Tunable Thiazolium\nCarbenes for Enantioselective Radical\nThree-Component Dicarbofunctionalizations

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