Chiral Synthesis of Heterosubstituted Nucleoside Analogs from Noncarbohydrate Precursors

Abstract

The discovery of the potent antiviral activity of oxathiolanyl and dioxolanyl nucleosides prompted the extensive exploration of the chemistry and biology of heterosubstituted nucleoside analogs, in which the sugar moiety is replaced by a diheterocyclic ring. Carbohydrate-based synthetic approaches allowed the stereoselective synthesis of enantiomerically pure D- and L-analogs. However, due to the chemical nature of these molecules, approaches based on non-chiral starting materials and including chemical or enzymatic resolution steps proved advantageous for large scale syntheses. For the synthesis of isoxazolidinyl nucleosides, 1,3-dipolar cycloaddition has been a favorite approach, and the necessity to obtain optically active molecules has been addressed by asymmetric induction using chiral dipoles or dipolarophiles. This review will summarize the most interesting syntheses of heterosubstituted nucleoside analogs from non-carbohydrate precursors.