β,β-Difluoro analogs of α-oxo-β-phenylpropionic acid and phenylalanine

A simple three-step procedure converted the readily accessible (2-bromo-1,1-difluoroethyl)arenes () into α-aryl-α,α-difluoroacetaldehydes (). Subsequent hydrocyanation, hydrolysis, oxidation and again hydrolysis afforded β-aryl-β,β-difluoro-α-oxopropionic acids (). Reductive amination transformed the oxoacids into a separable mixture of α-hydroxyacids and racemic β,β-difluoro-β-phenylalanine derivatives (). Enantiomerically pure β,β-difluorophenylalanine () was obtained when α,α-difluoro-α-phenylacet-aldehyde () was condensed with homochiral 1-phenylethylamine, hydrogen cyanide added to the resulting imine, the diastereomeric mixture thus produced hydrolyzed to the carboxamides () which were found to be separable by fractional crystallization or chromatography. The pKa values of the β-aryl-β,β-difluoroalanines () were measured and biological profile of the latter probed. 3-(4-Chlorophenyl)-3,3-difluoro-2-oxopropionic acid () proved to be a potent (Ki 27 μM) and selective inhibitor of arogenate dehydratase, a key enzyme catalyzing the last step of the phenylalanine biosynthesis.