Pseudomonas aeruginosa is an opportunistic pathogen responsible for severe nosocomial infections. This multidrug-resistant bacterium can cause pneumonia and cystic fibrosis, both of which are associated with high morbidity and mortality rates. The lipopolysaccharide of P. aeruginosa serves as an attractive target for the development of effective glycoconjugate vaccines. In this article, we report the first chemical synthesis of the highly challenging tetrasaccharide repeating unit of the P. aeruginosa serotype O3 O-antigen using a two-directional [1+(2 + 1)] glycosylation strategy. The synthesis is particularly challenging due to the poor nucleophilicity of the axial C4 hydroxyl group of l-galactose and the steric hindrance imposed by the 3S-hydroxybutyryl (Hb) chain. Furthermore, the presence of an acetyl group at the ortho position relative to the glycosylation site on l-galactose can lead to undesirable acetyl migration. Additionally, it is noteworthy that the selective removal of a 2-naphthylmethyl ether (Nap) during the late stages of synthesis, particularly in the presence of multiple benzyl groups, can be somewhat challenging to predict. Through the careful selection of synthetic strategies, building blocks, and optimized reaction conditions, we achieved the stereoselective glycosylations, selective oxidation of primary alcohols, remarkable enhancement of acceptor activity, and efficient introduction of the 3S-Hb group. The synthetic methodology presented in this work serves as a valuable reference for the preparation of structurally related oligosaccharides. By incorporating an aminopropyl linker, the target tetrasaccharide facilitates glycan microarray preparation and in vivo immunological assessments, thereby accelerating progress toward a synthetic glycoconjugate vaccine for P. aeruginosa.
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