The synthesis and biological activity of novel spiro-isoxazoline C-disaccharides based on 1,3-dipolar cycloaddition of exo-glycals and sugar nitrile oxides

A series of novel spiro-isoxazoline C-disaccharides were synthesized by the key step of 1,3-dipolar cycloaddition reactions of exo-glycals and sugar nitrile oxides, and followed by catalytic debenzylation in the presence of Pd(OH)₂/C. The cycloaddition reactions were carried out stereoselectively and afforded α-isomers exclusively except in the case of galactose. The biological activities of the novel disaccharides against the glycosidases (α-amylase, α-glucosidase, and β-glucosidase) and HIV and BVDV were evaluated.     

Efficient access to disubstituted exo-glycals. Application to the preparation of C-glycosyl compounds

Efficient methods of preparation of disubstituted exo-glycals by palladium cross-coupling reaction on the readily available dibromo exo-glycal and methoxycarbonyl exo-glycal have been developed. Hydrogenation of these new monosubstituted and disubstituted exo-glycals proceeded with a high stereocontrol and led to original C-glycosyl compounds.     

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.     

Povarov reactions of exo-glycals: preparation of C-linked, quinoline analogues

A one-pot approach based upon the Povarov reaction has been efficiently employed with a number of exo-glycals and para-substituted benzanilines to synthesize novel open-ring, carbohydrate-derived quinolines. The mechanism of this reaction was studied and an explanation for the observed stereoselectivity is proposed. Treatment of the compounds with the Lewis acid, boron trichloride, successfully removes the benzyl ether protecting groups in good yields. Several of the prepared compounds have been screened in the National Cancer Institute’s (NCI’s) 60 cell line model. Moderate activity was observed for several leukemia cell lines.     

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.     

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.     

Total synthesis of (−)-centrolobine: β-C-glycoside formation via a tandem Grignard addition and stereoselective hemi-ketal reduction

It has been demonstrated that an aryl-β-C-glycoside can be efficiently constructed via a sequence consisting of Brown asymmetric allylation, ring-closing metathesis, hydrogenation, nucleophilic addition, and stereoselective Et₃SiH reduction. The antibiotic natural product (−)-centrolobine was synthesized in this manner utilizing only five steps with an overall 53% yield.     

Total synthesis of puerarin, an isoflavone C-glycoside

We completed the first total synthesis of puerarin (1), an isoflavone C-glycoside. The key intermediate, β-d-glucopyranosyl-2,6-dimethoxybenzene (9), was obtained by coupling of a lithiated aromatic reagent (3) with pyranolactone (2) in 56% yield. Condensation of (16) with p-methoxybenzaldehyde gave the chalcone (17). The protected chalcone (18) was cyclized to (19) in the presence of Tl(NO₃)₃. Demethylation of (19) was accomplished by refluxing with TMSI in CH₃CN to give puerarin (1).     

Structure of N,C,N-chelated organotin(IV) fluorides

The set of starting tri-, di- and monoorganotin(IV) halides containing N,C,N-chelating ligand (L^NCN = {1,3-[(CH₃)₂NCH₂]₂C₆H₃}⁻) has been prepared (1-5) and two compounds structurally characterized ([L^NCNPh₂Sn]⁺I₃⁻ (1c), L^NCNSnBr₃ (5)) in the solid state. These compounds were reacted with KF with 18-crown-6, NH₄F or L^CNnBu₂SnF to give derivatives containing fluorine atom(s). Triorganotin(IV) fluorides L^NCNMe₂SnF (2a) and L^NCNnBu₂SnF (3a) revealed monomeric structural arrangement with covalent Sn-F bond both in the coordinating and non-coordinating solvents, except the behaviour of 3a that was ionized in the methanol solution at low temperature. The products of fluorination of L^NCNSnPhCl₂ (4) and 5 were described by NMR in solution as the ionic hypervalent fluorostannates or the oligomeric species reacting with chloroform, methanol or moisture to zwitterionic monomeric stannate L^NCN(H)⁺SnF₄⁻ (5c), which was confirmed by XRD analysis in the solid state.     

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.     

A novel entry to C-glycals via diethylzinc-mediated umpolung of π-allyl palladium derived from 1-exo-methylene 2,3-anhydrofuranoses

The reaction of aldehydes with allylzinc reagents resulting from the umpolung of π-allyl palladium complexes from 1-exo-methylene 2,3-anhydrofuranoses provides a novel entry to C-glycals.     

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.     

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.     

Synthesis of a C3-symmetric macrocycle with alternating sugar amino acid and tyrosine residues

A C₃-symmetric macrocycle with alternating sugar amino acid and tyrosine residues was synthesized in seven steps from tyrosine tert-butyl ester and a sugar amino acid precursor derived from D-glucosamine. An Fmoc-protected D-glucosamine derivative was oxidized at C-6 to give the sugar amino acid, which was immediately coupled to tyrosine tert-butyl ester to produce an orthogonally protected building block. This building block was subsequently elongated to the trimer via the dimer, and finally cyclized to give the C₃-symmetric macrocycle.     

Anomeric spiroannelated 1,4-diazepine 2,5-diones from furano exo-glycals: towards a new class of spironucleosides

The first synthesis of 1,4-diazepine 2,5-dione peptides containing a β-amino acid in which the β carbon is also the anomeric carbon of a furanoid sugar is described. These new anomeric spirosugars obtained with a stereoselective control in the d-gulo, d-manno, d-allo and d-ribo series can be regarded as the first members of a new class of spironucleosides. In the course of our study, two symmetrical tetrameric cyclopeptides comprising two identical sugar β-amino acid and α-amino acid residues were also isolated, these structures could be of interest as new potential host molecules.     

Cyclobutanone photoadducts of HCN and malononitrile: useful intermediates for the synthesis of C-nucleosides

Photochemistry of cyclobutanones in the presence of HCN or malononitrile give photoadducts derived from oxacarbene insertion into C-H. These intermediates are useful for the preparation of C-nucleosides by structural elaboration of the CN groups.     

A practical, solvent free, one-pot synthesis of C2-symmetrical secondary amines

A novel one-pot reductive amination of ketones using the combination Ti(OⁱPr)₄/H₂/Pd-C is reported. This practical procedure does not require any solvent, and affords C₂-symmetrical secondary amines in high yields and excellent diastereoselectivities.     

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.     

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.     

Synthesis of protected derivatives and short peptides of antAib, a novel C-tetrasubstituted α-amino acid of the Ac5c type possessing a fused anthracene fluorophore

The N^α-Boc and N^α-Fmoc protected derivatives of 2-amino-2,3-dihydro-1H-cyclopenta[b]anthracene-2-carboxylic acid (antAib), a novel fluorescent, achiral, α-amino acid, rigid analogue of the known 9-antAla and 2-antAla residues, and belonging to the class of C_i^α→C_i^α cyclized, C^α,α-disubstituted glycines (strong β-turn and helix inducers in peptides), were synthesized in seven steps from 1,2,4-trimethylbenzene. The UV absorption and fluorescence properties of Boc-antAib-OEt and Boc-antAib-OH are also described. Solution syntheses of the short peptides Boc-antAib-l-Ala-OMe, Fmoc-l-Ala-antAib-l-Ala-OMe, as well as Boc-Aib-antAib-l-Ala-OMe and the side product 2,5-dioxopiperazine cyclo-[antAib-l-Ala], are presented as examples of the coupling ability at both C- and N-termini of the antAib residue.