Synthesis of anticancer agents using Prins cyclization

使用 Prins 环化合成抗癌药物

• 批准号: 6865345
• 负责人: SCOTT D. RYCHNOVSKY
• 金额: $ 24.77万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-04 至 2008-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865345
• 关键词: alkenes; antineoplastics; biological products; biotherapeutic agent; chemical synthesis; cyclization; drug design /synthesis /production; enol; lactones; method development; rifabutin; sesquiterpenes

DESCRIPTION (provided by applicant): The goals of this proposal are to develop new reactions based on the Prins cyclization and to apply these new reactions to the synthesis of complex natural products. New methods to be developed include the second generation Mukaiyama aldol Prins (MAP) reaction with unactivated alkenes. A new cascade cyclization reaction between enones and enol ethers has been discovered that will be investigated. The mechanism of the Prins cyclization will be studied, and the role of 2-oxonia Cope rearrangements will be investigated. The surprising axial selective in Prins cyclizations promoted by TMSBr cyclization will be studied both mechanistically and as a practical preparative procedure. Syntheses based on this new methodology include routes to calyxin I, a second-generation synthesis of leucascandrolide A, lasonolide A and kendomycin. Both leucascandrolide A and lasonolide A have shown potent cytotoxicity against human cancer cell lines, and the planned syntheses are more concise and efficient than any yet reported for these important compounds. The work described herein will advance the state of synthetic chemistry and provide new tools for organic chemists. These tools will facilitate the synthesis of many new structures that may be important as new pharmaceutical agents.

描述（由申请人提供）：本提案的目标是开发基于Prins环化的新反应，并将这些新反应应用于合成复杂的天然产物。待开发的新方法包括第二代Mukaiyama aldol Prins（MAP）反应与未活化的烯烃。发现了一种新的烯酮和烯醇醚之间的级联环化反应，并对其进行了研究。将研究Prins环化的机制，并研究2-氧代科普重排的作用。令人惊讶的轴向选择性的Prins环化促进TMSBr环化将研究的机制，并作为一个实际的制备过程。基于这种新方法的合成包括到calyxin I的路线，calyxin I是leucascandrolide A、lasonetrium A和kendomycin的第二代合成。leucascandrolide A和lasoncandrolide A都显示出对人类癌细胞系的有效细胞毒性，并且计划的合成比这些重要化合物的任何报道都更简洁和有效。本文所述的工作将推动合成化学的发展，并为有机化学家提供新的工具。这些工具将促进许多新结构的合成，这些新结构可能作为新的药剂是重要的。