Christian Cavé

Ortho-metalated aromatic tertiary amides: New synthetic applications

Abstract Ortho-lithio-cuprate species derived from aromatic tertiary amides exhibited a significantly larger field of application than the lithio precursors.

A NOVEL ASYMMETRIC SYNTHESIS OF 2,5 -DIALKYLPYRROLIDINES

Abstract ZnCl 2 -promoted cyclization of enamino ester 8 furnished a 1.5:1 mixture of pyrrolidines 9 and 10 . NaBH 4 -reduction of this mixture gave cis and trans -2,5-dialkylpyrrolidines 12 and 13 in the ratio 2:1. The latter derivative was obtained in its 2 S , 5 S enantiomerically pure form.

Asymmetric bridging annulation reaction involving the intramolecular conjugate addition of chiral imines to enoates: Access to a polycyclic system related to the taxane core

Abstract (R)-1-phenylethylamine-induced cyclization of ketoenoate 24 led to a 2:1 mixture of “all-cis” polycyclic adducts 25 and 26 , structurally related to the taxane series.

In silico analysis of a therapeutic target in Leishmania infantum: the guanosine-diphospho-D-mannose pyrophosphorylase.

Leishmaniases are tropical and sub-tropical diseases for which classical drugs (i.e. antimonials) exhibit toxicity and drug resistance. Such a situation requires to find new chemical series with antileishmanial activity. This work consists in analyzing the structure of a validated target in Leishmania: the GDP-mannose pyrophosphorylase (GDP-MP), an enzyme involved in glycosylation and essential for amastigote survival. By comparing both human and L. infantum GDP-MP 3D homology models, we identified (i) a common motif of amino acids that binds to the mannose moiety of the substrate and, interestingly, (ii) a motif that is specific to the catalytic site of the parasite enzyme. This motif could then be used to design compounds that specifically inhibit the leishmanial GDP-MP, without any effect on the human homolog.

Synthetic approaches to Cinchona alkaloids: the C-8/C-9 disconnection strategy

When conducted in DMSO, the Hunigs base-promoted condensation of 3-quinuclidinone with quinoline-4-carboxaldehyde gave an equimolar mixture of epimeric aldols 8 with an excellent yield.

Regio- and stereoselective aspects in the oxidation of (R) and (S) 4a-methyl-(4,4a,5,6,7,8)-hexahydro-2(3H)naphthalenones in living rats

Abstract The bioconversion of (R)-1 and (S)-1 in living rats was studied. The urinary hydroxylated metabolites obtained were identified by using GC-MS and 1H NMR spectroscopy. Oxidation of octalenones (R)-1 and (S)-1 in living rats took place at three sites: positions 6,7 and 8. However, for a given site, this oxidation was highly stereoselective: only one hydroxylated diastereomer was always obtained. With the exception of metabolite 6, the oxidation always occurred in the syn position relatively to the angular methyl group. These results are significantly different from those observed, using “alternative methods”, such as microsomal and microbial biodegradations. These data show that from a stereochemical and a regiochemical viewpoint, “alternative methods” need to be validated by controls in living animals.

Phenobarbital metabolism by hepatocytes isolated from rat.

In order to test the validity of the use of hepatocytes as an alternative to studies of metabolism in live animals, phenobarbital (PB) was applied at 37 degrees C to isolated rat hepatocytes, which had been previously induced by PB. The metabolites were extracted by ethyl acetate, at various pH, and identified and evaluated by GC-MS. PB was not metabolized to p-hydroxyphenobarbital as is usually the case in living animals, but it was transformed into sulphoconjugated 2-phenyl-gamma-butyrolactone. This pathway, beta-hydroxylation of the ethyl side chain followed by lactonization, previously described as a secondary metabolic pathway occurring during intoxications, was here the only observed biodegradation. These results show that it is not possible to use hepatocytes as an alternative to live animals.

Mechanism of the formation in vivo of α-phenyl-γ-lactones in the glutethimide series

Abstract The isolation of γ-lactones from the urines of humans or animals treated with glutethimide or aminoglutethimide required an explanation. The question was studied on the glutethimide model. Potential metabolites such as β-hydroxymetabolite, γ-lactone amide, and γ-lactone acid were synthesized. Glutethimide was first administered to rats at high and normal doses. The corresponding γ-lactone amide, resulting from alcoholysis of β-hydroxyglutethimide, was also administered to rats. The amounts of the various γ-lactone derivatives isolated from the urine were discussed and it was concluded that the α-phenyl-γ-lactone was formed in vivo via β-hydroxylation of glutethimide followed by intramolecular alcoholysis. The lactone amide was then oxidized and dealkylated via an intramolecular mechanism leading to the corresponding α-phenyl-γ-lactone.

Asymmetric reduction of β-ketoesters and chiral β-iminoesters: impact of a α-quaternary stereocenter.

Diastereomeric reduction of nonactivated, hindered β-keto and chiral β-iminoesters are described. The influence of a α-stereocontrolled center on the efficiency and stereoselectivity of the reduction was studied. Reaction conditions were optimized to synthesize β-hydroxy- and β-aminoesters in good yields. In the case of chiral β-iminoesters, influence of matched/mismatched diastereomeric pairs has been assessed.