APPLICATION OF THIOGLYCOSIDE CHEMISTRY TO THE SYNTHESIS OF TRISACCHARIDES AND DEOXY-TRISACCHARIDES RELATED TO THE SHIGELLA-FLEXNERI Y-POLYSACCHARIDE

The Shigella flexneri lipopolysaccharide has a biological repeating un it, -Rhap(1-->3)alpha-L-Rhap(1-->3)beta-D-GlcNAcp(1--> ABCD, but the r esidue segment BCD suffices to fill the binding site of an O-antigen s pecific monoclonal antibody, SYA/J6. Synthetic modifications to this t risaccharide have been designed to investigate the involvement in bind ing of the acetamido moiety, the 4- and 6-OH groups of the GlcNAc resi due D, the 4'-OH group of the Rha residue C, and the 3''- and 4''-OH g roups of the Rha residue B. Sequential chain extension provided the pr otected trisaccharides 18, 24, 26, 28, 30, 32, and 35 using thioglycos ide glycosyl donors activated by iodonium ions generated in situ from N-iodosuccinimide and triflic acid. Trisaccharides each monodeoxygenat ed in either ring B 25 and 27 or ring C 29 were accessed by the use of 3,6-dideoxy or 4,6-dideoxy glycosyl donors 14 and 17 and when these w ere used in sequential steps trisaccharides 31 and 33, each deoxygenat ed at double sites in adjacent residues, were obtained. Selective prot ection of the glucosamine residue as its N-benzyloxycarbonyl derivativ e provided a facile route to the trisaccharide amino compound 20, from which N-acetyl 21, N-propionyl 22, and N-trifluoroacetyl 23 derivativ es were directly prepared. Orthoester intermediates were detected in s everal glycosylation reactions and culminated in an orthoacetate 34 as a major product rather than the target trisaccharide 35. When triflic acid concentration was increased these products were avoided but acid -catalyzed migration of a 2-O-acetyl group led to both 1-->2 and 1-->3 linked trisaccharides 35 and 37. To avoid similar undesirable 1,2-lin ked products, a block synthetic strategy using the 2-O-benzoylated dis accharide glycosyl donor 40 was chosen so that the propensity for orth oester formation was n-minimized in reactions leading to the trisaccha ride analogue deoxygenated at C-6 of the glucosamine unit D.