Reaction Rate and Stereoselectivity Enhancement in Glycosidations with O‑Glycosyl Trihaloacetimidate Donors due to Catalysis by a Lewis Acid–Nitrile Cooperative Effect

Activation of O-glycosyl trihaloacetimidate glycosyl donors with AuCl3 as a catalyst and pivalonitrile (tBuCN) as a ligand led to excellent glycosidation results in terms of yield and anomeric selectivity. In this way, various β-d-gluco- and β-d-galactopyranosides were obtained conveniently and efficiently. Experimental studies and density functional theory (DFT) calculations, in order to elucidate the reaction course, support formation of the tBuCN–AuCl2–OR­(H)+ AuCl4 – complex as a decisive intermediate in the glycosidation event. Proton transfer from this acceptor complex to the imidate nitrogen leads to donor activation. In this way, guided by the C-2 configuration of the glycosyl donor, the alignment of the acceptor complex enforces the stereoselective β-glycoside formation in an intramolecular fashion, thus promoting also a fast reaction course. The high stereocontrol of this novel ‘Lewis acid–nitrile cooperative effect’ is independent of the glycosyl donor anomeric configuration and without the support of neighboring group or remote group participation. The power of the methodology is shown by a successful glycoalkaloid solamargine synthesis.