New Methods for Nitrogen Heterocycle Synthesis

氮杂环合成新方法

• 批准号: 7135231
• 负责人: Sherry R Chemler
• 金额: $ 26.92万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135231
• 关键词: alkenes; amination; chemical registry /resource; chemical synthesis; combinatorial chemistry; copper; diamines; drug discovery /isolation; heavy metals; indoles; isoquinolines; ligands; method development; microwave radiation; nitrogenous heterocyclic compound; oligopeptides; pyrrolidines; small molecule

DESCRIPTION (provided by applicant): Nitrogen heterocycles are found in a large proportion of biologically active molecules. Chemical methods that enable the concise, selective and efficient de novo synthesis of nitrogen heterocycles empower the scientific community to gain access to known biologically active small molecules as well as provide an opportunity to create as yet unknown compounds with potential biological activity, which may be discovered through medicinal chemistry studies. The discovery, development and application of two new nitrogen heterocycle forming reactions, the intramolecular carboamination and diamination of olefins, are presented in this proposal. These reactions are enabled by novel copper(ll) chemistry discovered in our labs. Copper is an especially attractive transition metal to use in reaction processes due to its low cost and relatively low toxicity. Modern organic chemistry methods such as asymmetric synthesis and transition metal ligand design as well as technologies such as microwave reaction promotion are used to facilitate these studies. The full mechanistic understanding and synthetic application of these methods may inspire the development of other new methods and the design of small molecule libraries for biological studies. The optically enriched nitrogen heterocycles accessible through these transformations, hexahydro-1 H-benz[f]indoles, isoquinolines, pyrrolidines, vicinal diamines and potentially aporphines and azepines demonstrate a broad range of biological activity such as 1) dopamine antagonists, important in mood regulation conditions such as anxiety and depression, 2) anticancer activity and 3) protease inhibitory activity, important in the treatment of AIDS, Alzheimer's disease, hypertension and Malaria. In particular, the intramolecular diamination reaction provides a concise and unique access to compounds that may be useful as peptide isosteres. The study and development of novel methods for the concise synthesis of optically active small molecule nitrogen heterocycles is presented. Nitrogen heterocycles are found in a large proportion of biologically active molecules. The optically enriched nitrogen heterocycles accessible through these transformations demonstrate a broad range of biological activity such as 1) dopamine antagonists, important in mood regulation conditions such as anxiety and depression, 2) anticancer activity and 3) protease inhibitory activity, important in the treatment of AIDS, Alzheimer's disease, hypertension and Malaria.

描述（由申请人提供）：氮杂环存在于大部分生物活性分子中。化学方法能够简洁、选择性和高效地从头合成氮杂环，使科学界能够获得已知的生物活性小分子，并提供创造具有潜在生物活性的未知化合物的机会，这些化合物可能会被发现通过药物化学研究。该提案介绍了两种新的氮杂环形成反应，即烯烃的分子内碳胺化和二胺化反应的发现、开发和应用。这些反应是由我们实验室发现的新型铜（II）化学物质实现的。由于其低成本和相对较低的毒性，铜是一种在反应过程中特别有吸引力的过渡金属。现代有机化学方法如不对称合成和过渡金属配体设计以及微波反应促进等技术被用来促进这些研究。这些方法的完整机制理解和综合应用可能会激发其他新方法的开发和用于生物学研究的小分子库的设计。通过这些转化可得到光学富集的氮杂环、六氢-1H-苯并[f]吲哚、异喹啉、吡咯烷、邻位二胺以及潜在的阿朴啡和氮杂卓，表现出广泛的生物活性，例如1)多巴胺拮抗剂，对情绪调节很重要焦虑和抑郁等病症，2) 抗癌活性和 3) 蛋白酶抑制活性，对治疗艾滋病、阿尔茨海默病很重要疾病、高血压和疟疾。特别是，分子内二胺化反应提供了一种简洁而独特的途径来获得可用作肽电子等排体的化合物。介绍了光学活性小分子氮杂环的简洁合成新方法的研究和开发。氮杂环存在于大部分生物活性分子中。通过这些转化获得的光学富集氮杂环表现出广泛的生物活性，例如 1) 多巴胺拮抗剂，在焦虑和抑郁等情绪调节条件下很重要，2) 抗癌活性和 3) 蛋白酶抑制活性，在治疗艾滋病、阿尔茨海默病、高血压和疟疾。