Anomer-Selective Vorbrüggen Reaction for the Catalytic Synthesis of C ₂ -Deoxynucleoside Analogues

The stereoselective formation of N-glycoside linkages in 2-deoxycarbohydrates remains challenging, with relevance to antiviral and anticancer nucleoside analogues. Here, we identify imidodiphosphorimidate (IDPi) silylium Lewis acid catalysts as highly effective for the anomer-selective, high-yield coupling (up to 98%) of 2-deoxy and 2,6-dideoxy donors with TMS–N-based acceptors. The highest performing catalyst was general with respect to glycosyl donors, including 2-deoxyriboses, galactosides, and 2,6-dideoxypyranosides, and nitrogen-containing heterocycles, including carbazoles, indoles, and purines. Catalyst structure–selectivity relationships indicated the importance of matching the stereochemistry of the catalyst to the sugar as well as the electron-deficient aryl groups on the BINOL scaffold of IDPi. Mechanistic studies, including density functional theory (DFT), VT NMR spectroscopy, and HRMS suggested the viability of an IDPi–oxocarbenium covalent intermediate that is analogous to the powerful glycosyl triflate. Should it be capable of SN2-like reactivity, this structure could compete with the classic ion-paired scenario (SN1).