New Methods for Nitrogen Heterocycle Synthesis

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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 isosters. 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.