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）：提出了一种对映选择性合成miyakaline的策略，miyakaline是一种有效的抗肿瘤海洋天然产物。Miyakastatin是从Polyfibrospongia属的海绵中分离出来的，并且与有效的抗癌苔藓抑素具有许多相似的结构特征。Miyakaline不仅是一个有趣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哪些功能部分是重要的肿瘤抑制相比，结构相似，生物活性化合物。这条通往miyakaline的路线说明了过渡金属催化的偶联反应如何以原子经济的方法用于构建复杂的天然产物。一个串联的钯催化的烯-炔偶联/钯催化的不对称烯丙基烷基化立体选择性组装的关键中间体。利用独特的钯（II）催化的炔-炔偶联/环化级联来构建更具挑战性的氢吡喃环之一。催化的对映选择性反羟醛缩合反应，然后大环内酯化完成全合成的miyakaltine。所提出的路线的收敛性质允许合成结构相关的类似物。该合成还将提供大量的miyakaline用于其作为新型治疗剂的开发，以及用于与抗肿瘤苔藓抑素的生物学比较研究。