Synthesis of some nucleoside cyclic phosphoramidates and related compounds via phosphoramidites

Abstract

Reaction of 2-chloro-3-methyl-1-oxa-3-aza-2-phosphacyclopentane with thymidine and with 2′-deoxy-5-fluorouridine gave their 3′,5′-bis-O-(3-methyl-1-oxa-3-aza-2-phosphacyclopentan-2-yl) derivatives (5) and (6). Reaction of these nucleosides with 2-chloro-1,3-dimethyl-1,3-diaza-2-phosphacyclopentane gave 3′,5′-bis-O-(1,3-dimethyl-1,3-diaza-2-phosphacyclopentan-2-yl) derivatives (7) and (8). The phosphoramidites, (7) and (8) were oxidised with dinitrogen tetraoxide to the corresponding phosphoramidates (9) and (10). Attempts to oxidise (5) and (6) in a similar way resulted in opening of the phosphoramidate ring. Treatment of compounds (5)–(8) with sulphur gave the corresponding phosphorothioamidates (11)–(14). The hydrolysis of 3′,5′-bis-O-(1,3-dimethyl-2-oxo-1,3-diaza-2-phosphacyclopentan-2-yl)thymidine (9) was studied using ³¹P n.m.r. spectroscopy. At pH 7.0 and 25 °C the half-life was 21 h. Both phosphorus heterocyclic rings opened at the same rate. The hydrolysis of the second ring proceeded at ca. three times the rate of hydrolysis of the first. 2′-Deoxy-5-fluoro-3′,5′-bis-O-(1,3-dimethyl-2-oxo-1,3-diaza-2-phosphacyclopentan-2-yl)-uridine (10) did not inhibit isolated purified thymidylate synthetase and was only a weak inhibitor of leukemia L1210 cell growth.