C-aryl Glycosides Research Articles

Recent Advances in Aryl C-Glycoside Synthesis

Aryl C-glycosides are stable analogs of the corresponding O-glycosides. Because of their favorable pharmacological profiles attributed primarily to the C-glycosyl moiety, aryl C-glycosides have gained increasing popularity as drug candidates. In this review we focus on the synthesis of aryl C-glycosides including puerarin and kendomycin. This review is organized based on the type of chemistry used in the assembly of the C-glycosides with the following sub-sections: electrophilic reaction, cross-coupling reaction, free radical reaction, cyclization, intramolecular O-C rearrangement, umpolung, and miscellaneous reactions.

Triisobutylaluminium (TIBAL) Promoted Rearrangement of C-glycosides

Triisobutylaluminium-promoted rearrangement of unsaturated glycosides containing electron-donating aglycons, such as C-aryl glycosides, provides direct access to highly functionalised cyclohexane derivatives.

Epoxidation and Bis-hydroxylation of C-Phenyl-∆2,3-glycopyranosides

Epoxidation and cis-hydroxylation of C-phenyl-Δ2,3-glycopyranosides have been carried out with a view to developing C-aryl glycoside synthesis. Epoxidation of (2,3- dideoxy-d-erythro-hex-2-enopyranosyl)benzene and (6-O-tert-butyldimethylsilyl-2,3- dideoxy-d-erythro-hex-2-enopyranosyl)benzene gave predominantly the allo-adducts whatever the configuration at the anomeric center. Epoxidation of (4,6-di-O-tert-butyl-dimethylsilyl-2,3-dideoxy-d-erythro-hex-2-enopyranosyl)benzene gave the manno- and allo-adducts in a 89:11 and 40:60 ratios for the α- and β-anomers, respectively. Hydroxylation of α-C-phenyl-Δ2,3-glycopyranosides using OsO4 afforded the manno-adduct only, whatever the substituents at positions 4 and 6, whereas hydroxylation of (2,3-dideoxy- β-d-erythro-hex-2-enopyranosyl)benzene and (4,6-di-O-tert-butyldimethylsilyl-2,3- dideoxy- β-d-erythro-hex-2-enopyranosyl)benzene gave the manno- and allo-adducts in 25:75 and 80:20 ratios, respectively.

Total synthesis of kendomycin: a macro-C-glycosidation approach.

Kendomycin, also known as (-)-TAN 2162, is a novel polyketide-derived ansamycin isolated from Streptomyces sp., which exhibits potent antagonist and agonist activities at the endothelin and calcitonin receptors, respectively. This bacterial metabolite also possesses a strong antibiotic activity against a range of gram-positive and -negative bacteria and cytostatic effects on the growth of human cancer cell lines. When a novel macroglycosidation reaction is employed as the key step, the first enantioselective total synthesis of kendomycin has been accomplished. A Friedel-Crafts-type ring closure of the acyclic precursor containing tetrahydropyran and benzofuran moieties produces the macrocycle as a single stereoisomer in good yield, thus establishing the aryl C-glycosidic linkage of the ansa core. This reaction requires a phenolic glycosyl acceptor and appears to proceed through a rapid O-glycosidation followed by a slow rearrangement to an aryl C-glycoside. The requisite secomacrocycle is prepared by the Pd(0)-catalyzed B-alkyl Suzuki-Miyaura cross-coupling of two subunits, which in turn can be expeditiously assembled from readily available building blocks in a modular fashion.

Aryl and Arylmethyl C‐Glycosides Through Desulfitative Stille and Carbonylative Stille Cross‐Coupling of Tinglycals and Sulfonyl Chlorides.

The palladium-catalyzed cross-coupling of tinglucal and tingalactal derivatives with arenesulfonyl chlorides provides aryl C-glycoside precursors. Desulfitative carbonylative Stille cross-coupling between 1-naphthalenesulfonyl chloride and a tinglucal derivative gives, after stereoselective reduction of the keto moiety and stereoselective oxidative hydroboration, a protected form of 1-[(11S)-2,6-anhydro-L-glycero-D-gulo-heptitol-1-C-yl]naphthalene [β-C-glucopyranoside of (S)-(naphtha-1-yl)methanol]. Benzyl C-glycoside precursors are obtained by desulfitative Stille coupling of phenylmethanesulfonyl chloride with the corresponding protected tinglycals.

Oxidative rearrangement processes in the biosynthesis of gilvocarcin V.

