Glycosyl Halides Research Articles

Ester Formation via Nickel-Catalyzed Reductive Coupling of Alkyl Halides with Chloroformates.

The synthesis of alkyl esters from readily available alkyl halides and chloroformates was achieved for the first time using a mild Ni-catalyzed reductive coupling protocol. Unactivated primary and secondary alkyl iodides as well as glycosyl, benzyl, and aminomethyl halides were successfully employed to yield products in moderate to excellent yields with high functional group tolerance.

ChemInform Abstract: Direct Coupling of Amides and Urea to Glycosyl Halides Using Silver Triflate.

We herein report the coupling of various amides and ureas to glycosyl halides in the presence of silver triflate at room temperature. A 1:1 mixture of α/β diastereomers was obtained when alkyl/heteroaryl amides and substituted ureas were added to gluco and galacto haloglycosides. The effect of temperature, halogen, protecting group of the sugar and substituent of the amide in the overall yields and stereoselectivity of the reaction was also explored. When the acetyl-protected glucuronamide was employed in the reaction, the β anomer of the corresponding pseudodissacharide was obtained as the major isomer in good yields at room temperature. The newly synthesized compounds were subjected to viability studies using HeLa cancer cells. The results obtained are also discussed in this study.

Direct Coupling of Amides and Urea to Glycosyl Halides Using Silver Triflate

We herein report the coupling of various amides and ureas to glycosyl halides in the presence of silver triflate at room temperature. A 1:1 mixture of α/β diastereomers was obtained when alkyl/heteroaryl amides and substituted ureas were added to gluco and galacto haloglycosides. The effect of temperature, halogen, protecting group of the sugar and substituent of the amide in the overall yields and stereoselectivity of the reaction was also explored. When the acetyl‐protected glucuronamide was employed in the reaction, the β anomer of the corresponding pseudodissacharide was obtained as the major isomer in good yields at room temperature. The newly synthesized compounds were subjected to viability studies using HeLa cancer cells. The results obtained are also discussed in this study.

Synthesis of Indoxyl-glycosides for Detection of Glycosidase Activities

Indoxyl glycosides proved to be valuable and versatile tools for monitoring glycosidase activities. Indoxyls are released by enzymatic hydrolysis and are rapidly oxidized, for example by atmospheric oxygen, to indigo type dyes. This reaction enables fast and easy screening in vivo without isolation or purification of enzymes, as well as rapid tests on agar plates or in solution (e.g., blue-white screening, micro-wells) and is used in biochemistry, histochemistry, bacteriology and molecular biology. Unfortunately the synthesis of such substrates proved to be difficult, due to various side reactions and the low reactivity of the indoxyl hydroxyl function. Especially for glucose type structures low yields were observed. Our novel approach employs indoxylic acid ester as key intermediates. Indoxylic acid esters with varied substitution patterns were prepared on scalable pathways. Phase transfer glycosylations with those acceptors and peracetylated glycosyl halides can be performed under common conditions in high yields. Ester cleavage and subsequent mild silver mediated glycosylation yields the peracetylated indoxyl glycosides in high yields. Finally deprotection is performed according to Zemplén.

ChemInform Abstract: Ni‐Catalyzed Reductive Coupling of Alkyl Acids with Unactivated Tertiary Alkyl and Glycosyl Halides.

AbstractThis reaction works with sterically hindered unactivated tertiary alkyl bromides, as well as with primary and secondary alkyl halides and glycosyl bromides.

Ni-catalyzed reductive coupling of alkyl acids with unactivated tertiary alkyl and glycosyl halides.

This work highlights Ni-catalyzed reductive coupling of alkyl acids with alkyl halides, particularly sterically hindered unactivated tertiary alkyl bromides for the production of all carbon quaternary ketones. The reductive strategy is applicable to α-selective synthesis of saturated, fully oxygenated C-acyl glycosides through easy manipulations of the readily available sugar bromides and alkyl acids, avoiding otherwise difficult multistep conversions. Initial mechanistic studies suggest that a radical chain mechanism (cycle B, Scheme 1) may be plausible, wherein MgCl2 promotes the reduction of Ni(II) complexes.

