NOVEL METHOD FOR THE STEREOSELECTIVE SYNT HESIS OF NUCLEOSIDE DERIVATIVES STARTING FROM THIOGLYCOSIDES

A novel method for the stereoselective synthesis of nucleoside derivat ives was developed by using the N-bromosuccinimide (NBS)-promoted coup ling reaction of thioglycosides with silylated nucleoside bases. The f ollowing features were found through this study. (1) 2'-Deoxp-beta-D-t hreo-pentofuranosyl nucleosides, which can be utilized as synthetic in termediates of 3'-substituted 2', 3'-dideoxynucleosides such as AZT, w ere synthesized with high stereoselectivity starting from the 3,5-O-is opropylidene derivative of the corresponding thioglycoside. (2) The re action of -triisopropylsilyl-2-deoxy-1-thio-D-ribofuranoside proceeded in an alpha-anomerselective fashion to afford 2'-deoxy-alpha-ribonucl eosides. (3) In the synthesis of 2', 3'-dideoxynucleosides: the beta-a nomers were predominatly obtained by lowering the reaction temperature . (4) When various O-benzylated 1-thioglycosides, derived from some he xoses and pentoses, were used under the NRS-promoted coupling con diti ons, 1,2-cis-N-glycosides were obtained stereoselectively in every cas e. Finally, the reaction mechanism for the stereoselective coupling wa s discussed. We assumed intimate ion pair intermediates consisting of oxonium ions, derived from thioglycosides, and imide ion derived from NBS. An S(N)2 type attack of nucleoside bases would take place against the sterically favored intermediates to produce nucleoside derivative s bearing the observed stereochemistry at the anomeric positions.