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(申请人提供)：提出了一种有效的抗肿瘤海洋天然产物miyakolide的对映选择性合成策略。Miyakolide是从聚纤维海绵属的海绵中分离出来的，它具有许多类似于强大的抗癌苔藓素类化合物的结构特征。Miyakolide不仅是一个有趣的目标，作为一种复杂的天然产物，它的分析也可能提供洞察力，通过与结构相似的生物活性化合物相比，哪些功能部分在抑制肿瘤方面具有重要意义。所提出的合成米亚科里德的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。串联的Ru催化的烯烃-烯烃偶联/钯催化的不对称烯丙基烷基化立体选择性地组装了一个关键的中间体。其中一个更具挑战性的氢化吡喃环是利用独特的钯(11)催化的炔-炔偶联/环化级联反应构建的。通过催化对映体选择性的反-羟醛缩合反应和大内酯反应，完成了米亚科利特的全合成。拟议路线的收敛性质允许合成结构上相关的类似物。该合成还将为其作为一种新的治疗剂的开发提供大量的miyakolide，并用于抗肿瘤bryostins的生物比较研究。