Access Type

Open Access Dissertation

Date of Award

January 2022

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Hien M. Nguyen

Abstract

Phenanthroline, a rigid and planar organic compound with two fused pyridine rings, has been used as a powerful ligand for metals and a binding agent for DNA/RNA. We recently discovered that phenanthroline could be used as a nucleophilic catalyst to 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 functionality. 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.An extensive mechanistic investigation showed two glycosyl phenanthrolinium ion intermediates, a 4C1 chair-liked β-conformer and a B2,5 boat-like α-conformer, in a ratio of 2:1 (β:α). Further, NMR studies show 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 levels of α-1,2-cis stereoselectivity, a Curtin-Hammett scenario was proposed wherein interconversion of the 4C1 β-conformer and B2,5 α-conformer is more rapid than nucleophilic addition. Hydroxyl attack takes place from the α-face of the more reactive 4C1 chair-like β-phenanthrolinium intermediate to give an α-anomeric product. The phenanthroline catalysis system is applicable to a number of furanosyl bromide donors to provide the challenging 1,2-cis substitution products in good yield with high anomeric selectivity. While arabinofuranosyl bromide provides β-1,2-cis products, xylo- and ribofuranosyl bromides favor α-1,2-cis products. NMR experiments and density-functional theory calculations support an associative mechanism in which the rate-determining step occurs from an invertive displacement of the faster reacting phenanthrolinium ion intermediate with alcohol nucleophile.

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