Stereocontrolled synthesis of 4′-C-cyano and 4′-C-cyano-4′-deoxy pyrimidine pyranonucleosides as potential chemotherapeutic agents

Abstract

A new series of 4′-C-cyano and 4′-C-cyano-4′-deoxy pyrimidine pyranonucleosides has been designed and synthesized. Commercially available 1,2,3,4,6-penta-O-acetyl-d-mannopyranose (1) was condensed with silylated 5-fluorouracil, uracil, and thymine, respectively to afford after deacetylation 1-(α-d-mannopyranosyl)nucleosides (2a–c). Subjecting 2a–c to the sequence of specific acetalation, selective protection of the primary hydroxyl group and oxidation, the 4′-ketonucleosides 6a–c and 7c were obtained. Reaction of compounds 6a,b, and 7c with sodium cyanide and subsequent deprotection gave the target 1-(4′-C-cyano-α-d-mannopyranosyl)nucleosides 12a–c. Deoxygenation at the 4′-position of cyanohydrins 8a,b, and 11c followed by deprotection led to the desired 1-(4′-C-cyano-4′-deoxy-α-d-talopyranosyl)nucleosides (15a–c). The newly synthesized compounds were evaluated for their potential antiviral and cytostatic activities in cell culture.