DFT study on Rh(II)/guanidine-catalyzed asymmetric N-H bond insertion of benzophenone imines

The enantioselective carbene insertion into the N-H bond of N-sp²-hybridized imines has proven to be an efficient method for synthesizing optically active N-unprotected amino acids. In this work, the mechanism of Rh₂(esp)₂/chiral guanidine-catalyzed asymmetric N-H bond insertion of benzophenone imine with α-diazoester was explored using DFT calculations with the B3LYP-D3(BJ) functional. The reaction proceeded through the formation of a C-N bond, followed by an enantioselective H-shift. Due to the high activation barriers in the generation of carbene species and C-H bond construction as well, the noncatalytic reaction could not occur under mild conditions. In Rh(II)/guanidine co-catalysis, the Rh(II) catalyst promoted the denitrification of α-diazoester and the generation of an enol/ylide intermediate via a highly active Rh-carbene species. The in situ-formed guanidinium acted as a chiral proton shuttle, creating a hydrogen bonding network that enabled stereo-determinant protonation. In the chiral-controlling H-shift process, the CHPh₂ group, Cy group, and chiral skeleton were identified as key structural elements governing the chiral induction of the guanidine catalyst. Moreover, the difference in energy (ΔΔE) was mainly caused by the difference in activation strain (ΔΔE_strain) during the formation of TSs along the two competing pathways. The observed "enantiodivergent phenomenon" in the experiment was attributed to the steric repulsion between the Cy group and the amide moiety in the guanidine catalyst, along with the substituent group at the prochiral carbon of the enolate ion, leading to stereoinversion of the product.