Pyrimidines pteridine ring

Vitamins are substances essential for a healthy life humans must ingest vitamins via their diet because there is no mechanism for their biosynthesis in the body. There are 14 vitamins - the name was coined when the first vitamin chemically identified (vitamin Bi in 1910) turned out to be an amine - a vital amine. A typical vitamin is folic acid, a complex molecule in which the functionally important unit is the bicyclic pyrazino[2,3- f pyrimidine (pteridine) ring system, and its arylaminomethyl substituent. Folic acid is converted in the body into tetrahydrofolic acid (FH4) which is crucial in carrying one-carbon units, at various oxidation levels, for example in the biosynthesis of purines, and is mandatory for healthy development of the foetus during pregnancy. Other essential co-factors that contain pteridine units must and can be biosynthesised in humans - without them we cannot survive - aud are incorporated into oxygen-transfer enzymes based on molybdenum, in which the metal is liganded by a complex ene-dithiolate. 

The pteridine ring system is composed of fused pyrazine and pyrimidine rings, either of which might be attacked by a complex metal hydride. The reaction of pteridine (145), 2,4-dichloropteridine (146), or 2,4-dimethoxypteridine (147) with lithium aluminum hydride was reported to occur with reduction of the pyrazine ring to give the 5,6,7,8-tetrahydropteridine (148-150, respectively).150... 

The known chemistry is almost entirely limited to the fully conjugated systems which have received a great deal of attention in recent years. Most systems are readily available and a number of these have been prepared for biological purposes. Others like the furazano[3,4-cf]pyrimidines can be used as intermediates in the preparation of purine or pteridine ring systems. 

Kuyper et al. (208) modeled the binding of the bacterial DHFR-selective antibiotic trimethoprim (11 A) using the X-ray structure of the . coli-methotrexate complex. They assumed that the pyrimidine ring of trimethoprim would bind analogously to the corresponding pteridine ring of methotrexate (their model was later shown to be qualitatively correct by... 

Pyrazino[2,3-d/]pyrimidines are known as pteridines , because the first examples of the ring system, as natural products, were found in pigments, like xanthopterin (yellow), in the wings of bntterflies (Lepidoptera). The pteridine ring system has subsequently been found in coenzymes that use tetrahydrofolic acid (derived from the vitamin folic acid), and in the cofactor of the oxomolybdoenzymes and comparable tungsten enzymes. 

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... 

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... 

A few examples have appeared of the formation of 3-amino-substituted pyrazine- and quin-oxalinecarboxylic derivatives by nucleophilic decomposition of their pyrimidine-fused ring systems (pteridines and analogues) (see also Section 6.03.4.1) <86JHC843,87JHC1013,91JHC1485>. 

Replacement of carbon by nitrogen at position 8 of the pteridine ring in MTX and AMT has been accomplished by Srinivasan and Broom [36]. Starting from 6-bromomethylpyrido[3,2-rf]pyrimidine-2,4(lf/,3/f)-dione (III. 115), the xV-oxide was prepared by w-chloroperbenzoic acid oxidation and subjected to Polonovski rearrangement (AcjO-AcOH) to obtain the 6-acetoxymethyl derivative (III.116). Treatment of (III.116) with POCI3 afforded the 2,4-dichloro derivative (III.117), which on being heated at 160-170 °C in liquid ammonia in a pressure vessel was converted to the... 

The pyridinium ylide (24) is obtained from the reaction of 8-bromotheophylline with pyridine. Alkylsulphonate salts of caffeine have been synthesized. A new purine-into-pteridine ring transformation has been discovered. For example, the quaternary salt (25) was obtained by direct alkylation of an appropriate xanthine with ethyl bromoacetate. Base-catalysed hydrolysis of (25) gave the pyrimidine (26), which could be cyclized to give the isoxanthopterin derivative (27). 

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). 

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. 

In pteridines, we have a pyrimidine ring fused to a pyrazine ring. There are, of course, a number of possible ways of combining these two six-membered ring systems pteridines are pyrazino[2,3-fi(]pyrimidines (see Section 11.9). 

Purines (purine = 7//-imidazo [4,5-rf]pyrimidine, C5H4N4) and pteridines (pteridine = pyrazino [2,3-d]pyrimidine, C6FI4N4) are compounds consisting of two fused A-heterocyclic rings. Adenine and guanine are important purines. They are used, for example, as building blocks for nucleotides (see discussion below). Folic acid (a vitamin), methopterin, and methotrexate are typical pteridines. 

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