Glycosylation Method Research Articles

Semisynthesis of fuscoside B analogues and eunicosides, and analysis of anti-inflammatory activity

A small library of semisynthetic analogues of fuscol and eunicol have been prepared and evaluated for in vivo topical anti-inflammatory activity using the mouse-ear edema assay. The first glycosylation of fuscol and eunicol has been achieved using a modified Koenigs–Knorr glycosylation to synthesize new fuscosides and eunicosides, a novel structural class of diterpene glycosides. The availability of adequate glycosylation methods for this synthesis was limited owing to the instability of the glycosyl acceptors. Glycosyl donor protecting group type had a pronounced effect on overall glycosylation yields of a model glycosyl acceptor. This synthesis provided access to the unnatural β-glycosides allowing for an evaluation of the effect of differing anomeric stereochemistry on anti-inflammatory activity. The PEGylated derivatives of fuscol and eunicol were also synthesized by a convenient acid-promoted solvolysis of the natural product aglycones. This work highlights the importance of the glycan portion of fuscoside B, notably the stereochemical configuration of the glycosidic linkage, in the observed anti-inflammatory activity.

Lipo-Chitooligosaccharidic Nodulation Factors: Synthesis and Agricultural Perspectives

Lipo-chitooligosaccharidic nodulation (Nod) factors produced by rhizobia are a class of signalling molecules that induce a symbiotic association between legumes and soil bacteria rhizobia leading to the formation of the nitrogen-fixing root nodule. They consist of a chitin oligomeric backbone N-acylated at the non-reducing unit and are equipped with a variety of substituents at both ends of the oligosaccharide. This brief account focuses on the different approaches developed for their synthesis with particular emphasis on glycosylation methods. Current use of these Nod factors or analogs as additives in agricultural applications has shown to be very promising for sustainable agriculture.

Glycosyloxyamine Neoglycosylation: A Model Study Using Calicheamicin

Glycosyloxyamine Neoglycosylation: A Model Study Using Calicheamicin

ChemInform Abstract: Direct Glycosylation with Anomeric Hydroxy Sugars by Activation with 3‐Fluorophthalic Anhydride and Trifluoromethanesulfonic Anhydride.

Abstract28 examples

Improved methods for profiling glycosylation of proteins

Improved methods for profiling glycosylation of proteins

Iron(iii) chloride as an efficient catalyst for stereoselective synthesis of glycosyl azides and a cocatalyst with Cu(0) for the subsequent click chemistry

A highly efficient and mild method for azido glycosylation of glycosyl β-peracetates to 1,2-trans glycosyl azides was developed by using inexpensive FeCl(3) as the catalyst. In addition, we demonstrated, for the first time, that FeCl(3) in combination with copper powder can promote 1,3-dipolar cycloaddition (click chemistry) of azido glycosides with terminal alkynes. Good to excellent yields were obtained with exclusive formation of a single isomer in both glycosyl azidation and subsequent cycloaddition processes.

Rapid method for glycan profiling and site specific glycosylation

Rapid method for glycan profiling and site specific glycosylation

Carbohydrate-Based Bioactive Compounds for Medicinal Chemistry Applications

In this article we review our work over the years on carbohydrates and carbohydrate mimetics and their applications in medicinal chemistry. In the first part of the review innovative synthetic methods, such as the chemoselective glycosylation method originally developed by our group and its applications to the synthesis of neoglycoconjugates (neoglycopeptides, oligosaccharide mimetics, neoglycolipids, etc…) will be presented. The high density of functional groups (hydroxyls) on the monosaccharides and the structural role of sugars forming the core of complex glycans in scaffolding and orienting the external sugar units for the interaction with receptors, inspired us and others to use sugars as scaffolds for the construction of pharmacologically active compounds. In the second part of this review, we will present some examples of bioactive and pharmacologically active compounds obtained by decorating monosaccharide scaffolds with pharmacophore groups. Sugar-derived protein ligands were also used as chemical probes to study the interaction of their target with other proteins in the cell. In this context, sugar mimetics and sugar-derived compounds have been employed as tools for exploring biology according to the "chemical genetic" approach.

Convergent synthesis of a common pentasaccharide corresponding to the O-antigen of Escherichia coli O168 and Shigella dysenteriae type 4

A convenient synthetic strategy of the common acidic pentasaccharide repeating unit corresponding to the O-antigen of enterotoxigenic E. coli O168 and Shigella dysenteriae type 4 has been successfully developed. A stereoselective [2 + 3] block glycosylation method has been exploited to get the target pentasaccharide derivative. Most of the synthetic intermediates were solid and prepared in high yields from commercially available reducing sugars following a series of protection-deprotection reactions. A α-D-mannose moiety has been used as the source of α-D-glucosamine moiety. A late-stage TEMPO mediated selective oxidation reaction finally resulted in the pentasaccharide containing a glucuronic acid unit.