Gilvocarcin V (GV), an antitumor agent produced by Streptomyces griseoflavus Gö 3592 and various other streptomycetes, is the most important representative of the distinct family of benzo[d]naphtho[1,2-b]pyran-6-one aryl C-glycoside antibiotics, which show excellent antitumor activity and a remarkably low toxicity. The most intriguing step of its biosynthesis is an oxidative rearrangement cascade, in which the C-5/C-6 of an angucyclinone precursor bond is broken. Although this oxidative cleavage is essential for the formation of GV's unique chromophore and for GV's biological activity, and is likely to occur similarly in the biosyntheses of other angucyclinone-derived antibiotics, such as the kinamycins and the jadomycins, it is only poorly understood. Herein we report various experiments which shed light onto this intriguing oxidative cleavage reaction. These include incorporation studies with 18O-labeled precursors and the isolation and structure determination of novel intermediates of gilvocarcin biosynthesis accumulated by mutants, in which two genes encoding monooxygenases responsible for the C-C-bond cleavage of the gilvocarcin pathway, gilOI and gilOIV, were deleted through targeted PCR.

Carbohydrates: From ‘Chirons’ to New Glycosubstances

Synthesis of C-glycosides, C-linked saccharides and new glycosubstances has been the subject of considerable interest in carbohydrate, enzymatic and metabolic chemistry, since some of such compounds exhibit exciting biological properties. As a consequence, the design and implementation of stereo selective strategies for preparing bio-active carbohydrates became a prominent issue. This article is mainly aimed at the presentation of the research findings of our group on the synthesis of C-alkyl and C-aryl glycosides, higher sugars; ‘de novo’ construction of disaccharides from furanyl and propargyl sugars; [3+3] annulation routes to carbocycles and pseudo saccharides; 1,3-dipolar cycloaddition to isoxazolidine sugars and saccharides; radical routes to spiro acetal saccharides and ulosonic acid derivatives. Keywords: Carbohydrates, 1,3-dipolar cycloaddition, spiro acetal saccharides, C-aryl glycosides

A new access to C-arylglycosides related to the gilvocarcins

A new strategy has been developed for the synthesis of C-aryl glycosides based on a xanthate-mediated free radical addition–cyclization sequence of an acetophenone xanthate to a vinylic carbohydrate followed by aromatization.

Synthesis of C-aryl-Δ 2,3-glycopyranosides via uncatalyzed addition of triarylindium reagents to glycals

2,3-Unsaturated- C-aryl glycopyranosides are important intermediates in the synthesis of medicinally important C-aryl glycosides. Treatment of glycal acetates with triarylindiums in ether at room temperature gives good yields of C-aryl-Δ 2,3-glycosides of predominantly α-configuration. The mechanism of this reaction likely involves the formation of an oxocarbenium ion intermediate via indium(III) Lewis acid-assisted ionization of the glycal C.3 acetate. Coupling of trivinyl- and tris(alkynyl)indiums with glycals similarly led to C-vinyl- and C-alkynyl-Δ 2,3-glycosides in good yield.

Regioselective Synthesis of Unsymmetrical C‐Aryl Glycosides Using Silicon Tethers as Disposable Linkers.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Aryl and ArylmethylC-Glycosides through Desulfitative Stille and Carbonylative Stille Cross-Coupling of Tinglycals and Sulfonyl Chlorides

The palladium-catalyzed cross-coupling of tinglucal and tingalactal derivatives with arenesulfonyl chlorides provides aryl C-glycoside precursors. Desulfitative carbonylative Stille cross-coupling between 1-naphthalenesulfonyl chloride and a tinglucal derivative gives, after stereoselective reduction of the keto moiety and stereoselective oxidative hydroboration, a protected form of 1-[(1S)-2,6-anhydro-l-glycero-d-gulo-heptitol-1-C-yl]naphthalene [β-C-glucopyranoside of (S)-(naphtha-1-yl)methanol]. Benzyl C-glycoside precursors are obtained by desulfitative Stille coupling of phenylmethanesulfonyl chloride with the corresponding protected tinglycals.

Diastereoselective Synthesis of Substituted 2-Phenyltetrahydropyrans as Useful Precursors of Aryl C-Glycosides via Selenoetherification

The cyclization of several substituted 5-phenyl-pent-4-en-1-ols with selenium electrophiles along some mechanistic considerations is discussed. In particular, an efficient diastereoselective synthesis of a 2,3,5,6-tetrasubstitued tetrahydropyran is reported. These findings open an interesting approach: the use of chiral selenium electrophiles for cyclization of chiral substrates. The cyclized products are useful starting material for the synthesis of D- or L-aryl C-glycosides.

A novel approach toward the synthesis of kendomycin: selective synthesis of a C-aryl glycoside as a single atropisomer.

[reaction: see text] A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a S(N)1 ring cyclization as a key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, but after MOM protection of the o-hydroxyl of the phenol, the conformation was frozen to the desired kendomycin-like atropisomer.

