Allyl Glycosides Research Articles

Chemical synthesis of a synthetically useful L-galactosaminuronic acid building block.

Most bacterial cell surface glycans are structurally unique, and have been considered as ideal target molecules for the developments of detection and diagnosis techniques, as well as vaccines. Chemical synthesis has been a promising approach to prepare well-defined oligosaccharides, facilitating the structure-activity relationship exploration and biomedical applications of bacterial glycans. L-Galactosaminuronic acid is a rare sugar that has been only found in cell surface glycans of gram-negative bacteria. Here, an orthogonally protected L-galactosaminuronic acid building block was designed and chemically synthesized. A synthetic strategy based on glycal addition and TEMPO/BAIB-mediated C6 oxidation served well for the transformation of commercial L-galactose to the corresponding L-galactosaminuronic acid. Notably, the C6 oxidation of the allyl glycoside was more efficient than that of the selenoglycoside. In addition, a balance between the formation of allyl glycoside and the recovery of selenoglycoside was essential to improve efficiency of the NIS/TfOH-catalyzed allylation. This synthetically useful L-galactosaminuronic acid building block will provide a basis for the syntheses of complex bacterial glycans.

Chemical synthesis of the pentasaccharide related to the anti-inflammatory oleanane type saponins isolated from medicinal plant Aster tataricus L. f.

Total synthesis of the pentasaccharide related to the saponin isolated from the medicinal plant Aster tataricus L. f. is reported in the form of its allyl glycoside. The synthesis is accomplished by following a [3 + 2] block synthesis strategy where the trisaccharide acceptor and the disaccharide donor are rationally designed and obtained from semi-protected monosaccharides through stereoselective glycosylations either by activation of the thioglycoside or glycosyl trichloroacetimidate. The apiose moiety has been synthesized by literature procedure with little modification. The target pentasaccharide in the form of its allyl glycoside will be beneficial for further biological evaluation of the said structure and possible glycoconjugate formation as per need.

Transglycosylation by β-mannanase TrMan5A variants and enzyme synergy for synthesis of allyl glycosides from galactomannan

Retaining β-mannanases are glycoside hydrolases (GHs) that can potentially be applied for synthesis of glycosides by catalysis of transglycosylation reactions. A novel active-site double mutant (R171K/E205D) of the catalytic module (CM) of the family GH5 Trichoderma reesei β-mannanase (TrMan5A) was expressed in Pichia pastoris and purified. TrMan5A, CM and CM-variants R171K and R171K/E205D had pH optima between pH 4.0–5.3 and showed >80 % remaining activity after incubation at 40 °C for 48 h. The enzymes were screened for transglycosylation capacity toward oligomeric and polymeric donor substrates and alcohol acceptors using mass-spectrometry. Hydrolysis and transglycosylation products were analysed by a novel HPLC procedure using an NH2 column. R171K/E205D was superior in reactions with mannotetraose and the acceptor allyl alcohol, it had twice as high propensity for transglycosylation as wild-type TrMan5A. Wild-type TrMan5A produced the highest amounts of allyl β-mannosides (with 1–3 mannosyls) from locust bean galactomannan. Applying enzyme synergy, adding the GH27 guar α-galactosidase to the reaction (to cleave off galactomannan side-groups), gave a 2.1-fold increase of allyl mannosides and simultaneously a significant production of allyl galactopyranoside, increasing overall yield of allyl glycosides 4.4-fold, from 2.2% to 9.8%. The enzymatic synthesis of reactive allyl glycosides opens up for production of novel biomaterials and glycopolymers.

Carbon tetrachloride-free allylic halogenation-mediated glycosylations of allyl glycosides.

The allylic bromination of allyl glycosides is conducted using NBS/AIBN reagents in (EtO)2CO and PhCF3 solutions, without using CCl4 as a solvent. The activated mixed halo-allyl glycosides led to glycosylations, mediated by a triflate, in a latent-active manner, with the allyl glycosides acting as donors and acceptors. Systematic glycosylation studies are performed with different triflate promoters, non-glycosyl acceptors and various allyl glycosyl donors. One-pot allylic halogenations and subsequent glycosylations are developed in PhCF3 solutions. This newer glycosylation method is utilized to obtain xylo-pyranoside di- and trisaccharides.

