Selective Methylation of Nucleosides via an In Situ Generated Methyl Oxonium

Abstract

A very mild and efficient procedure has been developed for the preparation of N-methylated uridine, pseudouridine, guanosine and inosine derivatives. This process was compatible with free hydroxyls within the ribose and did not require precautions on the protection or deprotection of other functionalities. The key to this extremely mild methylation without protection relied on the in situ generated methyl oxonium from the Wittig reagent and methanol. A putative mechanism for the selective methylation was also proposed.

More than just Alkene Construction – Re‐Using Wittig Reactions/Reagents in Biomacromolecular Labeling, Imaging, Sequencing and Modification

“…Our laboratory has recently developed a reaction that leverages the electrophilic and Lewis basic properties of Wittig reagents to alkylate the characteristic N-H sites of nucleosides (Scheme 7a). [21] While the chemistry community has successfully identified methods for modifying natural nucleosides, these approaches have several limitations. For example, the commonly used method for methylation involves selectively protecting the hydroxyl groups on the ribose, followed by deprotonation of nucleobases using strong bases and subsequent functionalization with methylating reagents like methyl iodide or dimethyl sulfate.…”