Alain Tomas

Asymmetric synthesis of (R)- and (S)-piperidin-2-yl-phosphonic acid by diastereoselective addition of trialkyl phosphite onto potential iminium salt

Abstract Two strategies have been developed to synthesize both enantiomers of piperidin-2-yl-phosphonic acid. The first one uses the double condensation of glutaraldehyde with ( R )-(−)-phenylglycinol and triethylphosphite to give 2-ethylphosphonate-6-oxazolopiperidine 2 which furnished in few steps ( S )-(+)-piperidin-2yl-phosphonic acid ( 5 ) in 58% ee. The second strategy utilizes the 2-cyano-6-oxazolopiperidine synthon 1 which upon treatment with trimethyl phosphite gave 2-cyano-6-oxazaphosphorinane 7 which gave pure ( R )-(−)-piperidin-2-yl-phosphonic acid ( 10 ) in good overall yield.

The first example of a substrate spanning the calix[4]arene bilayer: the solid state complex of p-sulfonatocalix[4]arene with L-lysine

The complex of p-sulfonatocalix[4]arene with L-lysine shows a new type of intercalation behaviour with regard to the achiral hydrophobic bilayer assembly of the calixarenes, and represents the first structural example of a cationic organic substrate spanning such a bilayer.

A convenient asymmetric synthesis of thalidomide

Abstract Benzyloxyamine reacted with BOC-glutamic-α-phenyl ester in the presence of carbodiimide to give BOC-amino-N-benzyloxypiperidinedione. Deprotection of the amino group followed by phthaloylation led to N-benzyloxythalidomide which was then converted into thalidomide.

Expeditious Enantioselective Biomimetic Synthesis of the Nitraria Alkaloids (+)‐Isonitramine and (−)‐Sibirine

The reaction of glutaraldehyde with (R)- or (S)-phenylglycinol as the source of nitrogen and the chirality inductor directly provides the spiropiperidine skeleton [Eq. (a)] of the alkaloids sibirine and isonitramine. The title compounds are available in a total of three and four steps, respectively.

Diastereoselectivity and enantioselectivity in the addition of chiral imines of 2-methylcyclohexanone to crotonic and methacrylic acid esters

Abstract Additions of the chiral imine (reacting as its secondary enamine tautomer) obtained from ( S )-1-phenylethylamine and 2-methylcyclohexanone were performed with the phenyl ester of crotonic and methacrylic acid as well as with their methyl ester. In each example, the stereochemical relationship of the substituents in the major adduct was shown to be the one predicted in a previous theoretical calculation which established that the reactants complex has a chairlike geometry. In all the examples, the diastereoselectivity is superior to 98%. The enantioselectivity of the reactions is excellent as is usually the case with unsubstituted electrophilic olefins, the example with phenyl methacrylate being particularly remarkable ( de and ee >99%). In each case the favored diastereofacial selectivity is again in accordance with the rule elaborated previously. Relevant facts about the influence of the substituents upon the reactivity, the proportion of regioisomers, the stereoselectivity, and the enantioselectivity of the reaction are given.

Hydroxamic Acids as Potent Inhibitors of Fe(II) and Mn(II) E. Coli Methionine Aminopeptidase: Biological Activities and X-Ray Structures of Oxazole Hydroxamate-Ecmetap-Mn Complexes.

New series of acids and hydroxamic acids linked to five‐membered heterocycles including furan, oxazole, 1,2,4‐ or 1,3,4‐oxadiazole, and imidazole were synthesized and tested as inhibitors against the FeII, CoII, and MnII forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild‐type and acrAB E. coli strains. 2‐Aryloxazol‐4‐ylcarboxylic acids appeared as potent and selective inhibitors of the CoII MetAP form, with IC50 values in the micromolar range, whereas 5‐aryloxazol‐2‐ylcarboxylic acid regioisomers and 5‐aryl‐1,2,4‐oxadiazol‐3‐ylcarboxylic acids were shown to be inefficient against all forms of EcMetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the MnII and FeII forms, with IC50 values between 1 and 2 μM. One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against EcMetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X‐ray crystal structures of EcMetAP‐Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo‐MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild‐type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2‐substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine–arginine–β‐naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors.

