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 (ß:α up to 66:1, α:ß 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.
Subject(s)
Anti-HIV Agents , COVID-19 , Humans , Nucleosides , Stereoisomerism , Antiviral Agents/pharmacologyABSTRACT
β-Nucleosides are fundamental building blocks of biological systems and are widely used as therapeutic agents for the treatment of cancer and viral infections, among others. In the last two years, nucleoside analogues have been investigated with renewed urgency in the search for agents that are effective against SARS-CoV-2, the cause of the ongoing global pandemic of COVID-19. This has resulted in an explosion of activities in the field of β-nucleoside synthesis. This review summarizes the historical perspective and the recent advances in the stereoselective synthesis of β-nucleosides and their analogues. The synthetic strategies to obtain β-nucleosides can be divided into three categories: (1) N-glycosylation;(2) intramolecular sugar ring formation;and (3) enzymatic transglycosylation.