Disaccharide Mimetics Research Articles

Oxocarbenium ion cyclizations for the synthesis of disaccharide mimetics of 2-amino-2-deoxy-pyranosides: Application to the carbasugar of β-galactosamine-(1,4)-3-O-methyl-D-chiro-inositol

The synthesis of the carbasugar of β-galactosamine-(1,4)-3-O-methyl-D-chiro-inositol (INS-2), a potential tool for studying glucose metabolism, is described. The synthetic strategy, entails an oxocarbenium ion cyclization on a chiro-inositol derived, thioacetal-enol ether to give a carbocyclic enol ether, which is elaborated to the 2-amino-2-deoxy carbasugar framework via a 2-oximo derivative.

Stereoselective Construction of Orthogonally Protected, N-O Interlinked Disaccharide Mimetics Using N-Substituted β-Aminooxy Donors.

Orthogonally protected N-substituted β-aminooxy sugars can be stereoselectively synthesized from sugar epoxides and nitrones derived from aromatic aldehydes. Both the ether- and ester-protected sugar epoxides can be employed. The synthesized aminooxy sugars could be reacted with aldehyde bearing/free reducing sugars under the heating condition to afford N-O-linked 1,1-/1,5/1,6-disaccharide mimetics in a good yield.

Rapid On-Chip Synthesis of Complex Glycomimetics from N-Glycan Scaffolds for Improved Lectin Targeting.

C-type lectin receptor (CLR) carbohydrate binding proteins found on immune cells with important functions in pathogen recognition as well as self and non-self-differentiation are increasingly moving into the focus of drug developers as targets for the immune therapy of cancer autoimmune diseases and inflammation and to improve the efficacy of vaccines. The development of molecules with increased affinity and selectivity over the natural glycan binders has largely focused on the synthesis of mono and disaccharide mimetics but glycan array binding experiments have shown increased binding selectivity and affinity for selected larger oligosaccharides that are able to engage in additional favorable interactions beyond the primary binding site. Here, a platform for the rapid preparation and screening of N-glycan mimetics on microarrays is presented that turns a panel of complex glycan core structures into structurally diverse glycomimetics by a combination of enzymatic glycosylation with a nonnatural donor and subsequent cycloaddition with a collection of alkynes. All surface-based reactions were monitored by MALDI-TOF MS to assess conversion and purity of spot compositions. Screening the collection of 374 N-glycomimetics against the plant lectin WFA and the 2 human immune lectins MGL ECD and Langerin ECD produced a number of high affinity binders as lead structures for more selective lectin targeting probes.

Sequential one-pot synthesis of (1→6) amide-linked oligosaccharide mimetics under mild conditions

An efficient and practical synthetic strategy, suitable for one-pot synthesis, for novel amide-linked oligosaccharide mimetics from sugar amino acid precursors is described. Twenty substrates, including twelve amide-linked disaccharide mimetics, four amide-linked trisaccharide mimetics and four amide-linked tetrasaccharide mimetics, were synthesized based on this strategy and its optimal conditions. This potentially general method is featured by high yields, gram-scale synthesis, wide substrate scope, and mild reaction conditions.

Stereoselective Synthesis of Carbon-Sulfur-Bridged Glycomimetics by Photoinitiated Thiol-Ene Coupling Reactions

Oligosaccharides and glycoconjugates are abundant in all living organisms, taking part in a multitude of biological processes. The application of natural O-glycosides in biological studies and drug development is limited by their sensitivity to enzymatic hydrolysis. This issue made it necessary to design hydrolytically stable carbohydrate mimetics, where sulfur, carbon, or longer interglycosidic connections comprising two or three atoms replace the glycosidic oxygen. However, the formation of the interglycosidic linkages between the sugar residues in high diastereoslectivity poses a major challenge. Here, we report on stereoselective synthesis of carbon-sulfur-bridged disaccharide mimetics by the free radical addition of carbohydrate thiols onto the exo-cyclic double bond of unsaturated sugars. A systematic study on UV-light initiated radical mediated hydrothiolation reactions of enoses bearing an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions of the pyranosyl ring with various sugar thiols was performed. The effect of temperature and structural variations of the alkenes and thiols on the efficacy and stereoselectivity of the reactions was systematically studied and optimized. The reactions proceeded with high efficacy and, in most cases, with complete diastereoselectivity producing a broad array of disaccharide mimetics coupling through an equatorially oriented methylensulfide bridge.

Synthesis and photoinitiated thiol-ene reactions of exo-mannals - a new route to C-β-d-mannosyl derivatives.

