The Role of the Transient Atropisomerism and Chirality of Flurbiprofen Unveiled by Laser-Ablation Rotational Spectroscopy.

The combination of atropisomerism and chirality in flurbiprofen is shown to be relevant concerning its pharmacological activity. The two most stable conformers of a total of eight theoretically predicted for each R- or S- flurbiprofen enantiomers have been isolated in the cooling conditions of a supersonic jet and structurally characterized by laser ablation Fourier transform microwave spectroscopy. The detected conformers, whose structure is mainly defined by three dihedral angles, only differ in the sign of the phenyl torsion angle giving rise to Sa and Ra atropisomers. A comparison with the structures available for the R- and S- enantiomers complexed to COX isoforms reveals that the enzymes select only the Sa atropisomers, resulting in a diastereoisomer-specific recognition. The most stable gas phase conformer is exclusively selected when using the S- enantiomer while the second is recognized only for the R- enantiomer. These experimental results highlight the importance of atropisomerism in drug design.

The Conformations of Isolated Gallic Acid: A Laser-Ablation Rotational Study.

The rotational spectrum of laser-ablated gallic acid has been recorded using CP-FTMW spectroscopy. Two rotamers have been detected, and their rotational spectra have been assigned and analyzed to obtain the molecular spectroscopic parameters. The observed rotamers have been unambiguously identified in the light of theoretical computations, based on the comparison of the experimental line intensities and rotational parameters with the rotational constants and electric dipole moments predicted from theoretical calculations. The values of the planar inertial moments confirm that the observed conformers are planar, and their relative stability and population have been determined from relative intensity measurements. The B3LYP-D3/6-311++G(2d,p) level has been shown to be the best method among a series of levels normally used to predict the rotational parameters in rotational spectroscopy. In the observed conformers, the three adjacent OH groups are arranged in a sequential form, and the only difference between them lies in the orientation of the COOH group. Although weak attractive OH···O interactions seem to exist, the analysis of the electron density topology does not show the existence of any critical point corresponding to these interactions.

Decoding the Structure of Non-Proteinogenic Amino Acids: The Rotational Spectrum of Jet-Cooled Laser-Ablated Thioproline.

The broadband rotational spectrum of jet-cooled laser-ablated thioproline was recorded. Two conformers of this system were observed and identified with the help of DFT and ab initio computations by comparison of the observed and calculated rotational constants and 14N quadrupole coupling constants as well as the predicted energies compared to the observed relative populations. These conformers showed a mixed bent/twisted arrangement of the five-membered ring similar to that of the related compound thiazolidine with the N-H bond in axial configuration. The most stable form had the COOH group in an equatorial position on the same side of the ring as N-H. The arrangement of the C=O group close to the N-H bond led to a weak interaction between them (classified as type I) characterized by a noncovalent interaction analysis. The second form had a trans-COOH arrangement showing a type II O-H···N hydrogen bond. In thioproline, the stability of conformers of type I and type II was reversed with respect to proline. We show how the conformation of the ring depends on the function associated with the endocyclic N atom when comparing the structures of isolated thioproline with its zwitterion observed in condensed phases and with peptide forms.