Enantioselective Total Synthesis of Miyakolide

Miyakolide的对映选择性全合成

• 批准号: 6969905
• 负责人: Brandon Lee Ashfeld
• 金额: $ 4.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/6969905
• 关键词: Porifera; alkenes; alkylation; alkynes; antineoplastics; aquatic organism; biological products; biotechnology; biotherapeutic agent; bryostatin; catalyst; chemical synthesis; cyclization; drug design /synthesis /production; palladium; postdoctoral investigator; stereochemistry

DESCRIPTION (provided by applicant): 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 reaction followed by macrolactonization completes the total synthesis of miyakolide. The convergent nature of the proposed route allows for the synthesis of structurally related analogs. The synthesis will also provide significant quantities of miyakolide for its development as a novel therapeutic agent, and for biological comparison studies to the anti-neoplastic bryostatins.

描述（由申请人提供）：提出了一种有效抗肿瘤的海洋天然产物miyakolide的对映选择性合成策略。Miyakolide是从多纤维海绵属的海绵中分离出来的，具有与强效抗癌苔藓抑素相似的许多结构特征。宫素内酯不仅作为一种复杂的天然产物是一个有趣的靶点，而且通过与结构相似的生物活性化合物进行比较，它的分析也可以提供对肿瘤抑制中哪些功能部分是重要的见解。提出的通往宫酰胺的途径说明了如何利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。钌催化的烯-炔串联偶联/钯催化的不对称烯丙基烷基化反应立体选择性地组装了一个关键中间体。其中一个更具挑战性的氢吡喃环是利用独特的钯（ll）催化炔-炔偶联/环化级联构建的。一个催化的对映选择性抗醛醇反应，然后进行大内酯化反应，完成了宫烷内酯的全合成。所提出的路线的收敛性质允许合成结构相关的类似物。该合成还将为其作为一种新型治疗药物的开发以及与抗肿瘤苔藓虫抑制素的生物学比较研究提供大量的宫酰胺内酯。