Purine 8-methyl-, ring synthesis

The value of some nucleosides for use as flavor enhancers,1348 and the possible antiviral or antitumor activity of certain nucleosides,135 have led to the synthesis of purine nucleosides containing analogs of D-apiose in which the ring-oxygen atom of the furanose forms has been replaced.136 Monomolar p-toluenesulfonylation of 3-C-(hydroxy-methyl)-l,2-0-isopropylidene-/3-L-threofuranose (50) yielded 3-C-(hydroxymethyl)-l,2-0-isopropylidene-31-0-p-tolylsulfonyl-/3-L-thre-ofuranose (51) which, through a series of steps, was converted into either methyl 2,3-O-isopropylidene- [3-C-(hydroxymethyl)-4-thio-/3-D-... 

Aminopterin and amethopterin are 4-amino analogues of folic acid (Fig. 11.5) and as such are potent inhibitors of the enzyme dihydrofolate reductase (EC 1.5.1.3) (Blakley, 1969). This enzyme catalyses the reduction of folic acid and dihydrofolic acid to tetrahy-drofolic acid which is the level of reduction of the active coenzyme involved in many different aspects of single carbon transfer. As is clear from Fig. 11.6, tetrahydrofolate is involved in the metabolism of (a) the amino acids glycine and methionine (b) the carbon atoms at positions 2 and 8 of the purine ring (c) the methyl group of thymidine and (d) indirectly in the synthesis of choline and histidine. 

The structures of the vast majority of PD-5 inhibitor compounds aimed at erectile dysfunction consist of modified purines. The structure of the recently approved drug for this indication tadalafll (113) differs markedly from the prototypes. Tryptophan methyl ester (108) provides the starting material for large scale enantioselective synthesis. Condensation of that compound with piperonal (109) in the presence of acid leads to formation of the tricyclic intermediate (110). This transform involves initial addition of the amine to the aldehyde. The carhocation from the newly formed carhinolamine then attacks the indole 2-position to form the the fused piperidine. The stereochemistry of the new chiral center is guided by that from the tryptophan carhon across the ring. The secondary amine is next acylated with chloroacetyl chloride in the presence of triethylamine to afford 111. Reaction of this intermediate with methylamine goes on to form the desired product in a single step. This reaction can he rationalized... 

The preparation of 9-niethyl and 9-butyl-2-hydroxy-8,9-dihydro-7H-purine-8-thione (XXVa Table 7) is somewhat unusual. Brown [45) has obtained these compounds from carbon disulfide and respectively f-methyl and 1 -butyl-5,6-diamino-1,2-dihydropyrimidin-2-one (XXIVa.). Evidently a shift of the alkyl group from the 3-N to the 9 N atom must occur during the ring closure. The structure of these two purines has been confirmed by their independent synthesis from 4-methylamino and 4-butylamino-5-amino-2-hydroxy pyrimidine. 

A synthesis of sildenafil, which contains a bicyclic system (a l//-pyrazolo[4,3- f pyrimidine) isomeric with that of a purine, starts with a routine synthesis of a pyrazole (cf. 25.12.1.1) followed by M-methylation and ring nitration. Functional group manipulation provides a pyrazole equivalent to AICA (27.11.1.2) from which the pyrimidone ring is formed via reaction with an aromatic acid chloride. 

Compounds with a peri-fused imidazole ring to the purine ring 257 were only little studied. Their synthesis involved an intramolecular alkylation of 8-alkyl- or 8-aryl-9-(2-mesyloxyethyl)-l-methyl-purinediones 260b. The necessary intermediates 260b were achieved by hydrogenation of the 6-[2-(hydroxyethyl)-amino]-3-methyl-5-nitroso-pyrimidinedione 258 to 5-amino-6-[2-(hydroxyethyl)amino] compound 259 further reactions with the respective ortho-carboxylates and mesyl chloride gave 8-alkyl- or 8-aryl-9-(2-hydroxyethyl)-purinediones 260 or 261 (98CCC407) (Scheme 76). 

N-Methylation yields the monomethyl derivative sarcosine and also dimethylglycine, compounds that may function as osmoprotectants (Box 20-C). Many bacteria produce sarcosine oxidase, a fla-voprotein that oxidizes its substrate back to glycine and formaldehyde, which can react with tetrahydro-folate. The formation of porphobilinogen and the various pyrrole pigments derived from it and the synthesis of the purine ring (Chapter 25) represent two other major routes for glycine metabolism. 

Several processes described above use one-carbon derivatives of tetrahydrofolic acid (Fig. 14-22). E.g., the synthesis of the purine ring (Eig. 14-18) requires N °-formyl tetrahydrofolate. Thymidylate synthetase, a key enzyme in pyrimidine synthesis, uses FP,N -methylene tetrahydrofolate both as a donor of a methyl group... 

A well-known purine is the central nervous stimulant (CNS) caffeine (9.134), which is found in coffee and chocolate. Its synthesis (Scheme 9.77) illustrates the technique of forming the fused imidazole ring of purines. It was noted in Chapter 4 that diaminobenzenes reacted with carboxylic acids or esters to form benzimidazoles this process is known as the Phillips synthesis. It is this reaction that is used to fuse imidazoles to pyrimidines. Here, the process is known as the Traube purine synthesis. The initially formed purine is tri-methylated with methyl chloride and base to form caffeine (9.134). Note that under these conditions it is the 7-nitrogen that is methylated. 

Formate serves as a precursor of carbons 2 and 8 of the purine ring and of the 5-methyl group of thymine. Thus one may obtain information on the dynamic state of nucleic acids in tissues by measuring the rate of incorporation of injected formate-C into nucleic acids. It must be emphasized that the specific activities of isolated nucleic acids taken at early time intervals after injection of formate-C may reflect changes in pool size and specific activities of the precursors, either formate or the nucleotides, which are the immediate precursors of the nucleic acids, in addition to reflecting changes in the rate of nucleic acid synthesis. 

Attempted synthesis of 3-methylinosine by treatment of JV,iV-dimethyI-adenosine with excess methyl iodide failed because glycosyl cleavage occurred. Although the synthesis was successful with the 2, 3, 5 -tri-0-benzyl derivative, hydrogenolysis to deblock the product resulted in reduction of the purine ring. The problem was overcome by use of the 2, 3, 5 -tribenzoate. The ribosyl bond in 3-methylinosine was found to be unusually susceptible to acid... 

Both the pyrimidines and the purines are built up from small precursor molecules which are readily available in the metabolic pool (page 185). The free bases are not synthesized as such but, while being assembled, the partially constructed ring structure reacts with a special phosphorylated pentose known as PRPP (5-phosphoribosyl-l-pyrophosphate) and forms a ribonucleotide. The deoxyribonucleotides, with the exception of TMP which is formed by methylation of deoxyuridylate, are formed by reduction of the corresponding ribonucleoside diphosphate. The conversion is precisely controlled by allosteric effects which ensure that all four deoxyribonucleotides are available in amounts appropriate for nucleic acid synthesis. 

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