New Methods for Nitrogen Heterocycle Synthesis

描述（由申请人提供）：氮杂环合成的新方法提出了使用铜催化反应合成氮和氧杂环的新可行技术。形成的杂环可用于在化学工业中用作配体和催化剂，以及在制药工业中用作生物功能调节剂和生物活性化合物合成中的中间体。大多数反应的产物中都存在一个或多个立体中心，并且在大多数情况下，这些立体中心可以以高对映选择性和非对映选择性形成。手性化合物的选择性合成对制药行业产生影响，能够优化活性，同时最大限度地减少剂量和副作用。从催化剂而不是化学计量的手性底物中产生手性是一种有效的做法，可以大大扩展底物范围，同时降低成本。该提案涉及新铜催化反应的优化（反应条件、选择性、催化剂负载）、扩展（宽底物范围和提出的几种新反应）和应用（商业药物和生物活性天然产物的合成）。起始化合物是稳定的、容易获得的胺、醇和烯烃。该反应方法通过明智地选择反应组分，能够实现各种烯烃双官能化产物（二胺化、碳胺化、氨基氧化、氨基卤化、加氢胺化、碳醚化）的多功能立体选择性合成。该项目中开发的几种催化对映选择性方法是科学界此类技术的第一个也是唯一的例子（例如第一个也是唯一的催化对映选择性分子内烯烃氨基氧化、二胺化和氨基卤化反应），从而填补了公认的技术空白。 公共卫生相关性：手性有机化合物的有效合成对于药物发现和开发非常重要。该提案中描述的新合成方法的发现和开发将扩展可用于药物发现的工具。提出了这些方法在抗癌天然产物、抗精神病药物和临床使用的利尿剂的合成中的应用。

DESCRIPTION (provided by applicant): New Methods for Nitrogen Heterocycle Synthesis New enabling technologies for the synthesis of nitrogen and oxygen heterocycles using copper-catalyzed reactions is proposed. The heterocycles formed can be useful for application as ligands and catalysts in the chemical industry and as modulators of biological function and intermediates in the synthesis of bioactive compounds in the pharmaceutical industry. One or more stereocenter is present in the products of most of the reactions and these stereocenters can be predictably formed with high enantio- and diastereoselectivity in most cases. The selective synthesis of chiral compounds impacts the pharmaceutical industry, enabling the optimization of activity while minimizing dosing and side-effects. Originating chirality from catalysts instead of stoichiometric amounts of chiral substrates is an efficient practice that greatly expands substrate scope while reducing cost. This proposal involves the optimization (reaction conditions, selectivity, catalyst loading), expansion (wide substrate scope and several new reactions proposed) and application (the synthesis of commercial drugs and bioactive natural products) of the new copper-catalyzed reactions. The starting compounds are stable, readily available amines, alcohols and alkenes. The reaction methodology enables the versatile stereoselective synthesis of various alkene difunctionalization products (diamination, carboamination, aminooxygenation, aminohalogenation, hydroamination, carboetherification) by judicious choice of reaction components. Several of the catalytic enantioselective methods being developed in this program are the first and only examples of such technology in the scientific community (e.g. the first and only catalytic enantioselective intramolecular alkene aminooxygenation, diamination and aminohalogenation reactions), and thus fill a recognized technology gap. PUBLIC HEALTH RELEVANCE: The efficient synthesis of chiral organic compounds is important to drug discovery and development. The discovery and development of the new synthetic methods described in this proposal will expand the tools available for drug discovery. Application of these methods in the synthesis of an anti-cancer natural product, an antipsychotic medication and a clinically used diuretic are proposed.