Glycosyl Halides Research Articles

Facile Preparation of Aryl C-Glycosides by Nickel-Catalyzed Reductive Coupling of Glycosyl Halides with Aryl Halides

Facile Preparation of Aryl <i>C-</i>Glycosides by Nickel-Catalyzed Reductive Coupling of Glycosyl Halides with Aryl Halides

Ferrocenium complex aided O-glycosylation of glycosyl halides.

A new strategy for the activation of glycosyl halide donors to be utilized in glycosylation reactions is presented, utilizing the ferrocenium (Fc) complexes [FcB(OH)2]SbF6 and FcBF4 as promoters. The scope of the new system has been investigated using glycosyl chloride and glycosyl fluoride donors in combination with common glycosyl acceptors, such as protected glucose. The corresponding glycosylation products were formed in 95 to 10% isolated yields with α/β ratios ranging from 1/1 to β only (2 to 14 h reaction time at room temperature, 40 to 100% ferrocenium promoter load).

Bismuth(iii) triflate as a novel and efficient activator for glycosyl halides.

Presented herein is the discovery that bismuth(iii) trifluoromethanesulfonate (Bi(OTf)3) is an effective catalyst for the activation of glycosyl bromides and glycosyl chlorides. The key objective for the development of this methodology is to employ only one promoter in the lowest possible amount and to avoid using any additive/co-catalyst/acid scavenger except molecular sieves. Bi(OTf)3 works well in promoting the glycosidation of differentially protected glucosyl, galactosyl, and mannosyl halides with many classes of glycosyl acceptors. Most reactions complete within 1 h in the presence of only 35% of green and light-stable Bi(OTf)3 catalyst.

Stereocontrolled α-Galactosylation under Cooperative Catalysis.

A recent discovery of a cooperative catalysis comprising a silver salt and an acid led to a dramatic improvement in the way glycosyl halides are glycosidated. Excellent yields have been achieved, but the stereoselectivity achieved with 2-O-benzylated donors was poor. Reported herein is our first attempt to refine the stereoselectivity of the cooperatively catalyzed galactosylation reaction. Careful optimization of the reaction conditions along with studying effects of the remote protecting groups led to excellent stereocontrol of α-galactosylation of a variety of glycosyl acceptors with differentially protected galactosyl donors.

Halogenation and anomerization of glycopyranoside by TESH/bromine and BHQ/bromine

AbstractTreatment of peracetylated glycosides and β‐isopropyl glycosides with halogen in the presence of TESH and BHQ has been found to result in the halogenation and the anomerization, respectively. Peracetylatedglycosides treaded with I2/TESH or Br2/TESH leading tothe formation of corresponding glycosyl halides, and b‐isopropyl glycosidesreacted with Br2/BHQ resulting in the formation of a‐glycosides. The anomerizationof glycosidic bond was considered to be catalyzed by in situ formation of hydrogenbromide from the mixing of Br2/BHQ.

Defining the Scope of the Acid-Catalyzed Glycosidation of Glycosyl Bromides.

Following the recent discovery that traditional silver(I) oxide-promoted glycosidations of glycosyl bromides (Koenigs-Knorr reaction) can be greatly accelerated in the presence of catalytic TMSOTf, reported herein is a dedicated study of all major aspects of this reaction. A thorough investigation of numerous silver salts and careful refinement of the reaction conditions led to an improved mechanistic understanding. This, in turn, led to a significant reduction in the amount of silver salt required for these glycosylations. The progress of this reaction can be monitored by naked eye, and the completion of the reaction can be judged by the disappearance of characteristic dark color of Ag2 O. Further evidence on higher reactivity of benzoylated α-bromides in comparison to that of their benzylated counterparts has been acquired.

Synthesis and Antioxidant Activity of Novel 5-amino-2-alkyl/glycosylthio-1,3,4- thiadiazoles: Regioselective Alkylation and Glycosylation of the 5-amino-1,3,4- thiadiazole-2-thiol Scaffold.

