Optically Active Antifungal Azoles. I. Synthesis and Antifungal Activity of (2R, 3R)-2-(2, 4-Difluorophenyl)-3-mercapto-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol and Its Stereoisomers

Abstract

(2R, 3R)-2-(2, 4-Difluorophenyl)-3-mercapto-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol [(2R, 3R)-7] and its stereoisomers [(2S, 3R)-, (2S, 3S)- and (2R, 3S)-7] were prepared from the optically active oxiranes 6 by a newly developed ring-opening reaction and evaluated for antifungal activity. The thiol (2R, 3R)-7 showed extremely potent antifungal activity in vitro and in vivo.The optically active oxirane (2R, 3S)-6, a useful intermediate for the synthesis of sulfur-containing antifungal azoles 5, was synthesized from methyl (R)-lactate [(R)-8] via eight steps in a stereocontrolled manner. The key step in the synthesis is the Grignard reaction of an amide derivative [(R)-12a] of (R)-lactic acid with 2, 4-difluorophenylmagnesium bromide (13).