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. 2025 Dec 12;11(50):eaeb4065.
doi: 10.1126/sciadv.aeb4065. Epub 2025 Dec 12.

Total synthesis of zwitterionic PS A2 oligosaccharides from Bacteroides fragilis

Xinxin Li  1 , Qingzhi Pan-Gao  1 , Yongyong Wan  1 , Fuxing Zeng  1 , Jianying Qi  1 , Yuanhong Tu  1 , Liming Wang  1 , Zhen Wang  1 , Jeroen D C Codée  2 , Qingju Zhang  1   3
Affiliations

Total synthesis of zwitterionic PS A2 oligosaccharides from Bacteroides fragilis

Xinxin Li et al. Sci Adv. .

Abstract

Zwitterionic polysaccharides have unique structures and can elicit T cell-dependent immune responses. To unravel their molecular mode of action and develop potential alternatives for carrier proteins in carbohydrate-based vaccines, we here describe a total synthesis of zwitterionic PS A2 oligosaccharides from Bacteroides fragilis. The pentasaccharide and decasaccharide bearing one or two repeating units were efficiently synthesized via convergent glycosylation strategy. The ingenious protecting groups have enabled the stereoselectivity of glycosylation. A unique synthetic approach was developed to introduce the chiral 3-hydroxybutanoic acid side chain on mannoheptose, which proved very challenging to form in this skeleton.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1.
Fig. 1.. Immunological activity and representative structures of ZPS.
(A) ZPS elicit T cell–dependent immune response. (B) Representative structures of ZPS. (C) This work: Total synthesis of PS A2 oligosaccharide repeating units.
Fig. 2.
Fig. 2.. The retrosynthesis analysis for PS A2 oligosaccharides 1 and 2.
Fig. 3.
Fig. 3.. Synthesis of monosaccharide building blocks 13, 15′, 16, and 17.
(A) Synthesis of 13; (B) Synthesis of 15’; (C) Synthesis of 16–17.
Fig. 4.
Fig. 4.. Synthesis of mannoheptose building block 14.
(A) Synthesis of heptose intermediate 37; (B) Intermolecule nucleophilic substitution; (C) Oxa-Michael addition; (D) Pd(II)-catalyzed C(sp3)-H activation alkoxylation; (E) Successful synthetic route for installation side chain ether; (F) Determination of the configuration of C3’ on compound 39.
Fig. 5.
Fig. 5.. Synthesis of target PS A2 repeating unit pentasaccharide 2.
Fig. 6.
Fig. 6.. Synthesis of target decasaccharide 1 containing two repeating units of PS A2.
(A) Synthesis of tetrasaccharide donor 9’; (B) Synthesis of decasaccharide 1.
See this image and copyright information in PMC

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