Determination of the Preferred Stereoisomer of Natural Product Bisabolol in Chloroform Solution through Quantum Chemical Calculations of ¹ H NMR Chemical Shifts

The elucidation of natural product structures and the differentiation of stereoisomers are important issues in organic chemistry. An example is the sesquiterpene (-)-α-bisabolol (αBis), having two stereogenic centers, αBis and a flexible side chain that generates high conformational freedom. Recently, new tools named DP4+ and ANN-PRA, which are probabilistic approaches, were used in combination to solve the relative configuration of αBis (α and epi-α diastereomers). Nuclear magnetic resonance (NMR) chemical shifts obtained from density functional theory (DFT) calculations in the vacuum were used by the DP4+ and ANN-PRA computational algorithms averaged by the Boltzmann population. Although such a procedure can provide an indication of the most probable enantiomer, no information on the spatial arrangement of the preferred molecular structure present in the NMR experiment (in CDCl₃) could be obtained. In this work, we used the DFT methodology and the polarizable continuum model approach, with the inclusion of explicit CHCl₃ solvent molecules, to calculate ¹H NMR spectra for various distinct trial molecular structures of αBis, encompassing α and epimeric forms, varying relevant torsion angles to find plausible minimum energy structures on the potential energy surface, including solvent effects. Through comparison between the experimental and theoretical ¹H NMR profiles in chloroform solution, we were able to unambiguously elucidate the predominant molecular structure (enantiomer α) that reproduced faithfully the experimental ¹H NMR pattern. This could not be done in previous work employing the DP4+ and ANN-PRA tools; however, there is an agreement that the α stereoisomer should be predominant. The preferred α-Bis molecular structure reported here will most probably interact with biological targets.