Thioglycoside Donors Research Articles

Additive-Controlled Stereoselective Glycosylations of Oxazolidinone-Protected Glucosamine and Galactosamine Thioglycoside Donors Based on Preactivation Protocol

Based on a pre-activation protocol, the stereoselectivity of oxazolidinone-protected amino sugar thioglycoside donors towards glycosylations can be controlled by additives. Either α- or β-selectivity could be obtained by changing additives. 2,4,6-Tri-tert-butylpyrimidine (TTBP) was the best β-directing additive, while thiophene worked as the best α-directing additive. The bifunctional additives such as tetrabutyl ammonium iodide (TBAI) afforded either α- or β-selectivity depending on the amount added. Poor α-­selectivity of some glycosylations without any additives was greatly improved by adding TBAI or thiophene.

Synthesis of glycosaminoglycan oligosaccharides. Part 5: Synthesis of a putative heparan sulfate tetrasaccharide antigen involved in prion diseases

The synthesis of the putative prion-associated heparan sulfate tetrasaccharide containing two d-glucuronic acid units is reported. Key to the synthesis were the differentiation of the N-acetylated and N-unsubstituted glucosamine units, the high-yielding glucosylation at O-4 of an N-acetyl-d-glucosamine derivative and the α-selective glycosylation of the 4′-OH group of a β-d-GlcpA-(1→4)-d-GlcpNAc disaccharide building block with a disaccharide thioglycoside donor.

Synthesis of 6-PEtN-α-D-GalpNAc-(1->6)-β-D-Galp-(1->4)-β-D-GlcpNAc-(1->3)-β-D-Galp-(1->4)-β-D-Glcp, a Haemophilus influenzae lipopolysacharide structure, and biotin and protein conjugates thereof.

Background: In bacteria with truncated lipopolysaccharide structures, i.e., lacking the O-antigen polysaccharide part, core structures are exposed to the immune system upon infection and thus their use as carbohydrate surface antigens in glycoconjugate vaccines can be considered and investigated. One such suggested structure from Haemophilus influenzae LPS is the phosphorylated pentasaccharide 6-PEtN-α-D-GalpNAc-(1→6)-β-D-Galp-(1→4)-β-D-GlcpNAc-(1→3)-β-D-Galp-(1→4)-β-D-Glcp.Results: Starting from a spacer-containing lactose derivative a suitably protected lacto-N-neotetraose tetrasaccharide structure was constructed through subsequential couplings with two thioglycoside donors, a glucosamine residue followed by a galactose derivative, using NIS/AgOTf as promoter. Removal of a silyl protecting group at the primary position of the non-reducing end residue afforded an acceptor to which the terminal α-galactosamine moiety was introduced using a 2-azido bromo sugar and halide assisted coupling conditions. Global deprotection afforded the non-phosphorylated target pentasaccharide, whereas removal of a silyl group from the primary position of the non-reducing end residue produced a free hydroxy group which was phosphorylated using H-phosphonate chemistry to yield the phosphoethanolamine-containing protected pentasaccharide. Partial deprotection afforded the phosphorylated target pentasaccharide with a free spacer amino group but with a protected phosphoethanolamino group. Conjugation of the spacer amino group to biotin or dimethyl squarate followed by deprotection of the phosphoethanolamino group and, in the case of the squarate derivative, further reaction with a protein then afforded the title conjugates.Conclusion: An effective synthesis of a biologically interesting pentasaccharide structure has been accomplished. The target pentasaccharide, an α-GalNAc substituted lacto-N-neotetraose structure, comprises a phosphoethanolamine motif and a spacer aglycon. Through the spacer, biotin and protein conjugates of the title compound have been constructed to allow further use in biological experiments.

Synthesis of glycosaminoglycan oligosaccharides. Part 4: Synthesis of aza-l-iduronic acid-containing analogs of heparan sulfate oligosaccharides as heparanase inhibitors

The synthesis of three azasugar-containing analogs of the disaccharide units of heparan sulfate, which are potential inhibitors of the enzyme heparanase, is reported. Synthetic routes were developed for the preparation of l-ido-nojirimycin type glycosyl acceptors with O-4 free. Glycosylation of these acceptors with an O-6 functionalized 2-azido-2-deoxy-d-glucose thioglycoside donor afforded the α-linked disaccharides in good yields. The advantages of using the 4-nitrobenzenesulfonyl group for the protection of the ring nitrogen of azasugars were demonstrated.

