Stereochemical and conformational study on fenoterol by ECD spectroscopy and TD-DFT calculations.
Fenoterol and its derivatives are selective β2-adrenergic receptor (β2-AR) agonists whose stereoselective biological activities have been extensively investigated in the past decade; a complete stereochemical characterization of fenoterol derivatives is therefore crucial for a better understanding of the effects of stereochemistry on β2-AR binding. In the present project, the relationship between chiroptical properties and absolute stereochemistry of the stereoisomers of fenoterol (1) was investigated by experimental ECD spectroscopy and time-dependent density functional theory (TD-DFT). DFT geometry optimizations were carried out at the RI-B97D/TZVP/IEFPCM(MeOH) level and subsequent TD-DFT calculations were performed using the PBE0 hybrid functional. Despite the large pool of equilibrium conformers found for the investigated compounds and the known limitations of the level of theory employed, the computational protocol was able to reproduce the experimental ECD spectra of the stereoisomers of 1. The main contribution to the overall chiroptical properties was found to arise from the absolute configuration of the chiral center in α-position to the resorcinol moiety. Based on this evidence, a thorough conformational analysis was performed on the optimized DFT conformers, which revealed the occurrence of a different equilibrium between conformational patterns for the diastereomers of fenoterol: the (R,R')/(S,S') enantiomeric pair showed a higher population of folded conformations than the (R,S')/(S,R') pair.
Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
Daniele
D
Tedesco
Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Italy.
Riccardo
R
Zanasi
Intramural Research Program, National Institute on Aging-National Institutes of Health (NIA-NIH), Baltimore, MD 21224-6825, United States.
Irving W
IW
Wainer
Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy. Electronic address: carlo.bertucci@unibo.it.
Carlo
C
Bertucci
D002942:Circular Dichroism / Q000379:methods; D005280:Fenoterol / Q000737:chemistry*; D008968:Molecular Conformation; D013057:Spectrum Analysis / Q000379:methods; D013237:Stereoisomerism
D005280:Fenoterol
Absolute stereochemistry; Conformational analysis; ECD spectroscopy; Fenoterol; TD-DFT calculations