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

对映体选择性催化是有机合成中必不可少的方法。过去，以钯、铂、铱和铑为基础的稀有而昂贵的贵金属催化剂占据主导地位，现在的研究越来越多地集中在铁、镍和铜等更便宜的同系物上。近年来的研究表明，新型铜催化剂能够催化多组分的对映选择性反应。这种模块化的方法可以快速有效地合成分子络合物。研究项目旨在开发第一个以腈为实际反应伙伴和氮源的铜催化的对映选择性多组分反应。与常用的亚胺相比，它们具有许多优势，例如优越的空气和湿度稳定性以及广泛的商业供应。此外，通过简单地改变反应条件，中间体酮胺可以很容易地多样化：烯丙基胺和高烯丙基胺应该以立体选择性的方式获得，就像高度取代的烯类一样。在第一阶段，将优化反应条件并绘制反应范围。在手性铜催化剂的优化后，该反应也将以对映选择性的方式进行。所有的产品类都是高度官能化的，因此，各种进一步的衍生化将在不同的反应部位进行，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。第一个目标将是表巴替丁，毒镖蛙的毒素和广受欢迎的合成目标。使用我们的方法，通过手性高烯丙基胺只需五到六个合成步骤就可以对映体选择性地获得它。在第二步，烯丙基胺将被用来提供迄今已知的外消旋形式的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有价值的方法的开发，并展望了对合成医学相关分子做出贡献的前景。

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.