Study on metal-induced reactions of α-diazocarbonyl glucosides.

Conversions of diazocarbonyl carbohydrate compounds catalyzed by a series of rhodium and copper catalysts in conventional heating or microwave conditions were investigated. C-H insertion product was obtained in the presence of Rh(2)(OAc)(4). Intermolecular reactions rather than intramolecular reactions occurred in the presence of copper catalysts.

Conjugation of cyclodextrin with fullerene as a new class of HCV entry inhibitors.

An α-cyclodextrin-[60]fullerene conjugate with a flexible linker at the secondary face of α-cyclodextrin has been prepared, which displays significant water solubility and, more importantly, acts as a new class of HCV entry inhibitor with IC(50) at 0.17 µM level.

Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase.

The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.

Stereochemical assignment and first synthesis of the core of miharamycin antibiotics.

The relative configuration at C-6' of nucleoside antibiotic miharamycin A has been elucidated by NMR spectroscopy and proved to be S. The total synthesis of miharamycin B has also been investigated, which has led to the unprecedented construction of its core. The bicyclic sugar moiety has been elaborated by means of a SmI(2)-based keto-alkyne coupling. Elongation of its C-6 position towards a bicyclic sugar amino acid and conversion into a suitable glycosyl donor enabled efficient N-glycosylation with 2-aminopurine to take place to afford the nucleosidic part of miharamycin B. Final peptide coupling with arginine afforded the skeleton of miharamycin B. Unfortunately, attempts to deprotect this scaffold failed to afford the complex nucleoside antibiotic.

Tandem Staudinger-azaWittig mediated ring expansion: rapid access to new isofagomine-tetrahydroxyazepane hybrids.

New seven-membered iminosugars with potent and selective inhibition towards glycosidases have been prepared as 1-N-iminosugar homologues via a tandem Staudinger-azaWittig mediated ring expansion.

Conformational behaviour of glycomimetics: NMR and molecular modelling studies of the C-glycoside analogue of the disaccharide methyl beta-D-galactopyranosyl-(1-->3)-beta-D-glucopyranoside.

The conformational behaviour of the C-glycoside beta-C-Gal-(1-->3)-beta-Glc-OMe (1) has been studied using a combination of molecular mechanics and NMR spectroscopy (proton-proton coupling constants and nuclear Overhauser effects). It is shown that the C-disaccharide populates two distinctive conformational families in solution, the normal syn-psi conformation, which is the predominating conformation of parent O-glycoside 2, and the anti-psi conformation, which has not been detected for the O-disaccharide.

Synthesis of a bicyclic analog of L-iduronic acid adopting the biologically relevant 2S0 conformation.

The synthesis of a bicyclic analogue of the naturally occurring alpha-L-iduronic acid locked in a biologically active (2)S0 skewboat conformation is disclosed. The desired (2)S0 conformation has been obtained by tethering the C-2 and C-5 carbon atoms of the sugar ring with a dimethyloxy bridge and confirmed by NMR and molecular modeling. The new mimic displays the exact hydroxyl pattern of alpha-L-iduronic acid, a major monosaccharide component of glycosaminoglycans and thus represents a closer mimic of the latter, compared to previously reported bicyclic analogs.

gem-Difluoro-carbasugars, the cases of mannopyranose and galactopyranose.

5a-Difluoro-5a-carbamannopyranose (gem-difluoro-carbamannopyranose) and 5a-difluoro-5a-carbagalactopyranose (gem-difluoro-carbagalactopyranose), close congeners of their respective natural sugars, in which the endocyclic oxygen atom has been replaced by a gem-difluoromethylene group, were synthesized from D-mannose and D-galactose, using a rearrangement strategy.

The conformation of the C-glycosyl analogue of N-acetyl-lactosamine in the free state and bound to a toxic plant agglutinin and human adhesion/growth-regulatory galectin-1.

The conformational behavior of the C-glycoside analogue of N-acetyl-lactosamine, beta-C-Gal-(1-->4)-beta-GlcNAc-OMe, 1, has been studied using a combination of molecular mechanics calculations and NMR spectroscopy (J and NOE data). It is shown that the C-disaccharide populates three distinctive conformational families in solution, the major one being the anti-psi conformation. Of note, this conformation is only marginally populated for the O-disaccharide. Due to its conspicuous role in the regulation of adhesion, growth and tissue invasion of tumors and its avid binding to N-acetyl-lactosamine human, galectin-1 was tested as a receptor. This endogenous lectin recognizes a local minimum of 1, the syn-PhiPsi conformer, and thus a conformational selection process is correlated with the molecular recognition event.

Diastereoselective synthesis of aminobacteriohopanetetrol, a biomarker for methanotrophic bacteria: confirmation of the absolute configuration.

