Application of glycosyl thioimidates in solid-phase oligosaccharide synthesis

Two stable classes of thioimidoyl derivatives, S-benzoxazolyl (SBox) and S-thiazolinyl (STaz) glycosides, were investigated as glycosyl donors for solid-phase oligosaccharide synthesis. It was demonstrated that these derivatives are suitable for both glycosyl acceptor-bound and glycosyl donor-bound strategies, commonly employed in resin-supported oligosaccharide synthesis.     

S-Benzoxazolyl (SBox) glycosides as novel,versatile glycosyl donors for stereoselective 1,2-cis glycosylation

[reaction: see text] Novel glycosyl donors, S-benzoxazolyl (SBox) glycosides, have been synthesized, tested toward various protecting group manipulations, and applied to the highly stereoselective 1,2-cis glycosylation. These compounds fulfill the requirements for a modern glycosyl donor such as accessibility, high stability toward protecting group manipulations, and mild activation conditions. It was also demonstrated that SBox glycosides withstand other glycosyl donor activation conditions and therefore allow selective glycosylations of O-pentenyl and thioglycosides.     

Glycosyl thioimidates as versatile building blocks for organic synthesis

This review discusses the synthesis and application of glycosyl thioimidates in chemical glycosylation and oligosaccharide assembly. Although glycosyl thioimidates include a broad range of compounds, the discussion herein centers on S-benzothiazolyl (SBaz), S-benzoxazolyl (SBox), S-thiazolinyl (STaz), and S-benzimidazolyl (SBiz) glycosides. These heterocyclic moieties have recently emerged as excellent anomeric leaving groups that express unique characteristics for highly diastereoselective glycosylation and help to provide a streamlined access to oligosaccharides.     

Thiomidoyl approach to the synthesis of α-sialosides

Novel sialosyl donors, S-benzoxazolyl (SBox) and S-thiazolyl (STaz) sialosides, have been synthesized and applied to the stereoselective synthesis of α-sialosides. It was also demonstrated that it is possible to selectively activate SBox sialyl donor over ethyl thioglycoside, allowing the direct synthesis of disaccharide donors that could be used in subsequent glycosylations without further manipulations.     

Glycosyl alkoxythioimidates as complementary building blocks for chemical glycosylation

It is reported that S-glycosyl O-methyl phenylcarbamothioates (SNea carbamothioates) have a fully orthogonal character in comparison to S-benzoxazolyl (SBox) glycosides. This complete orthogonality was revealed by performing competitive glycosylation experiments in the presence of various promoters. The results obtained indicate that SNea carbamothioates have a very similar reactivity profile to that of glycosyl thiocyanates, yet are significantly more stable and tolerate selected protecting group manipulations. These features make the SNea carbamothioates new promising building blocks for further utilization in oligosaccharide synthesis.     

N-benzyl-2,3-oxazolidinone as a glycosyl donor for selective alpha-glycosylation and one-pot oligosaccharide synthesis involving 1,2-cis-glycosylation

Glycosylation reactions using N-benzyl-2,3-trans-oxazolidinones as the glycosyl donors were shown to be highly alpha-selective. Advantages of the donor include facile preparation in gram-scale preparation and simple deprotection procedures. Subsequently, a one-pot oligosaccharide synthesis involving 1,2-cis glycosidic linkages was demonstrated using the novel glycosyl donors.     

How the arming participating moieties can broaden the scope of chemoselective oligosaccharide synthesis by allowing the inverse armed-disarmed approach

A new method for stereocontrolled glycosylation and chemoselective oligosaccharide synthesis has been developed. It has been determined that complete 1,2-trans selectivity can be achieved with the use of a 2-O-picolyl moiety, a novel neighboring group that is capable of efficient participation via a six-membered intermediate. The application of the picolyl concept to glycosidations of thioimidoyl, thioglycosyl, and trichloroacetimidoyl glycosyl donors is demonstrated. The picolyl moiety also retains the glycosyl donor in the armed state, as opposed to conventional acyl participating moieties. We name this new approach the "inverse armed-disarmed" strategy, because it allows for the chemoselective introduction of a 1,2-trans glycosidic linkage prior to other linkages. In the context of the oligosaccharide synthesis, the strategy provides trans-trans and trans-cis patterned oligosaccharides as opposed to classic Fraser-Reid's armed-disarmed approach leading to cis-trans and cis-cis linkages.     

Rapid assembly of oligosaccharides: 1,2-diacetal-mediated reactivity tuning in the coupling of glycosyl fluorides

This paper describes the application of 1,2-diacetal protecting groups to control the reactivity tuning of glycosyl fluorides in oligosaccharide coupling reactions. The synthetic potential of this new methodology is demonstrated by the ‘one-pot’ synthesis of a linear pentasaccharide and the efficient assembly of the core oligosaccharide of the GPI anchor of yeast (Saccharomyces cerevisiae).     

