Nucleosides are typically synthesized through the coupling of a nucleophilic pyrimidine, purine, or other basic heterocycle with a derivative of ribose or deoxyribose that is electrophilic at the anomeric carbon. When an acyl-protected ribose is employed, selective formation of the β-nucleoside (possessing the S configuration at the anomeric carbon) results from neighboring group participation. Stereoselective synthesis of deoxyribonucleosides directly from deoxyribose derivatives is more difficult to achieve because neighboring group participation cannot take place.
Three general methods have been used to synthesize nucleosides from nucleophilic bases and electrophilic sugars. The fusion method involves heating the base and acetyl-protected 1-acetoxyribose to 155 °C and results in the formation of the nucleoside with a maximum yield of 70%.
The metal salt method involves the combination of a metal salt of the heterocycle with a protected sugar halide. Silver and mercury salts were originally used; however, more recently developed methods use sodium salts.
The silyl-Hilbert-Johnson (SHJ) reaction (or Vorbrüggen reaction), the mildest general method for the formation of nucleosides, is the combination of a silylated heterocycle and protected sugar acetate (such as 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose) in the presence of a Lewis acid. Problems associated with the insolubility of the heterocyclic bases and their metal salts are avoided; however, site selectivity is sometimes a problem when heterocycles containing multiple basic sites are used, as the reaction is often reversible.