Enantioselective Total Synthesis of Miyakolide

Miyakolide的对映选择性全合成

• 批准号: 6834658
• 负责人: Brandon Lee Ashfeld
• 金额: $ 4.11万
• 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 2006-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6834658
• 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）：提出了有效的抗肿瘤海洋天然产物的宫颈对照合成的策略。从宫烷属从多纤维化属的海洋海绵中分离出来，并具有类似于有效的抗癌bryostatins的许多结构特征。 Miyakolide不仅是一种复杂的天然产物的吸引人目标，而且与结构相似的生物学活性化合物相比，其功能部分在肿瘤抑制中很重要。提出的通向宫甲酰胺的途径说明了如何使用过渡金属催化的耦合反应用于以原子经济方法构建复杂的天然产物。串联的氟苯烷烷烃偶联/钯催化的不对称烯丙基烷基化立体选择会组装一个钥匙中间体。使用独特的钯（LL） - 催化的炔烃耦合/环化级联层构建了更具挑战性的水胶环之一。催化对映选择性抗醛醇反应，然后进行大分钟化完成了宫烷酸酯的总合成。所提出的途径的收敛性允许合成结构相关的类似物。该合成还将提供大量的宫藻醇，以作为一种新型治疗剂的发展，并为抗肿瘤性乳突蛋白的生物学比较研究。