NEW CATALYTIC AND ENANTIOSELECTIVE REACTIONS

新的催化和对映选择性反应

• 批准号: 2561838
• 负责人: AMIR H HOVEYDA
• 金额: $ 22.82万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2561838
• 关键词: aminoacid; catalyst; chemical addition; chemical synthesis; cyanides; epoxides; imines; ligands; stereochemistry

The primary goal of the proposed research project is to develop two new asymmetric catalytic carbon-carbon bond forming processes. The overall objective is to increase the opportunities for efficient and enantioselective construction of molecules important to human healthcare. Reactions that are catalytic, that proceed with outstanding selectivity, that are efficient and use inexpensive materials can dramatically diminish the time span between the conception of a therapeutic candidate and its large scale preparation and marketing. In this regard, the utility of the new asymmetric catalytic transformations will be highlighted with efficient and selective synthesis of several medicinally important agents. The first reaction to be explored is the asymmetric addition of trimethylsilylcyanide to epoxides. Preliminary results have shown the feasibility of this new transformation. Subsequent studies will optimize the process through convenient yet systematic modifications to the peptidyl ligand structure of the novel catalytic system; developing a better mechanistic understanding of the reaction, and applying this transformation toward the synthesis of various anti-HIV agents. Similarly, the addition of trimethylsilylcyanide to imines (Strecker reaction) will be developed into a general catalytic asymmetric transformation. Again the scope of the reaction will be delineated with catalysts containing metals coordinated to peptidic ligands. Reaction mechanism will be probed and applications toward important molecules will be demonstrated. Both of the reactions to be developed will employ Lewis acidic metals that are modified with chiral peptidyl ligands as catalysts. Of particular significance is the speed at which the new catalysts can be prepared and optimized. This unique and useful feature is the direct result of using amino acids as the chiral building blocks of the ligand system. Since amino acids are readily available and peptide synthesis has been worked out in both solution and solid phase, simultaneous preparation of multiple ligand structures is relatively straightforward. The large number of ligands that can be prepared and screened for both reactivity and selectivity in a systematic manner allows for the rapid selection of an optimal catalytic system.

拟议研究项目的主要目标是开发两种新的 不对称催化碳-碳键形成过程。 整体 目标是增加高效、高效的机会 对人类重要分子的对映选择性构建 卫生保健。 具有催化作用且进展顺利的反应 选择性、高效且使用廉价材料可以 大大缩短了受孕之间的时间跨度 候选治疗药物及其大规模制备和营销。 在这方面，新型不对称催化的效用 转型将突出高效、有选择性 几种重要药物的合成。 要探索的第一个反应是不对称加成 三甲基甲硅烷基氰化物转化为环氧化物。 初步结果表明 这一新转变的可行性。 后续研究将 通过方便而系统的修改来优化流程 新型催化体系的肽基配体结构；发展 对反应的机理有更好的理解，并应用它 转向合成各种抗HIV药物。 类似地，将三甲基甲硅烷基氰化物加成到亚胺上（Strecker 反应）将发展成通用的催化不对称反应 转变。 再次，反应范围将被描述为 含有与肽配体配位的金属的催化剂。 反应 将探讨其机制并在重要分子中应用 将被证明。 两个待开发的反应都将采用路易斯酸性金属 用手性肽基配体作为催化剂进行修饰。 的 特别重要的是新催化剂的速度 准备并优化。 这个独特而有用的功能是直接 使用氨基酸作为配体的手性构件的结果 系统。 由于氨基酸很容易获得并且肽合成 已在溶液和固相中同时进行 多个配体结构的制备相对简单。 可以制备和筛选大量配体 以系统的方式进行反应性和选择性，可以快速 选择最佳的催化体系。