C-glycosyl Compounds Research Articles

Palladium-catalyzed Suzuki-Miyaura cross-couplings of stable glycal boronates for robust synthesis of C-1 glycals

C-1 Glycals serve as pivotal intermediates in synthesizing diverse C-glycosyl compounds and natural products, necessitating the development of concise, efficient and user-friendly methods to obtain C-1 glycosides is essential. The Suzuki-Miyaura cross-coupling of glycal boronates is notable for its reliability and non-toxic nature, but glycal donor stability remains a challenge. Herein, we achieve a significant breakthrough by developing stable glycal boronates, effectively overcoming the stability issue in glycal-based Suzuki–Miyaura coupling. Leveraging the balanced reactivity and stability of our glycal boronates, we establish a robust palladium-catalyzed glycal-based Suzuki-Miyaura reaction, facilitating the formation of various C(sp2)-C(sp), C(sp2)-C(sp2), and C(sp2)-C(sp3) bonds under mild conditions. Notably, we expand upon this achievement by developing the DNA-compatible glycal-based cross-coupling reaction to synthesize various glycal-DNA conjugates. With its excellent reaction reactivity, stability, generality, and ease of handling, the method holds promise for widespread appication in the preparation of C-glycosyl compounds and natural products.

Flow Chemistry for Synthesis of 2-(C-Glycosyl)acetates from Pyranoses via Tandem Wittig and Michael Reactions.

C-Glycosyl compounds (C-glycosides) are a class of saccharide derivatives with improved stability over their O-linked counterparts. This paper reports the synthesis of several trans-2-(C-glycosyl)acetates via a tandem Wittig-Michael reaction from pyranoses (cyclic hemiacetals) using continuous flow processing, which gave improvements compared to reactions conducted in round-bottom flasks. Products were isolated in yields of >60% from reactions of benzyl-protected xylopyranoses, glucopyranoses, and galactopyranoses at higher temperatures and pressures, which were superior to yields from batch procedures. A two-step procedure involving the Wittig reaction followed by Michael reaction (intramolecular oxa-Michael) of the unsaturated ester obtained in the presence of DBU was developed. Reactions of protected mannopyranose gave low yields in corresponding reactions in flow due to competing C-2 epimerization.

Synthesis of non-anomeric C-glycosyl pyrazolidinone derivatives via visible-light photoredox catalysis.

C-Glycosyl compounds have gained considerable attention over the last few decades due to their high chemical stability and promising applications in drug discovery. Herein we disclose an operationally simple, metal-free, photocatalytic approach for the glycosylation of azomethine imines using 4-glycosyl-1,4-dihydropyridines (DHPs) as radical precursors. The protocol features mild reaction conditions, scalability, broad substrate scope, and good functional group tolerance. Moreover, the resulting pyrazolidinone moiety can be easily deprotected, acylated or reduced into a glycosyl β-alanine analog.

Synthesis of anti-proliferative [3.3.0]furofuranone derivatives by lactonization and functionalization of C-glycosyl compounds

The [3.3.0]furofuranone structure is found in numerous families of biologically active natural products. We took advantage of the stereodiversity afforded by carbohydrate derivatives to prepare several compounds structurally similar to goniofufurone and crassalactones which are natural cytotoxic agents. We designed and synthesized several stereoisomers of these natural compounds via lactonization of C-glycosyl compounds bearing an hydroxyl on position 4 and a methyl ester on the pseudo-anomeric positionThe reactivity of this bicyclic moiety was explored through etherification of hydroxyls in position 5 and 7 and various substituants (halogen, phenyl, benzyl, cynanmoyl) were introduced. The anti-proliferative properties of these mimics were then evaluated on various cancer cell lines and two compounds 24 and 35 demonstrated IC50 value of 1.34 µM (U251) and 7.60 µM (U87) respectively.

Iridium-Catalyzed Direct Hydroarylation of Glycals via C–H Activation: Ligand-Controlled Stereoselective Synthesis of α- and β-C-Glycosyl Arenes

Diastereoselective direct hydroarylation of glycals with aromatic compounds was realized by use of an iridium/binap catalyst, giving the corresponding C-glycosyl compounds in high yields. The use o...

