Application of the Michaelis–Arbusov reaction to the synthesis of internucleoside 3′-S-phosphorothiolate inkages

Abstract

The 5′-O-monomethoxytrityl-3′-S-(aryldisulfanyl)-3′-deoxythymidines 7 and 8 have been prepared by the reaction of 5′-O-monomethoxytrityl-3′-thiothymidine with the appropriate arenesulfenyl chloride. These disulfides undergo a Michaelis–Arbusov reaction with simple trialkyl phosphites to yield 5′-O-monomethoxytrityl-3′-thiothymidin-3′-yl O,O-dialkyl phosphorothiolates. More interestingly, 3′-deoxy-3′-S-(2, 4-dinitrophenylsulfanyl)-5′-O-monomethoxytritylthymidine 8 reacts with a variety of thymidin-5′-yl dialkyl phosphites to give dithymidine phosphorothiolate triesters with the phosphorothiolate group protected with either a methyl or a 2-cyanoethyl group.

3′-O-(tert-Butyldimethylsilyl)thymidin-5′-yl triethylammoniumphosphonate 17 is converted into the corresponding bis-(O-trimethylsilyl) phosphite by treatment with bis(trimethylsilyl)trifluoroacetamide. in situ Reaction of this phosphate with disulfide 8 gives, after work-up, the dithymidine phosphorothiolate diester directly. Methylation of compound 17 with methyl chloromethanoate, followed by silylation and subsequent reaction with disulfide 8, gives the methyl-protected dithymidine phosphorothiolate triester.