Insights into Cu(I)-Catalyzed Decarboxylation of Propargylic Cyclic Carbonates with Amines: Origins of Regioselectivity and Enantioselectivity

Chiral α-functionalized α-amino ketones are sought-after compounds for drug development; however, their acyclic enantioselective synthesis with amines as nucleophiles remains challenging. The catalytic decarboxylation of propargylic cyclic carbonates through metal-allenylidene intermediates has proven to be an efficient route to chiral quaternary centers, but its enantioselective mechanisms require clarification. Herein, we computationally investigate the Cu(I)-catalyzed decarboxylation of propargyl cyclic carbonates with aniline [Guo, W. <i>J. Am. Chem. Soc.</i> 2021, 143, 7629-7763]. The calculation results elucidate the mechanistic details of the reaction and reveal that enantioselectivity stems from the distinct noncovalent interactions in the (<i>R</i>)- and (<i>S</i>)- transition states, while regioselectivity arises from the lower steric hindrance for aniline attack at C5 versus C1 atom in the zwitterionic metal-allenylidene intermediate. IGMH analysis further validates the enantiocontrol. The theoretical results offer insights into the mechanisms of Cu(I)-catalyzed decarboxylation of propargyl cyclic carbonates with amines as nucleophiles, advancing the understanding of propargylic amination and aiding the development of this research field.