Diastereomer Configurations from Joint Experimental–Computational Analysis

The potential of the approach combining nuclear magnetic resonance (NMR) spectroscopy, relaxed grid search (RGS), molecular dynamics (MD) simulations, and quantum mechanical (QM) calculations for the determination of diastereomer configurations is demonstrated using four diastereomers of a trisubstituted epoxide. Since the change in configuration of the chiral center is expected to change the distribution of conformer populations (including those of side-chain rotamers), changes in NMR parameters [chemical shifts, <i>J</i> couplings, and nuclear Overhauser effects (NOEs)] are expected. The method therefore relies on (1) identification of possible conformations in each diastereomer using relaxed grid search analysis and MD simulations; (2) geometry optimizations of conformers selected from step (1), followed by calculations of their relative energies (populations) using QM methods; (3) calculations of averaged NMR parameters using QM methods; (4) matching calculated and experimental values of NMR parameters of diastereomers. The diastereomer configurations are considered resolved, if three NMR parameters different in nature, chemical shifts, <i>J</i> couplings, and NOEs, are in agreement. A further advantage of this method is that full structural and dynamics characterization of each of the diastereomers is achieved based on the joint analysis of experimental and computational data