Pascale Lemoine

Rh(II) carbene-promoted activation of the anomeric C-H bond of carbohydrates: a stereospecific entry toward α- and β-ketopyranosides.

In this communication we report a new strategy toward ketopyranosides based on a carbene-mediated activation of the anomeric C-H bond of carbohydrates. By forming a new carbon-carbon bond after a glycosylation step, this approach enables the preparation of both α- and β-ketopyranosides from advanced precursors.

Carbene‐Mediated Functionalization of the Anomeric CH Bond of Carbohydrates: Scope and Limitations

Herein we investigate the scope and limitations of a new synthetic approach towards α- and β-ketopyranosides relying on the functionalization of the anomeric C-H bond of carbohydrates by insertion of a metal carbene. A key bromoacetate grafted at the 2-position is the cornerstone of a stereoselective glycosylation/diazotransfer/quaternarization sequence that makes possible the construction of a quaternary center with complete control of the stereochemistry. This sequence shows a good tolerance toward protecting groups commonly used in carbohydrate chemistry and gives rise to quaternary disaccharides with good efficiency. In the case of a disaccharide with a more restricted conformation, this functionalization process can be hampered by the steric demand next to the targeted anomeric position. In addition, the formation of transient orthoesters during the glycosylation step may also reduce the overall efficiency of the synthetic sequence.

Evaluation of the antiprion activity of 6-aminophenanthridines and related heterocycles.

Series of 6-aminophenanthridines and related heterocyclic compounds such as benzonaphtyridines were prepared. Reduction of one of the three aromatic rings was also performed. The compounds were first tested for their antiprion activity in a previously described yeast-based colourimetric prion assay. The most potent derivatives were then assayed ex vivo against the mammalian prion PrP(Sc) in a cell-based assay. Several of the new compounds were found more potent than the parent lead 6-aminophenanthridine. The most promising compounds against yeast and mammalian prions were 8-azido-6-aminophenanthridine (3m), and 7,10-dihydrophenanthridin-6-amine (14). In the mammalian cell-based assay, the IC50 of these two compounds were around 5 μM and 1.8 μM, respectively.

Comprehensive determination of the solid state stability of bethanechol chloride active pharmaceutical ingredient using combined analytical tools

The use of an integrative analytical approach allowed us to establish the intrinsic solid state stability of bethanechol chloride (BC), an active pharmaceutical ingredient used in the treatment of urinary retention. First, the crystal structure of the monoclinic form has been described using single crystal X-ray diffraction studies. Second, thermal analyses revealed that the compound degrades upon melting, with an apparent melting temperature estimated to be 231 °C. No transition from the monoclinic to the orthorhombic form has been observed, suggesting that the monoclinic form is the stable one. Third, the two-step melting–decomposition process has been elucidated by liquid chromatography and thermogravimetry coupled to mass spectrometry. The first step corresponds to the sample liquefaction, which consists of the gradual dissolution of bethanechol chloride in its liquid degradant, i.e. betamethylcholine chloride. This step is in agreement with Bawn kinetics and the activation energy of the reaction has been estimated at 35.5 kcal mol−1. The second step occurs with accelerated degradation in the melt. Elucidation of secondary decomposition pathways evidenced autocatalytic properties conferred by the formation of both isocyanic acid and methyl chloride. Finally, dynamic water vapor sorption analysis showed a substantial hygroscopicity of the drug substance. A deliquescent point has been determined at 56% relative humidity at 25 °C.

Syntheses, characterization, spectroscopy, and quantum chemical calculation of two 2-(N-2′-aminopyridylo)pyridinium salts: observation of an acyclic water pentamer

Syntheses, characterization, and studies of two 2-(N-2′-aminopyridylo)pyridinium salts, [DPA1HA [Fe(CN)6]3− · 5H2O (1) and [DPA1HA]+Cl− · 2H2O (2; DPA1HA = monoprotonated 2,2′-dipyridylamine (DPA) having one pyridine nitrogen protonated) are described. X-ray single crystal structure of 1 has been determined. This complex crystallizes in monoclinic P21/n space group with a = 18.691(8) Å, b = 11.685(6) Å, c = 20.392(9) Å, β = 117.03(3)°, and Z = 4. Quantum chemical calculations on neutral, monoprotonated, and diprotonated 2,2′-dipyridylamine have been performed to understand the site of protonation in 1. The water molecules in 1 are interlinked to result in the generation of the rare example of an acyclic water pentamer. The water pentamer is hydrogen bonded with the ferricyanide anion to generate a two-dimensional water-ferricyanide sheet. The overall supramolecular structure of 1 is three-dimensional due to hydrogen bonding interactions of the organic cations with both the ferricyanide anion and water cluster. Compound 2 has been characterized by elemental analyses and IR spectrum. Quantum chemical calculations in the gaseous state and the isolation of 1 and 2 in the solid state indicate that monoprotonation of DPA at one pyridine nitrogen is more favorable. However, spectrophotometric titration of DPA with acid indicates that di-(or tri-) protonation takes place in solution.

