Methanesulfonyl chloride → HCID 18647800, compound

Participants

Reaction Conditions

Reaction Steps

3'2-O-Anhydro-5'-tritylthymidine (10.5 g, 22.4 mMol) was added to a solution of sodium (0.52 g, 22.4 mMol) in dry ethanol (1.2 L) and the reaction was refluxed for six hours. The reaction was cooled and neutralized with 1N HCl. The solvent was removed in vacuo and the resultant all purified by flash chromatography on silica gel by elution with CHCl3 :MeOH (96.4 v/v). A 30% yield of 1-(2'-deoxy-5'-trityl-D-lyxofuranosyl)-2-ethoxythymine was obtained. The 2-ethoxythymidine derivative (3.5 g, 16.8 mMol) was dissolved in 35 mL of DMF containing 2.2 mL of triethylamine. The cold solution was saturated with H2S. The reaction was placed in a steel bomb and heated at 95° C. After twenty seven hours TLC indicated no starting material remained. The reaction was purged with N2 for several hours and poured onto ice water. The product was collected by filtration and purified by flash chromatography on silica gel by elution with CHCl2 :MeOH (97:3 v/v). A 37% yield of 1-(2'-deoxy-5'-trityl-β-D-lyxofuranosyl)-2-thiothymine was obtained. The UV max at pH1 of 277 nm and at pH11 of 241 nm indicated the formation of a 2-thiothymidine. The 3'-hydroxyl of the thiothymidine derivative was mesylated as follows: methanesulfonyl chloride (665 μL, 3.5 eq.) was added in four portions over six hours to a solution of 1-(2'-deoxy-5'-trityl-β-D-lyxofuranosyl)-2-thiothymidine (1.25 g) in dry pyridine (15 mL) at 5° C. The reaction was maintained at 5° C. overnight. The reaction was poured onto ice water and the product collected by filtration. Purification was accomplished by flash chromatography on silica gel by elution with ethyl acetate:hexane (1:1 v/v). The yield was 30%. Lithium azide (0.3 g, 6 mMol) was dissolved in 20 mL of dry DMF and 1-(2'-deoxy-3'-mesyl-5'-trityl-β-D-lyxofuranosyl)-2-thiothymine (0.72 g, 1.2 mMol) was added. The DMF solution was heated at 85° C. for 2.5 hours. The reaction was poured onto ice water and the product collected by filtration. Purification was accomplished by flash chromatography on silica gel by elution with CHCl3 :MeOH (98:2 v/v). The yield was 78%. A band in the IR at 2100 CM-1 indicated the presence of an alkyl azide. The UV confirmed the presence of a 2-thiothymidine. The final product was prepared by deblocking the 5'-hydroxyl of 3'-azido-2-thio-5'-tritylthymidine (0.1 g) in 80% acetic (5 mL) on a steambath for fortyfive minutes. 3'-Azido-2-thiothymidine (0.021 g) was obtained by chromatography on silica gel by elution with CHCl3 :MeOH (96:4 v/v) in 37% yield.

Provenance & Evidence