Hydroxymethyl pyrimidine

Scheme 32.—Decarboxylation of 4-amino-2-carboxymethyl-5-hydroxymethyl-pyrimidine.

The phenomenon of 5-hydroxymethylation is a standard case of electrophilic attack. Thus uracil (83 R = H) and paraformaldehyde in aqueous alkali furnish 5-hydroxymethyl-pyrimidine-2,4(lJF/,3JF7)-dione (83 R = CH2OH) in good yield (59JA2521). Aromatic aldehydes react differently to yield 5-benzylidene derivatives of, for example, 1-methylbar-bituric acid (78CC764). 

Figure 4 Biosynthesis of thiamine (vitamin ). 37, aminoimidazole ribotide 38, 2-methyl-4-amino-5-hydroxymethyl-pyrimidine phosphate 39, pyridoxal 5 -phosphate 40, histidine 41, 2-methyl-4-amino-5-hydroxymethyl-pyrimidine pyrophosphate 42, 4-methyl-5-p-hydroxyethylthiazole phosphate 43,1 -deoxy-D-xylulose 5-phosphate 44, 5-ADP-D-ribulose 45, thiamine phosphate 46, thiamine pyrophosphate.

The bases always present in DNA are adenine, guanine, cytosine, and thymine, while in RNA the bases are adenine, guanine, cytosine, and uracil. Trace amounts of other bases are occasionally present in DNA and RNA. For example, DNA may contain 5-hydroxymethyl cytosine and several N-methyl purines. The tRNA may contain several unusual bases such as certain methyl purines or hydroxymethyl pyrimidines. 

Cyclization of 6-(hydroxymethyl)pyrimidine-2,4(l//,3/7)-dione-5-carboxaldehyde 135 with Bp3/Et20 in thioacetic acid gave 133 (R = R = H) (73TL2055). 

Vitamin Bi is an essential co-factor for several enzymes of carbohydrate metabolism such as transketolase, pyruvate dehydrogenase (PDH), pyruvate decarboxylase and a-ketoglutarate dehydrogenase. To become the active co-factor thiamin pyrophosphate (TPP), thiamin has to be salvaged by thiamin pyrophosphokinase or synthesized de novo. In Escherichia coli and Saccharomyces cerevisiae thiamin biosynthesis proceeds via two branches that have to be combined. In the pyrimidine branch, 4-amino-5-hydroxymethy-2-methylpyrimidine (PIMP) is phosphorylated to 4-amino-2-methyl-5-hydroxymethyl pyrimidine diphosphate (PIMP-PP) by the enzyme HMP/HMP-P kinase (ThiD) however, the step can also be catalyzed by pyridoxine kinase (PdxK), an enzyme also responsible for the activation of vitamin B6 (see below). The second precursor of thiamin biosynthesis, 5-(2-hydroxyethyl)-4-methylthiazole (THZ), is activated by THZ kinase (ThiM) to 4-methyl-5-(2-phosphoethyl)-thiazole (THZ-P), and then the thia-zole and pyrimidine moieties, HMP-PP and THZ-P, are combined to form thiamin phosphate (ThiP) by thiamin phosphate synthase (ThiE). The final step, pyrophosphorylation, yields TPP and is carried out by thiamin pyrophosphorylase (TPK). 

Bestrahlt man 5-Brom-2-methoxy-pyrimidin in Methanol unter Zusatz von Diathyl-amin, so lauft neben der Alkylierung und Hydroxyalkylicrung eine Debrotnierung ab (s. a. S. 1456)3. Es entstohen mit geringen Ausbeuten 5-Brom-2-methoxy-4-methyl-pyrimi-din bzw. -4-hydroxymethyl-pyrimidin und 2-Methoxy-pyrimidin neben 2-Methoxy-4-hydroxy-methyl-pyrifnidin und 2-Me.lhoxy-v-nielhyl-p jrimidin ... 

Biosynthesis of the pyrimidine ring of thiamin (vitamin Bi) from aminoimidazoleribonucleotide. The 2-methyl-4-amino-5-hydroxymethyl-pyrimidine ring present in thiamin is synthesized from aminoimida-zoleribomlcleotide, which is an intermediate in purine biosynthesis (Fig. 4). 

Thiamine monophosphate is built from 2-methyl-4-amino-5-hydroxymethyl pyrimidine pyrophosphate and 4-methyl-5-(j8-hydroxyethyl)-thiazole (Fig. 183). The pyrimidine part is derived from 5-aminoimidazole ribonucleotide, an intermediate of purine biosythesis (D 10.4). As yet the origin of C-5 and the CH2OH-group as well as that of the CHg-group is stiU unknown. The thiazole moiety is derived from the precursors given in Fig. 184. Intermediates were not identified. 

Strains of Corynebacterium and Mycobacterium oxidized thymine and uracil to 5-methylbarbituric acid and barbituric acid, respectively, and it appeared that a single enzyme, uracil-thymine oxidase, was responsible for the oxidation of both bases (896) (Fig. 23). Uracil oxidase (398) and uracil-thymine oxidase (896) may be identical, since on purification of the former, the rates of oxidation of uracil and thymine remmned constant. A phosphorylated uracil-5-carbinol (2,4-dihydroxy-5-hydroxymethyl-pyrimidine) was isolated as an oxidation product of thymine by resting bacterial cells (398). However, the spectroscopic characteristics of the compound suggested that this compound may have been 5-methylbarbituric acid (896). 