Synthesis of tri- and pentasaccharide fragments corresponding to the O-antigen of Shigella boydii type 6

A convenient synthetic strategy for the synthesis of the acidic pentasaccharide repeating unit and its trisaccharide fragment corresponding to the O-antigen of Shigella boydii type 6 has been successfully developed. A stereoselective sequential glycosylation method has been exploited to obtain the target tri- and pentasaccharide derivatives. Most of the synthetic intermediates were solid and prepared in high yields from commercially available reducing sugars following a series of protection–deprotection reactions. A late-stage TEMPO mediated selective oxidation reaction finally resulted in the pentasaccharide containing a glucuronic acid unit. A 2-(4-methoxyphenoxy) ethyl group has been chosen as the anomeric protecting group to provide trisaccharide and pentasaccharide derivatives linked to an ethylene glycol linker.

ChemInform Abstract: Glycosylation with Glycosyl N‐Phenyltrifluoroacetimidates (PTFAI) and a Perspective of the Future Development of New Glycosylation Methods

AbstractReview: 23 refs.

ChemInform Abstract: Preactivation‐Based, One‐Pot Combinatorial Synthesis of Heparin‐Like Hexasaccharides for the Analysis of Heparin—Protein Interactions.

Heparin (HP) and heparan sulfate (HS) play important roles in many biological events. Increasing evidence has shown that the biological functions of HP and HS can be critically dependent upon their precise structures, including the position of the iduronic acids and sulfation patterns. However, unraveling the HP code has been extremely challenging due to the enormous structural variations. To overcome this hurdle, we investigated the possibility of assembling a library of HP/HS oligosaccharides using a preactivation-based, one-pot glycosylation method. A major challenge in HP/HS oligosaccharide synthesis is stereoselectivity in the formation of the cis-1,4-linkages between glucosamine and the uronic acid. Through screening, suitable protective groups were identified on the matching glycosyl donor and acceptor, leading to stereospecific formation of both the cis-1,4- and trans-1,4-linkages present in HP. The protective group chemistry designed was also very flexible. From two advanced thioglycosyl disaccharide intermediates, all of the required disaccharide modules for library preparation could be generated in a divergent manner, which greatly simplified building-block preparation. Furthermore, the reactivity-independent nature of the preactivation-based, one-pot approach enabled us to mix the building blocks. This allowed rapid assembly of twelve HP/HS hexasaccharides with systematically varied and precisely controlled backbone structures in a combinatorial fashion. The speed and the high yields achieved in glycoassembly without the need to use a large excess of building blocks highlighted the advantages of our approach, which can be of general use to facilitate the study of HP/HS biology. As a proof of principle, this panel of hexasaccharides was used to probe the effect of backbone sequence on binding with the fibroblast growth factor-2 (FGF-2). A trisaccharide sequence of 2-O-sulfated iduronic acid flanked by N-sulfated glucosamines was identified to be the minimum binding motif and N-sulfation was found to be critical. This provides useful information for further development of more potent compounds towards FGF-2 binding, which can have potential applications in wound healing and anticancer therapy.

Direct glycosylation with anomeric hydroxy sugars by activation with 3-fluorophthalic anhydride and trifluoromethanesulfonic anhydride

An efficient and direct one-pot glycosylation method using anomeric hydroxy sugars as glycosyl donors, employing 3-fluorophthalic anhydride and triflic anhydride as activating agents, has been developed. The present glycosylation utilizing 3-fluorophthalic anhydride resulted in few to no undesired self-condensed esters than the glycosylation using phthalic anhydride. Intermediates in the present glycosylation were identified by an NMR study.

ChemInform Abstract: Synthesis of 14,14-Difluoro-4-demethoxydaunorubicin.

The title compound, (+)-14,14-difluoro-4-demethoxydaunorubicin hydrochloride (9), was prepared starting from the readily available (−)-hydroxy ester (10). This synthesis featured the efficient synthetic route to (−)-14,14-difluoro-4-demethoxy-7-deoxydaunomycinone (20) employing the Reformatsky reaction of ethyl bromodifluoroacetate with the (−)-siloxy aldehyde (14) and previously developed glycosylation method in which trimethylsilyl trifluoromethanesulfonate was used as an activator. In P388 in vitro test, 9 was found to be fifty times more active than adriamycin (1). Prominent antitumor activity was also observed for 9 in P388 in vivo test.

