b,b-Difluoro analogs of a-oxo-b-phenylpropionic acid and phenylalanine

A simple three-step procedure converted the readily accessible (2-bromo-1,1-difluoroethyl)arenes into a-aryl-a,a-difluoroacetaldehydes. Subsequent hydrocyanation, hydrolysis, oxidn. and again hydrolysis afforded b-aryl-b,b-difluoro-a-oxopropionic acids. Reductive amination transformed the oxo acids into a separable mixt. of a-hydroxy acids and racemic b,b-difluoro-b-phenylalanine derivs.. Enantiomerically pure b,b-difluorophenylalanine was obtained when a,a-difluoro-a-phenylacetaldehyde was condensed with homochiral 1-phenylethylamine, hydrogen cyanide added to the resulting imine, the diastereomeric mixt. thus produced hydrolyzed to the carboxamides which were found to be separable by fractional crystn. or chromatog. The pKa values of the b-aryl-b,b-difluoroalanines were measured and biol. profile of the latter probed. 3-(4-Chlorophenyl)-3,3-difluoro-2-oxopropionic acid proved to be a potent (Ki 27 mM) and selective inhibitor of arogenate dehydratase, a key enzyme catalyzing the last step of the phenylalanine biosynthesis. [on SciFinder (R)]