Copper(II)–l-glutamine complexation study in solid state and in aqueous solution

Abstract Among copper transport alterations in humans, Menkes disease is due to a lethal genetic disorder. The current treatment is the administration of physiological Cu(II)– l -histidine complex. However, this therapy is only effective in some cases and when started early in life. In order to distribute copper in all the biological compartments for Menkes disease patients, the administration of other Cu(II) amino acids complexes has been considered. Several ternary Cu(II)–amino acids complexes were detected in human serum playing an important role in the copper pathway, in particular l -histidine–Cu(II)– l -glutamine. Before the biopharmaceutical studies of l -histidine–Cu(II)– l -glutamine complex, a physicochemical characterisation of binary Cu(II)– l -glutamine complex must be conducted. Indeed, the identification of Cu(II)– l -glutamine species has not been clearly determined at physiological pH in the past. In the present work, the stoichiometry, formation constants and distribution of the various Cu(II)– l -glutamine species have been determined by polarography and UV–Vis spectroscopy in a large pH range. [Cu(II)(Gln) 2 ] complex is the major component at physiological pH and its formation constant is equal to 10 12.5 l 2 mol −2 . For the first time, the structure of [Cu(II)(Gln) 2 ] has been determined in the solid state and in solution. Given the small size of the obtained crystals, it has been necessary to use an X-ray synchrotron source to collect the diffraction data. X-ray crystal structure showed a 4-2 distorted octahedral geometry. In the basal plane Cu–O and Cu–N distances ranged from 1.93 to 1.98 A. Two additional oxygen atoms at 2.70 and 2.86 A complete a severely distorted octahedron. EXAFS and EPR results have shown that the structure of [Cu(II)(Gln) 2 ] is preserved at physiological pH in aqueous solution.

Asymmetric synthesis. XXXIX.1 Synthesis of 3-substituted piperidin-2-ones from chiral non-racemic lactams

Abstract A series of 3-substituted piperidines in enantiomerically pure form has been synthesized from lactam 1 via the bromo derivative 2i. t-Butyl acetate and 5-methylpyridine derivatives 2g and 2h were obtained optically pure by direct alkylation of 1 with corresponding halides. Azido, amino or benzyloxy products were obtained by diastereoselective substitution of 2i.

ADDITION OF DIAZOMETHANE TO 3 AND 4-NITROPHTHALODINITRILES

The reaction of two nitrophthalodinitriles with diazomethane is described. If the nitro group is at position 3, only one of the two nitrile functions reacts giving three isomeric N-methyl 1,2,3-triazoles. In contrast, if the nitro group is at position 4, both nitriles react, each producing a 2-N-methyl 1,2,3-triazole. The reactivity was accounted for in terms of electronic densities, which were determined for several nitrile compounds. Interestingly, for 4-nitrophthalodinitrile, original methylation of the aromatic ring at position 5 was also observed. I n t r o d u c t i o n In a previous study (1) on the addition of diazomethane to different nitriles, we showed that the addition reaction requires the presence of an electroattractive group. We describe here the reactivity of the 3and 4-nitrophthalodinitriles 2 and 3, and compare it with the unreactivity of phthalodinitrile 1. The nitrophthalodinitriles were stirred during several days with a solution of diazomethane in diethyl ether. The reaction was followed by thin-layer chromatography. Resu l t s In the case of 3-nitrophthalodinitrile 2, three N-methyl 1,2,3-triazoles 4, 5 and fLderived from the cyano group at position 2 were isolated (cf figure 1).

Synthesis, structural analysis and anticonvulsant activity of a ternary Cu(II) mononuclear complex containing 1,10-phenanthroline and the leading antiepileptic drug valproic acid

The synthesis and characterization of the binary complex of copper(II) with the antiepileptic drug valproic acid sodium salt (Valp) and the related ternary complex with 1,10-phenanthroline (phen) are reported, as well as the anticonvulsant properties of the latter. The characterization was carried out by means of elemental analyses, infrared (IR), UV-visible (UV-vis) spectrophotometry and Electron Paramagnetic Resonance (EPR). The X-ray crystal structure of the mononuclear complex bis(2-propylpentanoate)(1,10-phenanthroline)copper(II) [Cu(Valp)(2)phen] is showed for the first time. It crystallized in C2/c space group with unit cell dimensions of a = 14.939(1) A, b = 19.280(1) A, c = 9.726(1) A, beta = 97.27(2) degrees , V = 2778.8(4) A(3) and Z = 8. The carboxylates bond in an asymmetric chelating mode and the copper atom adopts a highly distorted octahedral coordination, characterized by the sum of the angles of 365.9 degrees around Cu(II) and its nearest atoms in the CuN(2)O(2) + O(2) chromophore instead of the expected 360 degrees for a basal square planar geometry found in most Cu(II) complexes. Molecules assemble three by three through slipped pi-pi stacking of the aromatic phen with respectively 3.519 and 3.527 A distances, in a head-to-tail arrangement. Studies of the anticonvulsant properties of this bioligand chelate evidenced its lack of efficacy in preventing MES-induced seizures. Interestingly, complex 4 protected mice against the Minimal Clonic seizures at doses that do not cause Rotorod toxicity, with an ED(50) documenting very potent anticonvulsant activity in this model of seizure, a particularly useful pharmacological profile of activity for the treatment of Petit Mal seizures.