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

• Applicant: Dr. Felix Hartrampf
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2018 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 400324235

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Amir H. Hoveyda