Stereospecific syntheses of all four stereoisomers of 4-fluoroglutamic acid

Article abstract of DOI:10.1016/S0022-1139(00)80034-2

(+)-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 1-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.