5-Amino-2-alkyl/glycosylthio-1,3,4-thiadiazoles have been synthesized by the reaction of 5-amino-1,3,4-thiadiazole-2-thiol with a variety of alkylating agents or glycosyl halides in the presence of anhydrous potassium carbonate in dry acetone. The structures of the newly synthesized compounds have been established based on their spectral data (FT-IR, 1H- and 13C-NMR) and mass spectrometry. They were tested for their antioxidant behaviour by the use of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. The in silico pharmacokinetics ADME properties of the potent antioxidant compounds were investigated by using Accelrys Discovery Studio (DS) 2.5 software. Regioselective alkylation and glycosylation of 5-amino-1,3,4-thiadiazole-2-thiol were noticed during its reaction with alkylating agents and glycosyl halides. Alkylating agents gave the Sfunctionalized derivatives, while the acetylated glycosyl halides afforded the S-glycosylated products together with their respective N-acetyl derivatives. The benzoylated glycosyl halide behaved in a different manner and gave N-glycoside analogue of 1,3,4-thiadiazole-2(3H)-thione, in addition to the expected sulfanyl S-glycoside. Most of the synthesized compounds showed noticeable antioxidant activity with respect to ceftriaxone as a standard drug. Some of the most active compounds showed acceptable predicted pharmacokinetics and druglikeness properties.

Establishment of Guidelines for the Control of Glycosylation Reactions and Intermediates by Quantitative Assessment of Reactivity

AbstractStereocontrolled chemical glycosylation remains a major challenge despite vast efforts reported over many decades and so far still mainly relies on trial and error. Now it is shown that the relative reactivity value (RRV) of thioglycosides is an indicator for revealing stereoselectivities according to four types of acceptors. Mechanistic studies show that the reaction is dominated by two distinct intermediates: glycosyl triflates and glycosyl halides from N‐halosuccinimide (NXS)/TfOH. The formation of glycosyl halide is highly correlated with the production of α‐glycoside. These findings enable glycosylation reactions to be foreseen by using RRVs as an α/β‐selectivity indicator and guidelines and rules to be developed for stereocontrolled glycosylation.

Establishment of Guidelines for the Control of Glycosylation Reactions and Intermediates by Quantitative Assessment of Reactivity.

Stereocontrolled chemical glycosylation remains a major challenge despite vast efforts reported over many decades and so far still mainly relies on trial and error. Now it is shown that the relative reactivity value (RRV) of thioglycosides is an indicator for revealing stereoselectivities according to four types of acceptors. Mechanistic studies show that the reaction is dominated by two distinct intermediates: glycosyl triflates and glycosyl halides from N-halosuccinimide (NXS)/TfOH. The formation of glycosyl halide is highly correlated with the production of α-glycoside. These findings enable glycosylation reactions to be foreseen by using RRVs as an α/β-selectivity indicator and guidelines and rules to be developed for stereocontrolled glycosylation.

A facile route to synthesize hyperbranched polyester derived from cellulose and serine and its biodegradability

Cellulose-based hyperbranched polyesters (CHBP) have many prospective applications and are therefore a highly explored area. In this work, a novel biomass-based CHBP has been successfully prepared via the polycondensation of an ABn-type glycopeptide-like monomer (A and B are different functional groups, one A and two or more B in each repeated unit). This monomer was synthesized by reacting acetylated oligomeric cellulose halide with a Fmoc (Fluorenylmethyloxycarbonyl) group-protected serine via the Koenigs-Knorr reaction, followed by the removal of the protecting group. The branching degree of CHBP-3 is 0.55. Different characterization methods show that we have successfully synthesized hyperbranched polyester. The thermal properties were analyzed by thermogravimetric analysis (TGA) with results showing a superior thermal stability for CHBP compared to raw cotton fibers. CHBP also displayed better biodegradability than cotton fibers according to a colony degradation experiment. The study demonstrated a novel and practical route for the design and preparation of hyperbranched polyester using ‘green’ natural resources.

Koenigs-Knorr Glycosylation Reaction Catalyzed by Trimethylsilyl Trifluoromethanesulfonate.

The discovery that traditional silver(I)-oxide-promoted glycosidations of glycosyl bromides (Koenigs-Knorr reaction) can be greatly accelerated in the presence of catalytic trimethylsilyl trifluoromethanesulfonate (TMSOTf) is reported. The reaction conditions are very mild that allowed for maintaining a practically neutral pH and, at the same time, providing high rates and excellent glycosylation yields. In addition, unusual reactivity trends among a series of differentially protected glycosyl bromides were documented. In particular, benzoylated α-bromides were much more reactive than their benzylated counterparts under these conditions.

Stereoselective Preparation of α- C-Vinyl/Aryl Glycosides via Nickel-Catalyzed Reductive Coupling of Glycosyl Halides with Vinyl and Aryl Halides.

