Decarboxylative Minisci Functionalization of Nucleosides toward PRMT5 Inhibitors

Protein Arginine Methyltransferases (PRMTs) catalyze arginine methylation and represent one of the most prevalent post-translational modifications. Among them, PRMT5 has been shown to be upregulated in various types of cancer and has emerged as an important therapeutic target in oncology.^1,2 5’-Alkyl and 5’-aryl derived nucleosides have demonstrated significant potential as PRMT5 inhibitors. In this context, we hypothesized that the development of a photoredox-catalyzed decarboxylative Minisci-type functionalization of 5’-carboxylic acid nucleosides would provide an efficient strategy for accessing this class of compounds. To explore this approach, we developed a synthetic route starting from uridine. Initial 2’,3’-O,O-acetalization afforded intermediates 1 in 60% yield.^3-6 Subsequent oxidation with TEMPO and PIDA provided the corresponding carboxylic acids 2 in 94% yield. ⁷ Photocatalytic decarboxylation then furnished the desired products 3 in 31% crude yield. Reaction optimization and its scope regarding radical acceptor is under investigation in order to build a library for biological test.