Synthesis of 5-substituted ether derivatives of 5-hydroxymethyldeoxyuridine and their α-anomers

The synthesis and properties of ether derivatives 6a–d of 5-hydroxymethyldeoxyuridine and their corresponding α-anomers 7a–d are described. Acid-catalyzed etherification of 5-hydroxymethyluracil (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-(O-p-toluoyl)-2-deoxy-D-ribofuranosyl chloride, furnished an anomeric mixture of substituted nucleosides, β-anomers 4a–e and a-anomers 5(a–e). The nucleosides with β-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 α-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.l.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.