| Summary: | 博士 === 國立清華大學 === 化學系 === 91 === Heparan sulfate (HS), ubiquitously distributed on the cell surface and in the extracellular matrix, play significant roles in a diverse set of biological processes, including virus infection, cell growth, tumor metastasis, and so on. Biosynthesis of HS involves the formation of an initial glycosaminoglycan structure, comprised of alternating N-acetyl-D-glucosamine (GlcNAc) and D-glucuronic acid (GlcA) jointed by 1,4-linkages. The structure may be modified through a series of enzymatic reactions that ultimately result in the formation of --1,4-GlcNSO3-(6-OSO3)--
1,4-IdoA(2-OSO3)- sequences. The L-iduronic acid (IdoA) is the C5-epimerization product of D-glucuronic acid (GlcA). With the discovery of increasing numbers of HS-binding proteins, there was a need to characterize the molecular properties, within the proteins and HS, responsible for specific recognition. To tackle this problem, we have developed new and efficient methodologies to synthesize various HS-oligosaccharides and studied their inhibitory activity with dengue virus.
In the first part of this thesis, we focus on the investigation of first regioselective combinatorial one-pot protection of D-glucopyranosides. A high-yielding per-O-acetylation of D-glucose 40 with stoichiometric amount of acetic anhydride to D-glucopyranosyl pentaacetate 59 employing 0.5 mol% Sc(OTf)3 as an efficient catalyst was successfully developed. A three-stepped transformation of the ester 59 led to the corresponding O-silylated thioglycoside 61, which was subjected to one-pot protection strategy in the presence of TMSOTf as the catalyst to provide the fully protected derivatives and the individual 2-, 3-, 4-, as well as 6-alcohols, respectively.
A novel synthesis of L-idopyranosyl sugars from diacetone -D-glucose 1 in four straightforward steps is described in the second part. The 5,6-diol 90, generated from 1 via sequential 3-O-benzylation and removal of the 5,6-O-isopropylidene group, underwent one-pot benzoylation-mesylation to yield the corresponding furanose 91 (81%) as a single isomer. Treatment of compound 91 with t-BuOK in t-BuOH followed by addition of a 1:2 mixture of 0.6 N H2SO4(aq) and diglyme and subsequent heating temperature (160 oC) for 16 h gave 1,6-anhydro-3-O-benzyl--L-idopyranose 89 (52%) in a one-pot manner. Regioselective benzoylation of the diol 89 exclusively furnished the corresponding 2-ester 96 (85%), which could be used as a valuable synthon for our purpose.
In the last part, we have summarized our strategy toward the synthesis of HS-oligosaccharides. The trichloroacetimi-
date 103, prepared from D-glucosamine hydrochloride 21 in eight steps, was coupled with the acceptor 96 to deliver the desired -disaccharide 104, which upon acetolysis catalyzed by Sc(OTf)3 and a series of reactions successfully furnish the imidate 139, a disaccharide building block. Coupling of 139 with the alcohol 126, derived from D-glucosamine, afforded the trisaccharide 140, which was treated with DDQ and further glycosylation with 139 ( a two-stepped elongation cycle) to produce the penta- (141), hepta- (142), and nonasaccharides 143. The expected HS target molecules 150-153, respectively, were smoothly obtained from 140-143 via functional group transformation in six consecutive steps, respectively.
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