Reverse-docking study of the organocatalyzed asymmetric Strecker hydrocyanation of aldimines and ketimines

A methodology for reverse-docking flexible organocatalysts to rigid transition state models of catalyst-free asymmetric reactions has been developed. The investigation of Jacobsenʹs chiral thiourea-based organocatalyst for the hydrocyanation of aldimines and ketimines (Strecker reaction) via reverse-docking is described. Results from reverse-docking Jacobsenʹs organocatalyst to both enantiomers of six Strecker TS-models (i.e., rigid transition state models of the catalyst-free asymmetric reaction) indicate a clear energetic preference for binding the organocatalyst to the R-enantiomer TS-model, which is in agreement with experimental results. The most favorable docking poses reveal structural features consistent with principles of molecular recognition, catalysis, and NMR data. These poses may represent simplified geometric models of the transition state for the catalyzed reaction.