Chiral NHC Ligands for the Copper-Catalyzed Asymmetric Conjugate Addition of Grignard Reagents

In this paper, we disclose our recent advances in the copper‐catalyzed enantioselective conjugate addition of Grignard reagents to 3‐substituted cyclic enones. Several new N‐heterocyclic carbene (NHC) ligands have been synthesized in high yields by starting from inexpensive materials. These new NHCs were evaluated as ligands for copper, for the Michaeladdition of ethylmagnesium bromide leading to chiral 3,3‐disubstituted cyclohexanones (up to 93 % ee). The best ligand was then engaged in conjugate additions of various Grignard reagents, allowing the formation of quaternary centers with high levels of regio‐ and enantioselectivity with only 0.75 mol‐% catalyst loading. The reaction is also robust to scale‐up. The addition of ethylmagnesium bromide for the construction of a 3,3‐disubstituted cyclopentanone (up to 86 % ee), a synthetically useful chiral synthon, is noteworthy. A tentative mechanism for the catalytic cycle is also discussed. Stepping up selectivity! New ligands were easily prepared by starting from cheap chiral materials. Thus, a new class of ligands and new conditions resulted in high product ee values in the copper‐catalyzed conjugate addition of Grignard reagents to cyclic enones. Diverse substituted quaternary centers were formed in a very regioselective and side‐reaction‐free process. This was achieved with only 0.75 mol‐% catalyst loading.