Photoredox-Mediated Three-Component Carboamination of Reverse Exo -Glycals: Modular Access to C 4-Quaternary Furanosides and Spironucleosides

Abstract

Quaternary stereocenters on densely functionalized furanoside frameworks are challenging to construct with high chemo-, regio-, and stereocontrol, especially in the presence of nitrogen-containing motifs and multiple downstream diversification handles. Here, we disclose a sequence-programmed three-component radical carboamination of reverse exo-glycals that provides modular access to C4-quaternary furanosides through a distinct radical retrosynthetic logic. In this photoredox process, an N-centered radical adds to an electron-rich reverse exo-glycal to form a pseudo-anomeric radical, which is then intercepted by a Giese acceptor, enabling concomitant C–N and C–C bond formation in a single step. The protocol accommodates diverse N-radical precursors and electron-deficient alkenes, is further extendable to distinct pyranose- and furanose-derived reverse exo-glycals, supports late-stage glyco-functionalization of structurally complex molecules, and furnishes a spiro-glycosyl donor on preparative scale. Subsequent Vorbrüggen glycosylation enables divergent entry to structurally distinct spironucleosides. Preliminary biological profiling of these compounds reveals a modest antiviral signal against influenza A (PR8) at 50 μM, supporting the utility of this platform for probing underexplored spironucleoside chemical space. Mechanistic experiments support the proposed photoredox-mediated radical relay, while DFT studies provide a plausible basis for the contrasting reactivity of representative N-radical precursors. Collectively, this work offers a concise and programmable strategy for the synthesis of quaternary-center furanosides and their downstream spirocyclic derivatives from readily available carbohydrate feedstocks.