Synthesis of Nucleoside Derivatives by Biomimetic Ester Migration

Abstract

Modified nucleosides play important roles as agents in medicinal chemistry due to their anti-inflammatory, antiviral, and antiproliferative properties, as well as in biochemical processes like protein biosynthesis. Aminoacylated nucleosides in tRNA represent the central transfer unit of amino acids in the biosynthesis of peptides. Consequently, their synthesis in a prebiotic context is of great significance for further elucidations regarding the origin of life. To verify the formation of these structures in complex mixtures of regio- and stereoisomers, reference structures and their synthesis are of fundamental importance. However, state-of-the-art methodologies for the synthesis of monomeric tRNA nucleoside derivatives frequently result in the production of regioisomeric mixtures or encounter challenges related to isomerization. In this context, a concise and comprehensive approach for the chemical synthesis of nucleosidic amino acid esters is presented. The three-step reaction sequence exploits the phenomenon of 2′-3′-transaminoacylation in nucleosides providing the desired compounds in high yields. This biomimetic approach is further expanded to the activation of hydroxy groups by application of sulfonic acid esters. This has the potential to facilitate extensive modification via substitution or cross-coupling reactions, enabling the stereo- and regio-controlled transformation of nucleosides into valuable target molecules or precursors in medicinal chemistry.