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

ABSTRACT

ß-Nucleosides and their analogs are dominant clinically-used antiviral and antitumor drugs. α-Nucleosides, the anomers of ß-nucleosides, exist in nature and have significant potential as drugs or drug carriers. Currently, the most widely used methods for synthesizing ß- 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 ß-nucleosides. The stereoselectivity at the anomeric carbon is controlled by the additive (NaI for ß-nucleosides; PPh3S for α-nucleosides). A series of ß- and α-nucleosides are prepared in high yields (up to 95%) and stereoselectivities (ßα up to 661, αß up to 701). 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.