Total Synthesis of the Conjugation-Ready Hexasaccharides of Pseudomonas aeruginosa Serotype O17 O-Antigen via One-Pot Glycosylation

Abstract

The eradication of Pseudomonas aeruginosa infections is becoming increasingly complex due to the emergence of multidrug-resistant strains, underscoring the urgent need for novel therapeutic strategies. Currently, no vaccine is available to prevent P. aeruginosa infections and the development of glycoconjugate vaccines based on P. aeruginosa lipopolysaccharides (LPS) presents significant challenges. To explore the immunological activity of the serotype O17 O-antigen, we present the first chemical synthesis of two hexasaccharides derived from the O17 O-antigen of P. aeruginosa, which possess distinct sequences. The synthesis of these two target hexasaccharides was accomplished using a chemoselective one-pot [2+2+2] assembly strategy and a common step-wise synthesis, respectively. The formation of β-mannosamine glycosidic linkages in products 1 and 2, was achieved through a direct stereoselective 1, 2- cis-glycosylation involving 4, 6- O-benzylidene-induced conformational locking facilitated by Ph ₂SO/Tf ₂O pre-activation, and an indirect 1, 2- trans-β-glycosylation alongside S N2 substitution of azide groups at C2, respectively. The efficient synthesis of these conjugation-ready oligosaccharides from the O-antigen of P. aeruginosa serotype O17 will provide foundational materials for identifying key antigens and developing glycoconjugate vaccines.

Keywords

Total synthesis / Oligosaccharides / Glycosylation / Stereoselectivity / One-pot / Pseudomonas aeruginosa / Lipopolysaccharide / O-Antigen

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2024 SIOC, CAS, Shanghai, & WILEY-VCH GmbH