A Direct Synthesis of Nucleoside Analogs Homologated at the 3 - and 5 -Positions

A new route is presented to prepare analogs of nucleosides homologated at the 3 and 5 -positions. This route, applicable to both the and -enantiomeric forms, is suitable for the preparation of monomeric bishomonucleosides needed for the synthesis of oligonucleotide analogs. It begins with the known monobenzyl ether 3 of pent-2-yne-1,5-diol, which is reduced to alkenol 4. Sharpless asymmetric epoxidation of 4, followed by opening of the epoxide 5 with allylmagnesium bromide, gives a mixture of diols 6 and 7. Protection of the primary alcohol as a silyl ether followed by treatment with OsO4, NaIO4, and mild acid in MeOH, followed by reduction, yields (2R,3R) {{[(tert-butyl)diphenylsilyl]oxy}methyl}tetrahydro-2-(2-hydroxyethyl)-5-methoxyfuran ( methyl 3-{{[(tert-butyl)diphenylsilyl]oxy}methyl}-2,3,5-trideoxy/ -erythro-hexafuranoside; 10) (Scheme 1). Protected nucleobases are added to this skeleton with the aid of trimethylsilyl triflate (Scheme 2). The o-toluoyl (2-MeC6H4CO) and p-anisoyl (4-MeOC6H4CO) groups were used to protect the exocyclic amino group of cytosine. The bis-homonucleoside analogs 11 and 14a are then converted to monothiol derivatives suitable for coupling (Schemes 3 and 4) to oligonucleotide analogs with bridging S-atoms. This synthesis replaces a much longer synthesis for analogous nucleoside analogs that begins with diacetoneglucose ( 1,2 :5,6-di-Oisopropylideneglucose), with the stereogenic centers in the final products derived from the Sharpless asymmetric epoxidation. The new route is useful for large-scale synthesis of these building blocks for the synthesis of oligonucleotide analogs.