Tuned Heteroleptic Aryl Borane Catalysts Enable Stereoselective 2-Deoxy Nucleoside Analog Synthesis

Nucleoside analogs are crucial pharmaceuticals that continue to present unsolved synthetic challenges, including achieving anomer-selective couplings when the sugar donor does not have a participatory C 2 -protecting group (e.g., C 2 -deoxy or C 2 -F) and Lewis acid compatibility when the N - nucleophile is basic. In light of these deficiencies, we report a solution that is mild, catalytic, and tolerates basic N- acceptors as well as the O3/O5 donor groups that find use as transannular directors of the C−N coupling. High yielding (up to 95%) and anomer selective examples (28) are reported, which are amenable to a variety of sugar donors and natural purine/pyrimidine acceptors. These advances are enabled by heteroleptic borane catalysts, including B(C 6 F 5 ) 2 (mesityl) ( MesBCF ) and B(C 6 F 5 ) 2 (C 6 Cl 5 ) . VT NMR spectroscopy supports a mechanistic scenario wherein the LA’s competence is a direct result of designed electronic and steric effects in its Lewis pairs with N- acceptors. Multiple pharmaceutically relevant targets (0.5 and 1 mmol) and an efficient one-pot synthesis of the MesBCF catalyst (>15 gram) are reported.