这个 提出的合成米亚科利特的路线说明了过渡金属催化的偶联反应是如何应用的。 以原子经济的方法构建复杂的天然产物。Ru催化的串联型催化剂 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 中级的。其中一个更具挑战性的氢化吡喃环是利用一种独特的钯(11)- 催化乙炔-乙炔偶联/环化级联反应。一种催化对映体选择性的反-羟醛反应 随后的大内酯化反应完成了米亚科利特的全合成。的汇聚性 _旋转路线允许合成结构相关的类似物。该合成还将提供_ 大量的米亚科利特作为一种新的治疗剂和生物制剂的开发 抗肿瘤苔藓他汀类药物的比较研究

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.