New Methods for Nitrogen Heterocycle Synthesis

描述（由申请人提供）：在大部分生物活性分子中发现了氮杂环。化学方法，使氮杂环的简洁，选择性和有效的从头合成授权科学界获得已知的生物活性的小分子，以及提供一个机会，以创造未知的化合物具有潜在的生物活性，这可能是通过药物化学研究发现。介绍了两种新的氮杂环生成反应--烯烃的分子内碳胺化反应和二胺化反应的发现、发展和应用。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。铜是一种特别有吸引力的过渡金属，由于其低成本和相对低的毒性而用于反应过程。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。这些方法的全面机理理解和综合应用可能会启发其他新方法的开发和小分子库的设计用于生物学研究。通过这些转化可获得的光学富集的氮杂环、六氢-1H-苯并[f]吲哚、异喹啉、吡咯烷、邻二胺和潜在的阿朴啡和氮杂卓显示出广泛的生物活性，例如1）多巴胺拮抗剂，在情绪调节病症如焦虑和抑郁中是重要的，2）抗癌活性和3）蛋白酶抑制活性，在治疗AIDS中是重要的，老年痴呆症、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方法来获得可能用作肽电子等排体的化合物。综述了近年来光学活性小分子氮杂环化合物的合成新方法的研究进展。氮杂环存在于大部分生物活性分子中。通过这些转化可获得的光学富集的氮杂环显示出广泛的生物活性，例如1）多巴胺拮抗剂，在情绪调节病症如焦虑和抑郁中是重要的，2）抗癌活性和3）蛋白酶抑制活性，在治疗AIDS、阿尔茨海默病、高血压和疟疾中是重要的。

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.