Preparation of chiral α-monofluoroalkylphosphonic acids and their evaluation as inhibitors of proteintyrosine phosphatase 1B

Abstract

Enantiomerically pure α-monofluoroalkylphosphonic acids 4–9 were synthesized by diastereoselective electrophilic fluorination of α-carbanions of asymmetric phosphonamidates bearing (−)-ephedrine as a chiral auxiliary. The diastereomeric excess of the fluorination reaction was highly dependent on the nature of the base and counterion with de’s ranging from 2–72%. Diastereomerically pure α-fluorophosphonamidates were obtained by column chromatography. The absolute stereochemistry of the fluorinated phosphonamidates was established by X-ray crystallography. Removal of the ephedrine auxiliary using MeOH–TFA followed by treatment with TMSBr afforded α-monofluoroalkylphosphonic acids 4–9 in modest to good yields. ¹⁹F-NMR analysis of the chiral phosphonic acids 4–9 in the presence of the chiral base quinidine indicated that the phosphonic acids were obtained in greater than 97% ee. Inhibition studies with 4–9 and protein tyrosine phosphatase 1B (PTP1B) revealed that the R-enantiomers were approximately 10-fold more potent inhibitors than the corresponding S-enantiomers, but 10-fold less potent than their α,α-difluoro analogues. Possible reasons for these differences are discussed.