Rhodium(I)-Catalyzed Enantioselective C(sp3)-H Functionalization via Carbene-Induced Asymmetric Intermolecular C-H Insertion†

Main observation and conclusion Transition-metal-catalyzed C-H insertion of metal-carbene represents an excellent and powerful approach for C-H functionalization. However, despite remarkable advances in metal-carbene chemistry, transition metal catalysts that are capable of enantioselective intermolecular carbene C-H insertion are mainly constrained to dirhodium(II) and iridium(III)-based complexes. Herein, we disclose a new version of asymmetric carbene C-H insertion reaction with rhodium(I) catalyst. A highly enantioselective rhodium(I) complex-catalyzed C(sp(3))-H functionalization of 1,4-cyclohexadienes with alpha-aryl-alpha-diazoacetates was successfully developed. By using chiral bicyclo[2.2.2]-octadiene as ligand, rhodium(I)-carbene-induced asymmetric intermolecular C-H insertion proceeds smoothly at room temperature, allowing access to a diverse variety of alpha-aryl-alpha-cyclohexadienyl acetates and gem-diaryl-containing acetates in good yields with good to excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the reaction was highlighted by facile synthesis of a novel cannabinoid CB1 receptor ligand. This method may offer a new opportunity for the development of therapeutically exploitable cannabinoid receptor type ligands in medicinal chemistry.