ChemInform Abstract: Synthetic Glycans and Glycooligopeptides of O-Glycoproteins

This review article is concerned with the recent aspects of synthetic studies on the O-glycoprotein glycans and the glycooligopeptides. Stereoselective formation of the α-glycosidic linkages between the derivatives of 2-azido-2-deoxy-D-galactopyranose, precursors of the 2-acetamido-2-deoxy-D-galactopyranosyl residue, and the protected amino acids (L-Ser or L-Thr) have been achieved through a variety of glycosylation methods. Of the glycosylated amino acids, those protected with N-Cbz, N-Fmoc, and N-Aloc groups have successfully been converted into the glycooligopeptides in solution or by solid phase methodology according to the routine programme of peptide chemistry.

Preactivation-based, one-pot combinatorial synthesis of heparin-like hexasaccharides for the analysis of heparin-protein interactions.

Heparin (HP) and heparan sulfate (HS) play important roles in many biological events. Increasing evidence has shown that the biological functions of HP and HS can be critically dependent upon their precise structures, including the position of the iduronic acids and sulfation patterns. However, unraveling the HP code has been extremely challenging due to the enormous structural variations. To overcome this hurdle, we investigated the possibility of assembling a library of HP/HS oligosaccharides using a preactivation-based, one-pot glycosylation method. A major challenge in HP/HS oligosaccharide synthesis is stereoselectivity in the formation of the cis-1,4-linkages between glucosamine and the uronic acid. Through screening, suitable protective groups were identified on the matching glycosyl donor and acceptor, leading to stereospecific formation of both the cis-1,4- and trans-1,4-linkages present in HP. The protective group chemistry designed was also very flexible. From two advanced thioglycosyl disaccharide intermediates, all of the required disaccharide modules for library preparation could be generated in a divergent manner, which greatly simplified building-block preparation. Furthermore, the reactivity-independent nature of the preactivation-based, one-pot approach enabled us to mix the building blocks. This allowed rapid assembly of twelve HP/HS hexasaccharides with systematically varied and precisely controlled backbone structures in a combinatorial fashion. The speed and the high yields achieved in glycoassembly without the need to use a large excess of building blocks highlighted the advantages of our approach, which can be of general use to facilitate the study of HP/HS biology. As a proof of principle, this panel of hexasaccharides was used to probe the effect of backbone sequence on binding with the fibroblast growth factor-2 (FGF-2). A trisaccharide sequence of 2-O-sulfated iduronic acid flanked by N-sulfated glucosamines was identified to be the minimum binding motif and N-sulfation was found to be critical. This provides useful information for further development of more potent compounds towards FGF-2 binding, which can have potential applications in wound healing and anticancer therapy.

ChemInform Abstract: Synthetic Study of C-1027 Chromophore. Highly Stereoselective Glycosylation.

A highly stereoselective method for glycosylation of tertiary alcohols with the amino sugar moiety of C-1027 chromophore was developed.

ChemInform Abstract: Novel Carbohydrate Scaffolds. Assembly of a Uridine-Mannose Scaffold Based on Tunicamycin.

Abstract A disaccharide scaffold based on tunicamycin was synthesized from d -uridine and l -mannose. The key step in disaccharide assembly was a β-mannosylation performed using Crich’s modification of the sulfoxide glycosylation method. The scaffold described contains two orthogonal derivatization sites and will be used in the search for novel biologically active compounds.

A selective electrochemical method of glycosylation of 3β-hydroxy-Δ 5-steroids

A new electrochemical glycosylation method is presented. According to the method cholesterol and other 3β-hydroxy-Δ 5-steroids can be selectively transformed to glycosides using non-activated sugars. The method is also useful for the synthesis of glycoconjugates with sugar linked to a steroid moiety by an ether bond.

Exploration of the use of an acylsulfonamide safety-catch linker for the polymer-supported synthesis of hyaluronic acid oligosaccharides

The synthesis of hyaluronic acid oligosaccharides on polyethylene glycol (PEG) using an acylsulfonamide linker has been explored. Hyaluronic acid is a challenging synthetic target that usually involves the condensation of highly disarmed glucuronic acid building blocks. Amine-ended PEG monomethyl ether was efficiently functionalized with a hydroxyl-terminated acylsulfonamide linker. Suitably protected d-glucosamine (GlcN) and d-glucuronic acid (GlcA) monosaccharide building blocks were coupled to the polymer acceptor using the trichloroacetimidate glycosylation method. The sulfonamide safety-catch linker enables simultaneous cleavage of the monosaccharide from the polymer and orthogonal functionalization for further (bio)-conjugation of the sugar sample. Subsequent glycosylation of PEG-bound glycosyl acceptor to generate hyaluronic acid oligosaccharide chain failed. Model glycosylation experiments in solution and on soluble support using the same unreactive acceptors and donors allows for the synthesis of an orthogonally protected hyaluronic acid disaccharide and suggest that the encountered difficulties could be attributed to the presence of the N-acylsulfonamide.