Preparation of nucleoside analogues: opportunities for innovation at the interface of synthetic chemistry and biocatalysis

Nucleoside analogues are used throughout nature. They comprise the key building blocks in nucleic acids and in second messenger small molecules. Additionally, modifications to the sugar and nucleobase moieties have been a pervasive feature in the development of nucleoside therapeutics. Despite their ubiquity across all facets of medicinal chemistry and biology, methods to prepare nucleoside analogues are challenging. Recent innovations in the chemical and biocatalytic syntheses of nucleosides offer new opportunities for the step-efficient and environmentally sustainable preparation of these high value analogues. This perspective outlines the key innovations between 2020–2025 and presents opportunities for further integration of these strategies to prepare nucleoside analogues not possible using each of these approaches in isolation.