Antithrombotic and antiplatelet activities of orientin in vitro and in vivo

Vaccinium bracteatum Thunb. is commonly used in staining and cooking rice. However, there are limited data regarding its active components and pharmacological effects that underlie its traditional use. Two flavonoid C-glycosyl compounds (orientin and isoorientin) found in V. bracteatum Thunb. are known for their antioxidant activity. Here, the anticoagulant activity of orientin and isoorientin was examined by monitoring the activated partial thromboplastin time (aPTT), prothrombin time (PT), and the thrombin and activated factor X (FXa) activity. Treatment with orientin and isoorientin prolonged the aPTT and PT and inhibited the thrombin and FXa activity and production in human umbilical vein endothelial cells (HUVECs). Furthermore, orientin and isoorientin inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. In exploring the mechanism underlying anti-platelet aggregation, we found that orientin and isoorientin specifically prevented protein kinase C (PKC) activation and calcium mobilization. Orientin and isoorientin also elicited anticoagulant effects in mice. In addition, treatment with orientin and isoorientin significantly decreased the plasminogen activator inhibitor-1 (PAI-1) to tissue plasminogen activator (t-PA) ratio. Collectively, foods containing orientin and isoorientin possess antithrombotic activity and may be used in preventing thrombus formation and improving blood circulation.

Rice Os9BGlu31 Is a Transglucosidase with the Capacity to Equilibrate Phenylpropanoid, Flavonoid, and Phytohormone Glycoconjugates

Glycosylation is an important mechanism of controlling the reactivities and bioactivities of plant secondary metabolites and phytohormones. Rice (Oryza sativa) Os9BGlu31 is a glycoside hydrolase family GH1 transglycosidase that acts to transfer glucose between phenolic acids, phytohormones, and flavonoids. The highest activity was observed with the donors feruloyl-glucose, 4-coumaroyl-glucose, and sinapoyl-glucose, which are known to serve as donors in acyl and glucosyl transfer reactions in the vacuole, where Os9BGlu31 is localized. The free acids of these compounds also served as the best acceptors, suggesting that Os9BGlu31 may equilibrate the levels of phenolic acids and carboxylated phytohormones and their glucoconjugates. The Os9BGlu31 gene is most highly expressed in senescing flag leaf and developing seed and is induced in rice seedlings in response to drought stress and treatment with phytohormones, including abscisic acid, ethephon, methyljasmonate, 2,4-dichlorophenoxyacetic acid, and kinetin. Although site-directed mutagenesis of Os9BGlu31 indicated a function for the putative catalytic acid/base (Glu(169)), catalytic nucleophile residues (Glu(387)), and His(386), the wild type enzyme displays an unusual lack of inhibition by mechanism-based inhibitors of GH1 β-glucosidases that utilize a double displacement retaining mechanism.

Fries-type Reactions for the C-Glycosylation of Phenols

C-Glycosylphenols and -polyphenols occur widely in nature and present a variety of biological properties, namely antitumor, antibacterial and antidiabetic activities. Synthetic access to such structures relies mainly on efficient methodologies for phenols C- glycosylation. In the past few years major advances have been described addressing the use of Fries rearrangement to obtain a diversity of C-glycosyl compounds. Herein we survey the glycosyl donors and the activators used for this reaction, covering both early work and recent developments in the area. Reaction mechanism and reaction outcome control, aiming at regio- and stereoselectivity are also dis- cussed.

Indium-mediated alkynylation of sugars: synthesis of C-glycosyl compounds bearing a protected amino alcohol moiety

The coupling of glycals with an alkynyl iodide bearing a protected amino alcohol moiety was achieved in the presence of metallic indium under Barbier conditions. It gave functionalized C-glycosyl compounds, precursors of C-glycosyl amino acids with α configuration.

ChemInform Abstract: Regioselective Acetyl Transfer from the Aglycon to the Sugar in C-Glycosylic Compounds Facilitated by Silica Gel.

Abstract 2′- O -Acetyl C -glycosylic compounds ( C -glycosides) were prepared via regioselective acetyl transfer from aglycons to sugar moieties with silica gel in the presence of unprotected primary and secondary hydroxyl groups.

ChemInform Abstract: Efficient Conditions for the Synthesis of C-Glycosylidene Derivatives: A Direct and Stereoselective Route to C-Glycosyl Compounds.

Abstract Efficient conditions for the synthesis of C -glycosylidene compounds from lactones based on Wittig reactions of cyanomethyl triphenylphosphoranylidene involving microwave heating are described: subsequent stereoselective reduction of the anomeric olefins gave the corresponding C -glycosides in good yields with high stereocontrol.

Efficient access to disubstituted exo-glycals. Application to the preparation of C-glycosyl compounds

Efficient methods of preparation of disubstituted exo-glycals by palladium cross-coupling reaction on the readily available dibromo exo-glycal and methoxycarbonyl exo-glycal have been developed. Hydrogenation of these new monosubstituted and disubstituted exo-glycals proceeded with a high stereocontrol and led to original C-glycosyl compounds.

