Enhanced Sampling Simulation Reveals How Solvent Influences Chirogenesis of the Intra-Molecular Diels-Alder Reaction

The timescale involved in chemical reactions is quite often beyond that of normal molecular dynamics simulations. Here, we combine metadynamics with selective integrated tempering sampling to simulate an intra-molecular Diels-Alder reaction in explicit solvents. Based on a one-dimensional collective variable obtained from harmonic linear discriminant analysis, four chiral isomers of products were observed in the simulation. Analyses of reactive trajectories showed that this reaction follows a concerted mechanism in all four solvents. In addition, the hydrogen bond between the reactant and water solvent plays an important role in the water-accelerated reaction mechanism. The dynamics of chirality formation varies significantly with solvents. The chirality of products forms significantly before the transition state, especially in ionic liquid.