|
Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. February 2004, Volume 3, Number 2, 55-72 |
Structure of β-Artelinic Acid Clarified Using NMR Analysis, Molecular
Modeling and Cyclic Voltammetry, and Comparison with α-Artelinic
Acid and β-Arteether
Apurba K. Bhattacharjee, David J. Skanchy, Rickey P. Hicks, Keith A. Carvalho, Gwendolyn N. Chmurny, John R. Klose, and John P. Scovill
Internet Electron. J. Mol. Des. 2004, 3, 55-72
|
Abstract:
A detailed analysis on the structure of β-artelinic acid has
been performed using proton, carbon-13, 1D and 2D NMR,
molecular modeling, and cyclic voltammetry methods. The
results are compared by carrying out similar experiments and
modeling studies with α-artelinic acid and β-arteether.
Certain critical non-bonded interactions between specific
protons and the ether oxygen atom in the neighborhood of the
anomeric carbon atom seem to be particularly significant in
the two isomers. Although the stereochemistry at the
anomeric carbon atom in the sesquiterpene skeleton of these
molecules is diastereomeric, the structural difference between
α and β isomers and ab initio quantum chemical
calculations on these compounds (using both RHF/3-21G*
and RHF/6-31G** basis sets) indicate significant difference
in the mode of interaction of the neighboring protons by this
atom. The difference in these interactions accounts for the
observed difference in NMR chemical shifts of the protons in
the two isomers. The peroxide oxygen atoms in the
diastereomers do not appear to be significantly affected by
these protons and the intrinsic nucleophilicity of the peroxide
oxygen atoms remain almost unchanged as evidenced from
the calculated electrostatic potentials on these atoms and
redox potentials determined by cyclic voltammetry
experiments. Calculated (HF/6-31G**/NMR) chemical shift
values are found to be consistent with the trends of the
experimental values. The present combined NMR chemical
shift assignments, molecular modeling and cyclic
voltammetry study focuses the role of electronic distribution
by the aromatic ring in the two isomers in relation to the
protons around the anomeric carbon atom in the
sesquiterpene skeleton to affect the activity of the isomers.
The results should aid in the design of new artemisinin
analogues with potent activity and reduced CNS toxicity.
|