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-butano l [(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-difluorophenyl-magnesium bromide (13).

Substituent effect of fluorine atoms in the 2,4-difluorophenyl group on antifungal activity of CS-758

“…The mixture was concentrated under reduced pressure to give an oily crude product, which was chromatographed on silica gel (100 g, EtOAc/Hexane = 1/1) to afford 7c (1.80 g, 59%) as a colorless oil. 1 The spectral data of 7a and 7b were identical with those described in the literature [33]. As a typical example of oxirane opening reaction, the preparation of 9a is described.…”

“…The Grignard reaction of morpholine amide 1 [33], derived from methyl (R)-lactate, with 2-F-, 4-F-, 2,3-F 2 -, and 2,5-F 2 -phenylmagnesium bromide in tetrahydrofuran (THF) at À30 8C, proceeded smoothly to afford (R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxypropiophenone derivatives 2a-d. The derivatives 2a-d were treated with (dimethylisopropoxysilyl)-methylmagnesium chloride, prepared from chloromethyldimethylisopropoxysilane and magnesium, in diethyl ether at 0 8C to give silyl alcohol derivatives 3a-d. Oxidative desilylation of 3a-d with hydrogen peroxide and sodium hydrogen carbonate in THF-MeOH afforded diol derivatives 4a-d, whose tetrahydropyranyl group was removed by acid treatment in MeOH at room temperature to give butantriol derivatives 5a-d.…”

Enantioselective Organocatalytic Rearrangement of α‐Acyloxy‐ β‐keto Sulfides to α‐Acyloxy Thioesters

“…Using the method described in Scheme , we were able also to prepare 4‐[( R )‐2‐hydroxypropionyl]morpholine 4 . The intermediate 4 can be easily modified to prepare optically active antifungal azoles12 and tricyclic NMDA‐glycine antagonists indole‐2‐carboxylic acids 13. Moreover, this formal synthesis allowed us to confirm the absolute stereochemistry of our α‐acyloxy thioester.…”

Drug Syntheses Beyond the Rule of 5

“…3.4.3 Isavuconazonium . Isavuconazonium ( 50 ) was synthesised starting from methyl ( R )‐lactate ( 87 ) by amidation with morpholine and protection of the alcohol as a THP ether to give amide 89 (Scheme ). Grignard addition gave ketone 90 , which was epoxidised with trimethyl sulfoxonium iodide to provide a diastereomeric mixture of 91 and 92 (4:1), which were not separated.…”