Glycosylation of 6α,12β-dihydroxy-20R,25-epoxydammaran-3-one

Glycosylation of 6α,12β-dihydroxy-20R,25-epoxydammaran-3-one (panaxatriol 3-ketone, 2) under Koenigs–Knorr reaction conditions and the Helferich modification was studied. Condensation of 2 with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide (5) in the presence of Ag2O and 4-A molecular sieves in CH2Cl2 gave acetylated 6α,12β-dihydroxy-20R,25-epoxydammaran-3-one 12-O-β-D-glucopyranoside whereas in the presence of Hg(CN)2 in nitromethane at 25°C the tetrahydropyran ring opened and, depending on the ratio of reagents, acetylated 12-, 12,25-di-, or 6,12,25-tri-O-β-D-glucopyranosides of 6α,12β,25-trihydroxydammar-20(22)E-en-3-one formed. 6α,12β-Dihydroxy-20R,25-epoxydammaran-3-one 12-O-β-D-glucopyranoside and 12-, 12,25-di-, and 6,12,25-tri-O-β-D-glucopyranosides of 6α,12β,25-trihydroxydammar-20(22)E-en-3-one were synthesized for the first time.

Synthesis of mixed glycosyl disulfides/selenenylsulfides using benzyltriethylammonium tetrathiomolybdate as a sulfur transfer reagent

An easy and mild method has been developed for the synthesis of mixed glycosyl disulfides/selenenylsulfides from glycosyl halides and diaryl/dialkyl dichalcogenides in the presence of benzyltriethylammonium tetrathiomolybdate [(BnEt3N)2MoS4]. The salient feature of this method is the sulfur transfer from [BnEt3N]2MoS4 to form glycosyl disulfides which with excess tetrathiomolybdate further undergo exchange reaction with other dichalcogenides in a one-pot operation.

Glucuronidation of bile acids under flow conditions: design of experiments and Koenigs-Knorr reaction optimization.

An efficient method for the C3-glucuronidation of bile acids is developed under flow conditions. A modular mesoreactor assisted flow set-up was combined with statistical design of experiments to speed up the optimization of the Koenigs-Knorr reaction in terms of yield, regioselectivity, costs, as well as technical and practical standpoints. Using the optimal conditions, selective glucuronidation of naturally occurring bile acids was successfully achieved offering a new, valuable route to C3-glucuronidated bile acids useful for biological, diagnostic and PK/ADMET investigations.

Useful approach to the synthesis of aryl thio- and selenoglycosides in the presence of rongalite

A simple, mild, and cost effective methodology has been developed for the synthesis of aryl thio-and selenoglycosides from glycosyl halides and diaryl dichalcogenides. Diaryl dichalcogenides undergo reductive cleavage in the presence of rongalite (HOCH2SO2Na) to generate a chalcogenide anion in situ followed by reaction with glycosyl halides to furnish the corresponding aryl thio- and selenoglycosides in excellent yields. Using this protocol, synthesis of 4-methyl-7-thioumbelliferyl-β-d-cellobioside (MUS-CB), a fluorescent non-hydrolyzable substrate analogue for cellulases has been achieved.

Activation of glycosyl halides by halogen bonding.

Halogen bonding is the formation of a non-covalent interaction between an electrophilic halogen substituent and a Lewis base, for instance, a halide. These kinds of relatively weak interactions have found applications in crystal engineering and initial applications in solution-phase chemistry are starting to appear. We report on the exploration of bis(iodoimidazolium) compounds as halogen-based Lewis acids in the activation of glycosyl halides. We show that these dicationic halogen-bond donors can be used to activate glycosyl halides if the carbohydrate core is sufficiently reactive enough. Furthermore, we provide comparison experiments which indicate that the mode of activation is indeed based on halogen bonding. This represents the first glycosylation reaction mediated by a (carbon-backbone-based) halogen-bond donor.

Stereoselective C-glycosylation of furanosyl halides with arylzinc reagents

Abstract Were are reporting a highly diastereoselective, transition-metal-free approach of C-aryl glycosides in the pyranoside and furanoside series by the direct coupling of glycosyl halides with diarylzinc reagents in a toluene/di-n-butyl ether solvent mixture.

Tri-isopropylsilyl thioglycosides as masked glycosyl thiol nucleophiles for the synthesis of S-linked glycosides and glyco-conjugates.

Tri-isopropylsilyl thio-glycosides (TIPS S-glycosides) were synthesized through base promoted SN2 substitution of glycosyl halides with TIPS-SH or by Lewis acid promoted glycosylation of TIPS-SH with glycosyl acetates or p-methoxyphenyl glycosides. Various thioglycoside derivatives were obtained in high yields by one-pot fluoride-mediated de-silylation and thiol alkylation with alkyl halides or Michael acceptors of one common TIPS S-glycoside.

