65981-90-0Relevant articles and documents
Large-scale Chemoenzymic Synthesis of Calcium (6S)-5-Formyl-5,6,7,8-tetrahydrofolate using the NADPH Recycling Method
Kuge, Yukihiro,Inoue, Kunimi,Ando, Kyoji,Eguchi, Tamotsu,Oshiro, Takashi,et al.
, p. 1427 - 1432 (2007/10/02)
Chemoenzymic large-scale synthesis of the calcium salt of (6S)-5-formyltetrahydrofolic acid was achieved from folic acid 1 via (6S)-tetrahydrofolic acid by using dihydrofolate reductase (DHFR) produced by Escherichia coli, harbouring a high-expression plasmid, pTP64-1.On the other hand, for the diastereoselective reduction of 7,8-dihydrofolic acid 2 to tetrahydrofolate (6S)-3, a new NADPH recycling system was constructed by coupling with glucose dehydrogenase from Gluconobacter scleroides.Having these enzymic systems to hand, compound 1 was reduced by zinc powder in alkaline solution to give compound 2 which, without isolation, was reduced enzymatically to afford tetrahydrofolate (6S)-3 (94 percent de).The pH adjustment of the reaction mixture containing dihydrofolate 2 was done with phosphoric acid in order to remove zinc ion which inhibited the following enzymic reduction.The formed tetrahydrofolate (6S)-3 was converted into entirely optically pure N-formyl compound (6S)-5 on a large scale.The specific rotation value of (-)-leucovorin was 20D -13.3 (c 1, water).For the comparison of pharmacological effects, a completely optically pure form of (+)-leucovorin was also prepared on a preparative scale.Compound (6S)-5 was 300-fold more active compared with the (6R)-diastereoisomer.
The Preparation of the (6R)- and (6S)-Diastereoisomers of 5-Formyltetrahydrofolate (Leucovorin)
Owens, Jonathan,Rees, Lilias,Suckling, Colin J.,Wood, Hamish C. S.
, p. 871 - 876 (2007/10/02)
The separation of the (6R)- and (6S)-diastereoisomers of tetrahydrofolic acid by derivatisation on N-5 with chiral auxiliary reagents followed by fractional crystallisation or extraction is described.Chloroformates of chiral alcohols were used as chiral auxiliaries and those derived from cyclic terpene alcohols were found to be most effective for the separation.The cleavage of the derivative and conversion in situ into 5,10-methenyltetrahydrofolic acid which was subsequently hydrolysed to afford 5-formyltetrahydrofolate (leucovorin) was investigated for the derivatised tetrahydrofolates; that from (-)-menthol was the only one that combined satisfactory separation with sufficient lability for efficient conversion into 5-fornyltetrahydrofolate.The characterisation and optical purity of the products is described.
ASYMMETRIC REDUCTION OF DIHYDROFOLATE USING DIHYDROFOLATE REDUCTASE AND CHIRAL BORON-CONTAINING COMPOUNDS
Rees, Lilias,Valente, Edward,Suckling, Colin J.,Wood, Hamish C. S.
, p. 117 - 136 (2007/10/02)
The reduction of dihydrofolic acid to chiral tetrahydrofolic acid has been investigated by enzymic and non-enzymic means.With dihydrofolate reductase from E.coli as catalyst and recycling systems for NADPH, up to 1 g of optically pure stable tetrahydrofolate derivatives was obtained.The technique makes the possibility of synthesising chiral 5-formyltetrahydrofolate (leucovorin) for use in cancer rescue therapy attainable.In contrast, although dihydrofolate was reduced by a number of chiral boranes and borates built from amino acids and amino alcohols, enantiomeric excesses were minimal.
