4'-Methoxyphenacyl-Assisted Synthesis of ß-Kdo Glycosides.

3-Deoxy-ß-d-manno-oct-2-ulosonic acid (ß-Kdo) glycosides are mainly found in capsular polysaccharides and extracellular exopolysaccharides from Gram-negative bacteria. These compounds have profound biological implications in immune response and act as virulence factors. We have developed a novel methodology for the stereoselective synthesis of ß-Kdo glycosides via the use of a 4'-methoxyphenacyl (Phen) auxiliary group at the C1 position of a peracetylated ß-Kdo thioglycoside. Under the promotion of NIS/AgOTf in acetonitrile, a series of Kdo glycosides was synthesized in good yield and ß-selectivity while minimizing the formation of undesirable glycals. Stereoselectivity of the glycosylation was shown to be modulated by various factors such as promotor, solvent, anomeric ratio of donor, nature of acceptor, and Phen substitution. Chemoselective cleavage of the Phen group was performed under the action of Zn/HOAc. DFT calculations together with experimental results suggested that α-triflate and a six-membered α-spiroPhen are plausible intermediates of the reaction, accounting for the enhanced formation of ß-Kdo glycosides. The developed methodology could be applied to the synthesis of ß-Kdo-containing glycans from pathogenic bacteria.

Synthesis of the Tetrasaccharide Repeating Unit of the ß-Kdo-Containing Exopolysaccharide from Burkholderia pseudomallei and B. cepacia Complex.

The synthesis of the repeating unit of the immunogenic ß-Kdo-containing exopolysaccharide produced by Burkholderia pseudomallei and bacteria of the B. cepacia complex is described. The target tetrasaccharide was synthesized via stereoselective 1,2-cis- and 1,2-trans-galactosylations and ß-Kdosylation. A [3 + 1] coupling reaction between a trigalactosyl N-phenyl-2,2,2-trifluoroacetimidate donor and a Kdo acceptor has been successfully achieved for the assembly of the tetrasaccharide skeleton.

Intramolecular aglycon delivery enables the synthesis of 6-deoxy-ß-D-manno-heptosides as fragments of Burkholderia pseudomallei and Burkholderia mallei capsular polysaccharide.

Burkholderia pseudomallei and Burkholderia mallei are potential bioterrorism agents. They express the same capsular polysaccharide (CPS), a homopolymer featuring an unusual [→3)-2-O-acetyl-6-deoxy-ß-D-manno-heptopyranosyl-(1→] as the repeating unit. This CPS is known to be one of the main targets of the adaptive immune response in humans and therefore represents a crucial subunit candidate for vaccine development. Herein, the stereoselective synthesis of mono- and disaccharidic fragments of the B. pseudomallei and B. mallei CPS repeating unit is reported. The synthesis of 6-deoxy-ß-D-manno-heptosides was investigated using both inter- and intramolecular glycosylation strategies from thio-manno-heptose that was modified with 2-naphthylmethyl (NAP) at C2. We show here that NAP-mediated intramolecular aglycon delivery (IAD) represents a suitable approach for the stereocontrolled synthesis of 6-deoxy-ß-D-manno-heptosides without the need for rigid 4,6-O-cyclic protection of the sugar skeleton. The IAD strategy is highly modular, as it can be applied to structurally diverse acceptors with complete control of stereoselectivity. Problematic hydrogenation of the acetylated disaccharides was overcome by using a microfluidic continuous flow reactor.

Deciphering minimal antigenic epitopes associated with Burkholderia pseudomallei and Burkholderia mallei lipopolysaccharide O-antigens.

Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm), the etiologic agents of melioidosis and glanders, respectively, cause severe disease in both humans and animals. Studies have highlighted the importance of Bp and Bm lipopolysaccharides (LPS) as vaccine candidates. Here we describe the synthesis of seven oligosaccharides as the minimal structures featuring all of the reported acetylation/methylation patterns associated with Bp and Bm LPS O-antigens (OAgs). Our approach is based on the conversion of an L-rhamnose into a 6-deoxy-L-talose residue at a late stage of the synthetic sequence. Using biochemical and biophysical methods, we demonstrate the binding of several Bp and Bm LPS-specific monoclonal antibodies with terminal OAg residues. Mice immunized with terminal disaccharide-CRM197 constructs produced high-titer antibody responses that crossreacted with Bm-like OAgs. Collectively, these studies serve as foundation for the development of novel therapeutics, diagnostics, and vaccine candidates to combat diseases caused by Bp and Bm.Melioidosis and glanders are multifaceted infections caused by gram-negative bacteria. Here, the authors synthesize a series of oligosaccharides that mimic the lipopolysaccharides present on the pathogens' surface and use them to develop novel glycoconjugates for vaccine development.