Pyrimidin-4 -ones, formation

Cyclization of the 5-(A -arylcarboxamido)-4-hydrazino-6methylpyrim-idin-2-ones 104 with two molar equivalents of formaldehyde in the presence of pyridine caused the concomittant triazole and pyrimidine ring formation to yield the 4-aryl-l,3,4,10-tetrahydro-6-methyl-l,2,4-tria-zolo-[2,3,4-c,d]pyrimido[4,5-d]pyrimidine-5,8-diones 105 (89AP599)... 

A particularly intuitive application of this concept may be the experimental anticancer drug N-(phosphonoacetyl)-L-aspartate (PALA). The first step in the de novo biosynthesis of the pyrimidine nucleotide formation in the cell involves the condensation of carbamoyl phosphate with L-aspartic acid catalyzed by the enzyme aspartate transcarbamylase (Eq. 2.14).2 One can postulate a transition state, as shown in Eq. 2.14. 

A Dakin-West reaction on plant scale is demonstrated by elaboration of a modified procedure avoiding uncontrolled release of carbon dioxide. It seems to be generally accepted that the mechanism involves dehydrative formation of an azlactone (oxazolinone), which is then C-acylated (in equilibria with G-acylation), undergoes ring-opening hydrolysis, and then decarboxylates to form the acylamino ketone. Pyrimidine ring formation is achieved in a simple one-pot reaction, which is followed by a simple isomerization. Laboratory experiments had made clear that the mechanism... 

One of the most prevalent examples of reaction involving DNA excited states is pyrimidine-pyrimidine dimer formation. Thymine and cytosine are the two pyrimidine bases present in DNA, and pyrimidine-pyrimidine dimers can form between any combination of these two bases. The most common of these is the thymine-thymine (TT) dimer [4-7]. Two types of TT dimers are known (shown in Fig. 13.1). The first, and sole focus of this chapter due to its prevalence, is called cyclobutane pyrimidine dimer (CPD) and is formed by the [2-1-2] addition of the C5-C6 double bonds. The second is called the 6 photoadduct and is formed by the addition of the C5-C6 double bond on one thymine to the C4-04 double bond on the other. This leads to an oxetane intermediate that subsequently rearranges to form the 6-4 product. Both of these photoproducts are thought to form starting with initial excitation to a state. There is some debate in the literature... 

The stability of these 2,5 -anhydro nucleoside derivatives (38-41) which displayed antiviral activity, as well as compound 42, were determined at pH 7.5 and 2.0 (Table 4).l This was performed to determine if the biological activity of this class of compounds was due to the anhydro compound itself, or whether hydrolysis of the 2,5 -anhydro linkage occurred in solution to yield the parent compound which, as previously shown, had antiviral activity. All of the compounds tested are stable at neutral pH, with half-life values ranging from 60.5 h for 2,5 -anhydro-3 -azido-5-bromo-2, 3 -dideoxyuridine (40) to >168 h for 3 -azido-2, 3 -dideoxy-5-methylisocytidine (42). At low pH, however, the compounds displayed shorter and more variable half-lives, ranging from 11.3 min for 2,5 -anhydro-3 -azido-2, 3 -dideoxyuridine (38) to 140 min for 3 -azido-2, 3 -dideoxy-5-methylisocytidine (42). Pyrimidine base formation was not detected from any of these compounds. Moreover, the compounds decomposed to yield 7.5% or less of the parent compound after one half-life at either neutral or acidic pH, except for 18% of 2,5 -anhydro-3 -azido-2, 3 -dideoxyuridine (38), which was recovered as AZDU (1). 

Conversion of 5-allylthioimidates into /V-allylthioamides is catalyzed by Pd(Il). 2-Allylthiopyridine (820) is converted into the less stable l-allyl-2-thio-pyridone 821 owing to Pd complex formation[509], Claisen rearrangement of 2-(allylthio)pyrimidin-4-(3//)-one (822) affords the A-l-allylation product 823 as the main product rather than the A -3-allylation product 824[510] The smooth rearrangement of the allylic thionobenzoate 825 to the allyl thiolo-benzoate 826 is catalyzed by both PdCl2(PhCN)2 and Pd(Ph3P)4 by different mechanisms[511],... 

Subsequent knowledge of the stmcture, function, and biosynthesis of the foHc acid coenzyme gradually allowed a picture to be formed regarding the step in this pathway that is inhibited by sulfonamides. The biosynthetic scheme for foHc acid is shown in Figure 1. Sulfonamides compete in the step where condensation of PABA with pteridine pyrophosphate takes place to form dihydropteroate (32). The amino acids, purines, and pyrimidines that are able to replace or spare PABA are those with a formation that requkes one-carbon transfer catalyzed by foHc acid coenzymes (5). 

A variation of this procedure is used for sulfisomidine because of the different character of the amino group in the 4-position of a pyrimidine ring. Two moles of the sulfonyl chloride are condensed with one mole of 4-amino-2,6-dimethy1pyrimidine in the presence of triethylamine. The resulting bis(acetylsulfanilyl) derivative is readily hydrolyzed to the product. The formation of the bis(acetylsulfanilyl) derivative has also been employed for other heterocycHc amines, eg, for synthesis of sulfathiazole and sulfamoxole (44), but the 1 1 reaction is probably preferable. 

In many pyrimidine ring syntheses, it is possible or even desirable to isolate an intermediate ripe for ring-closure by the formation of just one bond. For example, ethyl 3-aminocrotonate (502) reacts with methyl isocyanate to give the ureido ester (503) which may be isolated and subsequently converted into 3,6-dimethyluracil (504) by the completion of one bond. However, viewed pragmatically, the whole synthesis involves the formation of two bonds and therefore is so classified. On such criteria, only two pyrimidine/quinazoline syntheses involve the formation of only one bond. 

Enzymic oxidations at the 7-position of pyrido[2,3-oxygenated derivatives and of the 8-N-oxide have been observed in the metabolism of the pyrido[2,3-e/]pyrimidine analogues of the antiepileptic drug methaqualone (75MI21502, 74MI21500). 

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

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