Glycosyl Radicals Research Articles

Diastereoselective Synthesis of Aryl C‐Glycosides from Glycosyl Esters via C−O Bond Homolysis

AbstractC‐aryl glycosyl compounds offer better in vivo stability relative to O‐ and N‐glycoside analogues. C‐aryl glycosides are extensively investigated as drug candidates and applied to chemical biology studies. Previously, C‐aryl glycosides were derived from lactones, glycals, glycosyl stannanes, and halides, via methods displaying various limitations with respect to the scope, functional‐group compatibility, and practicality. Challenges remain in the synthesis of C‐aryl nucleosides and 2‐deoxysugars from easily accessible carbohydrate precursors. Herein, we report a cross‐coupling method to prepare C‐aryl and heteroaryl glycosides, including nucleosides and 2‐deoxysugars, from glycosyl esters and bromoarenes. Activation of the carbohydrate substrates leverages dihydropyridine (DHP) as an activating group followed by decarboxylation to generate a glycosyl radical via C−O bond homolysis. This strategy represents a new means to activate alcohols as a cross‐coupling partner. The convenient preparation of glycosyl esters and their stability exemplifies the potential of this method in medicinal chemistry.

Synthesis of C-acyl furanosides via the cross-coupling of glycosyl esters with carboxylic acids.

C-Acyl furanosides are versatile synthetic precursors to a variety of natural products, nucleoside analogues, and pharmaceutical molecules. This report addresses the unmet challenge in preparing C-acyl furanosides by developing a cross-coupling reaction between glycosyl esters and carboxylic acids. A key step is the photoredox activation of the glycosyl ester, which promotes the homolysis of the strong anomeric C–O bond through CO2 evolution to afford glycosyl radicals. This method embraces a large scope of furanoses, pyranoses, and carboxylic acids, and is readily applicable to the synthesis of a thymidine analogue and diplobifuranylone B, as well as the late-stage modification of (+)-sclareolide. The convenient preparation of the redox active glycosyl ester from native sugars and the compatibility with common furanoses exemplifies the potential of this method in medicinal chemistry.

Generation of Glycosyl Radicals from Glycosyl Sulfoxides and Its Use in the Synthesis of C-linked Glycoconjugates.

We here report glycosyl sulfoxides appended with an aryl iodide moiety as readily available, air and moisture stable precursors to glycosyl radicals. These glycosyl sulfoxides could be converted to glycosyl radicals by way of a rapid and efficient intramolecular radical substitution event. The use of this type of precursors enabled the synthesis of various complex C-linked glycoconjugates under mild conditions. This reaction could be performed in aqueous media and is amenable to the synthesis of glycopeptidomimetics and carbohydrate-DNA conjugates.

Generation of Glycosyl Radicals from Glycosyl Sulfoxides and Its Use in the Synthesis of C‐linked Glycoconjugates

AbstractWe here report glycosyl sulfoxides appended with an aryl iodide moiety as readily available, air and moisture stable precursors to glycosyl radicals. These glycosyl sulfoxides could be converted to glycosyl radicals by way of a rapid and efficient intramolecular radical substitution event. The use of this type of precursors enabled the synthesis of various complex C‐linked glycoconjugates under mild conditions. This reaction could be performed in aqueous media and is amenable to the synthesis of glycopeptidomimetics and carbohydrate‐DNA conjugates.

Synthesis of non-classical heteroaryl C-glycosides via Minisci-type alkylation of N-heteroarenes with 4-glycosyl-dihydropyridines

A radical-mediated method was reported for diastereoselective synthesis of non-classical heteroaryl C-glycosides via Minisci-type alkylation of N -heteroarenes with 4-glycosyl-1,4-dihydropyridine (DHP) reagents. These DHP reagents serve as convenient precursors for various glycosyl radicals under the activation of single electron transfer (SET) oxidation by persulfate and visible light irradiation with or without photocatalyst.

Recent development in the synthesis of C-glycosides involving glycosyl radicals.

