Synthesis and glycosidase inhibitory activity of aminocyclitols with a C6- or a C7-ring

The synthesis of carbasugars and various aminocyclitols, related to voglibose and acarbose used in the treatment of non-insulino-dependant diabetes, is described from C₂-symmetrical bis-epoxides derived from d-mannitol. The methodology involves two key steps: a domino alkylation-cyclization with 2-lithio-1,3-dithiane derivatives, and reduction or reductive amination with a primary amine. These compounds have been evaluated as inhibitors of several glycosidases, and this study indicates notably that the l-ido or d-manno 1-aminocycloheptane-3,4,5,6-tetrol are inhibitors of α-d-glucosidase with K_i in the micromolar range.     

Synthesis of branched tri- to pentasaccharides representative of fragments of Shigella flexneri serotypes 3a and/or X O-antigens

Fragments of the {2)-[α-d-Glcp-(1→3)]-α-l-Rhap-(1→2)-α-l-Rhap-(1→3)-[Ac→2]-α-l-Rhap-(1→3)-β-d-GlcpNAc-(1→}_n ((E)AB_AcCD)_n polymer were synthesized. D(E)A, CD(E)A, _AcCD(E)A were obtained according to a linear strategy, whereas BCD(E)A and B_AcCD(E)A were derived from the condensation of appropriate BC and D(E)A building blocks. Oligosaccharides were synthesized as their propyl glycoside, relying on (i) the efficient trichloroacetimidate chemistry, (ii) a common EA allyl glycoside, and (iii) a 2-trichloroacetamido-d-glucopyranose precursor to residue D. Final Pd/C-mediated deprotection, run under a high pressure of hydrogen, ensured O-acetyl stability. All targets are parts of the O-antigen of Shigella flexneri 3a, a prevalent serotype. Non-O-acetylated oligosaccharides are shared by the S. flexneri serotype X O-antigen.     

Molecular iodine-promoted N- and C-glycosylation of 1-C-alkyl (or phenyl)-glycopyranoses

Molecular iodine efficiently promoted the N- and C-glycosylation of hemiketals with Me₃SiN₃ and Me₃SiCN, respectively. Using this method we have prepared diverse functional N- and C-ketosides, which could serve as useful synthons for the preparation of unnatural glycosyl amino acids or glycopeptides.     

Synthesis of C-disaccharide analogues of the α-d-arabinofuranosyl-(1→5)-α-d-arabinofuranosyl motif of mycobacterial cell walls via alkynyl intermediates

Two C-glycosides related to the recurrent α-d-arabinofuranosyl-(1→5)-α-d-arabinofuranosyl structural motif of mycobacterial arabinan have been prepared by routes involving acetylenic intermediates.     

Synthesis and glycosidase inhibitory activity of new penta-substituted C8-glycomimetics

The syntheses of new C8-carbasugars and -aminocyclitols related to miglitol and voglibose are described. The key step involves the ring closing metathesis of 1,9-dienes derived from d-mannitol. Chemical transformations of the newly created double bond of the resulting cyclooctenes involved notably hydroboration and reductive amination. The inhibitory activity of the glycomimetics so-obtained has been evaluated towards 24 commercially available glycosidases.     

Synthesis of furan 4′-thio-C-nucleosides, their methylsulfonium and sulfoxide derivatives. Evaluation as glycosidase inhibitors

A series of furan C-nucleosides having a sulfur atom in the sugar ring were synthesised. The α and β anomers of 3-ethoxycarbonyl-2-methyl-5-(4′-thio-d-erythrofuranosyl)furans 10 and 11 were obtained by acid treatment of (4′-S-acetyl-4′-thio-d-arabino-tetritol-1-yl)furan 9. Oxidation of 10 with m-chloroperbenzoic acid gave sulfoxide 12 as one epimer at the sulfur atom whereas 11 was transformed into sulfoxide 13 as an epimeric mixture. S-Methylation of 10 and 11 with methyl triflate led to sulfonium salts 14 and 15. The prepared compounds were found to be moderate inhibitors of α-l-fucosidase.     

