Zwitterionic polysaccharides (ZPSs) are exceptional carbohydrates,
carrying both positively charged amine groups and negatively charged
carboxylates, that can be loaded onto MHC-II molecules to activate
T cells. It remains enigmatic, however, how these polysaccharides
bind to these receptors, and to understand the structural features
responsible for this “peptide-like” behavior, well-defined
ZPS fragments are required in sufficient quantity and quality. We
here present the first total synthesis ofBacteroides
fragilisPS A1 fragments encompassing up to 12 monosaccharides,
representing three repeating units. Key to our successful syntheses
has been the incorporation of a C-3,C-6-silylidene-bridged “ring-inverted”
galactosamine building block that was designed to act as an apt nucleophile
as well as a stereoselective glycosyl donor. Our stereoselective synthesis
route is further characterized by a unique protecting group strategy,
built on base-labile protecting groups, which has allowed the incorporation
of an orthogonal alkyne functionalization handle. Detailed structural
studies have revealed that the assembled oligosaccharides take up
a bent structure, which translates into a left-handed helix for larger
PS A1 polysaccharides, presenting the key positively charged amino
groups to the outside of the helix. The availability of the fragments
and the insight into their secondary structure will enable detailed
interaction studies with binding proteins to unravel the mode of action
of these unique oligosaccharides at the atomic level.