APPLICATION OF THE MICHAELIS-ARBUZOV REACTION TO THE SYNTHESIS OF INTERNUCLEOSIDE 3'-S-PHOSPHOROTHIOLATE LINKAGES

The oxytrityl-3'-S-(aryldisulfanyl)-3'-deoxythymidines 7 and 8 have be en 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 phosphorothi olates. More interestingly, 3'-deoxy-3'-S- trophenylsulfanyl)-5'-O-mon omethoxytritylthymidine 8 reacts with a variety of thymidin-5'-yl dial kyl phosphites to give dithymidine phosphorothiolate triesters with th e phosphorothiolate group protected with either a methyl or a 2-cyanoe thyl group. 3'-O-(tert-Butyldimethylsilyl)thymidin-5'-yl triethylammon iumphosphonate 17 is converted into the corresponding bis-(O-trimethyl silyl) phosphite by treatment with bis(trimethylsilyl)trifluoroacetami de. in situ Reaction of this phosphite with disulfide 8 gives, after w ork-up, the dithymidine phosphorothiolate diester directly. Methylatio n of compound 17 with methyl chloromethanoate, followed by silylation and subsequent reaction with disulfide 8, gives the methyl-protected d ithymidine phosphorothiolate triester.