Probing the Effect of Acylation on Arabinofuranose Ring Conformation in Di- and Trisaccharide Fragments of Mycobacterial Arabinogalactan

A major component of the cell wall of mycobacteria is the mycolyl-arabinogalactan (mAG) complex. The arabinose and galactose residues in mAG are found solely in the furanose form, and it has been suggested that the flexibility of these five-membered rings allows for the tight packing of mycolic acids. In order to probe the "flexible scaffold hypothesis", we designed and synthesized glycolipids 3-6 and 8-11 as simple models of the terminal portion of mAG. A set of donors and acceptors were explored for preparing the key beta-(1-->2) linkage in 2-6, and the best selectivity and yield can be obtained by using the electron-rich thioglycoside donor 14 and the O-5 p-methoxybenzyl-protected acceptor 17. Both alpha-linkages in the trisaccharides 7-11 were formed in a one-pot reaction. The conformations of compounds 2-11 were studied using solution-state NMR spectroscopy, but little change was observed in the coupling constants for the ring protons between 2 and 3-6 or between 7 and 8-11. However, the rotamer populations about the C-4-C-5 bond for the beta-linked ring in disaccharide 2 did change upon acylation at O-5.

ChemInform Abstract: Arabinofuranosyl Oligosaccharides from Mycobacteria: Synthesis and Effect of Glycosylation on Ring Conformation and Hydroxymethyl Group Rotamer Populations.

A series of α-d-arabinofuranosyl oligosaccharides (2−8) that are fragments of the arabinan portions of two polysaccharides present in the cell wall of Mycobacterium tuberculosis have been synthesized. Preparation of the oligosaccharides involved the sequential addition of arabinofuranosyl residues from thioglycoside donors to methyl glycoside acceptors. High-resolution NMR studies on the final products provided all 3JH,H values, which were in turn used in PSEUROT 6.2 calculations to determine both the identity and equilibrium populations of preferred conformers for each furanose ring in these glycans. Comparison of the ring conformers present in 2−8 with those available in the parent monosaccharide, methyl α-d-arabinofuranose (16), allowed the determination of the effect of glycosylation upon ring conformation. At equilibrium, 16 exists as an approximately equimolar mixture of OT4 (North, N) and 2T3 (South, S) conformers. These studies showed that glycosylation of 16 at OH5 resulted in no significant chan...

ChemInform Abstract: Synthesis of a Group of Diosgenyl Saponins with Combined Use of Glycosyl Trichloroacetimidate and Thioglycoside Donors.

With the combined use of glycosyl trichloroacetimidates and thioglycosides, a group of natural diosgenyl saponins (1–6) are efficiently synthesized, in either a stepwise or a ‘one-pot’ manner. The trichloroacetimidate is employed as an efficient temporary hydroxy protecting group in glycosylation with the glycosyl trichloroacetimidate. The intermolecular alkylthio-group transfer is demonstrated to be a common side-reaction during glycosylation with thioglycosides.

Intramolecular α-Glucosaminidation: Synthesis of Mycothiol

A protected cyclitol aglycon was tethered to an (N-arylsulfonyl)glucosamine donor by a methylene linker; the exclusively alpha-selective intramolecular glycosylation reaction was then initiated by electrophilic activation of the thioglycoside donor portion. Further transformations of the glycosylation product to give the M. tuberculosis detoxifier mycothiol and its oxidized congener, the disulfide mycothione, are detailed.

Convergent synthesis of a common pentasaccharide-repeating unit corresponding to the O-specific polysaccharide of Escherichia coli O4:K3, O4:K6, and O4:K12

A convergent chemical synthesis of a pentasaccharide found in the O-specific polysaccharide of Escherichia coli O4:K3, O4:K6, and O4:K12 has been achieved in excellent yield. A [3+2] block synthetic strategy has been adopted to couple a disaccharide donor 11 with a trisaccharide acceptor 10 for the construction of the pentasaccharide derivative 12 which on deprotection furnished target pentasaccharide 1 as its 4-methoxyphenyl glycoside. Disaccharide thioglycoside donor 11 and trisaccharide acceptor 10 were prepared from suitably protected monosaccharide intermediates. Yields were excellent in all steps.

Direct chemical glycosylation with pentenyl- and thioglycoside donors of N-acetylglucosamine

The use of pentenyl and thiophenyl glycosides of N-acetylglucosamine (GlcNAc) as glycosyl donors for the direct preparation of O-glycosides of GlcNAc promoted by N-iodosuccinimide (NIS) and metal triflates in dichloromethane has been investigated. Both glycosyl acceptors 1-octanol and (−)-menthol resulted in good glycosylation yields for both types of donors with pentenyl glycosides being somewhat superior in terms of yield. Carbohydrate-based acceptors were reacted with a benzylated GlcNAc-pentenyl donor but only provided disaccharides in poor to moderate yields. The results show that a variety of metal triflates are capable of acting as an activator for both NIS and the intermediate oxazoline.

