Synthesis Of Oligosaccharide Related To The O-antigen Of Shigella Dysteriae Type 10

Shigella infections cause an estimated 34000 deaths among children under five years of age annually.Increased antibiotic resistance of Shigella has limited treatment effect of traditional antibiotic therapy,thus,an efficacious Shigella vaccine is urgently needed.Despite intensive research efforts have been conducted on the development of Shigella vaccine,there is no licensed Shigella vaccine.Pathogenic bacteria present surface glycans,which can be regarded as promising target for the control of many infectious diseases.The O-antigen of lipopolysaccharide(LPS)of Shigella has been wildly used in the development of Shigella vaccine.The extracted polysaccharide from natural substances has many disadvantages,such as undefined structures,high difficulty of purification,and incorporation of unknown virulence factors.In order to understand the biological function of specific oligosaccharides,pure oligosaccharides through efficient chemical synthesis is the crucial step toward the development of glycoconjugate vaccines.Synthetic oligosaccharides have been widely used in the development of vaccines for infectious diseases.Shigella dysteriae type 10 O-antigen tetrasccharide repeating unit →2)-β-D-Manp4,6(S)Pyr-(1→3)-α-D-ManpNAc-(1→3)-β-L-Rhap-(1→4)-α-D-GlcpNAc-(→ contains four different monosaccaride units: two aminodideoxyhexoses,one rare suagr L-rhamonose and one glucose substituted with rare pyruvic acid acetals and has outstanding structural specificity which can be considered as key target in developing safe and effective Shigella vaccine.Considering the challenge of formating 1,2-cis-β-L-rhamonoside and 1,2-cis-β-D-manoside,this structure is thus attractive target for chemical synthesis.Here,we report the synthesis of target tetrasaccharide and its disaccharide and trisaccharide fragments employing four orthogonally protected building blocks,including glucose substituted with rare pyruvic acid acetals,L-quinovose,glucosamine and mannosamine from easily accessible compound.We construct the important building block L-quinovose from L-mannose via Lattrell-Dax epimerization and sequential oxidation/reduction inversion.Orthogonally protected L-quinovose donor,utilizing the participating effect of the neighboring 2-acetyl group,was reacted with glucosamine acceptor to form 1,2-trans-β-L-quinovoside efficiently.Similarly,1,2-cis-β-L-rhamonoside was efficiently prepared by epimerzation at C-2 using sequential oxidation/reduction inversion.The synthesis of second disaccharide was achieved by coupling mannosamine with pyruvated glucose.It should be however noted that the presence of pyruvic acid acetal hinders the inversion of disaccharide derivative at C-2 position.To avoid the obstacle of rare pyruvic acid acetals protection group on inversion reaction,it is decided to apply the pyruvation procedure after tetrasacchride assembly.