Chiral Bronsted Acid-Catalyzed Enantioselective alpha-Amidoalkylation Reactions: A Joint Experimental and Predictive Study

Enamides with a free NH group have been evaluated as nucleophiles in chiral Bronsted acid-catalyzed enantioselective alpha-amidoalkylation reactions of bicyclic hydroxylactams for the generation of quaternary stereocenters. A quantitative structure-reactivity relationship (QSRR) method has been developed to find a useful tool to rationalize the enantioselectivity in this and related processes and to orient the catalyst choice. This correlative perturbation theory (PT)-QSRR approach has been used to predict the effect of the structure of the substrate, nucleophile, and catalyst, as well as the experimental conditions, on the enantioselectivity. In this way, trends to improve the experimental results could be found without engaging in a long-term empirical investigation.