Total Synthesis of a Structurally Complex Tetrasaccharide Repeating Unit of Vibrio cholerae O43

Abstract

Vibrio cholerae is a causative agent of the deadly pandemic - cholera.\xa0 Among ~200 serogroups of V. cholerae, the O1 and O139 serogroups are mainly responsible for virulent cholera.\xa0 Some other serogroups are also found to be associated with diarrhoea and minor outbreaks of cholera type diseases. \xa0The deadly pathogen is a threat for many developing countries, predominately in Asia and Africa, and still causes millions of deaths every year. \xa0A multicomponent glycoconjugate vaccine covering all the strains of V. cholerae is highly desired to prevent the spread of this disease.\xa0 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. \xa0Synthesis 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.\xa0 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. \xa0The assembly of all-1,2-cis linked trisaccharide diol was expeditiously achieved in one-pot manner.\xa0 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. \xa0The synthetic strategy will be useful for accessing other structurally related complex bacterial glycans.