Free energy perturbation and molecular dynamics simulation studies on the enantiomeric discrimination of amines by dimethyldiketopyridino-18-crown-6

Discrimination of chiral amines by dimethyldiketopyridino-18-crown-6 (1) is studied by free energy perturbation (FEP) and molecular dynamics (MD) meth ods. 1 has two (S)-chiral centers and discriminates chiral amines through h ost-guest interactions. The optically active amines in this study are alpha -(1-naphthyl)ethylamine, methylbenzylamine, cyclohexylethylamine, and sec-b utylamine. The trends in binding free energy differences obtained from FEP calculations were in excellent agreement with experimental results obtained in the gas phase. In order to explain the enantioselectivity of the host i n terms of the host-guest interactions at the molecular level, we analyzed the structures generated by 10-ns MD simulations of host-guest complexes. T he suggested chiral discrimination mechanism, the pi-pi interaction and the steric repulsion between the guest and the host, was verified by our MD si mulation analysis.