Diastereotopic Fluorines of CF ₂ Group as Stereochemical Probes for Empirical ¹⁹ F NMR‐Based Assignment of Absolute Configuration of an Epimeric Center. 21,21‐Difluorothevinols

ABSTRACT The chemical shifts of diastereotopic fluorine atoms in compounds of the formula ArC(R)(OH)CF 2 R′ with unchanged R and R′ are weakly dependent on the substituents on the aryl group. In the presence of a chiral group R*, the chemical shifts of the fluorine atoms differ in the epimers. This feature can be used for the simple empirical assignment of an absolute configuration of the benzylic epimeric center in newly synthesized compounds of the formula ArC(R*)(OH)CF 2 R′ using routine 19 F or 19 F{ 1 H} NMR spectroscopy. In this work, this simple approach was applied to assign the configuration of the chiral center at C(20) in 20‐aryl‐ and 20‐alkyl‐21,21‐difluorothevinols, opioid receptor ligands. The results obtained by 19 F{ 1 H} NMR were validated by correlation with the X‐ray diffraction data. The method also enables configurational assignment of the corresponding 21,21‐difluoroorvinols, opioid ligands with higher efficacy, as they are usually obtained from the corresponding thevinols via the 3‐ O ‐demethylation reaction not affecting the chiral center at C(20).