Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

We report the metabolism of the recently introduced α,α-difluoroethyl thioether motif to explore further its potential as a substituent for bioactives discovery chemistry. Incubation of two aryl-SCF₂CH₃ ethers with the model yeast organism Cunninghamella elegans, indicates that the sulfur of the thioether is rapidly converted to the corresponding sulfoxide, and then significantly more slowly to the sulfone. When the substrate was (p-OMe)PhSCF₂CH₃, then the resultant (demethylated) phenol sulfoxide had an enantiomeric excess of 60%, and when the substrate was the β-substituted-SCF₂CH₃ naphthalene, then the enantiomeric excess of the resultant sulfoxide was 54%. There was no evidence of defluorination, unlike the corresponding oxygen ether (p-OMe)PhOCF₂CH₃, which was converted to the (demethylated) phenol acetate ester during C. elegans incubation. We conclude that the aryl-S-CF₂CH₃ motif is metabolised in a similar manner to aryl-SCF₃, a motif that is being widely explored in discovery chemistry. It is however, significantly less lipophilic than aryl-SCF₃ which may offer a practical advantage in tuning overall pharmacokinetic profiles of molecules in development.