Late-stage guanine C8-H alkylation of nucleosides, nucleotides, and oligonucleotides via photo-mediated Minisci reaction.

Chemically modified nucleosi(ti)des and functional oligonucleotides (ONs, including therapeutic oligonucleotides, aptamer, nuclease, etc.) have been identified playing an essential role in the areas of medicinal chemistry, chemical biology, biotechnology, and nanotechnology. Introduction of functional groups into the nucleobases of ONs mostly relies on the laborious de novo chemical synthesis. Due to the importance of nucleosides modification and aforementioned limitations of functionalizing ONs, herein, we describe a highly efficient site-selective alkylation at the C8-position of guanines in guanosine (together with its analogues), GMP, GDP, and GTP, as well as late-stage functionalization of dinucleotides and single-strand ONs (including ssDNA and RNA) through photo-mediated Minisci reaction. Addition of catechol to assist the formation of alkyl radicals via in situ generated boronic acid catechol ester derivatives (BACED) markedly enhances the yields especially for the reaction of less stable primary alkyl radicals, and is the key to success for the post-synthetic alkylation of ONs. This method features excellent chemoselectivity, no necessity for pre-protection, wide range of substrate scope, various free radical precursors, and little strand lesion. Downstream applications in disease treatment and diagnosis, or as biochemical probes to study biological processes after linking with suitable fluorescent compounds are expected.

Palladium-Catalyzed C-H Olefination for Nucleic Acid Production.

The palladium-catalyzed direct C-H olefination of unprotected uridine, 2'-deoxyuridine, uridine monophosphate, and uridine analogues are described here. This protocol provides an efficient, atom-economical, and environmentally friendly method for the introduction of an alkenyl group at the C5 position of the uracil without pre-functionalization. A series of C5-alkenylated uridine analogues, including some biologically significant compounds and potential pharmaceutical candidates, were synthesized with exposed hydroxyl groups on the ribose. © 2023 Wiley Periodicals LLC. Basic Protocol 1: The reaction of uridine, 2'-deoxyuridine, and sofosbuvir for the C-H olefination with methyl acrylate Basic Protocol 2: The reaction of uridine and 2'-deoxyuridine for the C-H olefination with styrene.

Palladium-catalyzed C-H olefination of uridine, deoxyuridine, uridine monophosphate and uridine analogues.

The palladium-catalyzed oxidative C-H olefinations of uridine, deoxyuridine, uridine monophosphate and uridine analogues are reported herein. This protocol provides an efficient, atom-economic and environmentally friendly approach to the synthesis of biologically important C5-alkene modified uracil/uridine-containing derivatives and pharmaceutical candidates.