Synthesis and in vitro antimalarial and antitubercular activity of gold(III) complexes containing thiosemicarbazone ligands

Gold(III) thiosemicarbazone complexes derived from [Au(damp-C¹,N)Cl₂] (2), where damp = dimeth-ylaminoethylphenyl, have been synthesized. The compounds were characterised using various spectroscopic and analytical techniques, including NMR spectroscopy, mass spectrometry, infrared spectroscopy and elemental analysis. The gold complexes were screened for in vitro antimalarial and antitubercular activity. Although incorporation of the gold(III) centre into thiosemicarbazone scaffolds enhanced their efficacy against the malaria parasite Plasmodium falciparum, this trend was not observed for the antitubercular activity of selected thiosemicarbazones against the Mycobacterium tuberculosis virulent strain H₃₇Rv.     

Microwave assisted solvent free amination of halo-(pyridine or pyrimidine) without transition metal catalyst

A solvent free direct amination of halo-(pyridine or pyrimidine) has been developed in good to high yields under computer-controlled microwave irradiation without transition metal catalyst. This reaction is a solvent and metal free, useful method for coupling of halo-(pyridine or pyrimidine) with pyrrolidine and piperidine derivatives by nucleophilic aromatic substitution (S_NAr).     

Synthesis of novel (NHC)Pd(acac)Cl complexes (acac=acetylacetonate) and their activity in cross-coupling reactions

The synthesis and characterization of two new complexes (IPr)Pd(acac)₂ (1) and (IPr)Pd(acac)Cl (2) (IPr=(N,N'-bis(2,6-diisopropylphenyl)imidazol)-2-ylidene, acac=acetylacetonate) are described. Complex 2 can be prepared in a one-pot protocol in high yield. A study detailing the versatility of 2 to effectively catalyze a series of cross-coupling reactions is discussed.     

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.     

A binaphtolate titanium complex featuring a linear tetradentate [OSSO]-bis(phenolato) ligand: Synthesis and partial hydrolysis to a homochiral dinuclear complex

Reaction of [{(R)-C₂₀H₁₂O₂}Ti(OⁱPr)₂] with 1,4-dithiaalkanediyl-2,2′-bis(6-tert-butyl-4-methyl-phenol) affords the chiral-at-metal complex [{(R)-C₂₀H₁₂O₂}Ti{(C₆H₂O-^tBu-6-Me-4)₂S(CH₂)₂S}] (1) in low diastereomeric excess. Complex 1 can be partially hydrolyzed to give a dinuclear species [μ-{(R)-C₂₀H₁₂O₂}-μ-O-{(Λ)-Ti[(C₆H₂O-^tBu-6-Me-4)₂S(CH₂)₂S]}₂] (2), in which the two titanium centers are homochiral. The molecular structure of 1 and 2 was confirmed by single crystal X-ray analysis, which shows C₂-symmetry in both complexes.     

Synthesis, structural determination and photo-antiproliferative activity of new 3-pyrazolyl or -isoxazolyl substituted 4-hydroxy-2(1H)-quinolinones

A convenient route to new 3-quinolinonyl-pyrazoles and isoxazoles is described through cyclization of 3-[(E)-3-(dimethylamino)-2-propenoyl]-4-hydroxy-1-methyl-2(1H)-quinolinone. The phototoxicity as well as the cytotoxic activities of the title compounds are evaluated against leukemia- and adenocarcinoma-derived cell lines in comparison to the normal human keratinocytes.     

Synthesis and evaluation of the glycosidase inhibitory activity of 5-hydroxy substituted isofagomine analogues

An efficient strategy for the synthesis of 5-hydroxy substituted isofagomine analogues and , having both -CH2OH/CH3 and -OH functionality at the C-5 position, and evaluation of their inhibitory potency is reported. The synthetic methodology involves the aldol-Cannizzaro reaction of easily available alpha-d-xylopentodialdose followed by hydrogenolysis to afford the triol . Selective amidation of the alpha- and beta-hydroxymethyl group at C-4, deprotection of the 1,2-acetonide group and hydrogenation gave the target molecules, which were found to be potent against beta-glycosidases with IC50 values in the micro molar range. Compound showed excellent potency against glycosidases and human salivary amylase.     

