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.     

Highly stereoselective addition of organozinc reagents to pentopyranose derived glycals: effect of protecting group and assignment of C-glycoside stereochemistry

The nucleophilic addition of ethyl 3-propionylzinc iodide to a variety of differently protected pentopyranose derived d-glycals 6a-g proceeds with good to high levels of diastereoselectivity to provide the corresponding β-C-glycosides 7. The stereochemistry of the para-nitrobenzoate derivative 7d has been confirmed by X-ray crystallography, and the stereochemistry of the other β-C-glycoside products has been correlated to 7d. The stereochemical outcome observed supports the earlier suggestion by Isobe that through-space effects are important in stabilising and controlling the reactivity of the intermediate oxonium species represented by 11.     

Triphenylphosphine: a catalyst for the synthesis of C-aryl furanosides from furanosyl halides

An array of C-aryl furanosides was prepared in good yields from furanosyl halides and aryl Grignard reagents in Et₂O using PPh₃ as a catalyst.     

A general and convenient synthesis of N-aryl piperazines

A general and convenient synthesis of N-aryl piperazines from bis(2-chloroethyl)amine hydrochloride and a broad range of anilines in diethylene glycol monomethyl ether is described.     

Stereoselective synthesis of novel C-azanucleoside analogues by microwave-assisted nucleophilic addition of sugar-derived cyclic nitrones

A series of C-azanucleoside analogues were synthesized by microwave-assisted nucleophilic addition of electron-rich hetero-aromatics to sugar-derived cyclic nitrones, and followed by reduction and deprotection. The nucleophilic addition afforded the 2′,3′-trans isomer as the dominant by the favorite exo attack and showed high stereoselectivity in polar solvent.     

Intramolecular C-glycosylation of 2-O-benzylated pentenyl mannopyranosides: remarkable 1,2-trans stereoselectivity

The IDCP-promoted intramolecular C-glycosylation of pentenyl α-mannopyranosides carrying, at O-2, an activated benzyl group gave, unexpectedly, the 1,2-trans-fused bicyclic product which corresponds to an α-C-aryl mannopyranose derivative. This remarkable, strained C-glycosyl compound was rapidly epimerized to the more stable 1,2-cis product on treatment with BF₃·Et₂O. The IDCP-reaction product could be elaborated into a 2-(α-C-mannopyranosyl)-3,4,5-trimethoxybenzyl alcohol derivative.     

Synthesis of C1-alkyl- and acylglycals from glycals using a B-alkyl Suzuki-Miyaura cross coupling approach

A B-alkyl Suzuki-Miyaura cross coupling approach provides a flexible, efficient means to convert glycals to C1-alkylglycals and C1-acylglycals that are versatile synthetic intermediates. This approach uses readily available glycal starting materials and overcomes major limitations associated with direct alkylation or acylation of glycals. Further, a commonly observed side reaction involving reduction of the halide coupling partner is suppressed by preincubation of the borane coupling partner with aqueous base, providing new mechanistic insights into the side reaction.     

First example of the carbon-Ferrier rearrangement of glycals with isocyanides: a novel synthesis of C-glycosyl amides

Glycals undergo smooth carbon-Ferrier rearrangement with isocyanides in the presence of a catalytic amount of FeCl₃ under mild reaction conditions to provide C-glycosyl amides in good yields with high α-selectivity. The use of FeCl₃ makes this method simple, convenient and cost-effective. This is the first report on carbon-Ferrier rearrangement using isonitriles as nucleophiles.     

Development of novel LpxC inhibitors: chiral-pool synthesis of C-triazolyl glycosides

The Zn²⁺-dependent deacetylase LpxC plays an important role in the biosynthesis of the cell wall of Gram-negative bacteria and therefore represents an interesting target for the development of novel antibiotics. In a 10-step, chiral pool synthesis starting from d-mannose (3), a series of C-aryl furanosidic hydroxamic acids bearing a 1,4-disubstituted triazole ring in α-configuration at the furanose moiety was stereoselectively synthesized and tested for inhibitory activity against LpxC. The key step of the synthesis comprises a Cu(I) catalyzed Huisgen cycloaddition of terminal alkyne 10 with various azides to introduce diversity to the potential LpxC inhibitors. The X-ray crystal structure of the click product 11e proves the stereochemistry at the anomeric center and the substitution pattern of the triazole ring. The synthesized compounds did not inhibit LpxC.     

