The role of chirality in a set of key intermediates of pharmaceutical interest, 3-aryl-substituted-γ-butyrolactones, evidenced by chiral HPLC separation and by chiroptical spectroscopies

摘要

Graphical abstract Display Omitted Highlights ? HPLC Separation of enantiomers of four 3-aryl-substituted-γ-butyrolactones (3AGBL). ? ECD, ORD, and VCD of four 3AGBL. Similarity indexes calculated for VCD and ECD. ? From AD-H columns ( S ) enantiomers of 3AGBL elute before ( R ) enantiomers. ? Molecular Docking explains elution order. ? Lactone-chirality rule based on VCD spectra. Abstract The enantiomers of four chiral 3-aryl-substituted-γ-butyrolactones, key intermediates for the preparation of compounds of pharmaceutical interest, were successfully isolated by enantioselective chromatography, employing the Chiralpak AD-H chiral stationary phase. For all compounds the same elution order was observed, as monitored by a full set of chiroptical methods that we employed, namely ORD (optical rotatory dispersion), ECD (electronic circular dichroism, or CD in the UV range), and VCD (vibrational circular dichroism, or CD in the IR range). By density functional theory (DFT) calculations we were able to determine that the first eluted enantiomer has ( S ) absolute configuration in all four cases. We were able to justify the elution order by molecular docking calculations for all four enantiomeric pairs and suitable modeling of the stationary and mobile phases of the employed columns. The optimal performance of the chiroptical spectroscopies and of the DFT calculations allows us to formulate a lactone chirality rule out of the CO stretching region of the VCD spectra.