Synthetic utility of α,α-difluoro-β-lactams as a divergent platform for accessing CF₂-containing β-amino acid derivatives

Abstract

We report a divergent synthetic approach to α,α-difluoro-β-amino esters and thioesters based on the nucleophilic ring-opening of α,α-difluoro-β-lactams. The high reactivity of the lactam scaffold arises from the combined effects of significant ring strain and the strong electron-withdrawing character of the CF₂ group without the need for external activating agents. The ring-opening reaction of α,α-difluoro-β-lactams with alcohols in the presence of diisopropylethylamine in 2,2,2-trifluoroethanol afforded the corresponding α,α-difluoro-β-amino esters in good to excellent yields. In contrast, switching the solvent to N,N-dimethyl formamide enabled efficient reactions with thiol nucleophiles, providing access to α,α-difluoro-β-amino thioesters in high yields. This study demonstrates that α,α-difluoro-β-lactams are a versatile platform for synthesizing fluorinated β-amino acid derivatives with potential applications in medicinal chemistry and peptide ligation chemistry.