STEREOSPECIFIC SYNTHESES OF ALL 4 STEREOISOMERS OF 4-FLUOROGLUTAMIC ACID

(+)-L-threo-4-Fluoroglutamic acid [(+)-(2S, 4S)-fluoroglutamic acid] has been synthesized starting with the natural (-)-4-trans-hydroxy-L-proline. Its acetylation at nitrogen followed by esterification with diazomethane afforded methyl I-acetyl-trans-4-hydroxy-L-prolinate which was converted to methyl 1-acetyl-cis-4-fluoro-L-prolinate by means of diethylaminosulfur trifluoride (DAST) or 2-chloro-1,1,2-trifluorotriethylamine. The mixture was oxidized by ruthenium tetroxide to methyl 1-acetyl-cis-4-fluoro-L-pyrrolidin-5-one-2-carboxylate, whose acid hydrolysis yielded the title compound. A similar sequence of reactions converted cis-4-hydroxy-D-proline to (-)-D-erythro-4-fluoroglutamic acid [(-)(2R, 4S)-fluoroglutamic acid]. (-)-D-threo-4-Fluoroglutamic acid [(-)-(2R, 4R)-fluoroglutamic acid] was prepared analogously from trans-4-hydroxy-D-proline, obtained from its diastereomer by inversion of configuration at carbon 4 of the pyrrolidine ring using the diethyl azodicarboxylate-triphenylphosphine procedure. cis-4-HydroXy-L-proline, necessary for the synthesis of(+)-L-erythro-4-fluoroglutamic acid [(+)-(2S, 4R)-fluoroglutamic acid], was prepared from trans-4-hydroxy-L-proline by benzyloxycarbonylation at the nitrogen, oxidation of the 1 -benzyloxycarbonyl-trans-4-hydroxy-L-proline to 1-benzyloxycarbonyl-4-oxo-L-proline, its reduction to 1-benzyloxycarbonyl-cis-4-hydroxy-L-proline and deprotection of the latter at the nitrogen. (-)-cis-4-Fluoro-L-proline and (+)-trans-4-fluoro-D-proline were isolated after the hydrolysis of incompletely oxidized methyl 1-acetyl-cis-4-fluoro-L-prolinate and methyl 1-acetyl-tranS-4-fluoro-D-prolinate, respectively.