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

对映选择性催化是有机合成的重要方法。过去，钯、铂、铱和铑等稀有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、镍和铜等更便宜的同类金属上。近年来研究表明，新型铜催化剂能够介导对映选择性多组分反应。这种模块化的方法允许分子复杂性的快速和有效的合成。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，例如优越的空气和湿度稳定性以及广泛的商业可用性。此外，中间体酮胺可以很容易地通过简单的反应条件变化而多样化：烯丙基胺和均烯丙胺应该以立体选择的方式可获得，正如高度取代的烯酮一样。第一阶段对反应条件进行优化，绘制反应范围。手性铜催化剂优化后，反应也将以对映选择性方式进行。所有的产品类别都是高度功能化的，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。第一个目标将是依比替丁，毒镖蛙的毒素和常用的合成目标。使用我们的方法，通过手性同丙烯基胺，只需5到6个合成步骤就可以获得对映体选择性。在第二步中，烯丙基胺将用于提供人类中性粒细胞弹性酶的杂环抑制剂，迄今为止仅以外消旋形式已知。因此，该项目结合了一种新颖而有价值的方法的发展，并有望为医学相关分子的合成做出贡献。

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.