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）： 2004年初，从Gorgonian珊瑚pseudopterogorgia kallos中分离出高度功能化的双萜生物素蛋白，据报道，在NCI的抗肿瘤筛查中表现出强，特异性的体外细胞毒性，并具有有效的抗肿瘤活性。从结构上讲，生物琴基辛的三轮烷骨架代表了独特的二萜架构。 Bielschowskysin的前所未有的结构结合了有效的抗癌和抗疟疾活性，使该二萜成为化学合成的高度吸引力的靶标。合成策略的亮点包括通过在分子内光化学[2+2]环载层中使用环状链硅烷基烯和分子内的Nozaki-Hiyama-kishi环化来构建尼尼·贝尔·贝尔塞尔·贝尔赛夫斯基蛋白的尼丁环。成功的Bielschowskysin的成功总合成将建立绝对构型，为生物学测试提供其他材料，并允许使用类似物和中间体（不容易从天然材料中获得），以评估这种迷人的生物活性天然产品的结构活动关系。