- A novel synthetic method for preparation of some folates
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An improved method was developed for preparation of 5,6,7,8-tetrahydrofolic acid (THF) and calcium-5-methyltetrahydrofolate (5-MTHF-Ca) by reduction of folic acid using KBH4 catalyzed by Pb(NO3)2. The yields of THF and 5-MTHF-Ca were 56.5 and 42.7 %, respectively. A convenient method for measurement of THF and 5-MTHF-Ca using liquid chromatography-mass spectrometry (LC-MS) was also established, enabling analysis of those folates within 10 min without application of gradient elution.
- Zhou, Minghao,Hong, Mei,Xiao, Guomin
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p. 2211 - 2218
(2013/06/05)
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- Large-scale Chemoenzymic Synthesis of Calcium (6S)-5-Formyl-5,6,7,8-tetrahydrofolate using the NADPH Recycling Method
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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.
- Kuge, Yukihiro,Inoue, Kunimi,Ando, Kyoji,Eguchi, Tamotsu,Oshiro, Takashi,et al.
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p. 1427 - 1432
(2007/10/02)
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- The Preparation of the (6R)- and (6S)-Diastereoisomers of 5-Formyltetrahydrofolate (Leucovorin)
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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.
- Owens, Jonathan,Rees, Lilias,Suckling, Colin J.,Wood, Hamish C. S.
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p. 871 - 876
(2007/10/02)
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- NADPH regeneration by glucose dehydrogenase from Gluconobacter scleroides for l-leucovorin synthesis.
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A new process for (6S)-tetrahydrofolate production from dihydrofolate was designed that used dihydrofolate reductase and an NADPH regeneration system. Glucose dehydrogenase from Gluconobacter scleroides KY3613 was used for recycling of the cofactor. The reaction mixture contained 200 mM dihydrofolate, 220 mM glucose, 2 mM NADP, 14.4 U/ml dihydrofolate reductase, and 14.4 U/ml Glucose dehydrogenase, and the reaction was complete after incubation at pH 8.0, and 40 degrees C for 2.5 hr. With (6S)-tetrahydrofolate as the starting material, l-leucovorin was synthesized via a methenyl derivative. The purity of the l-leucovorin was 100%, and its diastereomeric purity was greater than 99.5% d.e. as the (6S)-form.
- Eguchi,Kuge,Inoue,Yoshikawa,Mochida,Uwajima
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p. 701 - 703
(2007/10/02)
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- Asymmetric Catalysis, 67. - Diastereoselective Hydrogenation of Folic Acid with Optically Active Rhodium(I)-Diphosphane Complexes
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With immobilized rhodium(I)-diphosphane catalysts supported on silica gel, the C=N bonds of the pyrazine ring of folic acid (1) are reduced with hydrogen in aqueous solution to give 5,6,7,8-tetrahydrofolic acid.A mixture of the two diastereomers 2a and 3a is obtained with (6S)-and (6R)-configuration, respectively, at the newly formed asymmetric center in the pterine system and (S)-configuration in the L-glutamic acid moiety.The unstable hydrogenation products are derivatized with (-)-menthyl chloroformate.An improved HPLC procedure for the analysis of the products has been developed.By using optically active chelate phosphanes as cocatalysts together with 2, a diastereomeric excess of up to 24percent of the natural isomer 2a with (6S,S)-configuration is attained in the heterogeneous hydrogenation of folic acid. Key Words: Diastereoselective hydrogenation / Immobilized enantioselective rhodium(I)-diphosphan catalysts / Folic acid / (6S,S)-Folinic acid / 5,6,7,8-Tetrahydrofolic acid, N-5-(menthyloxycarbonyl)-
- Brunner, Henri,Huber, Christian
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p. 2085 - 2094
(2007/10/02)
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- ASYMMETRIC REDUCTION OF DIHYDROFOLATE USING DIHYDROFOLATE REDUCTASE AND CHIRAL BORON-CONTAINING COMPOUNDS
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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.
- Rees, Lilias,Valente, Edward,Suckling, Colin J.,Wood, Hamish C. S.
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p. 117 - 136
(2007/10/02)
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