Achiral NaI and 2-Mercaptobenzimidazole as Chiral Modulators for Stereodivergent Synthesis of Azanucleosides

The stereoselective construction of glycosidic bonds is crucial in nucleoside synthesis, yet it remains challenging. Herein, we report a strategy wherein stereochemical control at the anomeric center is governed by two achiral molecules respectively: NaI for α-azanucleosides, 2-mercaptobenzimidazole for β-azanucleosides. This approach enables switchable access to a series of β- and α-azanucleosides with high yields (up to 98%) and exceptional stereoselectivities (β:α ratios up to β only, α:β ratios up to 19:1). The highlight of our method is utilizing achiral molecules, rather than complex chiral catalyst, to direct stereodivergent iodocyclization to synthesize azanucleosides. A concise synthesis of forodesine was achieved, with significantly improved efficiency (8 steps, 20% overall yield, β:α > 20:1). This strategy offers a cost-effective, scalable platform facilitating nucleoside therapeutics.