Carbohydrates are essential components of many biologically important molecules in nature. However, efforts to elucidate their biological properties are often impeded by limitations in synthetic access to well-defined oligosaccharides. Most of the current methods relied on the design of specialized coupling-partners to control selectivity during formation of glycosidic bonds. 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. 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. 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.

Phenanthroline-catalyzed stereoselective glycosylations: Scope and mechanism

ACS Spring 2022

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