Total synthesis of the capsular polysaccharide repeating unit towards the development of a glycoconjugate vaccine against Klebsiella pneumoniae ST512

Klebsiella pneumoniae ST512 is an emerging multidrug-resistant pathogen whose capsular polysaccharide represents a prime target for vaccine development. Here, we report the first total synthesis of the branched hexasaccharide repeating unit of the K. pneumoniae ST512 CPS, together with four structurally related oligosaccharide analogues. Key synthetic challenges including the stereoselective construction of the 1,2- cis glycosidic linkage on the galacturonic acid core and the inherently low reactivity of elongated oligosaccharide intermediates were addressed employing orthogonally protected building blocks. The resulting library of conjugation-ready oligosaccharides, equipped with aminopentyl linkers, enables glycan microarray-based identification of minimal immunogenic epitopes. This work establishes a robust chemical foundation for the rational development of semi-synthetic glycoconjugate vaccines targeting K. pneumoniae ST512.