Elucidation of the absolute configuration of JNJ‐27553292, a CCR2 receptor antagonist, by vibrational circular dichroism analysis of two precursors

Abstract

The absolute configurations of two precursors, that is, 1-(3',4'-dichlorophenyl)-propanol and 1-(3',4'-dichlorophenyl)-propanamine, of a potent 2-mercapto-imidazole CCR-2 receptor antagonist, JNJ-27553292, were determined using vibrational circular dichroism. As a consequence, the absolute configuration of the antagonist itself was also determined. The two precursor compounds were subjected to a thorough conformational analysis and rotational strengths were calculated at the B3LYP/cc-pVTZ level of theory. Based on these data, vibrational circular dichroism spectra were simulated, which in turn were compared with experimental spectra. Agreement between the spectra allowed the assignment of the absolute configuration, which is in agreement with the proposed configuration based on stereospecific reactions on similar compounds.

Intermolecular Association of Tetrahydrofuran-2-carboxylic Acid in Solution: A Vibrational Circular Dichroism Study

“…These single conformation spectra are obtained by Lorentzian broadening (fwhm)10 cm -1 ) of the calculated discrete line spectra based on dipole and rotational strengths and harmonic vibrational frequencies and are transformed to molar absorptivity units. 49 The conformational populations are calculated on the basis of free energies at room temperature (298.15 K) and can be found in Tables 1 and 2, for the monomer and dimer, respectively. In Figure 5, the calculated single conformation spectra are shown for the C monomer and the CC dimer.…”

“…IR and VCD spectra can be simulated by averaging the single conformation spectra using Boltzmann statistics. These single conformation spectra are obtained by Lorentzian broadening (fwhm=10 cm -1 ) of the calculated discrete line spectra based on dipole and rotational strengths and harmonic vibrational frequencies and are transformed to molar absorptivity units . The conformational populations are calculated on the basis of free energies at room temperature (298.15 K) and can be found in Tables and , for the monomer and dimer, respectively.…”

“…Taking into account the approximations that are used to determine the monomer and dimer populations to simulate their IR and VCD spectra, it would be of no use to perform a quantitative comparison of simulated and experimental spectra which is sometimes performed, , for smaller molecules. In this study the situation is even more difficult because not only bands of different conformations, belonging to one species coincide, but also bands from dimer conformations can overlap with bands of the monomer conformations.…”

Vibrational Circular Dichroism versus Optical Rotation Dispersion and Electronic Circular Dichroism for diastereomers: the stereochemistry of 3-(1′-hydroxyethyl)-1-(3′-phenylpropanoyl)-azetidin-2-one

“…Therefore, it is not feasible to relate every experimental band to a computed rotational strength, as is often done for small molecules. 21,[53][54][55][56][57] In large and flexible molecules like 1, one must take into account the uncertainty in Boltzmann weights from DFT calculations. This is highly relevant here as there is no single conformation with a distinctively higher Boltzmann weight.…”

“…Although two classes of conformers with similar VCD-features can be found, only a few peaks can be assigned unambiguously to a normal mode of a certain class. Conformers of class (a) are responsible for peak 2 (normal mode 52) and the strong negative peak at 1160 cm À1 which is part of peak 3 (normal mode [55][56]. The negative signal at 1140 cm À1 , also part of peak 3 in the Boltzmann weighted spectrum, can be assigned to normal mode 53 of the (b)-conformers.…”