Modular Synthesis of a Tridecasaccharide Motif of Bacteroides vulgatus Lipopolysaccharides against Inflammatory Bowel Diseases through an Orthogonal One‐Pot Glycosylation Strategy

Abstract

Lipopolysaccharides from Bacteroides vulgatus represent interesting targets for the treatment of inflammatory bowel diseases. However, efficient access to long, branched and complex lipopolysaccharides remains challenging. Herein, we report the modular synthesis of a tridecasaccharide from Bacteroides vulgates through an orthogonal one-pot glycosylation strategy based on glycosyl ortho-(1-phenylvinyl)benzoates, which avoids the issues of thioglycoside-based one-pot synthesis. Our approach also features: 1) 5,7-O-di-tert-butylsilylene-directed glycosylation for stereoselective construction of the α-Kdo linkage; 2) hydrogen-bond-mediated aglycone delivery for the stereoselective formation of β-mannosidic bonds; 3) remote anchimeric assistance for stereoselective assembly of the α-fucosyl linkage; 4) several orthogonal one-pot synthetic steps and strategic use of orthogonal protecting groups to streamline oligosaccharide assembly; 5) convergent [1+6+6] one-pot synthesis of the target.

Recent Advances in Chemical Synthesis of Structural Domains of Lipopolysaccharides from the Commensal Gut‐Associated Microbiota

“…The immunological evaluations showed that the anti-inflammatory cytokines were produced and MD-2/TLR4-and TLR2synergistically mediated signaling pathways were induced by this Bacteroides vulgatus LPS, [30] which represent important structural motifs for therapeutic uses against inflammatory bowel diseases. [31] Intrigued by the unique structure and promising uses for the treatment of inflammatory bowel diseases, Xiao and coworkers accomplished the modular synthesis of well-defined LPS 54 with three O-antigen disaccharide repeating units [16] via an orthogonal one-pot glycan assembly strategy based on ortho-(1-phenylvinyl)benzoates (PVB) glycosylation (Scheme 3), [32] which precludes the issues such as aglycone transfer inherent to one-pot glycans assembly based on thioglycosides.…”

“…[9] However, due to regio-and stereoselective issues, [10] the efficient synthesis of long, branched, and complex glycans with many 1,2-cis glycosidic linkages remains a formidable task. [11][12][13][14][15] Herein, we highlight the recent chemical synthesis and functional studies of LPS from the commensal gut microbiota, including Bacteroides vulgatus [16] (Figure 1B) and gut-associated lymphoid-tissue-resident Alcaligenes faecalis [17] (Figure 1C).…”

“…Herein, we highlight the recent chemical synthesis and functional studies of LPS from the commensal gut microbiota, including Bacteroides vulgatus [16] (Figure 1B) and gut‐associated lymphoid‐tissue‐resident Alcaligenes faecalis [17] (Figure 1C).…”

“…Intrigued by the unique structure and promising uses for the treatment of inflammatory bowel diseases, Xiao and coworkers accomplished the modular synthesis of well‐defined LPS 54 with three O‐antigen disaccharide repeating units [16] via an orthogonal one‐pot glycan assembly strategy based on ortho ‐(1‐phenylvinyl)benzoates (PVB) glycosylation (Scheme 3), [32] which precludes the issues such as aglycone transfer inherent to one‐pot glycans assembly based on thioglycosides.…”

A Cu(OTf)2-Catalyzed Glycosylation with Glycosyl ortho-N-Phthalimidoylpropynyl Benzoates as Donors

“…Next, we moved forward to test the applicability of the present donors to the synthesis of oligosaccharides. We anticipated that Cu­(OTf) 2 would not interfere with the promotion of ABz donors or thioglycosides and thus examined two one-pot oligosaccharide syntheses (Scheme A) . First, addition of Cu­(OTf) 2 (0.5 equiv) to a solution of NPPB donor 1i (1.2 equiv) and thioglycoside 6 (1.0 equiv) at room temperature furnished cleanly the desired disaccharide, which was then coupled with 2l (0.9 equiv) in the presence of NIS and TMSOTf at −15 °C to afford trisaccharide 8 in a 91% yield in the same flask.…”