Cooperative Catalysis\nin Stereoselective <i>O</i>- and <i>N</i>‑Glycosylations\nwith Glycosyl Trichloroacetimidates\nMediated by Singly Protonated Phenanthrolinium Salt and Trichloroacetamide

The development of small-molecule catalysts that can\neffectively\nactivate both reacting partners simultaneously represents a pivotal\npursuit in advancing the field of stereoselective glycosylation reactions.\nWe report herein the development of the singly protonated form of\nreadily available phenanthroline as an effective cooperative catalyst\nthat facilitates the coupling of a wide variety of aliphatic alcohols,\nphenols, and aromatic amines with α-glycosyl trichloroacetimidate\ndonors. The glycosylation reaction likely proceeds via an S<sub>N</sub>2-like mechanism, generating β-selective glycoside products.\nThe developed protocol provides access to <i>O</i>- and <i>N</i>-glycosides in good yields with excellent levels of β-selectivity\nand enables late-stage functionalization of <i>O</i>- and <i>N</i>-glycosides via cross-coupling reactions. Importantly,\nthis method exhibits excellent β-selectivity that is unattainable\nthrough a C2-<i>O</i>-acyl neighboring group participation\nstrategy, especially in the case of glycosyl donors already containing\na C2 heteroatom or sugar unit. Kinetic studies demonstrate that the\nbyproduct trichloroacetamide group plays a previously undiscovered\npivotal role in influencing the reactivity and selectivity of the\nreaction. A proposed mechanism involving simultaneous activation of\nthe glycosyl donor and acceptor by the singly protonated phenanthrolinium\nsalt catalyst with the assistance of the trichloroacetamide group\nis supported by kinetic analysis and preliminary computational studies.\nThis cooperative catalysis process involves four consecutive hydrogen\nbond interactions. The first interaction occurs between the carbonyl\noxygen of the trichloroacetamide group and the hydroxyl group of alcohol\nnucleophile (CO···HO). The second involves\nthe trichloroacetamide-NH<sub>2</sub> forming a hydrogen bond with\nthe nitrogen atom of the phenanthroline (NH···N). The\nthird involves the donor trichloroacetimidate (NH) engaging\nin a hydrogen bond interaction with the phenanthrolinium-NH (NH···NH).\nLastly, the protonated trichloroacetimidate-NH<sub>2</sub> forms a\nhydrogen bond with the fluorine atom of the tetrafluoroborate ion.