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.     

On orthogonal and selective activation of glycosyl thioimidates and thioglycosides: application to oligosaccharide assembly

Discrimination among S-thiazolinyl (STaz), S-benzoxazolyl (SBox), and S-ethyl anomeric leaving groups was achieved by fine-tuning activation conditions. Preferential glycosidation of a certain leaving group is determined neither by the strength of the activating reagent nor by the stability of the leaving group itself; instead, the type of activation plays the key role. The activation conditions established herein were applied to a sequential five-step synthesis of a hexasaccharide using six monosaccharide building blocks equipped with six different leaving groups.     

Application of the superarmed glycosyl donor to chemoselective oligosaccharide synthesis

Recently, we discovered a novel method for "superarming" glycosyl donors. Herein, this concept has been exemplified in one-pot oligosaccharide syntheses, whereby the superarmed glycosyl donor was chemoselectively activated over traditional "armed" and disarmed glycosyl acceptors. Direct side-by-side comparison of the reactivities of the classic armed and superarmed glycosyl donors further validates the credibility of the novel concept.     

On-resin real-time reaction monitoring of solid-phase oligosaccharide synthesis

On-resin real-time monitoring by a combination of a color test of (p-nitrobenzyl)pyridine and Disperse Red was developed for oligosaccharide synthesis.     

Recent developments in oligosaccharide synthesis: tactics,solid-phase synthesis and library synthesis

Oligosaccharides, commonly found on the cell surfaces, are deeply involved in a variety of important biological functions, yet demanding difficulties synthesizing such structures limit the investigation of their functions. Technologies to chemically synthesize these oligosaccharides have dramatically advanced during the last two decades mainly due to the introduction of good anomeric leaving groups. In addition, tactical analyses have been addressed to enhance the overall efficiency of oligosaccharide synthesis. Based on the advancement of solution-phase chemistry, solid-phase technologies are being investigated in connection with the current trend of combinatorial chemistry and high throughput screening. This review summarizes the necessary solution-phase methodologies, the status of solid-phase synthesis of oligosaccharides, and combinatorial synthesis of oligosaccharide libraries.     

Rapid synthesis of a glycosylphosphatidylinositol-based malaria vaccine using automated solid-phase oligosaccharide synthesis

Described is an automated synthesis of hexasaccharide malarial toxin 1, currently under development as a malaria vaccine candidate. Using a combination of automated solid-phase methods and solution-phase fragment coupling, the target glycosylphosphatidylinositol was assembled in a matter of days, compared with several weeks for a comparable solution-phase synthesis.     

A novel strategy for oligosaccharide synthesis via temporarily deactivated S-thiazolyl glycosides as glycosyl acceptors

A new glycosylation strategy that allows chemoselective activation of the S-thiazolyl (STaz) moiety of a glycosyl donor over the temporarily deactivated glycosyl acceptor, bearing the same anomeric group, has been developed. This deactivation is achieved by engaging of the STaz moiety of the glycosyl acceptor into a stable palladium(II) complex. Therefore, obtained disaccharides are then released from the complex by simple ligand exchange. [reaction: see text]     

Application of serine- and threonine-derived cyclic sulfamidates for the preparation of S-linked glycosyl amino acids in solution- and solid-phase peptide synthesis

Cyclic sulfamidates were synthesized in 60% yield from L-serine and allo-L-threonine, respectively. These sulfamidates reacted with a variety of unprotected 1-thio sugars in aqueous bicarbonate buffer (pH 8) to afford the corresponding S-linked serine- and threonine-glycosyl amino acids with good diastereoselectivity (> or =97%) after hydrolysis of the N-sulfates. The serine-derived sulfamidate was incorporated into a simple dipeptide to generate a reactive dipeptide substrate that underwent chemoselective ligation with a 1-thio sugar to afford an S-linked glycopeptide. This sulfamidate was also incorporated into a peptide on a solid support in conjunction with solid-phase peptide synthesis. Chemoselective ligation of a 1-thio sugar with the cyclic sulfamidate was achieved on the solid support, followed by removal of the N-sulfate. Finally, the peptide chain of the resulting support-bound S-linked glycopeptide was extended using standard peptide synthesis procedures.     

Solid-phase synthesis of alpha-Gal epitopes: on-resin analysis of solid-phase oligosaccharide synthesis with 19F NMR spectroscopy

A route for solid-phase synthesis of the alpha-Gal epitopes Gal(alpha1-3)Gal(beta1-4)Glc and Gal(alpha1-3)Gal(beta1-4)GlcNAc is described. These trisaccharide antigens are responsible for hyperacute rejection in xenotransplantation of porcine organs. Optimization of the solid-phase synthesis relied on use of fluorinated protective groups for the carbohydrate building blocks and use of a fluorinated linker. This allowed convenient on-resin analysis of the reactions with gel-phase (19)F NMR spectroscopy. Conditions were established which allowed reductive ring-opening of 4,6-O-benzylidene acetals to be performed on the solid phase with high regioselectivity to furnish the corresponding 6-O-benzyl ethers. It was found that glycosylations could be conveniently carried out by using thioglycosides as donors with N-iodosuccinimide and trifluoromethanesulfonic acid as the promoter system. With use of these conditions a challenging alpha-glycosidic linkage was successfully installed with complete stereoselectivity in the final glycosylation. It was also established that fluorinated benzoates, benzyl ethers, and benzylidene acetals display almost identical chemical properties as their nonfluorinated counterparts, a finding that is essential for future use of fluorinated protective groups in solid-phase oligosaccharide synthesis.     

