Stereoselective C2'-Alkylation of Nucleosides Enabled by Electrochemical Ni-Catalyzed C(sp3)-C(sp3) Cross-Coupling
Pei-Yi Huang1, Yue-Ming Cai1, Jia-Wei Liu1
1State Key Laboratory of Synergistic Chem-Bio Synthesis, Frontiers Science Center for Transformative Molecules, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai200240, China.
Abstract:
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.
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