Toward a computational tool predicting the stereochemical outcome of asymmetric reactions: development of the molecular mechanics-based program ACE and application to asymmetric epoxidation reactions

The development and application of ACE, a program that predicts the stereochemical outcome of asymmetric reactions is presented. As major implementations, ACE includes a genetic algorithm to carry out an efficient global conformational search combined with a conjugate gradient minimization routine for local optimization and a corner flap algorithm to search ring conformations. Further improvements have been made that enable ACE to generate Boltzmann populations of conformations, to investigate highly asynchronous reactions, to compute fluctuating partial atomic charges and solvation energy and to automatically construct reactants and products from libraries of catalysts and substrates. Validation on previously investigated reactions (asymmetric Diels Alder cycloadditions and organocatalyzed aldol reactions) followed by application to a number of alkene epoxidation reactions and a comparative study of DFT-derived and ACE-derived predictions demonstrate the accuracy and usefulness of ACE in the context of asymmetric catalyst design.