New Methods for Nitrogen Heterocycle Synthesis

描述(申请人提供)：氮杂环在很大比例的生物活性分子中被发现。能够简明、选择性和高效地从头合成氮杂环的化学方法使科学界能够获得已知的生物活性小分子，并提供了创造具有潜在生物活性的未知化合物的机会，这可能通过药物化学研究来发现。本文介绍了两种新的氮杂环形成反应--分子内氨化反应和烯烃二胺化反应的发现、发展和应用。这些反应是由我们实验室发现的新的铜(II)化学实现的。铜是一种特别有吸引力的过渡金属，用于反应过程，因为它的低成本和相对低的毒性。现代有机化学方法，如不对称合成和过渡金属配体设计，以及微波促进反应等技术，为这些研究提供了便利。对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发展和生物学研究小分子文库的设计。通过这些转化可以获得光学富集型氮杂环，六氢-1H-Benz[f]吲哚、异喹啉、吡咯烷、邻二胺以及潜在的阿朴吗啡和氮杂环类化合物显示了广泛的生物活性，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，在艾滋病、阿尔茨海默病、高血压和疟疾的治疗中很重要。特别是，分子内缩合反应提供了一种简明而独特的方法来获得可能有用的多肽等位体化合物。介绍了光学活性小分子氮杂环的简捷合成新方法的研究和开发。氮杂环在很大比例的生物活性分子中被发现。通过这些转化可获得的光学富集型氮杂环显示了广泛的生物活性，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；3)蛋白酶抑制活性，在艾滋病、阿尔茨海默病、高血压和疟疾的治疗中很重要。

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.