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利用铜催化的反应合成氮杂环和氧杂环的新技术。形成的杂环在化学工业中可用作配体和催化剂，在制药工业中可用作生物功能调节剂和生物活性化合物合成的中间体。在大多数反应的产物中存在一个或多个立体中心，这些立体中心在大多数情况下可以预测地形成具有高对映和非对映选择性的立体中心。手性化合物的选择性合成对制药行业产生了影响，使活性得以优化，同时将剂量和副作用降至最低。从催化剂中产生手性而不是化学计量的手性底物是一种有效的做法，它在降低成本的同时大大扩大了底物的范围。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(底物范围宽和提出了几个新反应)和应用(合成商业药物和生物活性天然产物)。起始化合物是稳定的、容易获得的胺、醇和烯烃。该反应方法学通过对反应组分的合理选择，实现了多种烯烃双官能化产物(二氨化、氨化、氨氧化、氨卤化、氢胺化、碳醚化)的多用途立体选择性合成。该计划正在开发的几种催化对映体选择方法是科学界此类技术的第一个也是唯一的例子(例如，第一个也是唯一一个催化对映体选择性烯烃分子内氨氧化、二胺化和氨卤化反应)，从而填补了公认的技术空白。 与公众健康相关：手性有机化合物的有效合成对药物的发现和开发非常重要。本提案中描述的新合成方法的发现和开发将扩大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用利尿剂合成中的应用。

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.