Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

Abstract

Chemically modified oligonucleotides have garnered significant attention in medicinal chemistry, chemical biology, and synthetic biology due to their enhanced stability in vivo compared to naturally occurring oligonucleotides. However, current methods for synthesizing modified nucleosides, particularly at the C2′‐position, are limited in terms of efficiency, modularity, and selectivity. Herein, we report a new approach for the synthesis of highly functionalized C2′‐a‐aryl/alkenyl nucleosides via an electrochemical nickel‐catalyzed cross‐coupling of 2'‐bromo nucleosides with a variety of (hetero)aryl and alkenyl iodides. This method affords a diverse array of C2′‐ a‐aryl/ alkenyl nucleosides with excellent stereoselectivities, broad substrate scope, and good functional group compatibility. We further synthesized oligonucleotides incorporating C2′‐aryl‐modified thymidine moieties and demonstrated that their annealed double‐stranded DNAs exhibit decreased melting temperatures (Tm). Additionally, oligonucleotides with C2′‐aryl modifications at the 3′ end showed enhanced resistance to 3′‐exonuclease degradation and C2′‐aryl modifications did not impede the cellular uptake process, highlighting the potential of these modified oligonucleotides for therapeutic applications.