β- C-Glycosiduronic acids and β- C-glycosyl compounds: New PTP1B inhibitors

β- C-Glycosiduronic acid quinones and β- C-glycosyl compounds have been synthesized as sugar-based PTP1B inhibitors. Benzoyl protected quinone derivatives ( 14 and 35) as well as aryl β- C-glycosyl compounds ( 18, 22, 23 and 34) showed IC 50 values of 0.77–5.27 μM against PTP1B, with compounds 18 and 23 bearing an acidic function being the most potent.

A general route to pendant C-glycosyl 1,2- and 1,3-diamines

Practical and convenient preparations of C-glycosyl 1,2- and 1,3-alkanediamines are described. Two 1,2-ethylenediamine derivatives were synthesized from acetylated allyl α- C-glycosyl compounds via dibromination, azidation, carbohydrate deprotection, and azide reduction. Four 1,3-propanediamine derivatives were prepared from acetylated sugar halides via C-glycosylation with sodiomalononitrile, followed by the reduction of the nitrile moieties and the deacetylation of the carbohydrate moiety. These 1,3-propanediamine derivatives have the β-anomeric configurations. The methods reported here serve as general routes to access carbohydrate–diamine conjugates with C-glycosyl linkages.

Chromium(II)-complex mediated formation of C-glycosides from glycosyl halides under aqueous biphasic conditions

C-Glycosyl compounds were formed in the reactions of hydrolytically sensitive glycosyl halides with electron deficient alkenes mediated by the complex [Cr II(EDTA)] 2− under aqueous conditions.

Free-radical and ionic routes towards hydrolytically stable and bioactive C-glycosyl compounds

Photo-initiated addition of glycopyranosyl radicals to such radical acceptors as allyltributyltin, acrylonitrile, or diethyl vinylphosphonate was efficiently achieved to afford stereoselectively α-configured C-glycosyl compounds. With acrylonitrile or diethyl vinylphosphonate, catalytic amounts of organotin were used with NaBH3CN in excess. C-1 Sugar dihalides may be converted into the β-configured C-glycosyl analogues in two radical steps (C–C bond formation, reduction), or into bis-C,C-glycosides (two C–C bond forming reactions in one pot). These dihalides also opened the first access to C-glycodienes. C-Glycosyl-ethylphosphonic acids were elaborated into non-isosteric C-glycosyl mimics of natural sugar nucleotide diphosphates, which were evaluated as inhibitors of glycosyl transferases. In another approach, aromatic electrophilic substitution of 1,4-dimethoxybenzene by d-glycopyranosylium ions gave access to C-glycosyl derivatives of 1,4-dimethoxybenzene hydroquinone, and 1,4-benzoquinone. Some were found to inhibit protein tyrosine phosphatase 1B (PTP1B) and glycogen phosphorylase (GP), as shown by enzymatic and crystallographic studies. Extension of the synthetic work led to C-glycosyl-chromanols and C-glycosyl-tocopherols, which have been studied as anti-oxidants. L'addition photo-initiée de radicaux glycopyranosyl sur des accepteurs de radicaux comme l'allyltributyl étain, l'acrylonitrile, le diéthyl vinylphosphonate procède efficacement pour donner stéréosélectivement les composés α-C-glycosylés correspondants. Avec l'acrylonitrile et le diéthyl vinylphosphonate, l'addition s'obtient en présence de quantités catalytiques d'organo-étain et d'un excès de NaBH3CN. Les C-1 dihalogéno-sucres peuvent conduire aux analogues C-glycosylés de configuration β en deux étapes radicalaires (formation de liaison C–C, réduction), aux bis-C,C-glycosides (création de deux liaisons C–C en un pot), ou à des C-glycodiènes (formation de liaison C–C, élimination). Les acides C-glycosyl-éthylphosphoniques ont mené à des mimes C-glycosylés non isostères de nucléotides sucres diphosphates naturels, qui ont été évalués comme inhibiteurs de glycosyl transférases. L'un d'eux inhibe efficacement (IC50 = 40 μM) la β-1,4-galactosyltransférase du lait de vache (β-1,4-GalT, EC 2.4.1.22). Par ailleurs, la substitution électrophile du1,4-diméthoxybenzène par des ions d-glycopyranosylium donne accès à des dérivés C-glycosylés du1,4-diméthoxybenzène, de la 1,4-benzoquinone et de l'hydroquinone. Certains inhibent modérément la protéine tyrosine phosphatase 1B (PTP1B) ou la glycogène phosphorylase (GP), comme on l'a montré par enzymologie et cristallographie. Les synthèses ont été adaptées pour conduire à des chromanols C-glycosylés ou à des tocophérols C-glycosylés, dont les propriétés antioxydantes ont été étudiées.

