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

## TL;DR

This paper uses quantum chemical calculations to determine the preferred 3D structure of the natural product bisabolol in chloroform solution.

## Contribution

A novel computational approach combining DFT and solvent effects was used to identify the predominant enantiomer of bisabolol.

## Key findings

- The α stereoisomer of bisabolol was confirmed as the predominant structure in chloroform solution.
- Inclusion of solvent effects improved the accuracy of theoretical NMR predictions compared to previous methods.
- The identified structure is expected to interact effectively with biological targets.

## Abstract

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.