Indoxylic Acid Esters as Convenient Intermediates Towards Indoxyl Glycosides

AbstractIndoxylic acid methyl and allyl esters with varied halide‐substitution patterns were obtained in excellent yields using a scalable route. Phase‐transfer glycosylation of these key intermediates was carried out with various glycosyl halides. Subsequent mild silver‐mediated decarboxylation followed by Zemplén deacetylation led to indoxyl glycosides in good overall yields. Indoxyl glycosides are well‐established and widely used tools for enzyme screening and enzyme‐activity monitoring. In the past, their synthesis has been difficult, so this new approach has led to a variety of useful structures.

Isopropyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound, C17H26O10, was formed by a Koenigs–Knorr reaction of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide and propan-2-ol. The central ring adopts a chair conformation. The crystal does not contain any significant inter­molecular inter­actions.

N-Propyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound [systematic name: (2R,3R,4S,5R,6R)-2-(acet­oxy­meth­yl)-6-propoxytetra­hydro-2H-pyran-3,4,5-triyl triacetate], C17H26O10, was formed by a Koenigs–Knorr reaction of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide and n-propanol. The central ring adopts a chair conformation. The crystal does not contain any significant inter­actions such as hydrogen bonds.

Glycosylation of solasodine and pharmacological activity of the product

Solasodine tetra-O-acetyl-3β-D-glucopyranoside was synthesized from tetra-O-acetylbromo-D-glucose by the Koenigs–Knorr reaction using solasodine isolated from cultivated Solanum laciniatum. The structure of the product was established using IR, mass, PMR, 13C NMR, and 2D spectra. The pharmacological properties of the product were studied.

Acceptor-influenced and donor-tuned base-promoted glycosylation.

Base-promoted glycosylation is a recently established stereoselective and regioselective approach for the assembly of di- and oligosaccharides by using partially protected acceptors and glycosyl halide donors. Initial studies were performed on partially methylated acceptor and donor moieties as a model system in order to analyze the key principles of oxyanion reactivities. In this work, extended studies on base-promoted glycosylation are presented by using benzyl protective groups in view of preparative applications. Emphases are placed on the influence of the acceptor anomeric configuration and donor reactivities.

Koenigs–Knorr reaction of fusel alcohols with methyl (1-bromo-2,3,4-tri-O-acetyl-α-d-glucopyranosid)uronate leading to the protected alkyl glucuronides—crystal structures and high resolution 1H and 13C NMR data

Crystal structures and high resolution 1H and 13C NMR spectral data for methyl (alkyl 2,3,4-tri-O-acetyl-β-d-glucopyranosid)uronates (alkyl=methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, n-pentyl, 2-methyl-1-butyl and 3-methyl-1-butyl) are presented.

Synthesis, thermal properties, and cytotoxicity evaluation of hydrocarbon and fluorocarbon alkyl β-d-xylopyranoside surfactants

Alkyl β-d-xylopyranosides are highly surface active, biodegradable surfactants that can be prepared from hemicelluloses and are of interest for use as pharmaceuticals, detergents, agrochemicals, and personal care products. To gain further insights into their structure–property and structure–activity relationships, the present study synthesized a series of hydrocarbon (–C6H13 to –C16H33) and fluorocarbon (–(CH2)2C6F13) alkyl β-d-xylopyranosides in four steps from d-xylose by acylation or benzoylation, bromination, Koenigs–Knorr reaction, and hydrolysis, with the benzoyl protecting group giving better yields compared to the acyl group in the Koenigs–Knorr reaction. All alkyl β-d-xylopyranosides formed thermotropic liquid crystals. The phase transition of the solid crystalline phase to a liquid crystalline phase increased linearly with the length of the hydrophobic tail. The clearing points were near constant for alkyl β-d-xylopyranosides with a hydrophobic tail ⩾8, but occurred at a significantly lower temperature for hexyl β-d-xylopyranoside. Short and long-chain alkyl β-d-xylopyranosides displayed no cytotoxicity at concentration below their aqueous solubility limit. Hydrocarbon and fluorocarbon alkyl β-d-xylopyranosides with intermediate chain length displayed some toxicity at millimolar concentrations due to apoptosis.