The Synthesis of (2S)-4,4-Difluoroglutamyl γ-Peptides Based on Garner’s Aldehyde­ and Fluoro-Reformatsky Chemistry

Abstract

The development of optically active fluorinated synthetic building blocks of general utility is a current goal of organo­fluorine chemists. The serine-derived Garner aldehyde was converted to a general 4,4-difluoroamino acid building block via fluoro-Reformatsky reaction with ethyl bromodifluoroacetate. The utility of this building block was demonstrated by the synthesis of derivatives of (2S)-4,4-difluoroglutamine, (2S)-4,4-difluoroglutamic acid, and its incorporation into a fluorophore-containing isopeptide 2 designed as a mechanistic probe of γ-glutamyl hydrolase. Compound 2 proved to be a substrate for γ-glutamyl hydrolase and was hydrolyzed at a rate significantly slower than the corresponding non-fluorinated analog.

fluoroamino acids - fluoropeptides - stereoselective synthesis - γ-glutamyl hydrolase - fluorescence enzyme assay

References

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Current Address: Department of Immunology NB-30, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195.

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