One-pot oligosaccharide synthesis: latent-active method of glycosylations and radical halogenation activation of allyl glycosides

Abstract Chemical glycosylations occupy a central importance to synthesize tailor-made oligo- and polysaccharides of functional importance. Generation of the oxocarbenium ion or the glycosyl cation is the method of choice in order to form the glycosidic bond interconnecting a glycosyl moiety with a glycosyl/aglycosyl moiety. A number of elegant methods have been devised that allow the glycosyl cation formation in a fairly stream-lined manner to a large extent. The latent-active method provides a powerful approach in the protecting group controlled glycosylations. In this context, allyl glycosides have been developed to meet the requirement of latent-active reactivities under appropriate glycosylation conditions. Radical halogenation provides a newer route of activation of allyl glycosides to an activated allylic glycoside. Such an allylic halide activation subjects the glycoside reactive under acid catalysis, leading to the conversion to a glycosyl cation and subsequent glycosylation with a number of acceptors. The complete anomeric selectivity favoring the 1,2-trans-anomeric glycosides points to the possibility of a preferred conformation of the glycosyl cation. This article discusses about advancements in the selectivity of glycosylations, followed by delineating the allylic halogenation of allyl glycoside as a glycosylation method and demonstrates synthesis of a repertoire of di- and trisaccharides, including xylosides, with varied protecting groups.

Radical halogenation-mediated latent-active glycosylations of allyl glycosides.

Radical halogenation-mediated glycosylation using allyl glycosides as donors and as acceptors emerges to be an efficient and hither-to unknown glycosylation method, adhering to the concept of the latent-active methodology. Several di- and trisaccharides that possess the allyl moiety at their reducing end are prepared through this new glycosylation methodology.

Synthesis of an Orthogonally Protected Polyhydroxylated Cyclopentene from l-Sorbose.

The use of l-sorbose in the synthesis of functionalized cyclopentene derivatives was accomplished. These cyclopentene derivatives are related to those found in naturally occurring jatrophane frameworks and in other bioactive compounds. The formation of allyl α-l-sorbopyranoside was a key synthetic step. Regioselective introduction of protecting groups was followed by the hydrolysis of the allyl glycoside to furnish a fully protected acyclic l-sorbose derivative. This acyclic intermediate was subsequently used to give an orthogonally protected polyhydroxylated cyclopentene, which has potential for further synthesis of bioactive compounds. The protected cyclopentene itself showed a clear cytotoxic activity when tested against a panel of human cancer cell lines (HT29, LS174T, SW620, A549, and HeLa cells).

Detailed Investigation of the Immunodominant Role of O-Antigen Stoichiometric O-Acetylation as Revealed by Chemical Synthesis, Immunochemistry, Solution Conformation and STD-NMR Spectroscopy for Shigella flexneri 3a.

Shigella flexneri 3a causes bacillary dysentery. Its O-antigen has the {2)-[α-d-Glcp-(1→3)]-α-l-Rhap-(1→2)-α-l-Rhap-(1→3)-[Ac→2]-α-l-Rhap-(1→3)-[Ac→6]≈40 % -β-d-GlcpNAc-(1→} ([(E)ABAc CAc D]) repeating unit, and the non-O-acetylated equivalent defines S. flexneri X. Propyl hepta-, octa-, and decasaccharides sharing the (E')A'BAc CD(E)A sequence, and their non-O-acetylated analogues were synthesized from a fully protected BAc CD(E)A allyl glycoside. The stepwise introduction of orthogonally protected mono- and disaccharide imidate donors was followed by a two-step deprotection process. Monoclonal antibody binding to twenty-six S. flexneri types 3a and X di- to decasaccharides was studied by an inhibition enzyme-linked immunosorbent assay (ELISA) and STD-NMR spectroscopy. Epitope mapping revealed that the 2C -acetate dominated the recognition by monoclonal IgG and IgM antibodies and that the BAc CD segment was essential for binding. The glucosyl side chain contributed to a lesser extent, albeit increasingly with the chain length. Moreover, tr-NOESY analysis also showed interaction but did not reveal any meaningful conformational change upon antibody binding.

Synthesis of QS-21-Based Immunoadjuvants

Three structurally defined QS-21-based immune adjuvant candidates (2a-2c) have been synthesized. Application of the two-stage activation glycosylation approach utilizing allyl glycoside building blocks improved the synthetic accessibility of the new adjuvants. The efficient synthesis and establishment of the stand-alone adjuvanticity of the examined synthetic adjuvant (2b) open the door to the pursuit of a new series of structurally defined QS-saponin-based synthetic adjuvants.