C-Glycosylation involving glycosyl radical intermediates is a particularly effective approach to access C-glycosides, which are core units of a great number of natural products, bioactive compounds and marketed drugs. In this review, we summarize the progress of glycosyl radical-based C-glycoside synthesis between 1999-2020, focusing on the stereoselectivity and recently developed methodologies such as α-alkoxyacyl telluride-related, photo-mediated and transition-metal catalysed reactions. Metal-mediated reductive cross coupling is also covered due to its close relationship with the latter approaches. To introduce several strategies for achieving uncommon β-stereoselective C-glycosylation, we also briefly described organotin-based methods.

Photocatalyzed Efficient Synthesis of C-Glycoamino Acids

Key words glycoamino acids - imino esters - glycosyl radicals - photochemical reaction - metal-free

Visible-Light-Mediated, Chemo- and Stereoselective Radical Process for the Synthesis of C-Glycoamino Acids.

An approach for efficient synthesis of C-glycosyl amino acids is described. Different from typical photoredox-catalyzed reactions of imines, the new process follows a pathway in which α-imino esters serve as electrophiles in chemoselective addition reactions with nucleophilic glycosyl radicals. The process is highlighted by the mild nature of the reaction conditions, the highly stereoselectivity attending C-C bond formation, and its applicability to C-glycosylations using both armed and disarmed pentose and hexose derivatives.

Various Multicharged Anions of Ginsenosides in Negative Electrospray Ionization with QTOF High-Resolution Mass Spectrometry.

When characterizing components from ginseng, we found a vast number of multicharged anions presented in the liquid chromatography-mass spectrometry (LC-MS) chromatograms. The source of these anions is unclear yet, while ginsenosides, the major components of ginseng, are the main suspected type of molecules because of their sugar moiety. Our investigation using 14 pure ginsenosides affirmed that the multicharged anions were formed by ginsenosides rather than other types of ingredients in ginseng. Various anions could be observed for each ginsenoside. These anions contain ions ([M-2H]2-, [M+Adduct]2-), as well as those formed by polymerization of at least two ginsenosides, such as [nM-2H]2-, [nM-H+Adduct]2-, and [nM-3H]3-. The presence of so different types of ions from a ginsenoside explains the reason for the large number of anions in the LC-MS analysis of ginseng. We further found that formation of [nM-2H]2- ions was influenced by the number of sugar chains: ginsenosides containing two sugar chains produced all [nM-2H]2- ion types, whereas ginsenosides containing one sugar chain did not produce [2M-2H]2-. Thus, [2M-2H]2- and [3M-2H]2- can be utilized to rapidly identify monodesmosidic and/or bidesmosidic ginsenosides as joint diagnostic anions. The position of the glycosyl radical might be the key factor affecting the formation of multicharged multimer ions from monodesmosidic ginsenosides. Consequently, three groups of ginsenoside isomers were differentiated by characteristic [nM-2H]2- anions. Using concentration-dependent characteristics and collision-induced dissociation (CID), we confirmed that [nM-2H]2- ions are non-covalently bound multimers whose aggregation has marked distinction between monodesmosidic and bidesmosidic ginsenosides, accounting for the differentiated formation of [nM-2H]2- between them. Graphical Abstract.

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.

Photoinduced C-S Bond Cleavage of Thioglycosides and Glycosylation.

A glycosyl coupling reaction via photoinduced direct activation of thioglycosides and subsequent O-glycosylation in the absence of photosensitizer was developed for the first time. This reaction underwent a selectively homolytic cleavage of a C-S bond to generate a glycosyl radical, which was oxidized to an oxacarbenium ion by Cu(OTf)2, and a sequential O-glycosylation. A wide range of glycosides were synthesized in moderate to excellent yield using sugars, amino acids, or cholesterol as the acceptors.

Photochemical Generation of Glycosyl Radicals and Its Applications in Carbohydrate Synthesis

AbstractFor Abstract see ChemInform Abstract in Full Text.

