Synthesis of enantioenriched unprotected amines by an enantioselective copper-catalyzed addition reaction to nitriles: application to natural product and medicinal chemistry

通过对映选择性铜催化的腈加成反应合成对映富集的未保护胺：在天然产物和药物化学中的应用

• 批准号: 400324235
• 负责人: Dr. Felix Hartrampf
• 金额: --
• 依托单位: Catalytic Chemical Synthesis
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/400324235?language=en
• 关键词: Synthesis; enantioenriched; unprotected; amines; enantioselective

Enantioselective catalysis is an essential method in organic synthesis. Dominated in the past by rare and expensive noble metal catalysts based on palladium, platinum, iridium and rhodium, research now increasingly focuses on the cheaper congeners such as iron, nickel and copper. The last years have shown that novel copper catalysts are able to mediate enantioselective multicomponent reactions. This modular approach allows for the rapid and efficient synthesis of molecular complexity.The research project aims for the development of the first enantioselective copper-catalyzed multicomponent reaction that utilizes nitriles as practical reaction partners and nitrogen source. They have numerous advantages over the commonly used imines, such as superior air and moisture stability as well as broad commercial availability. Furthermore, the intermediate ketimines can easily be diversified by simple variation of the reaction conditions: allylic and homoallylic amines should be accessible in a stereoselective fashion, as are highly substituted enones.In the first phase, the reaction conditions will be optimized and the reaction scope mapped. The reaction will also be carried out in an enantioselective fashion after optimization with chiral copper catalysts. All product classes are highly functionalized, hence, a variety of further derivatizations will be undertaken at the different reactive sites to highlight their potential.In the second phase, the methodology will be applied to complex molecule synthesis. The first objective will be epibatidine, the toxin of the poison dart frog and popular synthesis target. Using our methodology, it should be accessed enantioselectively in only five to six synthetic steps via a chiral homoallylic amine.In a second step, an allylic amine will be used to furnish a heterocyclic inhibitor of human neutrophil elastase, which so far is only known in racemic form.The project thus combines the development of a novel and valuable methodology with the prospect of making contributions to the synthesis of medicinally relevant molecules.

对映选择性催化是有机合成中的重要方法。过去，以钯、铂、铱和铑为基础的稀有和昂贵的贵金属催化剂占主导地位，现在的研究越来越多地集中在铁、镍和铜等较便宜的同系物上。近年来，新型铜催化剂能够介导对映选择性的多组分反应。该研究项目旨在开发第一个利用腈作为实际反应伙伴和氮源的对映选择性铜催化多组分反应。与常用的亚胺相比，它们具有许多优点，例如上级空气和水分稳定性以及广泛的商业可用性。此外，中间体酮亚胺可以很容易地多样化，通过简单的反应条件的变化：烯丙基和高烯丙基胺应在立体选择性的方式，高度取代的烯酮。在用手性铜催化剂优化后，该反应也将以对映选择性方式进行。所有产品类别都是高度官能化的，因此，将在不同的反应位点进行各种进一步的衍生化，以突出其潜力。在第二阶段，该方法将应用于复杂分子的合成。第一个目标将是箭毒蛙毒素和流行的合成目标地棘蛙素。使用我们的方法，通过手性高烯丙基胺仅需5 - 6个合成步骤就可以对映选择性地获得。在第二步中，烯丙基胺将用于提供人中性粒细胞弹性蛋白酶的杂环抑制剂，因此，该项目结合了一种新的和有价值的方法学的发展，为合成药用相关的药物做出贡献的前景。分子。

项目成果

Different Strategies for Designing Dual-Catalytic Enantioselective Processes: From Fully Cooperative to Non-cooperative Systems.

• DOI: 10.1021/jacs.9b05464
• 发表时间: 2019-11
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Filippo Romiti;Juan del Pozo;Paulo H S Paioti;Stella A. Gonsales;Xinghan Li;Felix W W Hartrampf-Felix-W-W-Hartrampf-5045755;A. Hoveyda