Stereochemical analysis of the 3α‐ and 3β‐hydroxy metabolites of tibolone through NMR and quantum‐chemical investigations. An experimental test of GIAO calculations

The configuration at C‐3 of the 3α‐ and 3β‐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 the 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 the experimental values revealed that the density functional methods produced the best results for assigning proton and carbon resonances. Although steroids are relatively large molecules, the present approach appears accurate enough to allow the determination of relative configurations by using calculated ¹³C resonances; the chemical shift of pairs of geminal α/β hydrogen atoms can also be established by using calculated ¹H resonances. Copyright © 2002 John Wiley & Sons, Ltd.