Syntheses of acyl protected exo-mannal derivatives were developed starting from O-peracylated mannopyranoses via the corresponding anhydro-aldose tosylhydrazones under modified Bamford–Stevens conditions. The synthesis of analogous O-peralkylated (benzylated and isopropylenated) derivatives was carried out from pyranoid and furanoid mannonolactones using methylene transfer reagents. Photoinitiated thiol–ene additions of these exo-mannals resulted in the corresponding C-(mannopyranosyl/mannofuranosyl)methyl sulfides in medium to good yields with exclusive regio- and β(d) stereoselectivities.

Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors.

This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C. riparius trehalase was evaluated and the results showed that 8 was active in the μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9–11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain’s length in inducing inhibitory properties, since only compounds 9 (α,β-mixture), bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the β-glucoside 9β, which was active in the low micromolar range (IC50 = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase.

Synthesis of Oxaphosphinane‐Based Pseudodisaccharides

The synthesis of pseudodisaccharides based on an oxaphosphinane heterocycle is described. Disaccharide mimetics 5 and 6 were readily obtained through glycosylation of a hydroxy group with appropriately protected furanosyl or pyranosyl carbohydrates using a trichloroacetamidate coupling strategy. Selective or complete deprotection then produced the chiral pseudodisaccharides in good yields.

Non‐Glycosidically Linked Pseudodisaccharides: Thioethers, Sulfoxides, Sulfones, Ethers, Selenoethers, and Their Binding to Lectins

AbstractHydrolytically stable non‐glycosidically linked tail‐to‐tail pseudodisaccharides are linked by a single bridging atom remote from the anomeric centre of the constituent monosaccharides. Some such pseudodisaccharides with sulfur or oxygen bridges were found to act as disaccharide mimetics in their binding to the Banana Lectin and to Concanavalin A. A versatile synthetic route to a small library of such compounds is described.

Synthesis of non-glycosidically linked selenoether pseudodisaccharides

Non-glycosidically linked disaccharide mimetics with a selenoether functionality linking the two monosaccharide residues have been synthesised. Protected Glc(Se3–3)Glc, Glc(Se3–6)Glc and Glc(Se3–6)Man structures were obtained. Selenium was introduced by displacement of carbohydrate sulfonates with a selenobenzoate anion. Conversion into diselenides by methanolysis of the benzoate and aerial oxidation was followed by reduction of the diselenides to selenolates, and in situ displacement of a second carbohydrate sulfonate in an SN2 reaction to give selenoethers. Glc(Se3–3)Glc and Glc(Se3–6)Glc were also obtained in deprotected form.

ChemInform Abstract: Access to C‐Branched Sugars: Stereoselective Synthesis of C3—C5‐Linked Deoxy Disaccharide and C‐Linked Deoxy Aza Disaccharide Mimetics via a Ring‐Closing Metathesis Protocol.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Access to C-Branched Sugars: Stereoselective Synthesis of C3-C5-Linked Deoxy Disaccharide and C-Linked Deoxy Aza Disaccharide Mimetics via a Ring-Closing Metathesis Protocol

RCM mediated stereoselective synthetic approaches for the branched C-C disaccharide and its aza analog via Ring Closing Metathesis protocol are described. Keywords: C-C-disaccharide, C-linked aza disaccharide, Ring-closing metathesis, Cis-dihydroxylation

Design, synthesis, FGF-1 binding, and molecular modeling studies of conformationally flexible heparin mimetic disaccharides

Disaccharide mimetics of a heparin sequence that binds to fibroblast growth factors were prepared by coupling a D-galactose donor with a methyl beta-D-gluco- or xylopyranoside acceptor. When fully sulfated, the glucose or xylose moieties exist in solution in equilibrium between the (4)C1 and (1)C4 conformers, as confirmed by 1H NMR spectroscopy, thus mimicking the conformationally flexible L-iduronic acid found in heparin. Docking calculations showed that the predicted locations of disaccharide sulfo groups in the binding site of FGF-1 are consistent with the positions observed for co-crystallized heparin-derived oligosaccharides. Predicted binding affinities are in accord with experimental Kd values obtained from binding assays and are similar to the predicted values for a model heparin disaccharide.

