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。过去主要以基于钯、铂、铱和铑的稀有且昂贵的贵金属催化剂为主，现在的研究越来越集中在铁、镍和铜等更便宜的同系物上。过去几年的研究表明，新型铜催化剂能够介导对映选择性多组分反应。这种模块化方法可以快速有效地合成复杂的分子。该研究项目旨在开发第一个对映选择性铜催化多组分反应，该反应利用腈作为实际反应伙伴和氮源。与常用的亚胺相比，它们具有许多优点，例如卓越的空气和湿度稳定性以及广泛的商业可用性。此外，中间体酮亚胺可以通过简单改变反应条件轻松实现多样化：烯丙胺和高烯丙胺应以立体选择性方式获得，高度取代的烯酮也是如此。在第一阶段，将优化反应条件和反应范围映射。在使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。所有产品类别都高度功能化，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的分子合成。第一个目标是皮巴替丁，箭毒蛙的毒素，也是流行的合成目标。使用我们的方法，只需五到六个合成步骤即可通过手性高烯丙胺对映选择性地获得它。在第二步中，烯丙胺将用于提供人中性粒细胞弹性蛋白酶的杂环抑制剂，迄今为止仅在因此，该项目将开发一种新颖且有价值的方法与为医学相关分子的合成做出贡献的前景结合起来。

项目成果

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

设计双催化对映选择性过程的不同策略：从完全合作系统到非合作系统。

• DOI: 10.1021/jacs.9b05464
• 发表时间: 2019-11-01
• 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;A. Hoveyda
• 通讯作者: A. Hoveyda