Total Synthesis of Bielschowskysin

Bielschowskysin 的全合成

• 批准号: 6999898
• 负责人: ADAM Kenneth CHARNLEY
• 金额: $ 4.21万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-23 至 2007-01-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999898
• 关键词: analog; animal extract; antimalarial agents; antineoplastics; biotechnology; biotherapeutic agent; chemical structure function; chemical synthesis; coral; diterpenes; drug design /synthesis /production; photochemistry; postdoctoral investigator; stereochemistry

DESCRIPTION (provided by applicant): The highly functionalized diterpene bielschowskysin was isolated in early 2004 from the gorgonian coral Pseudopterogorgia kallos and is reported to exhibit strong and specific in vitro cytotoxicity in the NCI's antitumor screen as well as potent antimalarial activity. Structurally, the tricyclo[9,3,0,0]tetradecane skeleton of bielschowskysin represents a unique diterpene architecture. The unprecedented structure of bielschowskysin combined with the potent anticancer and antimalarial activity makes this diterpene a highly attractive target for chemical synthesis. Highlights of the synthetic strategy include construction the tricyclic core ring system through the use of a cyclic silyl enol ether in an intramolecular photochemical [2+2] cycloaddition, and an intramolecular Nozaki-Hiyama-Kishi cyclization to construct the nine-membered ring of bielschowskysin. Successful total synthesis of bielschowskysin will establish the absolute configuration, provide additional material for biological testing, and allow access to analogs and intermediates, not readily available from the natural material, to evaluate the structure activity relationship of this fascinating bioactive natural product.

描述(由申请人提供)： 高度功能化的二萜bielschowsky sin于2004年初从柳珊瑚Pseudopterogorgia Kolos中分离得到，据报道在NCI的抗肿瘤筛选中显示出强烈和特异的体外细胞毒性以及强大的抗疟疾活性。在结构上，Bielschowsky sin的三环[9，3，0，0]十四烷骨架代表了一种独特的二萜结构。Bielschowsky sin前所未有的结构与强大的抗癌和抗疟疾活性相结合，使这种二萜成为化学合成的极具吸引力的目标。该合成策略的亮点包括通过在分子内光化学[2+2]环加成反应中使用环硅烯醇醚来构建三环核心环体系，以及通过分子内Nozaki-Hiyama-Kishi环化来构建Bielschowsky sin的九元环。Bielschowsky sin的成功全合成将建立绝对构型，为生物测试提供额外的材料，并允许获得天然材料中不易获得的类似物和中间体，以评估这一迷人的生物活性天然产品的构效关系。