Molecular mechanics calculations as predictors of enantioselectivity for chiral nucleophile catalyzed reactions

We present molecular mechanics (MM) calculations as models of activated complexes for the β-lactam forming [2+2] cycloaddition between imino ester and the zwitterionic intermediates derived from ketenes and various chiral nucleophilic catalysts. Our method employs the use of Monte Carlo conformational searches utilizing the MMFF force field contained within the Macromodel program. These models accurately predict the sense of stereochemical induction observed experimentally. Also, the predicted energetic differences for minima leading to (R) or (S)-derived ketene facial selectivity correlate in a general sense with the magnitude of the enantioselectivity. This work establishes that our approach represents a viable method for the design of new nucleophilic catalysts a priori using MM calculations.