Pteridines ring synthesis

RING SYNTHESIS BY TRANSFORMATIONS OF OTHER RINGS 7.18.10.1 Biosynthesis of Pteridines... 

The pterins include the redox cofactors biopterin and molybdopterin, as well as various insect pigments. Folic acid is a conjugated pterin, in which the pteridine ring is linked to p-aminobenzoyl-poly-y-glutamate it is this linkage that renders folate a dietary essential, because it is the ability to condense p-aminobenzoate to a pteridine, rather than to synthesize the pteridine nucleus itself, which has been lost by higher animals. Biopterin (Section 10.4) and molybdopterin (Section 10.5) are coenzymes in mixed-function oxidases they are not vitamins, but can be synthesized in the body. Rare genetic defects of biopterin synthesis render it a dietary essential for affected individuals. 

A closer look at these events reveals that bacteria synthesize folic acid using several enzymes, including one called dihydropteroate synthetase, which catalyzes the attachment of p-aminobenzoic acid to a pteridine ring system. When sulfanilamide is present it competes with the p-amino-benzoic acid (note the structural similarity) for the active site on the enzyme. This activity makes it a competitive inhibitor. Once this site is occupied on the enzyme, folic acid synthesis stops and bacterial growth stops. Folic acid can also be synthesized in the laboratory. ... 

Dietary folates must be chemically reduced to their tetrahy-dro forms, with four hydrogens on the pteridine ring, to be active. The enzyme responsible for this reduction is dihydrofolate reductase (DHFR), a key enzyme whose actions are inhibited by methotrexate and other antifolates. The result of this inhibition is depletion of intracellular pools of reduced folates (tetrahydrofolates) essential for thymidylate and purine synthesis. Lack of either thymidine or purines prevents synthesis of DNA. The DHFR-mediated effects of antifolate drugs on normal and probably also on cancerous cells may be neutralized by supplying reduced folates exogenously. The reduced folate used clinically for rescue is leucovorin (folinic acid), which bypasses the metabolic block induced by DHFR inhibitors. ... 

The synthesis of the pteridine ring system has been approached by two obvious routes one is the fusion of the pyrazine ring onto a pre-formed 4,5-diamino-pyrimidine, and the second, the elaboration of the pyrimidine ring on a pre-formed pyrazine. The first of these, the Isay synthesis, suffers from the disadvantage that condensation of the heterocyclic 1,2-diamine with an unsymmetrical 1,2-dicarbonyl compound... 

The first synthesis of the pteridine ring system 1 was separately reported by Wohler1 and... 

A more versatile synthesis of the pteridine ring from pyrimidine-4,5-diamine involves the initial formation of a Schiff base by reaction with an aldehyde followed by cyclization with triethyl orthoformate or dimethylformamide diethyl acetal. The general reaction is shown below, and is exemplified by the synthesis of 6-phenylpteridine-2,4(1 //,3//)-dione (2)." 7... 

Although comparatively rarely used, the introduction of the N3 fragment to construct the pteridine ring can produce some very useful compounds. The reaction is exemplified by the synthesis of pteridin-4-amine (2) from 3-[(dimethylamino)methyleneamino]pyrazine-2-carboni-trile (1) and ammonium acetate.146... 

An alternative method of synthesis of (IV.91) from 2,4-diamino-6-bromo-methylpteridine was described in 1980 by Piper and Montgomery [120]. The bromo compound was treated with triphenylphosphine in DMA (60-63 °C, 1.5 h), and the resultant ylide was condensed with diethyl N- 4-formylbenzoyl)-L-glutamate to obtain diester (IV.97) in 78% yield. Catalytic reduction of the 9,10 double bond resulted in partial reduction of the pteridine ring to a 7,8-dihydro derivative. Reoxidation of ring B with HjOj followed by ester hydrolysis with NaOH afforded (IV.91) (62%). 

For a long time before the ring structure of pterins was known, compounds containing the pteridine ring were being prepared. In 1895, 2,4-dihydroxy-pteridine was prepared by oxidation of tolualloxazine and decarboxylation of the resulting 2,4-dihydroxypteridine-6,7-dicarboxylic acid, and the same compound was prepared in 1907 by the action of hypobromite on pyrazine-2,3-dicarboxamide. The condensation of 4,5-diaminopyrimidine and benziF to form 6,7-diphenylpteridine reported in 1906 was the first example of the most versatile general method of pteridine synthesis. 

The cleavage of heteroaryl sulfones from polymeric supports can be achieved by reaction with azide ions. Suckling el al. applied this strategy to the synthesis of pteridines. In fact, the starting pyrimidine was linked to polystyrene via a thioether 214. After con-stmction of the pteridine ring system, the activation of the sulfur linker by oxidation to the sulfone with dimethyldioxirane followed by nucleophilic substitution with sodium azide affords the target molecule 218 in 41% overall yield (Scheme 3.30). 

Amino-l,3-dimethyl-5-nitrosouracil (270), reported last year as a highly versatile precursor for the purine and pteridine ring systems, has again found use (Scheme 63) in a new synthesis of 6-hydroxy-pteridines (271). Photo-decomposition of 6-azido-l,3-dimethyluracil as a solution in a secondary or primary amine has been used as a convenient method of preparing 6-alkylamino-5-amino-uracils. The procedure has now been extended ... 

Proguanil (Fig. 3.16) was a relatively early antimalarial drug and it is still useful as a first line of defence against the erythrocytic stage of malaria. It is metabolised in the human body to an active metabolite which mimics the pteridine ring in folic acid and acts as a selective inhibitor of folate reductase in the parasite, thus inhibiting its DNA synthesis. 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

The substitution of pteridines at positions adjacent to the pyridine-like nitrogen atoms in either the pyrimidine or the pyrazine is a well-established synthetic procedure and remains an important contributor to the synthesis of complex substituted pteridines. Significant extensions of these methods have been described at both the pyrimidine and pyrazine rings. 

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