Disaccharide

A disaccharide (also called a double sugar or biose) is the sugar formed when two monosaccharides are joined by glycosidic linkage. Like monosaccharides, disaccharides are simple sugars soluble in water. Three common examples are sucrose, lactose, and maltose. Disaccharides are one of the four chemical groupings of carbohydrates (monosaccharides, disaccharides, oligosaccharides, and polysaccharides). The most common types of disaccharides—sucrose, lactose, and maltose—have 12 carbon atoms, with the general formula C12H22O11. The differences in these disaccharides are due to atomic arrangements within the molecule. The joining of monosaccharides into a double sugar happens by a condensation reaction, which involves the elimination of a water molecule from the functional groups only. Breaking apart a double sugar into its two monosaccharides is accomplished by hydrolysis with the help of a type of enzyme called a disaccharidase. As building the larger sugar ejects a water molecule, br

Synthesis of C-glycosides and C-linked disaccharides through carbonylative Stille coupling reactions

Peter Steunenberg

In the first part, we described the synthesis of C-(1'→1) and C-(1'→4) disaccharide precursors, which are readily obtained via the carbonylative Stille coupling of glucal and isolevoglucosenone derivatives. Tin glycals and triflates, derived from isolevoglucosenone, undergo the carbonylative Stille condensation under special conditions requiring AsPh3, LiCl and powdered charcoal as co-catalysts to give the corresponding cross-conjugated dienones, in which the bicyclic alkene moiety is more reactive than the glucal alkene moiety. The bicyclic part of the formed disaccharides precursors undergo selective nucleophilic additions with hydrogen, methoxybenzylamine and thiophenol. The other alkene moiety can undergo a selective epoxidation. The reactivity of the bicyclic part permitted a regio- and stereoselective hydrogenation of the bicyclic enone, that was then reduced with K-Selectride with high diastereoselectivity. The allylic alcohols so-obtained can undergo hydroboration giving a diol protected as an acetonide. The anhydro-moiety is then opened by a thioglycosidation reaction to form a partially protected glycoside-donor which can be used, in principle, for O-glycosidation. The C(1'→4) linked disaccharide so-obtained consists of a protected form of β-D-glucopyranose, attached at position C(4) of a α-D-3-deoxy-lyxo-hexopyranoside derivative via a (R)-hydroxymethanol linker. Another methodology based on 1,4-addition of thiophenol, allow one to form of several C-(1'→4) linked disaccharide precursors. Simple C-(1'→1)-disaccharides could also be prepared in similar fashion. In a second part the palladium-catalyzed cross-coupling reaction of tinglucal and tingalactal derivatives with arenesulfonyl chlorides provide aryl C-glycosides precursors. Desulfitative carbonylative Stille cross-coupling between 1-naphthalenesulfonyl chloride and a tinglucal derivative gives, after stereoselective reduction of the keto moiety and stereoselective oxidative hydroboration, C-glycosides consisting of a β-C-glucopyranoside and (R)-(naphtha-1-yl)methanol. Benzyl C-glycoside precursors are obtained by desulfitative Stille coupling of phenylmethanesulfonyl chloride with the corresponding protected tinglycals. In a third part we discussed the synthesis of carbohydrate based scaffolds for the deprotection of allylic alcohols by polysulfones. In this part we successfully applied the cleavage of allyl-protected carbohydrate derivatives by polysulfones, solid catalysts for the chemoselective cleavage of methyl substituted allyl ethers, such as prenyl, methylallyl and methylprenyl, developed by Markovic in our group. Allyl ethers are not cleaved under these conditions. This establishes a new method of selective polyol semi-protection in which a neutral, solid catalyst induces cleavage of ethers with the following reactivity sequence: 2-methylprenyl > prenyl > methallyl >> allyl.

