Synthesis of 2',4'- and 3',4'-Bridged Nucleosides via 4'-Carbon Radicals Generated by H-Abstraction

This unit describes a method for the synthesis of 2',4'- and 3',4'-bridged nucleosides from nucleosides bearing oxime imidate moieties at the 5' position. Hydrogen abstraction at the 4'-position of nucleosides by iminyl radicals derived from oxime imidates facilitates the facile generation of 4'-carbon radicals, which undergo cyclization and subsequent hydrolysis of the imidate residues to afford bridged nucleosides. Using this method, the eight-step syntheses of S-constrained ethyl-bridged 5-methyluridine (S-cEt-T) and 6'S-methyl-2'-O,4'-C-ethylene-bridged 5-methyluridine (6'S-Me-ENA-T), which are 2',4'-bridged nucleosides with five- and six-membered bridges, respectively, were achieved. Moreover, 3'-O,4'-C-bridged 2'-deoxynucleosides bearing various bases were prepared in five steps. Overall, this H-abstraction/cyclization strategy provides an efficient route for constructing 2',4'- and 3',4'-bridges in fewer steps than with existing methods. © 2026 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of S-constrained ethyl-bridged 5-methyluridine (S-cEt-T) Basic Protocol 2: Synthesis of 6'S-methyl-2'-O,4'-C-ethylene-bridged 5-methyluridine (6'S-Me-ENA-T) Basic Protocol 3: Synthesis of 3'-O,4'-C-bridged nucleosides Support Protocol: Preparation of (Z)-N-phenoxy-4-(trifluoromethyl)benzimidoyl chloride.