Synthesis of 3′,5′-dithiothymidine and related compounds

Abstract

When 3′,5′-di-O-mesylthymidine 7 is heated first with triethylamine in ethanol solution and then with the sodium salt of 4-methoxyphenylmethanethiol 9 in N,N-dimethylacetamide (DMA) solution, the bis(sulfide) 11a is obtained in high yield; when the dimesyl ester 7 is treated with the same thiolate salt in hexamethylphosphoric triamide (HMPA) solution at room temperature, the threo-bis(sulfide) 12a is obtained stereospecifically. Treatment of the two bis(sulfides) 11a and 12a first with 2-nitrobenzenesulfenyl chloride 10 in acetic acid–dichloromethane (1:9 v/v) at 0 °C and then with zinc in hot acetic acid gives 3′,5′-dithiothymidine 5a and the cyclic disulfide 16, respectively, as crystalline solids in good overall yields. Although attempts to isolate the pure threo-dithio compoun 12b lead to the formation of the cyclic disulfide 16, when the crude material is treated with 2,2-dimethoxypropane in the presence of acid, its 3′,5′-S-isopropylidene derivative 17 is obtained and isolated as a crystalline solid in good overall yield.