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Vibrio cholerae is a causative agent of the deadly pandemic - cholera. Among ~200 serogroups of V. cholerae, the O1 and O139 serogroups are mainly responsible for virulent cholera. Some other serogroups are also found to be associated with diarrhoea and minor outbreaks of cholera type diseases. The deadly pathogen is a threat for many developing countries, predominately in Asia and Africa, and still causes millions of deaths every year. A multicomponent glycoconjugate vaccine covering all the strains of V. cholerae is highly desired to prevent the spread of this disease. Here, we report the first total synthesis of a densely functionalized tetrasaccharide repeating unit of V. cholerae O43, which contains rare deoxy amino sugars D-quinosamine and D-viosamine attached with a rare amino acid N-acetyl-L-allothreonine. Synthesis of orthogonally protected rare sugars and unnatural amino acid building blocks, stereoselective construction of three consecutive 1,2-cis glycosidic linkages and the presence of five nitrogen atoms dispersed over four sugar units as well as carboxylic acid functionality makes the total synthesis a formidable task. The tetrasaccharide was assembled via a highly regio- and stereoselctive [3+1] glycosylation of fully functionalized, amino acid-bearing D-viosamine donor with the trisaccharide diol. The assembly of all-1,2-cis linked trisaccharide diol was expeditiously achieved in one-pot manner. Judicious selection of protecting groups and reaction conditions enabled access to the structurally complex, amino acid-attached tetrasaccharide repeating unit, which can be used for future biological studies directed towards development of vaccine. The synthetic strategy will be useful for accessing other structurally related complex bacterial glycans.

A high-yielding coupling of a new and stable type of glycosyl donors, namely 2-allyloxyphenyl glycoside, with a variety of alcohols via NIS/TfOH reagent combination as effective activators at room temperature is described here.