Stereocontrolled Synthesis and Conformational Analysis of a Series of Disaccharides α,β-d-GlcA-(1→3)-α-L-Fuc
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ABSTRACT:
SUBMITTER: Gerbst A
PROVIDER: S-EPMC10673560 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Reported herein is a scalable chemical synthesis of disaccharide building blocks for heparan sulfate (HS) oligosaccharide assembly. The use of d-glucuronate-based acceptors for dehydrative glycosylation with d-glucosamine partners is explored, enabling diastereoselective synthesis of appropriately protected HS disaccharide building blocks (d-GlcN-α-1,4-d-GlcA) on a multigram scale. Isolation and characterization of key donor (1,2 glycal)- and acceptor (ortho-ester, anhydro)-derived side products ensure methodology improvements to reduce their formation; protecting the d-glucuronate acceptor at the anomeric position with a para-methoxyphenyl unit proves optimal. We also introduce glycal uronate acceptors, showing them to be comparative in reactivity to their pyranuronate counterparts. Taken together, this gram-scale access offers the capability to explore the iterative assembly of defined HS sequences containing the d-GlcN-α-1,4-d-GlcA repeat, highlighted by completing this for two tetrasaccharide syntheses.
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Project description:The disaccharides IdoA(2SO3)-anManOH(6SO3) and IdoA-anManOH (where IdoA represents alpha-L-iduronate, anManOH represents 2,5-anhydro-D-mannitol and SO3 represents sulphate ester) were prepared from bovine lung heparin using HNO2 depolymerization, borohydride reduction and desulphation, and were examined by 400 MHz 1H-n.m.r. spectroscopy. Three-bond proton-proton coupling constants around the IdoA ring were determined under a range of experimental conditions. For unsulphated IdoA all four proton-proton coupling constants varied markedly as a function of temperature, pH and solvent, providing clear evidence for a rapid conformational equilibrium. These data were analysed in terms of the three most energetically stable IdoA conformers: 1C4, 4C1, and 2S0. Predicted coupling constants for these conformers were determined using a modified Karplus-type relationship. For unsulphated IdoA in dimethyl sulphoxide the equilibrium was provoked strongly in favour of a slightly distorted 4C1 'chair' IdoA conformer for which coupling constants have not previously been reported. For sulphated IdoA in aqueous conditions and at low pH the equilibrium is strongly in favour of the alternative 1C4 chair conformer. Under many conditions, however, significant contributions from all three conformers occur for the non-reducing terminal IdoA in these disaccharides.
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Project description:A 6-deoxy-α-L-talopyranoside acceptor was readily prepared from methyl α-L-rhamnopyranoside and glycosylated with thiogalactoside donors using NIS/TfOH as the promoter to give good yields of the desired a-linked disaccharide (69-90%). Glycosylation with a 2-azido-2-deoxy-D-glucosyl trichloroacetimidate donor was not completely stereoselective (α:β = 6:1), but the desired a-linked disaccharide could be isolated in good overall yield (60%) following conversion into its corresponding tribenzoate derivative. The disaccharides were designed to mimic the heparan sulfate (HS) disaccharide GlcN(2S,6S)-IdoA(2S). However, the intermediates readily derived from these disaccharides were not stable to the sulfonation/deacylation conditions required for their conversion into the target HS mimetics.
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