Catalyst-Free Regio- and Diastereoselective Synthesis of Heterocyclic Nucleosides in the Eco-friendly Solvent 2-Methyltetrahydrofuran

An efficient and practical synthesis of heterocyclic nucleosides is developed by a catalyst-free highly regioselective and diastereoselective [3+2] annulation of alpha-purine-substituted acrylates with nitrones. The reaction operates with excellent functional group tolerance, very mild reaction conditions, and with the green, sustainable, and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) as solvent. Compared with other reactions of electron-deficient olefin dipolarophiles with nitrones, different regioselective cycloaddition products were observed in this work. This 1,3-dipolar cycloaddition reaction gives a series of isoxazolidinyl nucleosides in good to excellent yields with promising applications in biochemistry and medicinal chemistry.

Automated summary

An efficient and practical method for synthesizing heterocyclic nucleosides is developed, employing a catalyst-free [3+2] annulation reaction between alpha-purine-substituted acrylates and nitrones. The reaction exhibits excellent tolerance towards functional groups and is conducted under mild conditions, using the green and sustainable solvent 2-methyltetrahydrofuran (2-MeTHF). Unlike other reactions with electron-deficient olefin dipolarophiles, different regioselective cycloaddition products were observed in this study. The resulting isoxazolidinyl nucleosides demonstrate good to excellent yields and hold promising applications in biochemistry and medicinal chemistry.