Natural nucleosides and their analogues are widely utilized as antiviral drugs, antitumor chemotherapeutic agents, and antibiotics. Currently, these compounds are mainly synthesized via glycosylation strategies, in which achieving the desired chirality in forming the glycosylic bond depends on the steric effect of glycosyl donor. Thus, obtaining desired stereoselectivities while synthesizing 2’-deoxynucleosides or nucleosides without bulky substituents on the sugar moieties remains challenging. Moreover, to synthesize nucleosides with structural diversity via glycosylation strategies require relatively complex chemical transformations. Hence, establishing flexible and stereo-controlled synthetic strategies is of great significance in nucleoside drug development.
Currently, Fener Chen and co-workers reported an additive-controlled stereodivergent iodocyclization method for the selective synthesis of α- or ꞵ-nucleosides. The stereoselectivity at the anomeric carbon is controlled by the additive (NaI for ꞵ-nucleosides; PPh3S for α-nucleosides). A series of ꞵ- and α-nucleosides are prepared in high yields (up to 95%) and stereoselectivities (ꞵ:α up to 66:1, α:ꞵ 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.
This work was published onNature Communications(Nat. Commun.,2023, 14, 138, DOI: 10.1038/s41467-022-35610-w) and supported from the National Natural Science Foundation of China (Grant No. 22201192). Fener Chen and Huijing Wang conceived the idea, guided the project. Huijing Wang wrote the manuscript with feedbacks from other authors. Qi Wang made the initial observations and analyzed the results.