Towards α- or β- d- C-glycosyl compounds by tin-catalyzed addition of glycosyl radicals to acrylonitrile and vinylphosphonate, and flexible reduction of tetra- O-acetyl-α- d-glucopyranosyl bromide with cyanoborohydride

Photo-induced radical addition of acetylated α- d-glucopyranosyl bromide ( 1) to acrylonitrile or diethyl vinylphosphonate, in the presence of catalytic amounts of tri- n-butyltin chloride and sodium (or tetra- n-butylammonium) cyanoborohydride in excess, allowed efficient preparations of α-configurated nonononitrile and 2-(α- d-glucopyranosyl)-ethylphosphonate (79, 70% yields, respectively). These conditions led to 2-(α- d-manno-, and galactopyranosyl)-ethylphosphonates in 68 and 76% yields. Similarly, radical addition of acetylated 1-bromo-β- d-glucopyranosyl chloride ( 2) to acrylonitrile or diethyl vinylphosphonate afforded mainly intermediate chlorides which, upon radical reduction with excess tri- n-butyltin hydride, afforded the corresponding β anomers (40 and 38%, respectively) by sequential CC and CH bond formation. Stereocontrol relies on the α-stereoselective quenching of d-glycopyranos-1-yl radicals. We found also that UV light irradiation of 1 with excess NaBH 3CN in tert-butanol afforded either 1,3,4,6-tetra- O-acetyl-2-deoxy-α- d- arabino-hexopyranose (65% after crystallization) or, when 10% mol thiophenol was added, 2,3,4,6-tetra- O-acetyl-1,5-anhydro- d-glucitol (79%). These are simple, tin-free, and easily controlled conditions, which compare well with known preparations of these reduced sugars.

ChemInform Abstract: Structure of Anomeric Glycosyl Radicals and Their Transformations under Reductive Conditions

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.

Structure of anomeric glycosyl radicals and their transformations under reductive conditions

Structure of anomeric glycosyl radicals and their transformations under reductive conditions

Diastereoselective free-radical synthesis of α-substituted C-glycosyl phosphonates, and their use as building blocks in the HWE-reaction

C-Glycosidic phosphonates were synthesized by the addition of pyranosidic and furanosidic glycosyl radicals to α-phosphonoacrylates which occurred with high diastereoselectivity towards the formation of α-C-glycosidic phosphonates. The products are useful substrates for the synthesis of complex higher-carbon sugars related to tunicamycin by Horner-Wadsworth-Emmons reactions.

ChemInform Abstract: Synthesis of Vinylic C‐Glycosides from Telluroglycosides. Addition of Photochemically and Thermally Generated Glycosyl Radicals to Alkynes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.

ChemInform Abstract: Reversible Generation of Glycosyl Radicals from Telluroglycosides under Photochemical and Thermal Conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.

Rapid Preparation of Variously Protected Glycals Using Titanium(III)

Glycosyl chlorides and bromides can be rapidly converted to glycals in high yield by reaction with (Cp2Ti[III]Cl)2. This reagent tolerates a wide range of common carbohydrate protecting groups, including silyl ethers, acetals, and esters; the methodology provides a general route for the preparation of glycals substituted with both acid- and base-labile functionality. A reaction mechanism is proposed that is based on heteroatom abstraction to give an intermediate glycosyl radical. This radical reacts with a second equivalent of Ti(III) to yield a glycosyltitanium(IV) species. β-Heteroatom elimination from the glycosyltitanium(IV) complex gives the glycal.

Reversible generation of glycosyl radicals from telluroglycosides under photochemical and thermal conditions

1-β-Telluroglycosides isomerize to α-isomers upon photolysis and thermolysis. The isomerization follows first-order reaction kinetics and proceeds through a glycosyl radical intermediate by homolytic CTe bond cleavage. The radicals so generated are trapped intermolecularly by TEMPO free radical, indicating that the glycosyl radicals are efficiently generated by a non-chain mechanism.