Chemistry of 4-fluoroglutamic acid. Part 2. Separation of the diastereomers on a large scale. Preparation of cis- and trans-4-fluoro-5-pyrrolidone-2-carboxylic acids (4-fluoropyroglutamic acids)

γ‐Fluorinated Analogues of Glutamic Acid and Glutamine

“…Finally, the ester derivatives of the erythro and threo isomers were hydrolysed and neutralised with pyridine to afford diastereomerically pure erythro 4-fluoroglutamic acid (1a ϩ 1c) and threo 4fluoroglutamic acid (1b ϩ 1d) in 54 and 52% overall yield, respectively, based on 1 (Fig. 5) (Tolman et al, 1993).…”

“…Aminolysis of the ester with methanolic ammonia in the presence of carbon disulfide afforded 4-fluoroglutamine 2 in 36% yield (Tolman and Veres, 1967). The importance of amino group protection of the γ-ester derivative of 4fluoroglutamic acid was recognised when aminolysis of the monoester of 4-fluoroglutamic acid 46 gave a mixture of cis and trans-4-fluoro-5-pyrrolidone-2carboxylic acids (Tolman et al, 1993).…”

“…After their successful separation of erythro and threo-4-fluoroglutamic acid (Tolman, 1993;Tolman et al, 1993), Tolman and Sedmera converted them to the corresponding diastereomeric 4-fluoroglutamine. Racemic erythro and threo-4-fluoroglutamic acid were individually converted into their 5-methyl ester hydrochloride salt with thionyl chloride and methanol.…”

Synthesis of fluorinated amino acids

“…76 Tolman and co-workers have also reported the large scale preparation of 4-fluoroglutamic acids as single diastereomers by recrystallisation of the dimethyl ester hydrochloride salts. 77 For the investigation of modulators of folate poly-γglutamate biosynthesis, Coward and co-workers have developed the synthesis of both -3,3and -4,4-difluoroglutamic acid. 78-80 They had previously prepared -threo-4-fluoroglutamic acid and shown this compound to be a chainterminating inhibitor of the enzyme folylpolyglutamate synthetase.…”