Convergent synthesis of the tetrasaccharide repeating unit related to the O-antigenic polysaccharide of Escherichia coli 78

A convergent synthesis of the tetrasaccharide repeating unit of the O-antigenic cell wall polysaccharide of Escherichia coli 78, as the corresponding methyl glycoside ( I), is being reported. It involved stereoselective glycosidation of a β-linked mannodisaccharide acceptor with a β-linked glucosamine based disaccharide thioglycoside donor, which were prepared from the corresponding functionalised monosaccharide based glycosyl donors and acceptors. The resulting tetrasaccharide derivative was finally converted to ( I) by selective deprotection and also by global protection and deprotection techniques.

Stereodirecting Effect of the Pyranosyl C-5 Substituent in Glycosylation Reactions

The stereodirecting effect of the glycosyl C-5 substituent has been investigated in a series of d-pyranosyl thioglycoside donors and related to their preferred positions in the intermediate (3)H(4) and (4)H(3) half-chair oxacarbenium ions. Computational studies showed that an axially positioned C-5 carboxylate ester can stabilize the (3)H(4) half-chair oxacarbenium ion conformer by donating electron density from its carbonyl function into the electron-poor oxacarbenium ion functionality. A similar stabilization can be achieved by a C-5 benzyloxymethyl group, but the magnitude of this stabilization is significantly smaller than for the C-5 carboxylate ester. As a result, the preference of the C-5 benzyloxymethyl to occupy an axial position in the half-chair oxacarbenium ions is much reduced compared to the C-5 carboxylate ester. To minimize steric interactions, a C-5 methyl group prefers to adopt an equatorial position and therefore favors the (4)H(3) half-chair oxacarbenium ion. When all pyranosyl substituents occupy their favored position in one of the two intermediate half-chair oxacarbenium ions, highly stereoselective glycosylations can be achieved as revealed by the excellent beta-selectivity of mannuronate esters and alpha-selectivity of 6-deoxygulosides.

Concise synthesis of two natural triterpenoid saponins, oleanolic acid derivatives isolated from the roots of Pulsatilla chinensis

The first synthesis of two natural triterpenoid saponins, which were isolated from the roots of Pulsatilla chinensis and exhibited excellent in vitro cytotoxic activity against HL-60 cells, was concisely achieved in a convergent approach. We employed an odourless 2-methyl-5- tert-butylphenyl (Mbp) thioglycoside and trichloroacetimidate donors in one-pot reaction as a key step.

Facile synthesis of a tetrasaccharide corresponding to the capsular polysaccharide of Streptococcus pneumoniae type 15B

A convergent synthetic approach is presented for the straightforward synthesis of the tetrasaccharide fragment of the capsular polysaccharide of Streptococcus pneumoniae type 15B. Coupling of a disaccharide thioglycoside donor with a disaccharide acceptor furnished the required tetrasaccharide in excellent yield.

Application and limitations of the methyl imidate protection strategy of N-acetylglucosamine for glycosylations at O-4: synthesis of Lewis A and Lewis X trisaccharide analogues

We describe here the synthesis of the allyl Le a trisaccharide antigen as well as that of an analogue of the Le x trisaccharide antigen, in which the galactose residue has been replaced by a glucose unit. Although successful fucosylations at O-4 of N-acetylglucosamine acceptors have been reported using perbenzylated thioethyl fucosyl donors under MeOTf activation, such conditions led in our case to the conversion of our acceptor to the corresponding alkyl imidates. Indeed, in this synthesis of the Le a analogue, we demonstrate that the temporary protection of the N-acetyl group as a methyl imidate is advantageous to fucosylate at O-4. In contrast, we report here that glucosylation at O-4 of an N-acetylglucosamine monosaccharide acceptor using the α-trichloroacetimidate of peracetylated glucopyranose as a donor proceeded in better yields under activation with excess BF 3·OEt 2 than that of the corresponding methyl imidate. Therefore, we conclude that activation of thioglycoside donors by MeOTf to glycosylate at O-4 of a glucosamine acceptor is best accomplished following the temporary protection of the N-acetyl group as a methyl imidate, especially when the donors are highly reactive and prone to degradation. In contrast, if donor and acceptor can withstand multiple equivalents of BF 3·OEt 2, glycosylations at O-4 of a glucosamine acceptor with a trichloroacetimidate donor does not benefit from the temporary protection of the N-acetyl group as a methyl imidate.