Synthesis and immunological activity of an oligosaccharide-conjugate as a vaccine candidate against Group A Streptococcus

The synthesis and immunogenicity of a tetanus toxoid (TT)-conjugate of the hexasaccharide portion of the cell-wall polysaccharide (CWPS) of the Group A Streptococcus (GAS) is described. The synthesis relies on the reaction of an allyl glycoside of the hexasaccharide with cysteamine, followed by the reaction of the resultant amine with diethyl squarate to give the monoethyl squarate adduct. Subsequent reaction with the lysine ε-amino groups on TT gives the glycoconjugate containing 30 hexasaccharide haptens per TT molecule. The immunogenicity in mice is similar to that obtained with a native CWPS–TT conjugate, validating the glycoconjugate as a vaccine candidate against GAS infections.

Synthesis of C-Glucosyl Aminooxy Esters

Glycosyl amino acids are constituents of glycopeptides and glycoproteins playing key roles in biological processes. We have synthesized C -glucosyl aminooxy acid derivatives as novel glycosyl amino acid building blocks for the generation of glycopeptide and glycoprotein mimics. These compounds can be readily prepared from C -allyl glucosides, through dihydroxylation, selective tritylation, Mitsunobu reaction with PhthNOH, detritylation, and oxidation. Both C -glucosyl l - and d -α-aminooxy esters have been successfully synthesized. With the ready availability of C -allyl glycosides, the present methodology could be applied to the synthesis of other C -glycosyl aminooxy acid derivatives.

Mechanistic Study of Glycosylation Using a Prop-1-enyl Donor

Studies have been conducted to elucidate the mechanism of glycosylation reactions using a prop-1-enyl donor isomerized directly from an allyl glycoside. The reactions promoted by NIS/TfOH can take place in high yields in acetonitrile at room temperature. Activation of the anomeric prop-1-enyl group often leads to both the desired glycoside (e.g., 9) and the addition-reaction product (e.g., the anomeric mixed acetal 10). TfOH perhaps has a dual role in the reaction: i.e., (a) producing IOTf in situ to activate the prop-1-enyl group and (b) catalyzing the transformation from the addition-reaction product to the desired glycoside (e.g., from 10 to 9). The latter process involves multiple competing pathways.

A high-yielding synthesis of allyl glycosides from peracetylated glycosyl donors

β-Configured peracetylated sugars are often used as easily accessible glycosyl donors that are typically activated with common Lewis acids such as boron trifluoride or trimethylsilyltrifluoromethane sulfonate. Often these glycosylations occur with unsatisfactory yields due to incomplete reactions or extensive byproduct formation, primarily as a result of loss of an additional acetyl group generating partially unprotected glycosides. Here we report a simple glycosylation–reacetylation protocol for the generation of predominantly β-configured peracetylated allyl glucoside, -galactoside, -lactoside, and -maltoside with substantially improved reaction yields.

Synthesis of Lipid A and Inner Core LPS ligands containing 4-amino-4-deoxy-l-arabinose units.

Attachment of 4-amino-4-deoxy-l-arabinose to phosphates or sugar hydroxyl groups of lipopolysaccharide contributes to bacterial resistance against common antibiotics. For a detailed study of antigenic properties and binding interactions, Ara4N-containing inner core ligands related to Burkholderia and Proteus LPS have been synthesized in good yields. Glycosylation at position 8 of allyl glycosides of oct-2-ulosonic acids (Ko, Kdo) has been accomplished using an N-phenyltrifluoroacetimidate 4-azido-4-deoxy-l-arabinosyl glycosyl donor followed by azide reduction and global deprotection. The β-l-Ara4N-(1→8)-α-Kdo disaccharide was further extended into the branched β-l-Ara4N-(1→8)[α-Kdo-(2→4)]-α-Kdo trisaccharide via a regioselective glycosylation of a protected triol intermediate. Synthesis of Ara4N-modified lipid A - part structure occurring in the LPS of Burkholderia, Pseudomonas and Klebsiellla strains was accomplished using the H-phosphonate approach. The stereocontrolled assembly of the phosphodiester linkage connecting glycosidic centres of two aminosugars was elaborated employing an anomeric H-phosphonate of cyclic silyl-ether protected 4-azido-4-deoxy-β-l-arabinose which was coupled to the hemiacetal of the lipid A GlcN-disaccharide backbone. Conditions for global deprotection which warrant the integrity of "double anomeric" phosphodiester linkage were successfully developed. Introduction of thiol-terminated spacer at the synthetic ligands allows both coupling to BSA and immobilization on gold nanoparticles as well as generation of glycoarrays.

