Stereochemical analysis of 3alpha- and 3beta- hydroxy metabolites of tibolone through NMR and quantum-chemical investigations : an experimental test of GIAO calculations

The configuration at C-3 of the 3alpha- and 3beta-hydroxy metabolites of tibolone was studied by extensive application of one- and two dimensional 1H and 13C NMR spectroscopy combined with molecular modeling performed at B3LYP/6-31G(d) level. Using HF and DFT GIAO methods, shielding tensors of the two molecules were computed; comparison of the calculated NMR chemical shifts with experimental values revealed that the density functional methods produced the best results for assigning proton and carbon resonaneces. Although steroids are relatively large molecules, the present approach appears accurate enough to allow the determinatio of relative configurations by using calculated 13C resonaces; the chemical shift of pairs of geminal alpha/beta hydrogen atoms can also be established by using calculated 1H resonances.