Pushing the Boundaries of DP4+: Enhancing the Limits of Structure Elucidation of Natural Products by Means of NMR Parameter Calculations

DP4+ is one of the most popular methods for the structural elucidation of natural products using NMR calculations. This method was developed with 16 statistical parameters, which depend on the level of theory. Therefore, using DP4+ outside its parameterized theoretical levels can compromise the reliability of the results. To address this limitation, a customizable DP4+ methodology was developed in 2021, allowing preliminary calculations at any desired level of theory, using a small set of training molecules. The customized DP4+ offers substantial flexibility but does not necessarily guarantee predictive reliability. Thus, to overcome these limitations and ensure reliability, we pushed the boundaries of DP4+ by undertaking a major expansion of the method through the reparameterization of 36 new DP4+ protocols, based on the customizable DP4+ methodology. This effort incorporated modern DFT functionals, basis sets, and solvent models that were not included in the original version of the tool, selected from among the most widely used in contemporary computational NMR studies. Among the 36 new DP4+ tools developed, some remained similar to the original method, while three of them yielded results that were statistically superior to the original method.