EPFL2005

Synthesis of C-linked Disaccharides and Analogues as Biomimetics of the TF Epitope

Maria Kolympadi

Glycoproteins and glycolipids are major components of the outer surface of mammalian cells. Their carbohydrate moieties, which are directed into the outer environment, serve as ligands for receptor proteins, such as lectins, pathogen proteins and antibodies. Recognition processes between the receptor proteins and the carbohydrates have a significant impact on different aspects of cell biology as they turn structure into biological response in a selective way. Cellular carbohydrate structures are found to change dramatically during embryonic development or under pathological conditions including malignant transformation. One example is the Thomsen-Friedenreich (TF) epitope, a disaccharide consisting of galactose-β-(1→3)-N-acetyl-galactosamine α-linked to a serine or threonine of a carrier protein. The TF epitope is considered as a cancer-specific carbohydrate antigen that is found on various epithelial carcinomas of human adults and can be recognized by the anti-TF antibody. It has been demonstrated that synthetic glycoconjugates of the TF epitope can act as anti-cancer vaccines by stimulating the immune system against tumor growth and proliferation. Native carbohydrates are liable to chemical and enzymatic hydrolysis of their glycosidic bonds and therefore short-lived in the blood. Their stable C-analogues in which the glycosidic oxygens have been replaced by methylene or substituted methylene units are particularly interesting as therapeutic agents. We report herein our efforts to synthesize non-hydrolysable methylene and fluorinated methylene linked disaccharides analogues of the TF epitope. Our synthesis follows a methodology previously developed in our laboratory for the preparation of C(1→3)-disaccharides. The key step is an Oshima-Nozaki coupling between a β-C-galactosyl carbaldehyde and an enone, isolevoglucosenone. The hydroxyl methylene linker that is created by this coupling can be deoxygenated or can be substituted by one fluorine atom (or two fluorine atoms via the corresponding ketone). 1,4-Addition of an amine to the enone derived from the Oshima-Nozaki coupling, ketone reduction and some protecting group manipulations gave an hydroxyl methylene linked disaccharide that could smoothly undergo Barton-McCombie deoxygenation. On the contrary, the attempts of nucleophilic fluorination of this substrate failed to give the desired outcome probably due to an intramolecular rearrangement. With the deoxygenated product in hand and after some protecting group transformations, we attempted C-allylation of the anomeric centre and at the same time cleavage of the 1,6-anhydro bridge. Some preliminary results are presented. An allyl-C-disaccharide can lead to a C-glycosyl amino acid according to the literature and therefore it can be used for preparing a C,C-analogue of the TF epitope. In our search for biomimetics of the TF epitope with less synthetic requirements, we attempted to replace the second saccharidic unit by a phenyl ring. Simple phenyl CH2- and CF2-galactosides were prepared starting from α- and β-C-galactosyl carbaldehydes. NMR studies in combination with theoretical calculations revealed that the conformational behaviour of these galactosides in solution depends on the substitution at pseudoanomeric center. Similarities and differences to their O-analogues are discussed. Additionally, NMR spectroscopy was used to detect binding to a lectin protein. The β-galactosyl carbaldehyde –common starting material for the synthesis of C-linked disaccharides and phenyl C-galactosides mentioned above – was also used to prepare a small library of CH2-galactosyl aryl ethers bearing different aromatic amides. The affinities of these derivatives towards some galactoside-specific lectins, the galectins, were measured. None of the synthesized C-galactosyl analogues appeared to be high-affinity ligand of galectins. However, such studies are useful for the future design of sugar analogues with the minimum of functionalities that assure strong binding to carbohydrate recognition proteins.

EPFL2011

Synthesis of C-linked Disaccharides and Analogues as Biomimetics of the TF Epitope

Maria Kolympadi

EPFL2011

Synthesis of C-glycosides and C-linked disaccharides through carbonylative Stille coupling reactions

Peter Steunenberg

EPFL2005

New approach to C-disaccharides

Synthesis of C-glycosides and C-linked disaccharides through carbonylative Stille coupling reactions

Synthesis of C-linked Disaccharides and Analogues as Biomimetics of the TF Epitope

Synthesis of C-linked Disaccharides and Analogues as Biomimetics of the TF Epitope

Synthesis of C-glycosides and C-linked disaccharides through carbonylative Stille coupling reactions

New approach to C-disaccharides