C‐Disaccharides as Probes for Carbohydrate Recognition – Investigation of the Conformational Requirements for Binding of Disaccharide Mimetics of Sialyl Lewis X

AbstractA set of C‐disaccharide analogs was designed to probe the recognition of a known O‐disaccharide mimetic of sialyl Lewis X, to P‐selectin. The synthesis of the C‐glycosides centered on the de novo construction of the galactose residue via an oxocarbenium ion/enol ether cyclization. Conformational analysis was performed by a combination of NMR spectroscopy and molecular mechanics (MM) and molecular dynamics (MD) calculations. The inhibition of P‐selectin binding was evaluated in a P‐selectin Biacore assay. At 12 mM, the O‐glycoside showed 48 % inhibition of binding, while the C‐glycoside analogs exhibited between 25–31 % inhibition. This data is discussed within the context of the active conformation of sLex and the conformational behavior of these ligands. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The Use of Levoglucosenone and Isolevoglucosenone as Templates for the Construction of C‐Linked Disaccharides

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

The use of levoglucosenone and isolevoglucosenone as templates for the construction of C-linked disaccharides

Because of their functionalities (enone, ketone, and acetal) and their bicyclic structure (steric factors), levoglucosenone (1,6-anhydro-3,4-dideoxy-β- d- glycero-hex-3-enopyran-2-ulose) and isolevoglucosenone (1,6-anhydro-2,3-dideoxy-β- d- glycero-hex-3-enopyran-4-ulose) are useful templates for the convergent and combinatorial synthesis of (1→2), (1→3), and (1→4)-linked C-disaccharides in reactions combining them with sugar-derived carbaldehydes. Synthetic methods relying on conjugate nucleophilic additions of these enones, their combination with aluminum reagents and aldehydes (Baylis–Hillman reaction) and modified Takai–Hiyama–Nozaki–Kishi couplings of enol triflates derived from them with sugar-derived aldehydes are reviewed. Highly stereoselective methods have thus been developed. These allow the generation of disaccharide mimetics with a high molecular diversity.

Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: Exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives

BackgroundMany polyhydroxylated piperidines are inhibitors of the oligosaccharide processing enzymes, glycosidases and glycosyltransferases. Aza-C-linked disaccharide mimetics are compounds in which saturated polyhydroxylated nitrogen and oxygen heterocycles are linked by an all-carbon tether. The saturated oxygen heterocycle has the potential to mimic the departing sugar in a glycosidase-catalysed reaction and aza-C-linked disaccharide mimetics may, therefore, be more potent inhibitors of these enzymes.ResultsThe scope, limitations and diastereoselectivity of the dihydroxylation of stereoisomeric 2-butyl-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-pyridin-3-ols is discussed. In the absence of a 6-substituent on the piperidine ring, the Upjohn (cat. OsO4, NMO, acetone-water) and Donohoe (OsO4, TMEDA, CH2Cl2) conditions allow complementary diastereoselective functionalisation of the alkene of the (2R*,3R*) diastereoisomer. However, in the presence of a 6-substituent, the reaction is largely controlled by steric effects with both reagents. The most synthetically useful protocols were exploited in the two-directional synthesis of aza-C-linked disaccharide analogues. A two-directional oxidative ring expansion was used to prepare bis-enones such as (2R,6S,2'S)-6-methoxy-2-(6-methoxy-3-oxo-3,6-dihydro-2H-pyran-2-ylmethyl)-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-3-one from the corresponding difuran. Selective substitution of its N,O acetal was possible. The stereochemical outcome of a two-directional Luche reduction step was different in the two heterocyclic rings, and depended on the conformation of the ring. Finally, two-directional diastereoselective dihydroxylation yielded seven different aza-C-linked disaccharide analogues.ConclusionA two-directional approach may be exploited in the synthesis of aza-C-linked disaccharide mimetics. Unlike previous approaches to similar molecules, neither of the heterocyclic rings is directly derived from a sugar, allowing mimetics with unusual configurations to be prepared. The work demonstrates that highly unsymmetrical molecules may be prepared using a two directional approach. The deprotected compounds may have potential as inhibitors of oligosaccharide-processing enzymes and as tools in chemical genetic investigations.

A General, Two‐Directional Approach to Aza‐C‐(1→1)‐Linked Disaccharide Mimetics.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Aza‐C‐disaccharides (Dideoxyimino‐alditols C‐Linked to Monosaccharides) and Analogues

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and NMR-characterization of three quinamide-based disaccharide mimetics with unusual cyclohexane twist-conformation

The synthesis of amide-linked disaccharide mimetics has been explored starting with carbohydrate-based amines and a protected quinic acid lactone. Benzyl-2-amino-4,6-Obenzylidene-2-deoxy-α/β-D-glucopyranose (12) and D-glucamine (14) were successfully coupled to give the corresponding quinamides (13 and 15), while the quinoylation of Oacetylated L-fucopyranosyl methylamine (7) failed. The latter was prepared from per-O-acetylL-fucopyranose via the improved multigram scale synthesis of the corresponding per-O-acetylL-fucopyranosyl cyanide (3). Compound 3 was subsequently hydrogenated to yield a mixture of compound 7 and the per-O-acetylated bis-(fucopyranosylmethyl) amine (5). The vicinal coupling constants in the NMR spectra of all quinamide products revealed considerable flexibility of the cyclohexane ring in solution and substantial contributions by twist-chair conformations.