An efficient method for the synthesis of 2′-O-modified nucleosides via double alkylation using cyclic sulfates

The alkylation of N-3-benzyloxymethyl-5-methyluridine with 1,3,2-dioxathiolane 2,2-dioxide or 1,3,2-dioxathiane 2,2-dioxide resulted in a 2′-O versus 3′-O selectivity of 3:1, respectively. The resulting product has a built-in sulfate leaving group at the terminal end of an ethyl or propyl carbon chain, which can be displaced with sulfur and nitrogen nucleophiles to produce modifications at the 2′-O or 3′-O positions.