Synthesis of Galactofuranose-Containing Acceptor Substrates for Mycobacterial Galactofuranosyltransferases

The major structural component of the cell wall in Mycobacterium tuberculosis, infection by which causes tuberculosis, is the mycolyl-arabinogalactan (mAG) complex. This large glycoconjugates has at its core a backbone of approximately 30 D-galactofuranose (Gal(f)) residues that are linked to peptidoglycan by way of a linker disaccharide containing L-rhamnose and 2-acetamido-2-deoxy-D-glucose. Recent studies have supported a model of galactan biosynthesis in which the entire structure is assembled by the action of two bifunctional galactofuranosyltransferases. These biochemical investigations were made possible, in part, by access to a panel of oligosaccharide fragments of the mAG complex (1-12), the synthesis of which we describe here. An early key finding in this study was that the iodine-promoted cyclization of galactose diethyl dithioacetal (19) in the presence of an alcohol solvent led to the formation Gal(f) glycosides contaminated with no pyranoside isomer, thus allowing the efficient preparation of furanoside derivatives of this monosaccharide. The synthesis of disaccharide targets 1, 2, 11 and 12 proceeded without difficulty through the use of thioglycoside donors and octyl glycoside acceptors, both carrying benzoyl protection. In the synthesis of the tri- and tetrasaccharides 3-6, we explored routes in which the molecule was assembled from the reducing to nonreducing end, and the reverse. The latter approach was found to be preferable for the preparation of 6, and in the case of 3 and 4, this strategy allowed the development of efficient one-pot methods for their synthesis. We have also carried out the first synthesis of three mAG fragments (8-10) consisting of the linker disaccharide further elaborated with one, two or three Gal(f) residues. A key step in the synthesis of these target compounds was the coupling of a protected linker disaccharide derivative (58) with a mono-, di-, or trigalactofuranosyl thioglycoside (17, 54, or 53, respectively).

Stereoselectivity investigation on glycosylation of oxazolidinone protected 2-amino-2-deoxy-d-glucose donors based on pre-activation protocol

Diverse 2,3-oxazolidinone protected 2-amino-2-deoxy-d-glucose thioglycosides were prepared and studied as glycosyl donors at low temperature by BSM/Tf2O pre-activation protocol before the addition of glycosyl acceptors. The stereochemistry outcomes of a series of glycosylations were investigated. Different stereoselectivities of the coupling reactions were obtained, arising from the different protecting groups in the oxazolidinone donors. 4,6-Di-O-benzyl-N-benzyl-oxazolidinone protected thioglycoside donor 1c underwent glycosylation with general β-anomeric selectivity and the stereoselectivity could be also affected by glycosylation conditions.

Electrochemical glycosylation in the presence of a catalytic chemical mediator

Electrochemical glycosylation of thioglycoside donors proceeds efficiently in an undivided cell in the presence of a catalytic amount of the chemical mediator (4-bromophenyl) ammoniumyl hexachloroantimonate (BAHA). In comparison with electrochemical glycosylation alone, the use of a catalytic amount of BAHA greatly increases the rate of reaction, reduces the potential required and inhibits ester-protecting group migrations. Copyright © 2008 John Wiley & Sons, Ltd.

Synthesis of a common tetrasaccharide motif of Haemophilus influenzae LPS inner core structures

A conserved tetrasaccharide structure, L-glycero-alpha-D-manno-heptopyranosyl-(1-->2)-(6-O-aminoethylphosphono-L-glycero-alpha-D-manno-heptopyranosyl)-(1-->3)-[beta-D-glucopyranosyl-(1-->4)]-L-glycero-alpha-D-manno-heptopyranose, from the LPS inner core of Haemophilus influenzae has been synthesised as its ethylamino glycosides to allow later conjugations. Starting from a previously synthesised suitably protected trisaccharide intermediate, the third heptose and subsequently the spacer were introduced using thioglycoside donor chemistry. The phosphoethanolamine was formed employing a Boc-protected phosphoamidite. Final deprotection and conjugation to biotin gave conjugates that will be used to study the specificity of MAbs raised against native LPS structures.

New thioglycoside derivatives for use in odourless synthesis of MUXF 3N-glycan fragments related to food allergens

Thioglycosides are valuable tools for complex oligosaccharides' constructions. They present precious advantages due to their stability and crystalline nature. However, their major drawbacks are the repulsive smell of thiols utilised as precursors and, often, their toxicity such as in case of the commonly employed thiophenol and thioethanol. The use of commercially available methyl tert-butyl phenyl thiol (MbpSH) avoids these problems and is compatible with gram scale synthesis of thioglycoside donors. In this paper, we describe that Mbp thioglycosides are useful and convenient precursors for odourless oligosaccharide synthesis and we further demonstrate, as a proof of their versatility, their use in the construction of most of the glycosidic linkages found in N-glycans.