Fourier transform near‐infrared vibrational circular dichroism used for on‐line monitoring the epimerization of 2,2‐dimethyl‐1,3‐dioxolane‐4‐methanol: A pseudo racemization reaction

Abstract

Near-infrared (near-IR) Fourier transform vibrational circular dichroism (FT-VCD) spectroscopy has been used to monitor the epimerization of (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (S-DDM). The near-IR-VCD spectra display clear isolated VCD bands at the range of 4700-5050 cm(-1) resulting from the OH stretch-bend combination bands of S-DDM, which were found to decrease in intensity with increasing reaction time. The near-IR-VCD spectra of 10 reference samples obtained were subjected to partial least-squares (PLS) regression analysis, and the results were used to build predictive models for enantiomeric excess (EE) determination. Multivariate regression was carried out on three different sets of spectra, corresponding to the epimerization of S-DDM in three different solvents: methylcyclohexane, carbon tetrachloride and tetrahydrofuran. The effects of solvent in DDM epimerization are discussed in terms of the relative stabilization of the reaction intermediate of the DDM epimerization reaction. The results of these near-IR-VCD studies for the determination of EE highlights the potential of VCD for in situ real-time process monitoring of the reaction kinetics of chiral molecules in solution.

Calculations of overtone NIR and NIR-VCD spectra in the local mode approximation: Camphor and Camphorquinone

“…Several near-infrared (NIR) vibrational circular dichroism (VCD) spectra have been recently presented mainly from two research groups [1][2][3][4][5][6][7][8][9]. For the sake of historical exactness we must say that the first observation of NIR-VCD spectra was made by Keiderling and Stephens [10].…”

“…Besides some possible applications pointed out in Refs. [7,9], NIR-VCD data are interesting since they pose a challenge to interpretation and theory. As the mid-IR VCD case [11], also NIR-VCD data can be really useful, NIR-VCD data can be made really useful, if they are preceded by the calculations of frequencies, dipole strengths and rotational strengths for vibrational transitions for CH stretching (or XH stretching in general) combination and overtone modes with minimal simplifying assumptions.…”

Role of racemization in optically active drugs development

“…Figure 5 shows the pseudo first order kinetics of the decomposition of polymyxin B 1 at pH 1.4 and 608C. Guo et al 105 described the effects of solvent on 2,2-dimethyl-1,3-dioxalane-4-methanol (DDM), which epimerizes according to relative stabilization of reaction intermediate of DDM epimerization reaction. Yang and Lu 44 studied the temperature dependent racemization of 3-methoxy-N-desmethyldiazepam in acetonitrile and methanol having 0.5 M H 2 SO 4 .…”

Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

“…304,[325][326][327] Also, VCD can be used for real-time reaction monitoring. [328][329][330] VCD has been used to determine the absolute stereochemistry of natural products, 320,331 compounds derived via asymmetric enzymatic catalysis, 332 as well as carboxylic acids 333,334 and alcohols 204 in derivatized form in order to improve calculations by obviating the presence of dimers or rigidifying the molecule of interest, respectively. There are numerous published examples of VCD being applied specifically to pharmaceutically-relevant molecules, 325,335,336 as well as numerous reports where various permutations of calculated versus measured VCD, ECD and/or OR have been used to determine absolute configuration.…”