Chiroptical study and absolute configuration of securinine oxidation products

Time-dependant density functional theory–electronic circular dichroism spectra prediction was carried out to study the absolute configuration of phyllanthidine-type derivatives 5 and 6, derived from securinine (1) and its enantiomer virosecurinine (2), respectively. This method demonstrated to be very reliable in this alkaloid series. Thus, 5 and 6 shared the same stereochemistry as their parent precursors, confirming the retentive nature of the oxidation sequence. In addition, this study highlighted the key role of the methylene bridge (BC ring) in the chiroptical activity of these compounds. These results fully clarified the stereochemical relationships between the phyllanthidine and the securinine subgroups.

Dibromidobis-(4-hydr-oxy-1,5-dimethyl-2-phenyl-3-pyrazolone)zinc(II).

In the title compound, [ZnBr2(C11H12N2O2)2], the Zn(II) ion is coordinated by two Br atoms and two O atoms from two 4-hydroxyantipyrine molecules via the carbonyl O atoms, which act as monodentate ligands, giving rise to a distorted tetrahedral geometry. The values of the bond angles at the Zn atom are in the range 99.4 (1) to 113.2 (1)°. The presence of O—H⋯O and O—H⋯Br intramolecular hydrogen bonds can explain the difference between the two Zn—O [1.961 (3)/2.015 (3) Å] and the two Zn—Br [2.350 (1)/2.378 (1) Å] bond lengths. The crystal structure is governed by C—H⋯O, C—H⋯Br and Zn—Br⋯Cg(π-ring) interactions.

Tetra-hydro-alstonine.

In the title compound, C21H24N2O3 [systematic name: methyl (20α)-16,17-didehydro-19α-methyl-18-oxayohimban-16-carboxylate], the molecule adopts an L-type conformation. The crystal packing is governed by one N—H⋯π and one C—H⋯π interactions. The crystal cohesion is ensured by intermolecular van der Waals contacts [shortest O⋯O contact = 3.199 (2) Å].

Bis(2,2′-bipyridyl-κ2N,N′)bis­(2-hydroxy­benzoato)-κO1;κ2O1,O1′-cadmium(II) methanol solvate

The title compound, [Cd(C7H5O3)2(C10H8N2)2]·CH3OH, contains one monomeric seven-coordinate cadmium complex and one methanol solvate molecule. The CdII atom is coordinated to two 2,2′-bipyridyl ligands via the N atoms and to two salicylate anions (Hsal−) via the carboxylate O atoms, which act as monodentate ligand for the one and bidentate ligand for the second. The CdII atom exhibits a {6 + 1} environment, approximately described as a distorted capped octahedron with the apical positions occupied by one of the two N atoms belonging to one bipyridyl ligand and one of the two carboxylate O atoms from the monodentate Hsal− ligand. Two intramolecular six-membered hydrogen-bonded rings are present, generated from interactions between the carboxylate and hydroxy groups of the salicylate ligands. There is one intermolecular hydrogen-bonding interaction involving the methanol solvent molecule and the carboxylate group from the monodentate Hsal− ligand. The crystal packing is governed by π–π stacking interactions [centroid–centroid distance = 3.783 (4) Å] which occur between bipyridyl ligands, by C—H⋯O and C—H⋯π interactions and by numerous van der Waals contacts.

Dichloridobis[(S)-2-hydroxy­propion­amide-κ2O,O′]manganese(II)

In the title compound, [MnCl2(C3H7NO2)2], the MnII ion is bound to two Cl atoms and to four O atoms from two lactamide molecules which act as bidentate ligands, giving rise to a highly distorted octahedral coordination geometry. The axial positions are occupied by one Cl atom and one O (hydroxy) atom. The values of the cis bond angles at the Mn atom are in the range 72.33 (5)–100.17 (6)°. Of the two possible coordination modes (N,O- or O,O-bidentate) in metal complexes with lactamide or its derivatives described in the literature, the title compound exhibits the O,O-bidentate mode. In the crystal structure, monomeric manganese(II) complexes are linked by several N—H⋯Cl, O—H⋯Cl and O—H⋯O hydrogen bonds, generating a three-dimensional network.