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的可行技术。所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的调节剂和生物活性化合物合成中的中间体。在大多数反应的产物中存在一个或多个立构中心，并且这些立构中心在大多数情况下可以以高的对映体和非对映体选择性可预测地形成。手性化合物的选择性合成影响了制药行业，使活性最优化，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量的手性底物中产生手性是一种有效的实践，可以极大地扩大底物范围，同时降低成本。这一建议涉及铜催化新反应的优化（反应条件、选择性、催化剂负载量）、扩展（广泛的底物范围和提出的几个新反应）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。该反应方法能够通过明智地选择反应组分来实现各种烯烃双官能化产物（二胺化、碳胺化、氨基氧合、氨基卤化、加氢胺化、碳醚化）的通用立体选择性合成。该计划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），因此填补了公认的技术空白。 公共卫生相关性： 手性有机化合物的高效合成对于药物的发现和开发具有重要意义。本提案中描述的新合成方法的发现和开发将扩大药物发现的可用工具。这些方法在合成抗癌天然产物，抗精神病药物和临床使用的利尿剂中的应用。

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.