Tunable Thiazolium Carbenes for Enantioselective Radical Three-Component Dicarbofunctionalizations

Asymmetric <i>N</i>-heterocyclic carbene (NHC) organocatalysis is a cornerstone of synthetic organic chemistry. The emerging concept of single-electron NHC catalysis broadened the scope of C-C bond-forming reactions, facilitating the synthesis of a variety of attractive racemic compounds. However, the development of effective and selective chiral NHC catalysts for asymmetric radical-mediated reactions has been challenging. In this report, we introduce a family of highly tunable chiral thiazolium carbenes with three distinct positions for broad electronic and steric modulation featuring bulky chiral flanking groups. We demonstrate the catalytic efficacy of these chiral carbenes in an enantioselective SET-type three-component acyl-difluoroalkylation of olefins using a broad range of aldehydes and difluoroalkyl bromides. This method provides straightforward access to a diverse set of β-difluoroalkylated α-chiral ketones (65 examples) with an up to 87% yield and excellent enantioselectivities of up to >99:1 er. The utility of this methodology is further outlined by enantio- and diastereoselective late-stage modifications of pharmaceutically relevant compounds and selective twofold orthogonal acyl-difluoroalkylations of linchpin reagents.