Synthesis of Neoglycoconjugates Containing 4‐Amino‐4‐deoxy‐L‐arabinose Epitopes Corresponding to the Inner Core of Burkholderia and Proteus Lipopolysaccharides

Disaccharides that contain 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) and d-glycero-d-talo-oct-2-ulosonic acid (Ko) substituted at the 8-position by 4-amino-4-deoxy-β-l-arabinopyranosyl (Ara4N) residues have been prepared. Coupling an N-phenyltrifluoroacetimidate-4-azido-4-deoxy-l-arabinosylglycosyl donor to acetyl-protected allyl glycosides of Kdo and Ko afforded anomeric mixtures of disaccharide products in 74 and 90 % yield, respectively, which were separated by chromatography. Further extension of an intermediate Ara4N-(1→8)-Kdo disaccharide acceptor, which capitalized on a regioselective glycosylation with a Kdo bromide donor under Helferich conditions, afforded the branched trisaccharide α-Kdo-(2→4)[β-l-Ara4N-(1→8)]-α-Kdo derivative. Deprotection of the protected di- and trisaccharide allyl glycosides was accomplished by TiCl4-promoted benzyl ether cleavage followed by the removal of ester groups and reduction of the azido group with thiol or Staudinger reagents, respectively. The reaction of the anomeric allyl group with 1,3-propanedithiol under radical conditions afforded the thioether-bridged spacer glycosides, which were efficiently coupled to maleimide-activated bovine serum albumin. The neoglycoconjugates serve as immunoreagents with specificity for inner core epitopes of Burkholderia and Proteus lipopolysaccharides.

Convergent Preparation of DimLex Hexasaccharide Analogues

AbstractWe report the convergent preparation of four hexasaccharides to be used towards the synthesis of a safe anticancer vaccine based on the tumor‐associated carbohydrate antigen dimLex. A common trisaccharide intermediate was first synthesized as a precursor to the tetrasaccharide backbones. These tetrasaccharides were then converted into diol acceptors and fucosylated at O‐3 of both glucosamine residues. The conditions required to promote fucosylation at O‐3 of the reducing end glucosamine units led to some loss of the fucosyl units already introduced at O‐3 of the nonreducing end glucosamine residues. Despite this hurdle, optimization of the glycosylation conditions provided the desired hexasaccharides in sufficient quantities to prepare the final analogues. Propyl glycosides and cysteamine adducts were prepared easily in two steps from the protected allyl glycoside hexasaccharides, and a one‐step deprotection under metal‐dissolving conditions was key to our deprotection strategy.

ChemInform Abstract: 2,3‐Unsaturated Allyl Glycosides as Glycosyl Donors for Selective α‐Glycosylation.

AbstractIn the presence of NBS and Zn(OTf)2, the glycosides (I) and (VI) undergo facile and stereospecific α‐glycosylation with a wide range of alcohols.

Concise synthesis of Bacillusanthracis exosporium tetrasaccharide via two-stage activation of allyl glycosyl donor strategy

A highly efficient glycosylation protocol recently developed in our laboratory has been utilized in the short synthesis of the tetrasaccharide 1, an antigen important to the development of carbohydrate-based diagnostic tools and vaccines against anthrax. The protocol employs allyl glycosides as building blocks and improves the overall synthetic efficiency.

2,3-Unsaturated Allyl Glycosides as Glycosyl Donors for Selective α-Glycosylation

In the presence of NBS and a catalytic amount of a Lewis acid, 2,3-unsaturated allyl glycosides [6-(allyloxy)-3,6-dihydro-2-(hydroxymethyl)-2H-pyran-3-ol] have been successfully used as versatile glycosyl donors for the stereoselective α-glycosylation of a variety of alcohols comprising sensitive functions such as acetonide, keto, nitro, and ester in 50-90% yields. The methodology offers an equally facile alternative to 4-pentenyl replacement in unsaturated sugars.

ChemInform Abstract: N‐Bromosuccinimide‐Mediated Conversion of Allyl Glycosides to Glycosyl Hemiacetals.

AbstractThe hydrolysis of differentially functionalized allyl glycosides to their corresponding glycosyl hemiacetal derivatives under mild and metal‐free conditions proceeds exceptionally fast and is compatible with most of the functional groups used in oligosaccharide synthesis.