Efficient Protocol for Accurately Calculating ¹³C Chemical Shifts of Conformationally Flexible Natural Products: Scope, Assessment, and Limitations

Abstract

An efficient protocol for calculating 13C NMR chemical shifts for natural products with multiple degrees of conformational freedom is described. This involves a multistep procedure starting from molecular mechanics and ending with a large basis set density functional model to obtain accurate Boltzmann conformer weights, followed by empirically corrected density functional NMR calculations for the individual conformers. The accuracy of the protocol (average rms <4 ppm) was determined by application to ∼925 diverse natural products, the structures of which have been confirmed either by X-ray crystallography or independent synthesis. The protocol was then applied to ∼ 2275 natural products, the structures of which were elucidated mainly by NMR and MS data. Five to ten percent of the latter compounds exhibited rms errors significantly in excess of 4 ppm, suggesting possible structural or signal assignment errors. Both data sets are available from an online browser (). The procedure can be and has been fully automated and is practical using present-generation personal computers, requiring a few hours or days depending on the size of the molecule and number of accessible conformers.

Radical Coupling Reactions of Hydroxystilbene Glucosides and Coniferyl Alcohol: A Density Functional Theory Study

“…These calculations were performed as implemented in Spartan'18 ("Spartan'18, 2019"). An automated version of this approach has been described (Hehre et al, 2019) in which accurate Boltzmann weighting of conformationally flexible molecules was reported. The 10 lowest energy conformations were next refined using the M06−2X density functional theory (DFT) method and the 6−31+G(d) basis set, with the GD3 empirical dispersion correction.…”

Minimizing the risk of deducing wrong natural product structures from NMR data

“…[124] Provided that there are a limited number of possible stereoisomers for a compound whose skeletal structure is known, it may be possible to use DFT calculations for each isomer to estimate the relative energies and 13 C chemical shifts for each of the local minima on its potential energy surface. [125] Then, the weight average chemical shifts for each of them can be compared with experimental values in the hope that this will identify the most probable stereoisomer. However, depending upon the number of possible choices, this can be a very slow process.…”

“…However, depending upon the number of possible choices, this can be a very slow process. [ 125 ] When this approach was applied to compounds whose previously reported structures had been deduced from only NMR data, 5 to 10% of them gave very poor agreement between calculated and experimental chemical shifts. This suggested that their reported stereochemistries (or possibly their skeletal structures) were wrong and that structure revisions were needed.…”

“…This suggested that their reported stereochemistries (or possibly their skeletal structures) were wrong and that structure revisions were needed. [ 125 ] Because no similar errors were found in cases where an X‐ray crystal structure was available, this indicates to us that, wherever possible, it is better to obtain a crystal structure to determine the stereochemistry of a molecule that is conformationally mobile in solution. NMR data and DFT calculations can then be used if one wants to investigate the conformational behavior of the molecule in solution.…”

Bioactive specialized metabolites produced by the emerging pathogen Diplodia olivarum

“…for the prediction of 13 C chemical shifts of flexible compounds [24]. For the two diastereomers, 6 or 10 conformers were found with detectable populations at room temperature.…”