UDP-Gal: GlcNAc-R β1,4-galactosyltransferase—a target enzyme for drug design. Acceptor specificity and inhibition of the enzyme

Galactosyltransferases are important enzymes for the extension of the glycan chains of glycoproteins and glycolipids, and play critical roles in cell surface functions and in the immune system. In this work, the acceptor specificity and several inhibitors of bovine beta1,4-Gal-transferase T1 (beta4GalT, EC 2.4.1.90) were studied. Series of analogs of N-acetylglucosamine (GlcNAc) and GlcNAc-carrying glycopeptides were synthesized as acceptor substrates. Modifications were made at the 3-, 4- and 6-positions of the sugar ring of the acceptor, in the nature of the glycosidic linkage, in the aglycone moiety and in the 2-acetamido group. The acceptor specificity studies showed that the 4-hydroxyl group of the sugar ring was essential for beta4GalT activity, but that the 3-hydroxyl could be replaced by an electronegative group. Compounds having the anomeric beta-configuration were more active than those having the alpha-configuration, and O-, S- and C-glycosyl compounds were all active as substrates. The aglycone was a major determinant for the rate of Gal-transfer. Derivatives containing a 2-naphthyl aglycone were inactive as substrates although quinolinyl groups supported activity. Several compounds having a bicyclic structure as the aglycone were found to bind to the enzyme and inhibited the transfer of Gal to control substrates. The best small hydrophobic GlcNAc-analog inhibitor was found to be 1-thio-N-butyrylGlcNbeta-(2-naphthyl) with a K(i) of 0.01 mM. These studies help to delineate beta4GalT-substrate interactions and will aid in the development of biologically applicable inhibitors of the enzyme.

Regioselective debenzylation of C-glycosyl compounds by boron trichloride

Boron trichloride has been found to promote selective deprotection of 1,2- or 1,3-cis oriented secondary benzyl ethers of per-benzylated C-glycosyl derivatives. The reactivity towards BCl 3 follows the order: C-4 ⩾ C-2 > C-6 > C-3 for C-glucopyranosyl derivatives and C-3 ⩾ C-4 > C-6 > C-2 for C-galactopyranosyl derivatives. Preparatively useful selective debenzylation at secondary positions was possible after careful control of reaction conditions.

Synthesis of C-glycosyl compounds of N-acetylneuraminic acid from d-gluconolactone

A general strategy towards the synthesis of C-glycosyl compounds of N-acetylneuraminic acid (Neu5Ac) has been developed and successfully applied to the synthesis of C-methyl and C-phenyl derivatives. The key strategic elements are (i) chain extension of a d-gluconolactone derivative as C 6-precursor with an allyl Grignard reagent as C 3-precursor having in 2 position the C-linked aglycon moiety, (ii) stereoselective C-4/C-5 erythro-diol formation, (iii) 6-exo-trig selective heterocyclization, and (iv) instalment of the 5-acetylamino and C-1 carboxylate functionalities. The efficiency and potential versatility of this approach was exemplified in the synthesis of C-methyl derivative 1 as target molecule.

One-pot synthesis of C-glycosylic compounds ( C-glycosides) from d-glucal, p-tolylsulfenyl chloride and aromatic/heteroaromatic compounds in the presence of Lewis acids

In the presence of Zn(CN) 2, benzylated 2-thio-2- S-( p-tolyl)pyranosyl chlorides ( 2) generated in situ from tri- O-benzyl- d-glucal and p-TolSCl, smoothly react with thiophene, 2-methylthiophene, furan, 2-methylfuran, and N-methylpyrrole to give heteroaryl 2-thio-2- S-( p-tolyl)- C-β- d-glucopyranosylic compounds ( C-glycosides) in good yields. Upon treatment with SnCl 4, the reaction of chlorides 2 with thiophene or 1,4-dimethoxybenzene provides the corresponding benzylated C-β- d-glucofuranosylic derivatives. Under the same conditions, the use of 2-methylthiophene, furan, 2-methylfuran, or N-methylpyrrole yields (2 S,3 R,4 R,5 S)-1,3,4-tribenzyloxy-6,6-diheteroaryl-5-( p-tolylthio)-2-hexanoles. Treatment of 2 and mesitylene with AgBF 4 yielded 1,6-anhydro-3,4-di- O-benzyl-2-thio-2- S-( p-tolyl)-β- d-glucose.