Efficient Iterative Synthesis of O‐Acetylated Tri‐ to Pentadecasaccharides Related to the Lipopolysaccharide of Shigella flexneri Type 3 a through Di‐ and Trisaccharide Glycosyl Donors

Abstract

Protection against bacterial infections, including shigellosis, can be achieved by antibodies against the bacterial surface polysaccharide. In line with our efforts to develop vaccine candidates for shigellosis, we report herein the synthesis of penta-, deca-, and pentadecasaccharides as well as tri-, octa-, and tridecasaccharides as the endchain and intrachain fragments, respectively, of the surface polysaccharide of Shigella flexneri 3 a, a prevalent serotype. The syntheses relied on the efficiency of the trichloroacetimidate glycosylation chemistry, whereby iteration with di- and trisaccharide building blocks provided fragments made of up to three mono-O-acetylated polysaccharide repeating units. Pd(OH) -mediated hydrogenation/hydrogenolysis enabled the concomitant removal or conversion of up to 31 protecting groups of 4 different origins to provide the targets as propyl glycosides. Oligosaccharides comprising the octasaccharide segment were shown to display high conformational similarities in solution.

Classical and novel strategies to develop aShigellaglycoconjugate vaccine: from concept to efficacy in human

“…Active developments toward this aim are in progress at Institut Pasteur. 54,117,118 Conclusions Despite years of investigation and the large diversity of vaccine candidates having reached clinical trials in an attempt to develop a safe and effective Shigella vaccine enabling broad serotype coverage, a largely distributed licensed vaccine is not available yet. Despite some limitations, Shigella surface polysaccharides, especially the O-Ags, remain important targets for vaccine development.…”

Exploratory N‐Protecting Group Manipulation for the Total Synthesis of Zwitterionic Shigella sonnei Oligosaccharides

“…We set to investigate a two‐step deprotection strategy whereby N ‐deacetylation at position 2 A would only occur post benzyl ester cleavage (Scheme 9). As a follow up of our previous achievements, [24, 28b] focus was on the Pd(OH) 2 /C‐catalyzed hydrogenolysis of the benzyl, naphthyl, and TCA groups and concomitant reduction of the azido and allyl moieties from the fully protected intermediates. A two‐step transformation supported by LC‐MS/HRMS monitoring to ensure full hydrodechlorination, and subsequent N ‐deacetylation of the crude intermediate gave the desired AB propyl glycoside 1 in a good 57 % yield from disaccharide 47 .…”

“…As an attempt to avoid the use of this toxic reagent at a late stage of the synthesis of a potential vaccine component, we have favored the N ‐TCA palladium‐mediated reductive hydrodechlorination concomitant to benzyl hydrogenolysis, plus azide and allyl reduction [24] . However, conditions used with success in the synthesis of oligosaccharides representative of the S. flexneri type 3a O‐Ag, [28b] resulted in complex mixtures in the S. sonnei context. For instance, whereas conversion of the N ‐TCA group into the corresponding N ‐chloroacetyl moiety often proceeds smoothly, further conversion of the latter into the expected acetamide may be sluggish [30] .…”

Multigram synthesis of an orthogonally-protected pentasaccharide for use as a glycan precursor in a Shigella flexneri 3a conjugate vaccine: application to a ready-for-conjugation decasaccharide

“…When considering large heteropolymers and highly branched targets, solution phase iterative block synthesis has remained an attractive strategy. [12][13][14][15][16][17][18][19][20] In particular, the successful delivery of glycans featuring several repeats strongly relies on the identification of building blocks empowering iterative homologation with high and reproducible glycosylation yields, while also obeying regio-and stereoselectivity criteria in addition to qualifying for efficient full deprotection. Another significant challenge for relevant building block design stems from the need for a synthesis enabling the large-scale production of these essential intermediates to subsequently deliver usable amounts of the extended glycan targets.…”