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bielschowskysin是在2004年初从柳珊瑚Pseudopterogorgia kallos中分离出来的，据报道在NCI的抗肿瘤筛选中表现出强烈和特异性的体外细胞毒性以及有效的抗疟疾活性。在结构上，bielschowskysin的三环[9，3，0，0]十四烷骨架代表了独特的二萜结构。比尔肖夫斯基素的前所未有的结构与有效的抗癌和抗疟疾活性相结合，使这种二萜成为化学合成的一个非常有吸引力的目标。其合成策略的重点包括通过分子内光化学[2+2]环加成反应和分子内Nozaki-Hiyama-Kishi环化反应构建三环核心环系统，从而构建bielschowskysin的九元环。成功地全合成bielschowskysin将建立绝对构型，为生物学测试提供额外的材料，并允许获得类似物和中间体，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物的构效关系。