Intermolecular reductive coupling of hindered N-aryl imines towards the modular synthesis of chiral N-heterocyclic carbenes

We describe a simple method for the synthesis of hindered N-aryl diamines. The diastereoselectivity for these processes are relatively low but the diamines can be separated using either chromatography or selective crystallization. Separation of enantiomers can be accomplished using HPLC equipped with a chiral stationary phase.     

Short, stereoselective synthesis of C-glycosyl asparagines via an olefin cross-metathesis

The Grubbs second generation ruthenium catalyst was employed for the cross metathesis between α- and β-C-allyl glycosides and suitably protected l-vinyl glycines to furnish olefinic products in 57-94% yields. Hydrogenation afforded the C-glycosyl asparagines in high yield.     

C-Glycopyranosyl-1,4-benzoquinones and -hydroquinones opening access to C-glycosylated analogs of vitamin E

2-(Per-O-acetyl-β-d-glycopyranosyl)-1,4-dimethoxybenzenes led to C-glycosyl-hydroquinones suitable for preparing C-glycosylated analogs of vitamin E, having the sugar moiety free or acetylated.     

A parallel synthesis approach towards a family of C-nucleosides

A synthetic route was devised for a sugar based α-chloroketone, which was subsequently used to generate a family of C-nucleosides via parallel synthetic methodology.     

Convenient method for the synthesis of C-phosphorylated N-arylformamidines

C-Phosphorylated (P^V) arylformamidines have been prepared by the reaction of N-arylamidotrichloromethyl derivatives of phosphorus, thiophosphorus, and selenophosphorus acids with secondary amines. Dependence of the reaction on the nature of chalcogene, electronic and steric factors has been studied. By reduction of N-arylformamidinophosphonoselenides the corresponding C-phosphorylated (P^III) arylformamidines have been synthesized.     

Concise total synthesis of flavone C-glycoside having potent anti-inflammatory activity

The total synthesis of anti-inflammatory active flavone C-glycoside isolated from oolong tea extract is achieved. Introducing a C-glucosyl moiety to an aryl system and constructing a fused tetracyclic ring characteristic to this natural product were conducted based on the O-to-C rearrangement of sugar moiety and the successive intramolecular Mitsunobu reaction, respectively. This concise and efficient synthetic pathway is applicable to the large-scale synthesis of target flavone and for constructing a large library of related compounds.     

Facile and efficient synthesis of C2-symmetrical 1,3,5-triazine polycarboxylate ligands under microwave irradiation

A rapid and efficient method for preparation of C₂-symmetrical 1,3,5-triazine polycarboxylate ligands was developed. The reactions included either selective mono- or di-substitution of 2,4,6-trichloro-1,3,5-triazine with various nucleophiles containing carboxyl group(s), followed by nucleophilic displacement of the remained chloride(s) in aqueous media under microwave irradiation. Novel C₂-symmetrical tripodal ligands were afforded in good yields and purities under short reaction time with simple work-up, which are potentially useful as structural directing units in metal-organic frameworks.     

Avoiding pyran ring opening during palladium acetate catalyzed C-glycosidation of peracetylated glycals

Palladium acetate catalyzed C-glycosidation of peracetylated glycals with arylboronic acids in acetonitrile (CH₃CN) yields the desired 1-substituted 2,3-unsaturated glycal as well as a byproduct corresponding to the ring-opened pyran, present in varying proportions depending on the reaction conditions used. The byproduct is not formed when toluene/EtOH is used as reaction solvent.     

Synthesis of C-aryl-Δ-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.     

InCl3-catalyzed synthesis of C-pyrrolyl glycosides via tandem condensation of aminosugars and 1,3-dicarbonyl compounds in water

Various C-pyrrolyl glycosides were obtained through tandem condensation of aminosugars (d-glucosamine and d-galactosamine) and 1,3-dicarbonyl compounds under green conditions in moderate to good yields. The reactions were carried out in the presence of 10 mol % InCl₃ in water at 50 °C. A reaction mechanism through carbocation intermediates was proposed.     

Microwave-assisted rapid and efficient synthesis of C-alkyl imidazoisoquinolinone derivatives

The synthesis of a set of 10-benzyl-2,3-dihydroimidazo[1,2-b]isoquinolin-5(1H)-one and 5-oxo-imidazo[1,2-b]isoquinolin-10-yl)-N-phenylacetamide derivatives was achieved by exposing the corresponding alkylating agent and imidazoisoquinolinone to microwave irradiation and traditional oil bath heating in the presence of K₂CO₃ and DMAP. The microwave technique as well as DMAP as base accelerated the alkylation reaction for 2-6 min giving 79-88% yields.