Access Type

Dissertation/Thesis

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

David Crich

Abstract

Legionaminic acid (Leg) and pseudaminic acid (Pse) are deoxy acetamido analogues of the most common sialic acid, N-acetylneuraminic acid (NeuAc) that are found in microorganisms. Leg and Pse are rare but important class of sialic acids, as their glycosides are found in lipopolysaccharides and glycoproteins of several pathogenic Gram-negative bacteria including Pseudomonas aeruginosa, Legionella pneumophila serogroup 1, Campylobacter jejuni, and Campylobacter coli. As such, the stereoselective glycosylation of the equatorial Leg and Pse donors, and the role played by their side chain conformations in anomeric reactivity and selectivity are the focus of this thesis.

Chapter two describes the synthesis of a Leg donor in 15 straightforward steps and 17% overall yield from the commercially available N-acetylneuraminic acid. The synthesized legionaminic acid donor showed excellent equatorial selectivity when glycosylated with various primary, secondary and tertiary acceptors when using NIS/TfOH as activator at -78 ºC in 1:2 acetonitrile/dichloromethane. The selectivity was, nevertheless, less than the 5-azido NeuAc donro synthesized in Chpater three. The 9-deoxy nature of the side chain made the donor less disarming and afforded greater oxocarbenium-like character in the transition state, a major factor attributing to some loss in the glycosylation selectivity.

Chapter three describes the synthesis of an intermediate 5-epi-NeuAc donor having the same C-5 configuration as pseudaminic acid. The glycosylation reactions of various primary and secondary alcohols including a sialic acid based acceptor with this donor under the standard glycosylation reaction conditions gave exquisite equatorial selectivity. Conformational analysis reveals the side chain of the donor to have undergone a conformational change from the predominant gg- to the less active gt-conformation in order to avoid the steric and dipolar repulsion between the C5-N5 bond and the side chain. This change in conformation offsets the negative effect of the axial azide at the 5-position. Additionally, the stereoselective synthesis of the NeuAc glycosides obtained from the 5-azido NeuAc donor was in apparent contradiction to the selectivity observed for the various literature 5-azido NeuAc donors, and showcased the importance of low temperature (-78 ºC) in the control of glycosylation selectivity.

Chapter four describes the synthesis of a pseudaminic acid donor in 20 steps and 5% overall yield from the commercially available N-acetylneuraminic acid. Glycosylation reactions of various primary and hindered secondary alcohols under the standard glycosylation reaction conditions gave exquisite equatorial selectivity and good to excellent yields. The excellent selectivity observed is attributed to the inversion of configuration at the 5- and 7-positions, which creates a strong dipolar and steric repulsion between the C5-N5 bond and the side chain. To avoid this, the donor undergoes a conformational change from the predominant gg- to the least active tg-conformation and and is rendered more selective in the glycosylation reaction. For selected glycosides, regioselective reductions of the azides were performed to afford deprotected glycosides with differentially blocked amines, suitable for accessing the bacterial lipopolysaccharides.

Chapter five includes the overall conclusion of the dissertation, which is followed by the detailed experimental procedures employed in synthesizing all the sialic acid derivatives in chapter six.

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