Stereospecific syntheses of all four stereoisomers of 4-fluoroglutamic acid

(+)- -threo-4-Fluoroglutamic acid (+)-(2S, 4S)-fluoroglutamic acid] has been synthesizedstarting with the natural (−)-4-trans-hydroxy- -proline. Its acetylation at nitrogen followedby esterification with diazomethane afforded methyl 1-acetyl-trans-4-hydroxy- -prolinatewhich was converted to methyl 1-acetyl-cis-4-fluoro- -prolinate by means of diethylaminosulfurtrifluoride (DAST) or 2-chloro-1,1,2-trifluorotriethylamine. The mixture wasoxidized by ruthenium tetroxide to methyl 1-acetyl-cis-4-fluoro- -pyrrolidin-5-one-2-carboxylate,whose acid hydrolysis yielded the title compound. A similar sequence of reactionsconverted cis-4-hydroxy- -proline to (−)- -erythro-4-fluoroglutamic acid (−)(2R, 4S)-fluoroglutamic acid]. (−)- -threo-4-Fluoroglutamic acid (−)-(2R, 4R)-floroglutamicacid] was prepared analogously from trans-4-hydroxy- -proline, obtained from its diastereomerby inversion of configuration at carbon 4 of the pyrrolidine ring using thediethyl azodicarboxylate-triphenylphosphine procedure. cis-4-Hydroxy- -proline, necessaryfor the synthesis of (+)- -erythro-4-fluoroglutamic acid (+)-(2S, 4R)-fluoroglutamicacid], was prepared from trans-4-hydroxy- -proline by benzyloxycarbonylation at thenitrogen, oxidation of the 1-benzyloxycarbonyl-trans-4-hydroxy- -proline to 1-benzyloxy-carbonyl-4-oxo- -proline, its reduction to 1-benzyloxycarbonyl-cis-4-hydroxy- -proline anddeprotection of the latter at the nitrogen. (−)-cis-4-Fluoro- -proline and (+)-trans-4-fluoro- -proline were isolated after the hydrolysis of incompletely oxidized methyl 1-acetyl-cis-4-fluoro- -prolinate and methyl 1-acetyl-trans-4-fluoro- -prolinate, respectively.