Synthesis of some 2′,3′-didehydro-2′,3′-dideoxynucleosides derived from modified pyrimidine bases

Abstract

3′,5′-Bis-O-(4-tolylsulfonyl)-thymidine and -2′-deoxyuridine (13a and 13b) reacted with sodium ethoxide in boiling ethanol to give the corresponding ethoxy-oxetanes 12a and 12b in 67 and 66% overall yield for the two-step processes starting from thymidine 4a and 2′-deoxyuridine 4b, respectively. Treatment of the ethoxy-oxetanes 12a and 12b with hydrogen sulfide and N¹, N¹, N³, N³-tetramethylguanidine in dry pyridine solution gave the 2-thiothymine- and 2-thiouracil-derived oxetanes 19a and 19b in 62 and 68.5% yield, respectively. When the latter compounds were treated with potassium tert-butoxide in dimethyl sulfoxide, the corresponding 2′, 3′-didehydro-2′, 3′-dideoxynucleosides (d4 nucleosides)10a and 10b were obtained in 66 and 60% yield, respectively. The 2-thiothymine-derived oxetane 19a was converted via the 5-methyl-2-thiocytosine-derived oxetane 21a into the 5-methyl-2-thiocytosine-derived d4 nucleoside 11a in 59.5% overall yield; the 2-thiouracil-derived oxetane 19b was similarly converted into the 2-thiocytosine- and 4-N-methyl-2-thiocytosine-derived d4 nucleosides 11b and 23 in 51 and 50% overall yield, respectively. Finally, the ethoxy-oxetane 12b was converted into the corresponding amino- and methylamino-oxetanes 25a and 25b in 74 and 83% yield, respectively. The latter compound, 25b, was successfully converted into the 2-N-methylisocytosine-derived d4 nucleoside 26b in 62% yield.