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Complex Carbohydrate Synthesis for Understanding Biological Phenomena
The bacterial cell surface contains rare sugar units, as monosaccharides and oligosaccharide glycoconjugates, that
are absent in mammalian cells. This unique feature highlights the potential of bacterial glycans as vaccines,
therapeutics, and inhibitors. However, synthesis of these rare sugars remains a significant challenge. Our lab has
established a regioselective one-pot nucleophilic displacement on C2, C4 bistriflates to access a panel of 6-deoxy
rare D- and L-sugars. This protocol enables the synthesis of less-explored functionalized rare sugars and provides
stereoselective routes to biologically important glycans. We elaborated this strategy for the first total synthesis of
trisaccharide and tetrasaccharide repeating units of Proteus penneri 26 and Proteus vulgaris TG155, both derived
from a common disaccharide unit, (3-α-L-QuipNAc-(1→3)-α-D-GlcpNAc-(1→). These Gram-negative Proteus
species, belonging to the Enterobacteriaceae, are listed by the World Health Organization as “critical priority”
antibiotic-resistant pathogens. The main challenges addressed were: (1) synthesis of rare sugar building blocks L-
quinovosamine and L-rhamnosamine, and (2) achieving 1,2-cis selectivity in L-quinovosamine, D-galactosamine,
and D-glucosamine units. We further targeted the tetrasaccharide repeating unit of Vibrio cholerae O43, [→3)-β-
D-Quip4NAcyl-(1→3)-α-D-GalpNAcA-(1→4)-α-D-GalpNAc-(1→3)-α-D-QuipNAc-(1→], a highly complex
structure and a biologically urgent target given that cholera infects 1.3–4.0 million people annually. This unit has
two rare sugars, D-QuipNAc (2-acetamido-2,6-dideoxy-D-glucose) and D-Quip4NAcyl (4-(N-acetyl-L-
allothreonyl)-amino-4,6-dideoxy-D-glucose), the latter featuring the unusual amino acid L-allothreonine. The
structure poses multiple synthetic challenges, including five nitrogen atoms, three consecutive 1,2-cis α-linkages,
and one 1,2-trans β-linkage. Additionally, we employed the protocol to prepare rare sugar analogues (fluoro,
fluorescent, thiobenzyl, and naphthylmethyl). These are under biological evaluation by Prof. Dube for their ability
to inhibit cellular glycan biosynthetic pathways. Recently, in my post-doc, I am involved in designing route to
access heparan sulfate tetrasaccharides bearing defined sulfation patterns using a convergent synthetic approach
involving selective protection, regioselective sulfation, and late-stage functional group transformations. These
diverse well defined GAGs oligosaccharides are utilised to understand how sulphation pattern modulates the
activities of chemokines and growth factors. |