Synthesis, structural characterization and electrochemistry of C,N-chelated organotin(IV) dicarboxylates with ferrocenyl substituents

A set of C,N-chelated organotin(IV) ferrocenecarboxylates, [L^CN(n-Bu)Sn(O₂CFc)₂] (1), [(L^CN)₂Sn(O₂CFc)₂] (2), [L^CN(n-Bu)Sn(O₂CCH₂Fc)₂] (3), [L^CN(n-Bu)Sn(O₂CCH₂CH₂Fc)₂] (4), [L^CN(n-Bu)Sn(O₂CCHCHFc)₂] (5), [L^CN(n-Bu)Sn(O₂CfcPPh₂)₂] (6), [(L^CN)₂Sn(O₂CfcPPh₂)₂] (7), and [L^CN(n-Bu)₂Sn(O₂CFc)] (8) (L^CN = 2-(N,N-dimethylaminomethyl)phenyl, Fc = ferrocenyl and fc = ferrocene-1,1′-diyl) has been synthesized by metathesis of the respective organotin(IV) halides and carboxylate potassium salts and characterized by multinuclear NMR and IR spectroscopy. The spectral data indicated that the tin atoms in diorganotin(IV) dicarboxylates bearing one C,N-chelating ligand (1 and 3-6) are seven-coordinated with a distorted pentagonal bipyramidal environment around the tin constituted by the n-butyl group, the chelating L^CN ligand and bidentate carboxylate. Compounds 2 and 7 possessing two chelating L^CN ligands comprise octahedrally coordinated tin atoms and monodentate carboxylate donors, whereas compound 8 assumes a distorted trigonal bipyramidal geometry around tin with the carboxylate binding in unidentate fashion. The solid state structures determined for 1⋅C₆D₆ and 2 by single-crystal X-ray diffraction analysis are in agreement with spectroscopic data. Compounds 1, 3-5, and 8 were further studied by electrochemical methods. Whereas the oxidations of ferrocene units in bis(carboxylate) 2 and monocarboxylate 8 proceed in single steps, compound 1 undergoes two closely spaced one-electron redox waves due to two independently oxidized ferrocenyl groups. The spaced analogues of 2, compounds 3-5, again display only single waves corresponding to two-electron exchanged.     

Synthesis of trisubstituted alkenes by reductive dehydroxylation of Baylis-Hillman adducts using polymethylhydrosiloxane (PMHS) and catalytic B(C6F5)3

B(C₆F₅)₃ as a catalyst and polymethylhydrosiloxane as a hydride source have been employed for the reductive dehydroxylation of Baylis-Hillman adducts wherein the hydride adds in an S_N2′ manner onto the unactivated allyl alcohol moiety with concomitant elimination of the hydroxy group along with double bond migration. The products formed were found to be E in the case of ester adducts and Z in the case of nitrile adducts.     

Synthesis and antitumor activity of 2-(m-substituted-benzoyl)baccatin III analogs from taxinine

2-m-Azidobenzoyl and 2-m-chlorobenzoyl baccatin III analogs were prepared from taxinine, a major component in Japanese yew leaves. In this study, a novel acetyl migration from 13- to 4-hydroxyl group was observed. The antitumor activity of these compounds was evaluated.     

Synthesis of α,β-unsaturated dioxanes, dioxolanes and dioxepanes by trans-acetalisation of dimethylacetals with meso or C2-symmetrical 1,2-, 1,3- and 1,4-diols

Several o-dibenzylic diols were prepared reacting organometallics with o-phthalaldehyde at room temperature in ether. The identity of the meso and C₂-symmetrical (d,l) isomers as well as their ratio were determined by chiral gas chromatography. The meso and C₂ (racemic) stereoisomeric diols were easily separated by flash chromatography on silica gel. A set of 18 α,β-unsaturated acetals were then prepared reacting those, as well as commercially available 1,2, 1,3 and 1,4 diols, with the corresponding methylacetals in acidic medium. A trans-acetalisation procedure adapted to the cases of fragile allylic alcohols or unfavorable 1,6 diols-derived dioxonanes based on a Dean-Stark trapping of methanol was also employed.     

Synthesis of glycosyl dipyrromethanes

Treatment of peracetylated sugar trichloroacetimidates with dipyrromethane in the presence of boron trifluoride diethyl etherate gave peracetylated glycosyl dipyrromethanes in good yields. Regio- and stereo-selectivity of the glycosylation reactions were established.