A critical assessment of possible pitfalls in absolute configuration assignment using Vibrational Circular Dichroism

Vibrational Circular Dichroism (VCD) is no longuer a curious novelty in the field of molecular spectroscopy as VCD spectrometers are commercially available as well as the algorithms to calculate the spectra, which are implemented in various software packages. This makes VCD routinely applicable for the determination of absolute configurations. The VCD technique is gaining interest in mainly pharmaceutical industry and the technique also has been accepted by regulatory agencies (e.g. FDA) as a proof of absolute configuration (AC). Since a misassignment can have serious consequences, it is of vital importance that all assignments are done correctly. Our experience, however, shows that assignemnt can be hindered by serious problems. First of all, VCD measurements are done in solution, while the calculations are usually performed for a single molecule in vacuum. Intermolecular interactions can cause discrepancies between experimental and theoretical spectra. Inclusion of the solvent in the calculations leads to an improved agreement with the experiments for the case of pulegone and camphor. The agreement of computed VCD spectra with experimental ones, is known to depend strongly on the extent to which all relevant conformations are included in the calculations. This means that conformational analysis, especially for large flexible molecules, has to be performed very carefully. This is illustrated using dipetidyl peptidases (DPP) inhibitors. It is also demonstrated how manipulation of the synthesis pathway may help skirt these problems. Finally, the influence of temperature on experimental VCD spectra was studied. First, it was assumed that the interpretation of the experimental spectra would be simplified at lower temperatures due to a decrease in the number of significantly populated conformations. The effect of lowering the temperature is demonstrated for borneol, 3-methylcyclohaxonon and limonene showing that, unfortunately, different effects counterbalance the expected simplification of the spectrum

Solvent effects on IR and VCD spectra of natural products: an experimental and theoretical VCD study of pulegone

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