A novel glycosyl donor for chemo-enzymatic oligosaccharide synthesis: 4,6-dimethoxy-1,3,5-triazin-2-yl glycoside

A novel activated glycosidic compound, 4,6-dimethoxy-1,3,5-triazin-2-yl beta-lactoside (DMT-beta-Lac), which can be prepared directly from lactose in water without using any protecting groups, was found to be an efficient glycosyl donor for enzymatic glycosylation catalyzed by an endo-1,4-beta-glucanase.     

Wang resin-type linker containing a nitro group for polymer support oligosaccharide synthesis: polymer-supported glycosyl donor

A nitro-introduced Wang resin-type linker for soluble and insoluble polymer support oligosaccharide synthesis is described. The linker was used for connecting glycosyl donors and polymer supports, and was completely stable under the glycosylation conditions tested. The cleavage of the linker was performed under reductive conditions without affecting the protecting groups to release disaccharides.     

Dispiroketals in synthesis (Part 5): A new opportunity for oligosaccharide synthesis using differentially activated glycosyl donors and acceptors

The reactivity of dispiroketal protected thioglycosides makes them useful new precursors for oligossaccharide synthesis as is illustrated by the preparation of a protected pentasaccharide unit common to the variant surface glycoprotein of Trypanosoma brucei.     

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.     

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.     

Automated oligosaccharide synthesis

Peptides and oligonucleotides are prepared by automated synthesizers that can be operated by non-specialists. Carbohydrates have been hard to assemble, but the increasing awareness of the biological importance of this class of complex repeating biopolymers has prompted efforts to accelerate their synthesis. This tutorial review defines the state of the art of automated solid phase oligosaccharide synthesis and identifies areas in need of further innovation. Application of the automated synthesis method to prepare a malaria vaccine candidate is briefly highlighted.     

Fluorous thiols in oligosaccharide synthesis

A new, almost odorless fluorous thiol is synthesized, which is utilized to prepare highly fluorinated thioglycosyl donors. These thioglycosides showed excellent reactivities in glycosylation reactions. The fluorous chain, stable under esterification, etherification, deacetylation, and glycosylation conditions, allowed facile purification of the thioglycosides by solid-phase extraction through fluorous silica gel. The fluorous thiol was readily recycled.     

Toward automated oligosaccharide synthesis

Carbohydrates have been shown to play important roles in biological processes. The pace of development in carbohydrate research is, however, relatively slow due to the problems associated with the complexity of carbohydrate structures and the lack of general synthetic methods and tools available for the study of this class of biomolecules. Recent advances in synthesis have demonstrated that many of these problems can be circumvented. In this Review, we describe the methods developed to tackle the problems of carbohydrate-mediated biological processes, with particular focus on the issue related to the development of the automated synthesis of oligosaccharides. Further applications of carbohydrate microarrays and vaccines to human diseases are also highlighted.     

HPLC-assisted automated oligosaccharide synthesis

A standard HPLC was adapted to polymer supported oligosaccharide synthesis. Solution-based reagents are delivered using a software-controlled solvent delivery system. The reaction progress and completion can be monitored in real time using a standard UV detector. All steps of oligosaccharide assembly including loading, glycosylation, deprotection, and cleavage can be performed using this setup.     

Simplifying oligosaccharide synthesis: efficient synthesis of lactosamine and siaylated lactosamine oligosaccharide donors

A practical sequence is described for converting d-glucosamine into peracetylated Gal(beta-1,4)GlcNTroc(beta1-S)Ph and Neu5Ac(alpha-2,3)Gal(beta-1,4)GlcNTroc(beta1-S)Ph building blocks using a synthetic strategy based on chemoenzymatic oligosaccharide synthesis. The known trichloroethoxycarbonyl, N-Troc, protecting group was selected as a suitable protecting group for both enzymatic and chemical reaction conditions. These oligosaccharide building blocks proved effective donors for the beta-selective glycosylation of the unreactive OH-3 of a polymeric PEG-bound acceptor and for the axial OH-2 of a mannose acceptor in good yields. The resulting complex oligosaccharides are useful for vaccine and pharmaceutical applications.     

Efficient one-pot synthesis of glycosyl disulfides

Methodology for the efficient and facile synthesis of glycosyl disulfides is reported. A one-pot procedure employing mild conditions using diethyl azodicarboxylate is described to synthesise a series of glycosyl disulfides in excellent yields.