Novel method for the stereoselective synthesis of nucleoside derivatives starting from thioglycosides

A novel method for the stereoselective synthesis of nucleoside derivatives was developed by using the N-bromosuccinimide (NBS)-promoted coupling reaction of thioglycosides with silylated nucleoside bases. The following features were found through this study. (1) 2′-Deoxy-β-D-threo-pentofuranosyl nucleosides, which can be utilized as synthetic intermediates of 3′-substituted 2′,3′-dideoxynucleosides such as AZT, were synthesized with high stereoselectivity starting from the 3,5-O-isopropylidene derivative of the corresponding thioglycoside. (2) The reaction of 3,5-di-O-triisopropylsilyl-2-deoxy-1-thio-D-ribofuranoside proceeded in an α-anomerselective fashion to afford 2′-deoxy-α-ribonucleosides. (3) In the synthesis of 2′, 3′-dideoxynucleosides, the β-anomers were predominantly obtained by lowering the reaction temperature. (4) When various O-benzylated 1-thioglycosides, derived from some hexoses and pentoses, were used under the NBS-promoted coupling conditions, 1,2-cis-N-glycosides were obtained stereoselectively in every case. Finally, the reaction mechanism for the stereoselective coupling was discussed. We assumed intimate ion pair intermediates consisting of oxonium ions, derived from thioglycosides, and imide ion derived from NBS. An SN2 type attack of nucleoside bases would take place against the sterically favored intermediates to produce nucleoside derivatives bearing the observed stereochemistry at the anomeric positions.