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Synthesis of novel C4-modified sialic acid analogues

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(Thesis) Ph.D.
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Sialic acids are a family of structurally-unique 9-carbon α-keto acid sugars that are often found on the termini of oligosaccharide chains on glycoproteins and cell surfaces. These sugars can be removed through sialidases-catalyzed hydrolysis and play a number of roles in biological recognition events, serving as receptor sites for sialic acid-recognizing proteins and masking other antigenic oligosaccharides. The influenza virus recognizes sialic acids on cell surfaces of the upper respiratory tract and produces a sialidase that is critical for viral infectivity. Inhibitors of influenza sialidase have been developed as therapeutic agents that will be useful in the event of an influenza pandemic; however, it is important to have a wide array of such drugs to counter viral resistance. The main objective of the research described in this thesis was to develop synthetic routes to 4-modified sialic acid analogues. These were intended as general routes, allowing the synthesis of many analogues. This initially involved coupling the nitronate of 2-acetamido-1,2-dideoxy-1-nitro-D-mannitol 2.1 with alkyl α-(bromomethyl)acrylate esters 2.6 and 2.12. These reaction products were subjected to ozonolysis, leading to 4-deoxy-4-nitrosialic acid esters 2.10 and 2.14. The synthetically versatile nitro group should allow the synthesis of a number of 4-derivatives. Glycosylation of 4-deoxy-4-nitrosialosyl donor sugars was attempted with phenol in order to generate substrates for sialidase-catalyzed hydrolysis; however, only 1-adamantyl thiosialoside 2.21 led to practical quantities of the desired phenyl α-sialoside product 2.25. An oxabicyclo[3.1.0]hexane-based sialic acid analogue 4.3 was isolated when the β-sialosyl chloride donor sugar 2.18 was treated with base. This potential sialidase inhibitor had a novel ring structure but the protecting groups could not be removed without destroying the bicyclic system. Isopropylidene-protected nitromannitol 2.6 was also reacted with ethyl α-(bromomethyl)acrylate to afford an enoate ester product that upon ozonolysis and chromatographic purification led to isolation of a β,γ-unsaturated α-keto ester 3.1. This enone, resulting from elimination of HNO2, was used in copper-catalyzed conjugate addition reactions of dialkylzinc reagents to synthesize 4-alkyl-4-deoxy-4-epi-sialic acid analogues that could be converted into analogues of DANA, the glycal of sialic acid. Unfortunately, only Me2Zn and Et2Zn underwent conjugate addition to give the less desirable 4R-configured products.
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