Facile preparation of the α- C-vinyl and -aryl glycosides has been developed via mild Ni-catalyzed reductive vinylation and arylation of C1-glycosyl halides with vinyl/aryl halides. Good to high α-selectivities were achieved for C-glucosides, galactosides, maltoside, and mannosides, which were dictated by the employment of pyridine type ligands. As such, the present work represents unprecedented control for a high level of α-selectivity for C-vinyl-glucosides using cross-coupling approaches and offers hitherto optimal α-selective preparation of C-aryl glucosides via catalyst-controlled coupling strategies.

Synthesis of New Glycosylated Flavonoids with Inhibitory Activity on Cell Growth.

Natural flavonoids and xanthone glycosides display several biological activities, with the glycoside moiety playing an important role in the mechanism of action of these metabolites. Herein, to give further insights into the inhibitory activity on cell growth of these classes of compounds, the synthesis of four flavonoids (5, 6, 9, and 10) and one xanthone (7) containing one or more acetoglycoside moieties was carried out. Acetyl groups were introduced using acetic anhydride and microwave irradiation. The introduction of one or two acetoglycoside moieties in the framework of 3,7-dihydroxyflavone (4) was performed using two synthetic methods: the Michael reaction and the Koenigs-Knorr reaction. The in vitro cell growth inhibitory activity of compounds 5, 6, 7, 9, and 10 was investigated in six human tumor cell lines: A375-C5 (malignant melanoma IL-1 insensitive), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), U251 (glioblastoma astrocytoma), U373 (glioblastoma astrocytoma), and U87MG (glioblastoma astrocytoma). The new flavonoid 3-hydroxy-7-(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl) flavone (10) was the most potent compound in all tumor cell lines tested, with GI50 values < 8 μM and a notable degree of selectivity for cancer cells.

O-Regioselective Synthesis with the Silver Salt Method.

The excellent O-regioselectivity of the glycosidation of the ambident 2-O-substituted 5-fluorouracil (5-FU) via the silver salt method is computationally investigated at the MP2/6-311++G(2d,p):DZP//B3LYP/6-31+G(d):DZP level of theory. The reactions studied are those between 1-bromo-1-deoxy-2,3,4,6-tetra-O-acetyl-α-d-glucopyranose and the silver salts of 5-FU, 2-O-butyl-5-FU, and 2-O-benzyl-5-FU. Two pathways are considered as follows: (A) one where the silver and bromide ion do not interact, and (B) another where the silver and bromide ion interact in the transition states. Because the O-reaction barriers are much lower (by 13.3–22.2 kcal/mol) than N-reaction barriers in both pathways, the O-regioselectivity of the silver salt method can be satisfactorily explained by either path A or path B. Furthermore, path B, where Ag and Br interact consistently, has lower activation barriers than the corresponding path A (by 6.8–17.4 kcal/mol) in both N- and O-reactions. This computational result can be attributed to the following reasons: (1) the speeding-up effect in Koenigs–Knorr reactions due to the addition of silver carbonate into the reaction mixture; (2) the halogens being pulled away by silver ions from halides, as proposed by Kornblum and co-workers; and (3) the oxocarbenium ion involvement in the glycosidation reactions. The large energy difference between N- and O-transition states originates from the association between Ag and N–(O−) of the ambident unit (−N3–C4=O4) that shows significant covalent character so that the O-reaction transition states of the silver salt method benefit from favorable ionic interaction (C+···O–) and favorable covalent interaction (Ag···N). These two favorable interactions are in agreement with the hard and soft acids and bases principle; the former is a hard–hard interaction and the latter is a soft–soft interaction.

Formation of and Glycosylation with Per‐O‐Acetyl Septanosyl Halides: Rationalizing Complex Reactivity En Route to p‐Nitrophenyl Septanosides

Protein–carbohydrate interactions are at the heart of many biological processes. For lectins, those interactions result simply in the association of two species, whereas for enzymes like glycosidases, association ultimately leads to cleavage and formation of covalent bonds. We have investigated lectin–septanose interactions in the past. Here we report on a route to synthesize p‐nitrophenyl septanosides via the corresponding septanosyl halides. During the investigation we observed differential rates of glycosyl halide formation of the per‐O‐acetyl septanoses based on the stereochemistry at C1 and C2. Further, we observed unexpected stereoselectivities in glycoside bond formation that depended on a number of factors including the electrophilic sugar species, the incoming nucleophile, and reaction conditions. The results provided new parameters to consider when approaching septanose glycosylations. Even more importantly, the synthesis of p‐nitrophenyl septanosides will enable them to be used to interrogate septanose‐glycosidase binding and hydrolysis.

