Vibrational circular dichroism spectroscopy study of paroxetine and femoxetine precursors

Abstract

ABSTRACT:The solution structures of (3R,4S)-and (3S,4R)-4-(4-fluorophenyl)-3-hydroxylmethyl-1-methylpiperidine, which are intermediates in the synthesis of the two pharmaceuticals paroxetine and femoxetine, were studied by vibrational circular dichroism (VCD) spectroscopy. In addition, six derivatives with different substituents attached to the C3 atom were prepared and their VCD and absorption spectra discussed with the aid of ab initio simulations. The VCD spectra were found to be sensitive to the geometry changes. In addition, a subtle variation caused by intermolecular aggregation was apparent in the spectra. The VCD technique can be applied for structural analysis of chiral pharmaceuticals in solutions.

Mediation of Conformationally Controlled Photodecarboxylations of Chiral and Cyclic Aryl Esters by Substrate Structure, Temperature, Pressure, and Medium Constraints

“…(ii) By VCD Spectroscopy. Recently, information about conformations of chiral molecules, including esters, − in solution have been deduced by analyses of vibrational circular dichroic (VCD) spectra combined with DFT calculations. − This approach has been applied to the conformational analysis of 1 . The VCD spectrum of 1 in dichloromethane- d 2 was compared with simulated spectra from the four conformations identified above (Figure ).…”

Absolute configuration determination of chiral molecules in the solution state using vibrational circular dichroism

“…49 Several groups have investigated biphenyl or binaphthyl molecules with VCD, including four PCB-methylsulfone enantiomers (Germany), 50 several 1,1V binaphthyl derivatives (Czech Republic), 51 and from our group, the cotton derivative gossypol, 52 a D 2 -symmetric dimer of 1,1V-binaphthyl and a C 2 -symmetric annelated heptathiophene, 53 and (R,4S)-2-[4,5-dihydro-4-(1-methylethyl)oxazol-2-yl]-2V-hydroxymethyl-1,1V-biphenyl. 54 The VCD laboratory in the Czech Republic has also reported studies on (3R,4S)-4-(4-fluorophenyl)3-hydroxymethyl-1-methylpiperidine, 55 paroxetine and femoxetine precursors, 56 and twistbendanedione (tricyclo[4.3.0.0 3,8 ]nonane-4,5-dione). 57 Polavarapu et al 58 at Vanderbilt University have investigated several volatile anesthetics, including 1,2,2,2-tetrafluoroethyl methyl ether, enflurane, 59 and a degradation product of sevoflurane (1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane).…”

Determination of Molecular Structure in Solution Using Vibrational Circular Dichroism Spectroscopy: the Supramolecular Tetramer of S -2,2‘-Dimethyl-Biphenyl-6,6‘-Dicarboxylic Acid

“…Our methodology utilizes ab initio density functional theory (DFT) . The reliability of DFT predictions of IR and VCD spectra is by now well-documented, and the methodology used here has been extensively utilized for the conformational and configurational analysis of chiral molecules . Our study of 1 extends prior work to the field of supramolecular chemistry.…”