STRUCTURAL STUDY OF TRIAZOLE ANTIFUNGALS .2. CRYSTAL AND MOLECULAR-STRUCTURES OF THE 2 DIASTEREOISOMERS (4R-STAR,5R-STAR)- AND (4S-STAR,5R-STAR)-5-(2,4-DIFLUOROPHENYL)-4-METHYL-5-[(1H-1,2,4-TRIAZOL-1-YL)METHYL]-3-[4-(TRIFLUOROMETHYL)BENZOYL]OXAZOLIDINE

The title compounds were designed and synthesized as potential inhibitors of cytochrome P-450 14-alpha-demethylase. The antifungal activity of (4R*,5R*)-isomer is markedly higher than that of (4S*,5R*)-isomer. The crystal structures of the two diastereoisomers were determined by X-ray diffraction technique. The final R indices of (4R*,5R*)- and (4S*,5R*)-isomers were 0.063 and 0.070 for 2840 and 2365 reflections, respectively. The different configuration at the 4-position in the oxazolidine ring causes the differences in the ring conformation and in some torsion angles. The three-dimensional structures of the two diastereoisomers are consequently different. Among the diastereoisomers and enantiomers, the (4R,5R)-enantiomer is superimposable on lanosterol, which is a substrate of cytochrome P-450 14-alpha-demethylase, suggesting that the 4-beta-methyl group plays an important role in the antifungal activity.