Chemoselective Glycosylation of Peptides through S-Alkylation Reaction.

An efficient and rapid procedure for synthesizing S-linked glycopeptides is reported. The approach uses activated molecular sieves as a base to promote the selective S-alkylation of readily prepared cysteine-containing peptides, upon reaction of appropriate glycosyl halides. Considering the very mild conditions employed, the chemoselective linkage of the electrophilic sugar with a peptide sulfhydryl group occurred in satisfactory yield, allowing the incorporation of mono and disaccharide moieties. The sugar-peptide conjugates obtained from α-d-glycosyl derivatives adopt a β-S-configuration, indicating the high stereoselectivity of the substitution reaction.

Metal-Free Synthesis of Unsymmetrical Organoselenides and Selenoglycosides.

A one-pot, metal-free procedure has been developed to synthesize unsymmetrical organoselenides. In the first step of the reaction, arylation of potassium selenocyanate (KSeCN) with an iodonium reagent proceeds in the absence of a metal catalyst to produce an arylselenocyanate. In the second step, treatment with sodium borohydride unmasks a second selenium nucleophile that engages an aliphatic electrophile, iodonium reagent, or glycosyl halide. The procedure represents an umpolung approach to the synthesis of aryl-selenides.

Recent Advances in the Chemical Synthesis of C-Glycosides.

Advances in the chemical synthesis of C-pyranosides/furanosides are summarized, covering the literature from 2000 to 2016. The majority of the methods take advantage of the construction of the glycosidic C-C bond. These C-glycosylation methods are categorized herein in terms of the glycosyl donor precursors, which are commonly used in O-glycoside synthesis and are easily accessible to nonspecialists. They include glycosyl halides, glycals, sugar acetates, sugar lactols, sugar lactones, 1,2-anhydro sugars, thioglycosides/sulfoxides/sulfones, selenoglycosides/telluroglycosides, methyl glycosides, and glycosyl imidates/phosphates. Mechanistically, C-glycosylation reactions can involve glycosyl electrophilic/cationic species, anionic species, radical species, or transition-metal complexes, which are discussed as subcategories under each type of sugar precursor. Moreover, intramolecular rearrangements, such as the Claisen rearrangement, Ramberg-Bäcklund rearrangement, and 1,2-Wittig rearrangement, which usually involve concerted pathways, constitute another category of C-glycosylations. An alternative to the C-glycosylations is the formation of pyranoside/furanoside rings after construction of the predetermined glycosidic C-C bonds, which might involve cyclization of acyclic precursors or D-A cycloadditions. Throughout, the stereoselectivity in the formation of the resultant C-glycosidic linkages is highlighted.

Synthesis of Saccharumoside-B analogue with potential of antiproliferative and pro-apoptotic activities

A new series of phenolic glycoside esters, saccharumoside-B and its analogs (9b-9n, 10) have been synthesized by the Koenigs-Knorr reaction. Antiproliferative activities of the compounds (9b-9n, 10) were evaluated on various cancer cell lines including, MCF-7 breast, HL-60 leukemia, MIA PaCa-2 pancreatic, DU145 prostate, HeLa cervical and CaCo-2 colon, as well as normal human MCF10A mammary epithelial and human peripheral blood mononuclear cells (PBMC) by MTT assay. Compounds (9b-9n, 10) exhibited considerable antiproliferative effects against cancer cells with IC50 range of 4.43 ± 0.35 to 49.63 ± 3.59 µM, but they are less cytotoxic on normal cells (IC50 > 100 µM). Among all the compounds, 9f showed substantial antiproliferative activity against MCF-7 and HL-60 cells with IC50 of 6.13 ± 0.64 and 4.43 ± 0.35, respectively. Further mechanistic studies of 9f were carried out on MCF-7 and HL-60 cell lines. 9f caused arrest of cell cycle of MCF-7 and HL-60 cells at G0/G1 phase. Apoptotic population elevation, mitochondrial membrane potential loss, increase of cytosolic cytochrome c and Bax levels, decrease of Bcl-2 levels and enhanced caspases-9 and -3 activities were observed in 9f-treated MCF-7 and HL-60 cells. These results demonstrate anticancer and apoptosis-inducing potentials of 9f in MCF-7 and HL-60 cells via intrinsic pathway.

Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals.

We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.