New Methods for Nitrogen Heterocycle Synthesis

描述（由申请人提供）：提出了利用铜催化反应合成氮和氧杂环的新技术。形成的杂环在化学工业中可作为配体和催化剂，在制药工业中可作为生物功能调节剂和合成生物活性化合物的中间体。大多数反应的产物中存在一个或多个立体中心，在大多数情况下，这些立体中心的形成具有高的对映选择性和非对映选择性。手性化合物的选择性合成影响着制药工业，使活性优化，同时最小化剂量和副作用。从催化剂中产生手性，而不是从化学计量量的手性底物中产生手性，这是一种有效的做法，大大扩大了底物的范围，同时降低了成本。本提案涉及铜催化新反应的优化（反应条件、选择性、催化剂负载）、扩展（广泛的底物范围和几种新反应的提出）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、容易得到的胺、醇和烯烃。该反应方法通过明智地选择反应组分，使各种烯烃双官能化产物（二胺化、碳胺化、氨基氧合、氨基卤化、氢胺化、碳醚化）的多用途立体选择性合成成为可能。在这个项目中开发的一些催化对映选择性方法是科学界第一个也是唯一的这种技术的例子（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合反应、二化反应和氨基卤化反应），从而填补了公认的技术空白。

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.