A short and convenient strategy was developed for the first stereoselective chemical synthesis of aminobacteriohopanetetrol (= (1R,2R,3S,4S)-5-amino-1-[(22R)-hopan-30-yl]pentane-1,2,3,4-tetrol; 1), a typical biomarker for methanotrophic bacteria. Comparison of the NMR spectra of the synthetic and natural (peracetylated) product enabled us to unambiguously corroborate the absolute configuration of the functionalized pentyl side chain of 1.

Sequential ring closing/opening metathesis for the highly selective synthesis of a triply bifunctionalized alpha-cyclodextrin.

Metathesis versatility has been exploited to reveal the cyclic directionality of cyclodextrins and to selectively synthesise a unique cyclodextrin bearing three pairs of orthogonal protecting groups on its primary rim.

Alkylalanes and methyl furanosides: regioselective O-debenzylation or acetal cleavage.

Perbenzylated methyl pentofuranosides were submitted to the action of three alkylalanes and regioselective debenzylation at O-2 of the four pentoses was observed when choosing the right match between anomeric configuration and aluminium reagent. Diisobutylalane (DIBAL-H) allowed an easy access to reduced open-chain compounds, whereas trimethylalane (TMAL) stereoselectively produced methylated open chain derivatives.

Concise syntheses of bacteriohopanetetrol and its glucosamine derivative.

This study describes the syntheses of bacteriohopanetetrol and its glucosamine derivative through a key direct coupling of a ribose derivative to the hopane skeleton.

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.

Synthesis of new conformationally constrained pentasaccharides as molecular probes to investigate the biological activity of heparin.

We have synthesized three new antithrombin activating pentasaccharides displaying various sulfation patterns on the reducing end unit (H). We found that when L-iduronic acid stands in the 2S(0) conformation, the sulfate groups at positions 3 and 6 of the reducing end unit are practically devoid of influence on the activation of antithrombin. This suggests that the positive role of these sulfates is more related to their ability to shift the conformational equilibrium of L-iduronic acid towards 3S(0) than to directly interact with the protein.

Transferred cross-relaxation and cross-correlation in NMR: effects of intermediate exchange on the determination of the conformation of bound ligands.

Exchange transferred effects in solution-state NMR experiments allow one to determine the conformation of ligands that are weakly bound to macromolecules. Exchange-transferred nuclear Overhauser effect spectroscopy ('TR-NOESY') provides information about internuclear distances in a ligand in the bound state. Recently the possibility of obtaining dihedral angle information from a ligand in the bound state by exchange-transferred cross-correlation spectroscopy ('TR-CCSY') has been reported. In both cases the analysis of the signal amplitudes is usually based on the assumption that rapid exchange occurs between the free and bound forms of the ligand. In this paper we show that the fast exchange condition is not easily attained for observing exchange-transferred cross-correlation effects even in systems where exchange-transferred NOE can be observed. Extensive simulations based on analytical expressions for signal intensities corresponding to fast, intermediate, and slow chemical exchange have been carried out on a test system to determine the exchange regimes in which the fast exchange condition can be fulfilled for successfully implementing TR-NOESY and TR-CCSY.

Efficient synthesis of a nucleoside-diphospho-exo-glycal displaying time-dependent inactivation of UDP-galactopyranose mutase.

A short and efficient synthesis of UDP-exo-galactofuranosyl-glycal is presented. This molecule displayed an interesting time-dependent inactivation of UDP-galactopyranose mutase, an essential enzyme of the mycobacterial cell wall biosynthesis.

Composite hopanoid biosynthesis in Zymomonas mobilis: N-acetyl-D-glucosamine as precursor for the cyclopentane ring linked to bacteriohopanetetrol.

A selective labelling of the two major composite hopanoids of Z. mobilis with deuterated N-acetyl-D-glucosamine showed that this carbohydrate is a common precursor of the glucosamine or the cyclopentitol moieties respectively linked to bacteriohopanetetrol by a glycosidic or an ether bond.

Synthesis and characterization of a sulfated pentasaccharide containing the Lewisx motif.

We report the synthesis of a sulfated pentasaccharide containing the Lewis(x) motif used for an NMR study described in Carbohydr. Res. 2003, 338, this issue, see following communication: doi:10.1016/S0008-6215(03)00243-X, using the dibutylstannylene acetal methodology.

An efficient preparation of 6(I,IV) dihydroxy permethylated beta-cyclodextrin.

We report on a straightforward synthesis of 2(I-VII),3(I-VII),6(II,III,V-VII)-nonadeca-O-methylcyclomaltoheptaose, a methylated beta-cyclodextrin derivative bearing two 6(I,IV) hydroxyl groups, from its easily available benzylated counterpart.