Synthesis of a d,d- and l,d-heptose-containing hexasaccharide corresponding to a structure from Haemophilus ducreyi lipopolysaccharides |
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| Affiliation: | 1. GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom;2. Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA;3. Northumbria University, Department of Applied Sciences, Faculty of Health and Life Sciences, Newcastle upon Tyne NE1 8ST, United Kingdom;1. Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, PR China;2. Graduate School of Chinese Academy of Sciences, Beijing 100049, PR China;1. Structural Glycobiology Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan;2. Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan;3. Disease Glycomics Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan;1. School of Marine Science and Technology, Harbin Institute of Technology at Weihai, Weihai 264209, China;2. Beijing National Laboratory for Molecular Sciences (BNLMS), and Key Laboratory of Molecular Recognition and Function, Institute of Chemistry Chinese Academy of Sciences, Beijing 100190, China;1. Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Photochemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China;2. Institute of BioPharmaceutical Research, Liaocheng University, 1 Hunan Road, Liaocheng, Shandong, 252000, China;3. School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China |
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| Abstract: | The synthesis of a linear hexasaccharide, 2-(4-trifluoroacetamidophenyl)ethyl (β-d-galactopyranosyl)-(1→4)-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→3)-(β-d-galactopyranosyl)-(1→4)-(d-glycero-α-d-manno-heptopyranosyl)-(1→6)-(β-d-glucopyranosyl)-(1→4)-l-glycero-α-d-manno-heptopyranoside, corresponding to a structure found in Haemophilus ducreyi LPS, is described. A Barbier reaction between benzyloxymethyl chloride and a properly protected 6-aldo-1-thio-mannopyranoside yielded both the d,d- and the l,d-heptopyranoside (2 and 3, ratio 2:3), which were separated and both used in the synthesis. p-Methoxybenzyl and chloroacetyl groups were employed as temporary protecting groups, selectively removed in the presence of the persistent benzyl, acetyl, benzoyl and isopropylidene groups by treatment with DDQ/H2O and hydrazine dithiocarbonate, respectively. Thioglycosides were utilised as donors throughout using either NIS/TfOH or DMTST as promoters. The introduction of the spacer into thioglycoside 5 was high-yielding (95%) but with low stereoselectivity (α:β 5:3). All other glycosylations are completely stereoselective. The target hexasaccharide is obtained via a 3+3 block approach with the yield in the final NIS/TfOH-promoted coupling between an N,N-diacetyl-trisaccharide thioglycosyl donor 20 and a 4′′-OH trisaccharide acceptor 13 being 75%. |
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