Additive-controlled asymmetric iodocyclization enables enantioselective access to both α- and β-nucleosides

Abstract

Abstractβ-Nucleosides and their analogs are dominant clinically-used antiviral and antitumor drugs. α-Nucleosides, the anomers of β-nucleosides, exist in nature and have significant potential as drugs or drug carriers. Currently, the most widely used methods for synthesizing β- and α-nucleosides are via N-glycosylation and pentose aminooxazoline, respectively. However, the stereoselectivities of both methods highly depend on the assisting group at the C2’ position. Herein, we report an additive-controlled stereodivergent iodocyclization method for the selective synthesis of α- or β-nucleosides. The stereoselectivity at the anomeric carbon is controlled by the additive (NaI for β-nucleosides; PPh3S for α-nucleosides). A series of β- and α-nucleosides are prepared in high yields (up to 95%) and stereoselectivities (β:α up to 66:1, α:β up to 70:1). Notably, the introduced iodine at the C2’ position of the nucleoside is readily functionalized, leading to multiple structurally diverse nucleoside analogs, including stavudine, an FDA-approved anti-HIV agent, and molnupiravir, an FDA-approved anti-SARS-CoV-2 agent.