Total Synthesis of the Tetrasaccharide Repeating Unit of Pseudomonas aeruginosa Serotype 4 O-Antigen

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen responsible for cystic fibrosis, bloodstream infections and hospital-acquired pneumonia. The O-antigen of lipopolysaccharide on the cell surface of P. aeruginosa has been identified as a promising target for the development of carbohydrate-based vaccines. In this study, we present the first total synthesis of the tetrasaccharide repeating unit of P. aeruginosa serotype 4 O-antigen using a linear [((1+1)+1)+1] glycosylation strategy. All rare amino sugars were synthesized from commercially available monosaccharides. The formation of 1,2-cis L-fucosamine glycosidic bonds was achieved with high efficiency and stereoselectivity by judicious choice of C3/C4-OH protecting groups of L-fucosamine. The N-phenyl trifluoroacetimidate glycosyl donors have proven to be more efficient than selenoglycoside or thioglycoside donors during glycosylation, particularly when coupling with the low-reactivity C3-OH group of the O4-Bz protected L-FucN₃ acceptor. TBSOTf has demonstrated higher efficacy as a catalyst compared to TMSOTf for promoting glycosylation with less reactive acceptors. The synthetic tetrasaccharide repeating unit of P. aeruginosa serotype 4 O-antigen, which incorporates a pentyl amine linker at the reducing end, has been prepared for conjugation with carrier proteins or for utilization in microarray studies aimed at further immunological investigations.

Keywords

Total synthesis / Glycosylation / Stereoselectivity / Tetrasaccharide / Protecting group / Leaving group / Pseudomonas aeruginosa / Lipopolysaccharide

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