Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols.
Phenylglycidols substituted in the 2-, 3-, and 4- positions with fluorine, chlorine, and trifluoromethyl, and with methoxy in the 3- position, were synthesized from the corresponding E-cinnamic acids and separated into their (R,R)- and (S,S)- enantiomers using subcritical fluid chromatography with mixtures of MeOH in CO(2), on either a Chiralpak AD or AS chiral stationary phase. These compounds and commercially-available (R,R)- and (S,S)-phenylglycidol were analyzed for their vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotation (OR) properties to exemplify a strategy whereby the absolute stereochemistry of common and key chiral intermediates is established early in the structure-activity and structure-property relationship phase of a drug discovery program in a pharmaceutical company. From this study, substituents in the phenyl group of the synthesized molecules were found not to grossly alter spectroscopic features, and therefore, diagnostic absorption bands in the respective VCD spectra, and the sign and shape of the measured ECD curves could be used to determine and track the absolute stereochemistry of analogs without necessarily requiring time-consuming ab initio calculations of all low energy conformers for all compounds. VCD, OR, and ECD calculations for the determination of absolute configuration carried out at the DFT level with the hybrid B3PW91 functional and the TZVP basis set were found to be especially useful in this study.
McConnell
Oliver
O
Wyeth Research, Chemical and Screening Sciences, Collegeville, PA 19426, USA. mcconno@wyeth.com
He
Yanan
Y
Nogle
Lisa
L
Sarkahian
Ani
A
D000438:Alcohols / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D025924:Chromatography, Supercritical Fluid / Q000379:methods*; D002934:Cinnamates / Q000737:chemistry; D002942:Circular Dichroism; D018360:Crystallography, X-Ray / Q000379:methods; D004581:Electronics; D004852:Epoxy Compounds / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008968:Molecular Conformation; D013053:Spectrophotometry / Q000379:methods*; D013055:Spectrophotometry, Infrared / Q000379:methods; D013237:Stereoisomerism; D013678:Technology, Pharmaceutical / Q000379:methods*
D000438:Alcohols; D002934:Cinnamates; D004852:Epoxy Compounds; C497968:phenylglycidol; C029010:cinnamic acid