Versatile synthesis and mechanism of activation of S-benzoxazolyl glycosides

As a part of a program for developing new efficient procedures for stereoselective glycosylation, a range of S-benzoxazolyl (SBox) glycosides have been synthesized. The mechanistic aspects of the SBox moiety activation for glycosylation via a variety of conceptually different pathways in the presence of thiophilic, electrophilic, or metal-based promoters have been investigated.     

Novel template-assembled oligosaccharide clusters as epitope mimics for HIV-neutralizing antibody 2G12. Design, synthesis, and antibody binding study

The synthesis of a new class of template-assembled oligomannose clusters as the mimics of the epitope of the HIV-neutralizing antibody 2G12 is described. The novel oligomannose clusters were successfully assembled on a cyclic decapeptide template using the Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides to alkynes by introducing four units of a synthetic D1 arm tetrasaccharide (Manalpha1,2Manalpha1,2Manalpha1,3Manalpha-) of high-mannose N-glycan on one face of the template and two T-helper epitope peptides on the other face of the template. Their binding to human antibody 2G12 was studied using surface plasmon resonance (SPR) technology. It was found that while the synthetic monomeric D1 arm oligosaccharide and its fluorinated derivative interacted with 2G12 only weakly, the corresponding template-assembled oligosaccharide clusters showed high affinity to antibody 2G12, indicating a clear clustering effect in 2G12 recognition. Interestingly, the fluorinated D1 arm cluster, in which the 6-OH of the terminal mannosyl residue was replaced with a fluorine atom, showed a distinct kinetic model in 2G12 binding as compared with the cluster of the natural D1 arm oligosaccharides. The oligosaccharide clusters with varied length of spacer demonstrated different affinity to 2G12, suggesting that an appropriate spatial orientation of the sugar chains in the cluster was crucial for high affinity binding to the antibody 2G12. It was also found that the introduction of two T-helper epitopes onto the template did not affect the structural integrity of the oligomannose cluster. The novel synthetic glycoconjugates represent a new type of immunogen that may be able to raise carbohydrate-specific neutralizing antibodies against HIV-1.     

Glycosyl thioimidates in a highly convergent one-pot strategy for oligosaccharide synthesis

Application of two classes of thioimidoyl derivatives, S-benzoxazolyl (SBox) and S-thiazolyl (STaz) glycosides to selective activation over thioglycosides is described. These results allowed us to synthesize a tetrasaccharide derivative using a leaving group differentiated one-pot strategy in 73% yield over three sequential glycosylation steps.     

A fascination with 1,2-diacetals

1,2-Diacetals are readily prepared, rigid structural motifs that provide a wide range of opportunities for applications in natural product assembly. These uses encompass selective 1,2-diol or alpha-hydroxy acid protection, enantiotopic recognition and desymmetrization methods, chiral memory applications, and reactivity control in oligosaccharide synthesis, as well as functioning as templating components, chiral auxiliaries, and building blocks. 1,2-Diacetals are often more stable and lead to products with enhanced crystallinity compared to their five-ring acetonide counterparts. Many 1,2-diacetals have favorable NMR parameters, which facilitate structural assignment, particularly during asymmetric reaction processes.     

Rapid Assembly of Oligosaccharides: Total Synthesis of a Glycosylphosphatidylinositol Anchor of Trypanosoma brucei

Six building blocks, six reaction steps : The recently developed innovative methodology facilitated the convergent synthesis of the complex oligosaccharide core 1 (shown here with protecting groups) for the total synthesis of a glycosylphosphatidylinositol (GPI) anchor. The key factors are the tuning of the reactivity of the building blocks by using 1,2-diacetal protecting groups and the desymmetrization of glycerol and myo-inositol with a chiral bis(dihydropyran).     

A Practical One‐Step Synthesis of 1,2‐Oxazoline Derivatives from Unprotected Sugars and Its Application to Chemoenzymatic β‐N‐Acetylglucosaminidation of Disialo‐oligosaccharide

A facile and practical method for synthesis of sugar oxazolines (=dihydrooxazoles) from the corresponding N‐acetyl‐2‐amino sugars has been developed by using 2‐chloro‐1,3‐dimethyl‐1H‐benzimidazol‐3‐ium chloride (CDMBI) as a dehydrative condensing agent. The intramolecular dehydrative reaction between the 2‐acetamido group and the anomeric OH group of unprotected N‐acetyl‐2‐amino sugars took place smoothly in H₂O, leading to the formation of a 1,2‐oxazoline (=4,5‐dihydrooxazole) moiety in good yield. Since the reaction proceeds in H₂O without using any protecting groups, the resulting oxazolines can be utilized as effective glycosyl donors for the subsequent enzymatic glycosylation. We have successfully demonstrated a highly efficient chemoenzymatic transglycosylation of a disialo‐oligosaccharide moiety to p‐nitrophenyl N‐acetylglucosaminide catalyzed by a mutant endo‐N‐acetylglucosaminidase without isolating disialo‐oligosaccharide oxazoline as synthetic intermediate.     

