Route efficiency assessment and review of the synthesis of β-nucleosides via N-glycosylation of nucleobases

Abstract

Nucleosides and their analogs are biomolecules central to nearly all areas of life science. Consequently, a variety of approaches have been developed to prepare these compounds. These methods typically employ N-glycosylation as a key step which installs a sugar moiety on a heterocyclic nucleobase. However, these methods vary drastically regarding their synthetic strategy, number of steps, yield, reagents, and conditions employed, making it difficult to compare and evaluate different approaches. Herein, we review the state of art for the synthesis of β-nucleosides by N-glycosylation and present a comprehensive sustainability assessment of these routes via an E-factor analysis. Our data reveal that the current methods and protocols are, in general, laborious and inefficient. Although impressive yields have been achieved in many cases, these typically came at the cost of long routes, leading to high overall E-factors (primarily composed of solvent contributions). Shorter routes using fewer protecting groups tended to perform equally well or better regarding their route E-factors, despite lower yields in many cases. Nearly all available approaches are currently hampered by a heavy reliance on chromatography, multiple protecting groups and bulky leaving groups. Biocatalytic methods bypass these limitations but suffer from poor substrate solubility and unfavorable reaction equilibria. To enable more efficient and sustainable nucleoside synthesis via N-glycosylation, future efforts should focus on using non-chromatographic purification steps, running shorter routes and higher substrate loading to minimize (solvent) waste accumulation.