Enantioselective synthesis of novel C1-symmetric N-heterocyclic carbene precursors

As organocatalysts and ligands, N-heterocyclic carbenes are pivotal in asymmetric catalysis, yet Type III C1-symmetric chiral N-heterocyclic carbenes remain underexplored despite their potential for superior stereocontrol. Here, we develop a family of C1-symmetric chiral N-heterocyclic carbene precursors based on the 1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline scaffold in high yields with excellent stereoselectivities (up to 92% yield, >20:1 dr, 99% ee). The synthesis was accomplished through a silver-catalyzed asymmetric [3 + 2] cycloaddition of isocyanoacetates with cyclic azomethine ylides, followed by direct alkylation of the cycloadducts without intermediate isolation. A mechanistic model consistent with experimental observations has also been proposed. This one-pot, two-step protocol is operationally simple, using a concise synthetic route with air- and moisture-stable catalysis and showing high functional group tolerance, with multiple modifiable sites and structural versatility. The utility of these synthesized dihydroimidazolium salts as precursors to chiral N-heterocyclic carbene ligands has been experimentally validated in the Cu-catalyzed asymmetric conjugate borylation of α,β-unsaturated esters followed by oxidation. N-heterocyclic carbenes (NHCs) are pivotal in asymmetric catalysis yet Type III C1-symmetric chiral NHCs remain underexplored despite their potential for superior stereocontrol. Here, the authors develop a family of C1-symmetric chiral compounds based on the 1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline scaffold and demonstrate their utility as precursors to chiral NHC ligands.