Silver-Catalyzed Asymmetric Aldol Reaction of Isocyanoacetic Acid Derivatives Enabled by Cooperative Participation of Classical and Nonclassical Hydrogen Bonds

The silver-catalyzed asymmetric aldol reaction of isocyanoacetic acid derivatives with aldehydes has been developed by employing a chiral prolinol-phosphine as a hydrogen-bond-donating P,N,O ligand. DFT calculations indicated that the reaction proceeds in a stepwise manner, involving C-C bond forming carbonyl addition and subsequent enantioselectivity-determining oxazoline ring formation. An O-H center dot center dot center dot O/sp(3) -C-H center dot center dot center dot O two-point hydrogen bond donated by the prolinol moiety of the ligand activates the aldehyde in the C-C bond formation step and facilitates the subsequent cyclization under stereocontrol by the catalyst. The calculations further suggest that additional nonclassical C-H center dot center dot center dot O hydrogen bonds as well as London dispersion interactions may also participate synergistically in the stereocontrol.

Automated summary

The silver-catalyzed asymmetric aldol reaction of isocyanoacetic acid derivatives with aldehydes has been developed using a chiral prolinol-phosphine ligand as a hydrogen-bond-donating P,N,O ligand. DFT calculations revealed a stepwise reaction mechanism, involving C-C bond formation and subsequent enantioselectivity-determining ring formation. The prolinol moiety of the ligand activates the aldehyde through a two-point hydrogen bond, facilitating the stereocontrolled cyclization. Additional nonclassical hydrogen bonds and London dispersion interactions may also contribute to stereocontrol.