Because most heterocyclic bases contain multiple nucleophilic sites, site selectivity is an important issue in nucleoside synthesis. Purine bases, for instance, react kinetically at N and thermodynamically at N (see Eq. (4)). Glycosylation of thymine with protected 1-acetoxy ribose produced 60% of the N nucleoside and 23% of the N nucleoside. Closely related triazines, on the other hand, react with complete selectivity to afford the N nucleoside.
The most nucleophilic nitrogen can be blocked through alkylation prior to nucleoside synthesis. Heating the blocked nucleoside in Eq. (6) in the presence of a protected sugar chloride provides the nucleoside in 59% yield. Reactions of this type are hampered by alkylation of the heterocycle by incipient alkyl chloride.
Silylated heterocyclic bases are susceptible to hydrolysis and somewhat difficult to handle as a result; thus, the development of a one-pot, one-step method for silylation and nucleoside synthesis represented a significant advance. The combination of trifluoroacetic acid (TFA), trimethylsilyl chloride (TMSCl), and hexamethyldisilazide (HMDS) generates trimethylsilyl trifluoroacetate in situ, which accomplishes both the silylation of the heterocycle and its subsequent coupling with the sugar.