寡糖和多糖的合成

本文重点介绍了寡塘及多馆在化学合成方面的进展,述及了寡掂经典合成方法及近年来发展的一些新方法,如三氯乙酸亚胺基作为离去基团的方法,以缩水内醚糖为糖的给体的方法等。对多糖的合成主要介绍了1,6-、1,4-、1,3-、1,2-缩水内醚搪的阳离子聚合制备均聚多塘,及用糖原酸醋衍生物通过缩聚反应制备多塘。     

MALDI-TOF and ESI-MS analysis of oligosaccharides labeled with a new multifunctional oligosaccharide tag

A new multifunctional oligosaccharide label with a 1 degree amino-group was synthesized and characterized. The oligosaccharide label was introduced into several neutral oligosaccharides by reductive amination, and the derivatives were analyzed by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) and by electrospray ionization (ESI) mass spectrometry. It was demonstrated that the labeling reaction was satisfactory, and that as little as 50 pmol of starting material could be efficiently labeled with minimal loss to side reactions. A mixture of high-mannose N-glycans released from ribonuclease B was labeled. The label did not appear to interfere with structural characterization of the oligosaccharides by mass spectrometry. N-quaternization of the labeled oligosaccharides resulted in significantly increased sensitivity of detection with as little as 100 fmol on the probe detected. Deuterium coding of labeled oligosaccharide mixtures and relative abundance of mixture components was investigated. A protocol for the chromatographic separation of mixtures of labeled oligosaccharides by HPLC was developed and is reported here.     

Synthesis of a conjugable hexasaccharide corresponding to the capsular polysaccharide of Campylobacter jejuni strain BH0142

The first assembly of a conjugation-ready hexasaccharide from the capsular glycan of C. jejuni. strain BH0142 has been accomplished. The synthesis features the efficient preparation of 6-deoxy-d-ido-heptopyranosyl fluoride donors proceeding from allyl α-d-C-glucopyranoside by a C1-to-C5 switch strategy with radical dehydroxymethylative fluorination as a key step, stereocontrolled construction of 1,2-trans-α-d-ido-heptopyranosidic bonds and of 1,2-cis-α-d-galactopyranosidic linkages. The obtained target oligosaccharide sets a solid foundation for making structurally-defined multivalent glycoconjugate vaccine candidates against C. jejuni. infections.     

Efficient stereoselective synthesis of oligosaccharides of Streptococcus pneumoniae serotypes 6A and 6B containing multiple 1,2-cis glycosidic linkages

The synthesis of the repeating units of pneumococcal polysaccharide serotypes 6A and 6B and derivatives thereof is described. Application of S-benzoxazolyl and S-thiazolinyl glycosides allowed rapid oligosaccharide assembly and provided complete stereoselectivity in challenging 1,2-cis glucosylations and galactosylations. The oligosaccharide assembly was accomplished in an efficient manner by selective activation of thioimidoyl leaving groups over thioglycosides.     

Stereoselective assembly of complex oligosaccharides using anomeric sulfonium ions as glycosyl donors

The development of selectively protected monosaccharide building blocks that can reliably be glycosylated with a wide variety of acceptors is expected to make oligosaccharide synthesis a more routine operation. In particular, there is an urgent need for the development of modular building blocks that can readily be converted into glycosyl donors for glycosylations that give reliably high 1,2-cis-anomeric selectivity. We report here that 1,2-oxathiane ethers are stable under acidic, basic, and reductive conditions making it possible to conduct a wide range of protecting group manipulations and install selectively removable protecting groups such as levulinoyl (Lev) ester, fluorenylmethyloxy (Fmoc)- and allyloxy (Alloc)-carbonates, and 2-methyl naphthyl ethers (Nap). The 1,2-oxathiane ethers could easily be converted into bicyclic anomeric sulfonium ions by oxidization to sulfoxides and arylated with 1,3,5-trimethoxybenzene. The resulting sulfonium ions gave high 1,2-cis-anomeric selectivity when glycosylated with a wide variety of glycosyl acceptors including properly protected amino acids, primary and secondary sugar alcohols and partially protected thioglycosides. The selective protected 1,2-oxathianes were successfully employed in the preparation of a branched glucoside derived from a glycogen-like polysaccharide isolated form the fungus Pseudallescheria boydii , which is involved in fungal phagocytosis and activation of innate immune responses. The compound was assembled by a latent-active glycosylation strategy in which an oxathiane was employed as an acceptor in a glycosylation with a sulfoxide donor. The product of such a glycosylation was oxidized to a sulfoxide for a subsequent glycosylation. The use of Nap and Fmoc as temporary protecting groups made it possible to install branching points.     

Synthesis of plant arabinogalactans

Plant arabinogalactans consisting of a β-(1→6)-linked D-galactopyranosyl oligosaccharide back-bone with α-(1→2)-L-arabinofuranosyl branches are synthesized based on the 1,2-anhydro galactopyranose technique, orthogonal (methoxydimethyl)methyl (MIP) and (2-naphthyl)methyl (NAP) protection strategy, and selective acylation or glycosylation method. The third method is the most simple and effective and it is also used for the synthesis of arabinogalactans composed of a β-(1→6)-linked D-galactopyranosyl oligosaccharide backbone with α-(1→3)-L-arabinofuranosyl branches.