A Mechanistic Probe into 1,2‐cis Glycoside Formation Catalyzed by Phenanthroline and Further Expansion of Scope

Abstract Phenanthroline, a rigid and planar compound with two fused pyridine rings, has been used as a powerful ligand for metals and a binding agent for DNA/RNA. We discovered that phenanthroline could be used as a nucleophilic catalyst to efficiently access high yielding and diastereoselective α‐1,2‐cis glycosides through the coupling of hydroxyl acceptors with α‐glycosyl bromide donors. We have conducted an extensive investigation into the reaction mechanism, wherein the two glycosyl phenanthrolinium ion intermediates, a 4C1 chair‐liked β‐conformer and a B2,5 boat‐like α‐conformer, have been detected in a ratio of 2:1 (β:α) using variable temperature NMR experiments. Furthermore, NMR studies illustrate that a hydrogen bonding is formed between the second nitrogen atom of phenanthroline and the C1‐anomeric hydrogen of sugar moiety to stabilize the phenanthrolinium ion intermediates. To obtain high α‐1,2‐cis stereoselectivity, a Curtin‐Hammett scenario was proposed wherein interconversion of the 4C1 chair‐like β‐conformer and B2,5 boat‐like α‐conformer is more rapid than nucleophilic addition. Hydroxyl attack takes place from the α‐face of the more reactive 4C1 β‐phenanthrolinium intermediate to give an α‐anomeric product. The utility of the phenanthroline catalysis is expanded to sterically hindered hydroxyl nucleophiles and chemoselective coupling of an alkyl hydroxyl group in the presence of a free C1‐hemiacetal. In addition, the phenanthroline‐based catalyst has a pronounced effect on site‐selective couplings of triol motifs and orthogonally activates the anomeric bromide leaving group over the anomeric fluoride and sulfide counterparts. magnified image