Alkylation of purines

Saito et al. achieved the first direct confirmation of double alkylation of purine bases by azinomycin B [140]. They incubated azinomycin B with the self-comple-mentary DNA duplex d(TAGCTA)2 and monitored the reaction by HPLC and ion spray MS. They observed initial formation of a monoadduct that was then converted into a crosslinked bisadduct. The crosslink position was identified as between the guanine of one strand and the 5 -adenine on the other strand by thermo-lytic depurination. Further decomposition prevented structural analysis of the azi-... 

Lindblom and Blander (1980) have given a number of examples of relevance in the pharmaceutical industry. These include C-alkylations, 0-alkylations, and A-alkylations. The C-alkylation of phenylacetonitrile, (mono- and di-) alkylation of benzylpenicillin with a-chlorodiethyl carbonate (where the acid part and the halide part in the esterification would have degraded quickly under normal conditions adopted for the reaction), A-alkylation of purines and adenine, etc. are discussed at some length and the supremacy of PTC is clearly shown. 

Alkylation of purine derivative 72 yields an N-7/N-9 regioisomer (73/ 74) mixture which can be purified using aluminium oxide/H+ to provide the N-9 isomer selectively as a parallel or chemoselective high-throughput purification <00TL3573>. 

Purines. Extensive information is available about the site of alkylation of purines.1, 185-187 Many of these reactions, although taking place at an... 

Ogilvie et al.ls0 have described facile alkylation of purines and pyrimidines in THF, using tetrabutylammonium fluoride (TBAF) at room temperature. Uracil, cytosine, and adenine give mainly 1,3-dialkylation. 

Ma J, Lin W, Wang W, Flan Z, Yao S, Lin N (2000) Triplet state mechanism for electron transfer oxidation of DNA. J Photochem Photobiol B Biol 57 76-81 Maeda M, Nushi K, Kawazoe Y (1974) Studies on chemical alterations of nucleic acids and their components VII. C-alkylation of purine bases through free radical process catalyzed by ferrous ion. Tetrahedron 30 2677-2682... 

As has already been pointed out, the Finkelstein reaction can be conducted in situ in the absence of solvents. For example, alkylations of purine and pyrimidine bases with alkyl halides and dimethyl sulfate have been carried out by solid/liquid phase-transfer catalysis in the absence of any additional solvent [48], as have cyanation of haloalkanes [49] and / -eliminations [50]. Noteworthy is the synthesis of glycosyl isothiocyanates by the reaction of potassium thiocyanate with molten glycosyl bromide at 190 °C [51]. 

An anomalous result arose from the alkylation of purine-6-thione with 2-bromoethylamine. The product was not the S-alkylated purine (80) but the adenine derivative (79) which, on acid treatment, reverted... 

Unfortunately, the results of the mathematical treatment normally only reflect ground-state values of the molecules (75UC668) since it is difficult to find formulae which include all the various intrinsic environmental and extraneous factors such as solvent effects. Thus in the case of purine, CNDO calculations suggest that the IH tautomer should have a slightly lower energy value than the 9H form. In the solid state this appears to be the case (65AX573> but in solution there is ample chemical evidence of the equivalence of the IH and 9H forms. Thus alkylation of purine with vinyl acetate leads to equal amounts of the 7- and 9-vinylpurines (27) and (28), respectively, but with other purines the reaction is kinetically rather than thermodynamically controlled and normally only one alkylated purine is produced (75JOC3296) (see also Section 4.09.5.2.2). 

Much of the earlier literature of purines was concerned with attack by nucleophiles but more recently there has been a marked increase in studies of electrophile attack. This is no doubt encouraged in part by work concerned with the mechanism of oncogenesis which involve arylation or alkylation of purines usually at C-8. 

Substituted purines may arise in mixtures with 9-substituted derivatives from direct alkylation of purine anions. They are best prepared however by Traube syntheses. Thus formylation of 4,5-diamino-6-benzylthiopyrimidine and ethylation of the formyl derivatives gave a formamidopyrimidine which readily cyclized to 6-benzylthio-7-ethylpurine in the presence of potassium carbonate (B-68MI40901, p. 31). The derivative is clearly a ready source of 7-substituted adenines by reaction with ammonia or amines, or of 7-substituted purines by dethiation with Raney nickel. 7-Methylguanine has also been obtained from 7-methyl-guanosine, sodium borohydride and aniline at pH 4.5 (B-78MI40903, p. 615). 

In addition to C8 alkylation, C2 alkylation of purines has been reported. The regioselectivity has been correlated with the site of cation formation, alkylation occurring mostly on the carbon where the proton resonates at lowest field. Details of methylation products and product ratios at different pH values for a series of free-radical, purine methylations are given in Table 41. "... 

Another C-alkylation of purines is the free-radical reaction with alkyl hydroperoxides catalyzed by iron(II) ions. This reaction has been applied to guanine, hypoxanthine, and adenine, as well as their nucleosides. A typical example is the 8-methylation of guanine to give 5 other examples are listed in Table 42. 

Father examples of C-alkylation of purines can be found in Table 42. 

It has been shown that direct alkylation of purines, e.g. adenine, leads mainly to the N3 and, to a lower extent, to the N9 alkylated products. If these alkyl groups (e.g., allyl) are removable (e.g., by hydrogenolysis) they can be used as intermediate protecting groups for further alkylation. ... 

The results of various alkylations of purines and purine nucleosides are collated in Table 44. Table 44. Alkylation of Purines and Purine Nucleosides by Various Methods... 

Trimethylsilylation of6a-c followed by treatment with l-acetoxy-2-(bromomethoxy)ethane in the presence of mercury(II) cyanide gives the N9 alkylated products 7a-c in high yield under effective elimination of the N7 isomers normally found in alkylations of purine sodium salts. From 7a-c, the acyclic adenine or guanine compounds are obtained by deacylation. A typical procedure is given. 

Alkylation of purines, in particular adenine and guanine, with bifunctional reagents may result in a new heterocyclic ring being fused to the purine. 

As would be expected from systems containing four nitrogen atoms, A-alkylation of purines is complex and can take place on the neutral molecule or via an A-anion. Purine reacts with iodomethane to give a... 

Fig. (11), previous page. Mechanism of DNA depurination promoted by the alkylation of purine bases by ptaquiloside, as proposed by Kushida et al. (1994). 

As part of programmes directed towards the synthesis of new potential biologically active compounds, a variety of cyclic xanthine derivatives, e.g., (37) and (38), have been prepared by Russian workers." During a detailed study aimed at elucidating modes of alkylation of purines, treatment of 6-methylthio-8-phenyl-purine (39 R = H) with methyl iodide in DMF was shown to yield a single methiodide, which upon hydrolysis gave exclusively the 3-methyl derivative (40). Similarly, the 7-methyl and 7-methyl analogues, (41) and (42), yielded 3-methyl... 

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