Stereoselective C2′-Alkylation of Nucleosides Enabled by Electrochemical Ni-Catalyzed C(sp3)–C(sp3) Cross-Coupling

Chemical modification at the C2' position of nucleosides is critical to nucleic acid therapeutic development, yet general and stereoselective methods for C2'-alkylation remain limited due to synthetic challenges associated with nucleoside substrates. Herein, we report an electrochemical Ni-catalyzed stereoselective C(sp3)-C(sp3) cross-coupling strategy for efficient C2'-α-alkylation of nucleosides. Readily accessible C2'-bromonucleosides and NHPI esters derived from abundant carboxylic acids serve as coupling partners under mild electrochemical conditions, enabling modular installation of diverse alkyl groups with broad functional-group tolerance and excellent diastereoselectivity. The protocol accommodates multiple nucleobases, is scalable, and provides products directly compatible with oligonucleotide synthesis. Biophysical studies indicate that these modifications can modulate DNA/RNA duplex thermal stability and improve resistance to exonuclease degradation. This electrochemical cross-coupling strategy provides an approach to C2'-alkyl-modified nucleosides and expands the toolbox for functional nucleic acid design.