Folic acid hydrogenation

Folic acid hydrogenated 3-4 hrs. with prehydrogenated PtOg in glacial acetic acid at 25° and atmospheric pressure until Hg-uptake practically ceases after 2 moles of Hg have been absorbed tetrahydrofolic acid. Y >95%. Y. Hatefi et al., Biochem. Prep. 7, 89 (1960). 

The use of chiral amide ligands has been restricted to rhodium, where the catalyst precursor is [Rh(BH4)(amide)py2Cl2]. The work has been reviewed (10, 35) cinnamate derivatives were reduced to up to 57% ee, and hydrogenation of a carbon- nitrogen double bond in folic acid leads to tetrahydrofolic acid with high biological activity (308). 

With slight modifications in procedure, one basic synthesis of leucovorin and the subsequent isolation of its salts have remained unchanged for nearly thirty years. The method involves hydrogenation of folic acid (pteroylglu-tamic acid) in the presence of a platinum or palladium catalyst, as first described by O Dell et al.15 This... 

Tetrahydrofolate (THF, 6) is a coenzyme that can transfer Cj residues in different oxidation states. THF arises from the vitamin folic acid (see p. 366) by double hydrogenation of the heterocyclic pterin ring. The Ci units being transferred are bound to N-5, N-10, or both nitrogen atoms. The most important derivatives are ... 

The formation of sulfa drugs is another excimple of a multistep synthesis. The sulfa drugs cire bactericides, effective c ainst a wide variety of bacteria because they mimic p-aminobenzoic acid (Figure 13-48). Many bacteria require p-aminobenzoic acid, which they cire unable to synthesize, and need to synthesize folic acid. Many types of sulfa drugs exist, and most of them involve the substitution of one of the hydrogen atoms on the -SO2-NH2. Prontosil (Figure 13-49) was the first commercially available sulfa drug. The metabolism of prontosil produced sulfanilamide. 

The only antimalarial drugs whose mechanisms of action are reasonably well understood are the drugs that inhibit the parasite s ability to synthesize folic acid. Parasites cannot use preformed folic acid and therefore must synthesize this compound from the following precursors obtained from their host p-aminobenzoic acid (PABA), pteridine, and glutamic acid. The dihydrofolic acid formed from these precursors must then be hydrogenated to form tetrahydrofoUc acid. The latter compound is the coenzyme that acts as an acceptor of a variety of one-carbon units. The transfer of one-carbon units is important in the synthesis of the pyrimidines and purines, which are essential in nucleic acid synthesis. 

L-Tetrahydrofolic acid is a versatile intermediate for the manufacture of various folates, e.g., L-leucovorin [19], which is used in cancer therapy, or Metafolin , which is used as a vitamin in functional food. To our knowledge optically pure L-tetrahydrofolic acid is still obtained by repeated fractional crystallization from an equimolar mixture of diastereoisomers formed by nondiastereoselective hydrogenation of folic acid. In order to increase the yield of l-tetrahydrofolic acid and to avoid recrystallization steps, we checked the utility of our ligand for the diastereoselective hydrogenation of folic acid dimethyl ester benzenesulfonate (Scheme 1.4.4). 

Scheme 1.4.4 Hydrogenation of folic acid dimethyl ester benzenesulfonate.

I 7.4 The Daniphos" Ligands Synthesis and Catalytic Applications Table 1.4.3 Results of the hydrogenation of folic acid dimethyl ester. 

The preparation of a cubic phase with supramolecular chirality was achieved using a branched folic acid derivative incorporating glutamic acid residues (Fig. 11) as the source of chirality [93]. The pterin rings of folic acid residues are able to form a cyclic tetramer as a result of two hydrogen bonds between the components. Depending on the number of carbon atoms in the alkyl substituents, the compounds form columnar phases over a wide temperature range, and for 8 and 9 form cubic phases at temperatures above 130 °C. Addition of sodium triflate stabilises the cubic phase for 7, and the salt is incorporated into the other mesophases. It was implied that the cation resides between stacked tetramers. Supramolecular chirality is expressed for both the columnar and the cubic phases, as revealed by vari-... 

Diastereoseiective Hydrogenation of C=N Double Bonds. Immobilized Rh-NORPHOS catalysts have been employed for diastereoseiective heterogeneous hydrogenation of the C=N double bonds in the pyrazine ring of folic acid (eq 2) With (S,S)-NORPHOS, optically active tetrahy-drofolic acid that possesses the (65)- configuration at the newly formed asymmetric center was obtained in 96-98% chemical yield (18-21% de). When (RR)-NORPHOS was used for this purpose, tetrahydrofolic acid with the (6R)- configuration at the new asymmetric center was... 

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. 

Hydrogenation solvent. The acid is preferred as solvent for hydrogenation (Pt or Rh) of pterines, since complete and selective hydrogenation of the pyrazine ring of pterine, its N-methylated derivative, and of folic acid is effected in short time. ... 

Reaction of 1 with ATP in presence of Mg and kinase gives 2-amino-4-hy-droxy-6-hydroxymethyldihydropteridine pyrophosphate (2, DHP pyrophosphate). The latter is converted into 7,8-dihydropteroate (3, DHP) by its reaction with p-ami-nobenzoic acid (PABA) and DHP synthetase. Addition of L-glutamic acid to DHP in the presence of the enzyme dihydrofolate synthetase (DHF synthetase) yields 7,8-di-hydrofolate (4, DHF), which undergoes reduction by the enzyme dihydrofolate reductase to afford 5,6,7,8-tetrahydrofolate (5, THF). DHF may also lose a hydrogen molecule in the presence of DHF dehydrogenase to form folic acid (6). 

The stereoselective hydrogenation of folic acid to tetrahydrofolic acid (Scheme 12.18) might represent an attractive alternative to the present unselective process which uses heterogeneous catalysts (diastereomeric excess (de) = 0%). One major problem here is the insolubility of folic acid in most organic solvents. Initial results with up to 42% de but very low TONs and TOFs were obtained by Brunner et al. using a Rh/BPPM complex adsorbed onto silica gel in aqueous buffer solutions [62]. Unfortunately, however, the originally claimed 90% de [62a] turned out to be an analytical artifact [62c]. 

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