C‐Glycosylation of Oxygenated Naphthols with 3‐Dimethylamino‐2,3,6‐trideoxy‐L‐arabino‐hexopyranose and 3‐Azido‐2,3,6‐trideoxy‐D‐arabino‐hexopyranose.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regioselective synthesis of unsymmetrical C-aryl glycosides using silicon tethers as disposable linkers.

Silicon tethers were employed to control the regiochemistry of Diels-Alder reactions between substituted benzynes and glycosyl furans as a key step in the syntheses of unsymmetrical representatives of three major groups of C-aryl glycosides. The cycloaddition precursors were readily prepared by O-alkylation of substituted phenols with various sugar-substituted furylsilane derivatives. Selective deprotonation on the benzene ring of these ethers led to a benzyne that underwent an intramolecular Diels-Alder reaction to give bridged cycloadducts. Fluoride-induced removal of the silicon tether and acid-catalyzed ring opening of the oxabicycloheptadiene subunit yielded the desired C-aryl glycosides as single isomers.

The complete gene cluster of the antitumor agent gilvocarcin V and its implication for the biosynthesis of the gilvocarcins.

Gilvocarcin V, an antitumor agent produced by the bacterium Streptomyces griseoflavus Gö 3592, is the most studied representative of the distinct family of benzo[d]naphtho[1,2-b]pyran-6-one aryl C-glycoside antibiotics, which show excellent antitumor activity and a remarkably low toxicity. Its biosynthesis contains many intriguing steps, including an oxidative rearrangement, the C-glycosylation, and the generation of a vinyl side chain. These steps all contribute to structural elements of the drug, which are essential for its biological activity, but only poorly understood. Herein we report the cloning and characterization of the gilvocarcin (gil) gene cluster from S. griseoflavus Gö 3592, and its heterologous expression in a foreign host (S. lividans). This is the first reported gene cluster encoding the biosynthesis of a benzo[d]naphtho[1,2-b]pyran-6-one aryl C-glycoside antibiotic, which not only provides insights regarding the biosynthesis of gilvocarcin V but also lays the foundation for the detailed studies of its intriguing biosynthetic steps and possibly for the generation of gilvocarcin analogues with improved biological activities through combinatorial biosynthesis.

C-Glycosylation of Oxygenated Naphthols with 3-Dimethylamino-2,3,6-trideoxy-L-arabino-hexopyranose and 3-Azido-2,3,6-trideoxy-D-arabino-hexopyranose

In connection with studies directed towards the synthesis of the pyranonaphthoquinone antibiotic medermycin, C-aryl glycosides were prepared by C-glycosylation of naphthols with glycosyl donors. Boron trifluoride diethyl etherate proved to be a suitable Lewis acid to promote the C-glycosylation, and use of the azido glycosyl donor proved more successful than using the dimethylamino glycosyl donor. 5-Hydroxy-1,4-dimethoxynaphthalene underwent facile C-glycosylation with two particular glycosyl donors, whereas 3-bromo-5-hydroxy-1,4-dimethoxynaphthalene was not an effective coupling partner with the same glycosyl donors. These studies indicate that subtle steric and electronic effects need to be considered in order to fine-tune C-glycosylations when using highly functionalized glycosyl donors.

General entries to C-aryl glycosides. Formal synthesis of galtamycinone

Utilizing a general entry we had developed for the synthesis of C-aryl glycosides, we have prepared the juglone derivatives 18– 20 as well as the juglone precursor 13 . Because 19 had been previously converted in two steps by Suzuki into galtamycinone ( 1 ), its preparation constitutes a total synthesis of 1 .

Unified strategy for the synthesis of C-aryl glycosides

Abstract A unified approach for the synthesis of the four major groups of C-aryl glycosides has been developed. The strategy incorporates two integrated approaches, the first of which features the [4+2] cycloaddition of a glycosyl furan with a substituted benzyne followed by the acid-catalyzed opening of the resultant adduct. The second route involves the sequential palladium-catalyzed opening of a benzyne-furan cycloadduct with an iodo glycal followed by oxidation of the resultant dihydronaphthol ring and reduction of the glycal moiety. The utility of this strategy has been established by a concise formal synthesis of the C-aryl glycoside antibiotic galtamycinone.

Catalytic FeCl3- or Yb(OTf)3-mediated synthesis of substituted tetrahydrofurans and C-aryl glycosides from 1,4-diols

A facile and mild protocol for the synthesis of substituted tetrahydrofurans, 2-deoxy C-aryl glycoside and C-aryl glycosides is described by use of 20 mol% FeCl3 or Yb(OTf)3 as acid catalysts. The benzylic carbocation generated undergoes intramolecular substitution by the oxygen nucleophile to result the tetrahydrofurans and C-aryl glycosides.