When not to rely on Boltzmann populations. Automated CASE-3D structure elucidation of hyacinthacines through chemical shift differences.

An Akaike Information Criterion (AIC) procedure (CASE-3D) has been successfully applied to the NMR based configurational assignment of reported hyacinthacines (1-3,5-8), recently target of configurational analysis using the popular DP4+ methodology. The present analysis makes use of reported H and C shifts and, in some particular cases, a few J couplings. The difficulty in proper computational prediction of relative energies, in molecules capable of inter-molecular hydrogen bonding, introduces large errors in the prediction of conformationally averaged NMR properties in methods based on Boltzmann averaging such as DP4 or DP4+. In contrast CASE-3D conformational amplitudes are free parameters in the model. Here we show that the CASE-3D conformational model selection strategy, when combined with a larger energy cutoff in the molecular-modelling conformational exploration, was sufficient to correctly assign the relative configuration in five of seven cases. Introduction of more information, either by supplementing H and C data with a few J-couplings, or using a cutoff based on computed DFT energies for the definition of the conformational ensembles, allowed the safe assignment of configuration for all compounds.