Stereodivergent Access to α-and β-Azanucleosides via Catalyst-Free, Achiral Modulator-Controlled Iodocyclization: A Concise Synthesis of Forodesine

Abstract

Stereoselective glycosidic bond formation remains a major challenge in nucleoside synthesis. Azanucleosides, a prominent class of nucleoside analogs wherein the sugar oxygen is replaced by nitrogen, exhibit unique biological activities but hard to achieve anomeric selectivity in synthesis. We disclose a catalyst-free iodocyclization strategy that uses simple achiral molecules—NaI or 2-mercaptobenzimidazole—to stereodivergently access both α- and β-azanucleosides in high yields (up to 98%) with excellent stereocontrol (β:α up to β only, α:β up to 19:1). The utility of this method is demonstrated by a concise synthesis of forodesine in 8 steps with 20% overall yield and >20:1 β:α selectivity—the shortest route and highest stereoselectivity reported to date. DFT studies reveal that hydrogen bonding/Na–O coordination and π–π stacking interactions govern the stereochemical outcomes. This work provides an efficient, scalable platform for accessing diverse azanucleoside therapeutics.