Tag-reporter and resin capture--release strategy in oligosaccharide synthesis

Low molecular weight poly(ethylene glycol) (LWPEG) has been found to be useful as a "tag" in oligosaccharide synthesis due to its high polarity. Real-time reaction monitoring was achieved by use of MALDI-TOF MS in the glycosylation reactions and color tests in the deprotection of the chloroacetyl group. Further, a cysteine-supported insoluble resin enables the purification of the chloroacetyl-bound compounds on soluble PEG.     

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.     

An orthogonal protection strategy for the synthesis of 2-substituted piperazines

Tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones are readily prepared from the bis-carbamate protected piperazine-2-carboxylic acids and serve as orthogonally protected piperazines from which a variety of 2-substituted piperazines can be prepared. Sodium benzylate and sodium phenoxides react at the C-5 carbon of the oxazolidinone to yield 2-(benzyloxymethyl)piperazines and 2-(phenoxymethyl)piperazines, respectively. The tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones also provide convenient scaffolds from which 2-benzyl- and 2-phenethylpiperazines are prepared.     

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]     

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.     

Novel orthogonal strategy toward solid-phase synthesis of 1,3,5-substituted triazines

[reaction: see text] To improve upon the previous orthogonal method for synthesis of a triazine library, an alternative strategy has been developed via oxidation-activation of the thioether to the sulfone. Through a comparison between these two methods, the sulfone strategy was demonstrated as an enhanced method in the generation of highly pure triazine library compounds.     

A new strategy in oligosaccharide synthesis using lipophilic protecting groups: synthesis of a tetracosasaccharide

The use of lipophilic, acyl-type protecting groups in the synthesis of higher-membered oligosaccharides is described by the example of oligosaccharides corresponding to the O-specific polysaccharide (O-SP) of Shigella dysenteriae type 1. Thus, O-stearoylated and O-lauroylated l-rhamnose and d-galactose precursors, respectively, were synthesized and were combined together with a 2-azido-2-deoxy-d-glucopyranosyl donor to form a fully protected lipidated repeating unit of the O-SP. This module was condensed with another tetrasaccharide containing conventional blocking groups. The resulting lipidated octasaccharide was isolated in a pure form by adsorption to a reverse phase adsorbent from which it could be selectively desorbed by alcoholic solvents. Subsequent chain elongation using the conventionally protected tetrasaccharide module as glycosyl donor afforded oligosaccharides up to and including a tetracosasaccharide. The proposed approach can substantially alleviate the difficulties associated with the conventional silica gel chromatographic purification of protected oligosaccharide intermediates and utilizes environmentally friendly solvents that are less expensive than the solvents used for silica gel chromatography. A new, highly efficient method is also proposed for the synthesis of carbohydrate acetals and cyclic orthoesters employing scandium trifluoromethanesulfonate as the catalyst.     

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.     

Iterative, orthogonal strategy for oligosaccharide synthesis based on the regioselective glycosylation of polyol acceptors with partially unprotected n-pentenyl-orthoesters: further evidence for reciprocal donor acceptor selectivity (RDAS)

An efficient iterative, orthogonal protocol based on the regioselective glycosyl coupling of D-mannose polyols with, partially unprotected, n-pentenyl orthoester donors permits the synthesis of linear and branched oligosaccharides with minimal protecting group tampering.     

S-thiazolinyl (STaz) glycosides as versatile building blocks for convergent selective, chemoselective, and orthogonal oligosaccharide synthesis

In the aim of developing new procedures for efficient oligosaccharide assembly, a range of S-thiazolinyl (STaz) glycosides have been synthesized. These novel derivatives were evaluated against a variety of reaction conditions and were shown to be capable of being chemoselectively activated in the armed-disarmed fashion. Moreover, the S-thiazolinyl moiety exhibited a remarkable propensity for selective activation over other common leaving groups. Conversely, a variety of leaving groups could be selectively activated over the STaz moiety, which, in turn, allowed STaz/S-ethyl and STaz/S-phenyl orthogonal approaches. To demonstrate versatility of novel STaz derivatives, a number of oligosaccharide targets have been synthesized in a convergent selective, orthogonal, and chemoselective fashion.     

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.     

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.     

Cap-and-tag solid phase oligosaccharide synthesis

A new "cap-and-tag" strategy is applied to solid phase oligosaccharide synthesis. Acetyl-capping and fluorous-tagging allowed for the facile separation of the desired F-tagged oligosaccharide from the acetyl-capped deletion sequences using fluorous solid phase extraction. To illustrate this approach, a protected Glc-beta-(1-->6)-Man-alpha-(1-->6)-Glc-beta-1-->pentenyl trisaccharide was synthesized.     

A novel "double-coupling" strategy for iterative oligothiophene synthesis using orthogonal Si/Ge protection

[reaction: see text] A new iterative synthesis of regioregular oligothiophenes has been developed in which "double-coupling" after each iteration minimizes deletion sequences. The method exploits the susceptibility of alpha-silyl- but not alpha-germyl-substituted thiophene derivatives toward nucleophilic ipso-protodemetalation and features an unusual "base-free" Suzuki-type cross-coupling protocol. The strategy has been designed for the solid-phase synthesis of high purity oligothiophenes using a germanium-based linker.     

Mono- vs. di-fluorous-tagged glucosamines for iterative oligosaccharide synthesis

Fluorous-tagged protecting groups are attractive tools for elongating carbohydrate chains in oligosaccharide synthesis. To eliminate the accumulation of failed sequences during automated oligosaccharide synthesis conditions, an additional C₈F₁₇ ester derived protecting group was attached to the glycosyl donor to better retain the desired doubly tagged glycosylation product on fluorous solid-phase extraction (FSPE) cartridges. Initial studies show that the double-fluorous-tagging strategy offers a robust enough separation using a commercial FSPE cartridge using simple gravity filtration to separate the desired product from the singly fluorous-tagged starting materials and their decomposition products. In addition, removal of the fluorous acetate and its by-products after sodium methoxide treatment and neutralization required only dissolution of the desired sugar in toluene and subsequent removal of the toluene layer from the denser fluorous by-products.     

A modular approach for the synthesis of oligosaccharide mimetics

To allow modular syntheses of oligosaccharide mimetics, the potentially trifunctional glycoside 7 was synthesized and used as a scaffold for the successive attachment of further monosaccharide derivatives to lead to the di-, tri-, and tetrasaccharide mimetics 11, 13, and 16. This synthetic strategy can also be used to prepare oligovalent neoglycoconjugates, e.g., 18, which contains nine mannosyl units. The applied concept implies numerous options for the synthesis of a wide array of structural variations, biolabeling, or solid-phase synthesis as well as combinatorial approaches.     

Polymer-supported oligosaccharide synthesis using ultrafiltration methodology

Polymer-supported oligosaccharide synthesis was carried out using an ultrafiltration technique in which the synthesized polymer-bound oligosaccharides were separated from the other reagents by ultrafiltration though membranes with specifically sized pores.