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

The pathways for thiamine biosynthesis have been elucidated only partiy. Thiamine pyrophosphate is made universally from the precursors 4-amino-5-hydroxymethyl-2-methylpytimidinepyrophosphate [841-01-0] (47) and 4-methyl-5-(2-hydroxyethyl)thiazolephosphate [3269-79-2] (48), but there appear to be different pathways ia the eadier steps. In bacteria, the early steps of the pyrimidine biosynthesis are same as those of purine nucleotide biosynthesis, 5-Aminoimidazole ribotide [41535-66-4] (AIR) (49) appears to be the sole and last common iatermediate ultimately the elements are suppHed by glycine, formate, and ribose. AIR is rearranged in a complex manner to the pyrimidine by an as-yet undetermined mechanism. In yeasts, the pathway to the pyrimidine is less well understood and maybe different (74—83) (Fig. 9). 

The concept and use of free radical attack on pyrimidines has been little developed. However, pyrimidine does react slowly with p-nitrobenzenediazonium chloride to yield some 2- and 4-p-nitrophenylpyrimidines (51JCS2323) in addition, 2,4-and 4,6-dimethyl-pyrimidine are converted by hydroxymethylene radicals (from ammonium peroxydisul-fate/methanol) into 6- and 2-hydroxymethyl derivatives, respectively (77H(6)525). Certain bipyrimidine photoproducts appear to be formed from two similar or dissimilar pyrimidinyl radicals (see Section 2.13.2.1.4). 

The simplest pyrimidine antibiotic is bacimethrin, 5-hydroxymethyl-2-methoxypyrimidin-4-amine (985), which was isolated in 1961 from Bacillus megatherium and is active against several yeasts and bacteria in vitro as well as against staphylococcal infections in vivo it has some anticarcinoma activity in mice (69MI21301). It may be synthesized by LAH reduction of ethyl 4-amino-2-methoxypyrimidine-5-carboxylate (984) which may be made by primary synthesis in poor yield, or better, from the sulfone (983) (B-68MI21304). 

H,4H-Oxazolo[5,4,3-y]pyrido[3,2-g]quinolin-4-one, 8-hydroxymethyl-6-methyl — see Nybomyein 5H-Oxazolo[2,3-[Pg.731]

The terc-butyldimethylsilyl groups of pyrido[l,2-c]pyrimidine 154 was eliminated with BU4NF to afford 6-hydroxy-8-hydroxymethyl derivative 155 (00TL1849). Compound 155 gave tricyclic derivative 156 under Mitsunobu conditions. 

Hydrolysis of 3-[(2,6-dimethoxy-4-pyrimidinyl)hydroxymethyl]perhydro-pyrido[l,2-c]pyrimidin-l-iminium salts 174-177 in boiling cone. HCl afforded the appropriate 3-[(2-hydroxy-6-oxo-l,6-dihydropyrimidin-4-yl) hydroxymethyl] derivative (98TL7021, 00JA5017). 

Thiamine is present in cells as the free form 1, as the diphosphate 2, and as the diphosphate of the hydroxyethyl derivative 3 (Scheme 1) in variable ratio. The component heterocyclic moieties, 4-amino-5-hydroxymethyl-2-methylpyrimidine (4) and 4-methyl-5-(2-hydroxyethyl)thiazole (5) are also presented in Scheme 1, with the atom numbering. This numbering follows the rules of nomenclature of heterocyclic compounds for the ring atoms, and is arbitrary for the substituents. To avoid the use of acronyms, compound 5 is termed as the thiazole of thiamine or more simply the thiazole. This does not raise any ambiguity because unsubstituted thiazole is encountered in this chapter. Other thiazoles are named after the rules of heterocyclic nomenclature. Pyrimidine 4 is called pyramine, a well established name in the field. A detailed account of the present status of knowledge on the biosynthesis of thiamine diphosphate from its heterocyclic moieties can be found in a review by the authors.1 This report provides only the minimal information necessary for understanding the main part of this chapter (Scheme 2). 

Thiamine can be considered to be the product of the quatemization of 4-methyl-5-(2-hydroxymethyl)thiazole (5) by an active derivative of 4-amino-5-(hydroxymethyl)-2-methyl pyrimidine (4) (Scheme 2). In living cells, pyramine can be activated by conversion into the diphosphate 7, via monophosphate 6, and the substrate of the enzyme responsible for the quatemization is not the thiamine thiazole, but its phosphate 8. The product of the condensation, thiamine phosphate (9), is finally converted into diphosphate 2—the biochemically active derivative—by hydrolysis to free thiamine, followed by diphosphorylation, or more directly, in some cases. Enzymes are known for all of the steps depicted in Scheme 2, and adenosine triphosphate (ATP) is, as usual, the phosphate donor. 

Zhou S, Breitenbach JM, Borysko KZ, Drach JC, Kern ER, GuUen E, Cheng YC, Zemhcka J (2004) Synthesis and antiviral activity of (Z)- and (E)-2,2-[bis(hydroxymethyl) cyclopropylidene]methylpurines and -pyrimidines second-generation methylenecyclopropane analogues of nucleosides. J Med Chem 47 566-575... 

The bromine atom of 4-aryl-2-(4-bromobutyl)-2,3,5,6,7,8-hexahydro-177- ancj -perhydropyrido[l,2-c]pyrimidine-l,3-diones was displaced with 4-substituted piperazines <2002FES959, 2004APH139, 2004PHA99>. Heating 3-hydroxymethyl derivatives of epimeric 6-methyl-l,3,4,6,7,llb-hexahydro-277-pyrimido[6,l-,2]isoquinolin-2-ones 152 resulted in the formation of the 3-unsubstituted derivatives 153 by loss of CH20 (Equation 26) <1997LA1165>. 

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