Anomer-Selective Vorbrüggen Reaction for the Catalytic Synthesis of C₂-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 S_N2-like reactivity, this structure could compete with the classic ion-paired scenario (S_N1).