The synthesis and properties of ether derivatives 6a-dof 5-hydroxymethyldeoxyuridine and their corresponding a-anomers 7a-d are described. Acid-catalyzed etherification of 5-hydroxymethyluraci1 (1) gave the corresponding 5-alkoxymethyluracils 2a-e in excellent yields. Treatment of compounds 2a-e with trimethylchlorosilane gave bis(trimethylsilyl)pyrimidines 3a-e in high yields which, upon condensation with 3,5-di-(0-p-to1uoyl)-2-deoxy-D-ribofuranosy chloride, furnished an anomeric mixture of substituted nucleosides, p-anomers 4a-e and a-anomers 5(a-e). The nucleosides with p-configuration were the major products in each case and were recovered as crystalline solids in good yields. Deblocking of compounds 4a-d by alcoholysis resulted in the corresponding ether derivatives 6a-d. From mother liquors, two substituted a-anomers, 5a, b were isolated as crystalline solids in small yields. Compounds 7c, d were obtained from mother liquors after hydrolysis by using preparative t.1.c. The structures were confirmed on the basis of p.m.r. studies, U.V. and i.r. absorption spectra, and elemental analysis. The compounds 2a-e and 6a-d did not inhibit thymidylate synthetase at a concentration of 2.5 mM. Canadian Journal of Chemistry, 48, 3147 (1970)The hydroxymethylpyrimidine deoxyribonu-corresponding blocked p-anomers 4a-e, and cleotides are unique constituents of viral DNA a-anomers, 5a-e; the p-anomers predominated (1-5); furthermire, 5-substituted pyrimidines have been suggested as possible intermediates during the transformation of thymine to RNA pyrimidines (6). The hydroxymethylation of pyrimidine deoxyribonucleotides is carried out by specific hydroxymethylases; the hydroxymethyl group originates from the Cl-unit of 5,lO-methylene tetrahydrofolic acid (7, 8). In this commuilication we report the synthesis of 5-substituted ether derivatives of 5-hydroxyin all cases.4 After removal of the silyl groups by aqueous ethanol, p-anomers IV (a-e), were isolated from the reaction mixture as crystalline solids in good yields (45-72 %). The F-configuration was assigned to 5-alkoxymethyl deoxyribonucleosides 4 (a-e) on the basis of a characteristic triplet in the p.m.r. spectrum; it exhibited a coupling constant (J,,,,, = J,.,,., of 7.0 + 0.1) c.p.s. for the anomeric proton at 6 6.30-6.35. Treatment of the substituted nucleosides 4a-e methyldeoxyuridine and their corresponding &-with hot sodium methoxide in methanol or with anomers (Scheme 1). We have prepared these ethanolic sodium hydroxide at room temperacompounds for the study of the bulk tolerance ture gave the corresponding 5-alkoxymethyl deof thymidylate synthetase to substituents on the rivatives of deoxyuridine 6a-e in excellent yields 5-position of the pyrimidine ring.(75-85%). In compounds 6a-e the signal of the The conversion of 5-hydroxymethyluracil (1) anomeric hydrogen (1 '-H) appeared in the form was successfully modified (9) to obtain 5-alkoxy-of a triplet as 6 6.16 with a coupling constant of methyluracils 2a-e in excellent yields (92-97%). J,,,,, = J,,,,., = 6.95 ...

The synthesis and properties of 5-hydroxymethyldeoxyuridine (6) and its a-anomer 7 are described. Treatment of 5-hydroxymethyluracil(2) with trimethylchlorosilane in the presence of triethylamine gave 2,4,5-tris(trimethylsily1)-5-oxymethyluracil (3) in excellent yield (92%) which, upon condensation with 3,5-di-(0-p-toluoyl)-2-deoxy-D-ribofuranoy chloride in acetonitrile at room temperature, furnished an anomeric mixture of substituted nucleosides p-anomer (4) and a-anomer (5) in high yield 90% (by a fusion method (12) yield of blocked nucleosides was 70%). Compound 4 was the major product formed by both methods and was recovered as a crystalline solid in high yield. However, condensation of 3 with chlorosugar in benezene with mercuric chloride as a catalyst at room temperature gave a mixture of protected nucleosides; the amount of 5 formed was appreciably higher (34%) and was isolated as a microcrystalline solid from mother liquors in low yield (without the catalyst nucleosides were formed in low yield 30%). Removal of the blocking groups by alcoholysis gave 6 and 7 in high yields. The structure was confirmed by n.m.r. studies, U.V. and i.r. absorption spectra, elemental analysis, and by conversion of 4 to p-thymidine (8).Canadian Journal of Chemistry, 49, 719 (1971) 5-Hydroxymethyl-2'-deoxyuridylate replaces thymidylate of the DNA of a virulent group of Bacillus subtilis bacteriophages (1-4). Its biosynthesis from deoxyuridylate and 5,10-methylene tetrahydrofolate is catalyzed by the enzyme, hydroxymethylase (5, 6), which is analogous to the hydroxymethylation of deoxycytidylate of Escherichia coli T-even bacteriophages (7). The enzymic transformation of thymidine to 5-hydroxymethyldeoxyuridine (6), has been demonstrated in Neurospora, and 5-substituted pyrimidines may be intermediates in the transformation of thymine to RNA pyrimidines (8).The synthesis of 6 from deoxyuridine under acidic conditions3 was reported by Cline et al. (9), and the base-catalyzed hydroxymethylation4 of deoxyuridine has been described by Baker et al. (10). Recently the chemical synthesis of 6 using a mercury procedure5 has been reported (I 1); in this method the removal of the benzyl group by 'This work was supported by the Medical Research Council of Canada (Grant MA-3136).2To whom correspondence should be sent. 3From a mixture of products, 6 was isolated by ion exchange chromatography in poor yield (19%). Using the described conditions, Baker et al. (10) reported an even lower yield (< 10%).4Although 6 was the main product under basic conditions, it could not be induced to crystallize and was difficult to isolate in the pure state. 5Mercury salt of 5-benzyloxymethyluracil was coupled with 3,5-di-(0-p-toluoy1)-D-ribofuranosylchloride, and from the reaction mixture, the blocked nucleoside 1-(2-deoxy-3,5-di-(O-p-toluoyl)-~-~-ribofuranosyl-5-benzyloxymethyluracil (9) was isolated in a yield of 57%. The removal of the benzyl group by catalytic hydrogenation yielded 4 which, upon deacylation gave 6. catalytic hydrogenation is a critic...

No abstract

No abstract

Treatment of 5-mercaptomethyluracil (I) with trimethylsilyl chloride in the presence of triethylamine gave 2,4,5-tris-(trimethylsilyl)-5-mercaptomethyluracil (II) which, upon coupling with 2-deoxy-3,5-di-O-(p-toluoyl)-D-erythro-pentofuranosyl chloride, furnished as anomeric mixture of fully substituted 2'-deoxy ribonucleosides. The nucleoside with beta configuration (III) was predominantly formed and was isolated as a crystalline solid. The free nucleoside IV was obtained by removal of blocking groups by sodium methoxide catalyzed deacylation, deionization under reducing atmosphere, and chromatography on neutral alumina. IV is oxidized to the corresponding disulfide V in solution in the absence of thiols. IV was found to be markedly inhibitory against the herpes virus of infectious bovine rhinotracheitis (IBR). Against this virus, IV was found to be as potent as 5-iododeoxyuridine and cytosine arabinoside when added 18 hr before virus infection.