Amino and hydroxyl functionalization of nucleosides via resonant acoustic mixing

Abstract

The synthesis of oligonucleotides for therapeutics faces significant challenges such as cost, waste generation, and energy-intensive processes. While synthesis of oligonucleotide strands has received a great deal of attention, sustainable synthesis of the crucial nucleoside monomers has been largely disregarded. Herein, we present an application of resonant acoustic mixing (RAM), a novel mechanochemical technique, to common functionalization reactions on nucleosides. Each stage of oligonucleotide synthesis was addressed and various protected nucleosides, as well as phosphitylated and succinylated nucleosides were synthesized with significant reduction in solvent and reagent consumption. Generally, RAM reactions proceeded faster compared to reactions carried out in solution, with significant reduction in solvent use, and could be easily scaled up while maintaining yields.