Highly Enantioselective Catalytic Asymmetric Synthesis of a (R)-Sibutramin Precursor

The first highly enantioselective, catalytic asymmetric synthesis of di-des-methylsibutramine 3 is described. Dienamide 10, prepared by acetic acid anhydride quenching of the condensation product of nitrile 4 with a methallyl magnesium chloride, proved to be an excellent substrate for ruthenium-catalyzed asymmetric hydrogenation with atropisomeric diphosphine ligands. Hydrogenation with a ruthenium/(R)- MeOBiPheP catalyst at S/C = 500, gave the chiral amide (R)-9 in 98.5% ee in almost quantitative yield. After acidic amide hydrolysis the desired amine (R)-3 was obtained without erosion of enantioselectivity. It is anticipated that the overall process will be amenable to large-scale production

Stabilité des suspensions reconstituées de la combinaison thérapeutique antipaludique à base d’artéméther-luméfantrine avec différents types d’eaux

Les combinaisons thérapeutiques antipaludiques à base d’artéméther-luméfantrine sous forme de poudres lyophilisées, sont des préparations multidoses destinées aux enfants pour le traitement du paludisme. Dans le but d’obtenir une bonne observance thérapeutique chez les enfants, ces poudres lyophilisées à reconstituer ont été mises sur le marché. La stabilité des suspensions obtenues après reconstitution avec différents types d’eau accessible à toutes les couches sociales dans les zones endémiques de paludisme a été évaluée. Les caractères organoleptiques et le pH des suspensions ont été recherchés. Les teneurs en artéméther et en luméfantrine ont été recherchés respectivement par chromatographie liquide et par spectrométrie UV. Les produits de dégradation de l’artéméther et de la luméfantrine ont aussi été recherchés par chromatographie sur couche mince de gel de silice. Des études microbiologiques ont été réalisées pour la recherche des germes anaérobies viables totaux et la recherche d’entérobactéries. L’étude a révélé que les caractères organoleptiques et le pH de chaque suspension ont été acceptables. Les principes actifs n’ont pas été dégradés après reconstitutions des poudres lyophilisées dans tous les échantillons durant la période d’étude. Les concentrations obtenues en artéméther et en luméfantrine de tous les échantillons analysés, étaient conformes aux normes. Les échantillons n’ont pas été contaminés par des bactéries, des levures et des moisissures au cours de cette période d’étude.© 2016 International Formulae Group. All rights reserved.Mots clés: Stabilité, artéméther, luméfantrine, suspension, spectrophotométrie, chromatographieEnglish Title: Stability of reconstituted suspension of artemether-luméfantrine lyophilized powders against malaria with different types of waterEnglish AbstractThe artemether-lumefantrine antimalarial therapeutic combinations in the form of lyophilized powders are multidoses preparations intended for the treatment of children against malaria. For obtaining a good therapeutic observance on the children, the lyophilized powders to be reconstituted were launched on the  market. The stability of the suspensions obtained after reconstitution with various types of water accessible to all sectors of society in the endemic zone of malaria was evaluated. The organoleptic characteristics and pH of the suspensions were evaluated. The concentrations of artemether and lumefantrine were respectively sought by liquid chromatography and UV spectrometry. Also the degradation products of artemether and lumefantrine were searched by thin layer chromatography. Microbiological studies were realized for the search of total viable anaerobic germs and anterobacteria. The study revealed that the organoleptic characteristics and pH of every suspension were acceptable. Active substances were not degraded after reconstitutions of lyophilized powders in all the samples during the period of study. The artemether and lumefantrine concentrations obtained were in agreement with the standards. Samples were not contaminated by bacteria, yeasts and molds during this period of study.© 2016 International Formulae Group. All rights reserved.Keywords: Stability, artemether, lumefantrine, , suspension, spectrophotometry, chromatograph

Comprehensive genetic dissection of wood properties in a widely-grown tropical tree: Eucalyptus

Background: Eucalyptus is an important genus in industrial plantations throughout the world and is grown for use as timber, pulp, paper and charcoal. Several breeding programmes have been launched worldwide to concomitantly improve growth performance and wood properties (WPs). In this study, an interspecific cross between Eucalyptus urophylla and E. grandis was used to identify major genomic regions (Quantitative Trait Loci, QTL) controlling the variability of WPs. Results: Linkage maps were generated for both parent species. A total of 117 QTLs were detected for a series of wood and end-use related traits, including chemical, technological, physical, mechanical and anatomical properties. The QTLs were mainly clustered into five linkage groups. In terms of distribution of QTL effects, our result agrees with the typical L-shape reported in most QTL studies, i.e. most WP QTLs had limited effects and only a few (13) had major effects (phenotypic variance explained > 15%). The co-locations of QTLs for different WPs as well as QTLs and candidate genes are discussed in terms of phenotypic correlations between traits, and of the function of the candidate genes. The major wood property QTL harbours a gene encoding a Cinnamoyl CoA reductase (CCR), a structural enzyme of the monolignol-specific biosynthesis pathway. Conclusions: Given the number of traits analysed, this study provides a comprehensive understanding of the genetic architecture of wood properties in this Eucalyptus full-sib pedigree. At the dawn of Eucalyptus genome sequence, it will provide a framework to identify the nature of genes underlying these important quantitative traits. (Résumé d'auteur

Chemical optimization of artificial metalloenzymes based on the biotin-avidin technology : (S)-selective and solvent-tolerant hydrogenation catalysts via the introduction of chiral amino acid spacers

The selective artificial metalloenzymes were designed by incorporation of amino acid spacer (phenylalanine or proline) between biotin anchor and the rhodium-diphosphate moiety. The two pairs of epimeric ligands, biotin-phenylalanine and biotin-proline, were prepd. in three steps from com. available N-Boc-protected amino acids (Boc = tert-butoxycarbonyl). Incorporation of biotinylated [rhodium(diphosphine)]+ complexes with enantiopure amino acid spacers in streptavidin affords solvent-tolerant and selective artificial metalloenzymes. Catalytic hydrogenation of N-protected dehydroamino acids using prepd. artificial metalloenzymes gives up to 91% ee (S). [on SciFinder(R)

Enantioselective copper-catalyzed SN2' substitution with Grignard reagents

Cinnamyl chlorides undergo selective SN2´ allylic substitution by Grignard reagents using catalytic amount (1 mol%) of CuCN and 1-2 mol% trivalent phosphorus ligands, in dichloromethane. With chiral phosphorus ligands derived from TADDOL ee's up to 73% could be obtained

Second-generation artificial hydrogenases based on the biotin–avidin technology: Improving selectivity and organic solvent tolerance by introduction of an (R)-proline spacer

We report on our efforts to create efficient artificial metalloenzymes for the enantioselective hydrogenation of N-protected dehydroamino acids using streptavidin as host protein. Introduction of an (R)-proline spacer between the biotin anchor and the diphosphine moiety affords a versatile ligand Biot-(R)-Pro-1 which displays good (S)-selectivities in the presence of streptavidin (91% ee). The resulting artificial metalloenzyme [Rh(Biot-(R)-Pro-1)(COD)]+ ⊂ WT-Sav displays increased stability against organic solvents

The Copper-Catalyzed Asymmetric Allylic Substitution

This mini-review discusses the rapidly growing field of asymmetric copper-catalyzed chemistry. Although the allylic substitution has been less studied than the conjugate addition, recent breakthroughs have made this methodology a very valuable synthetic tool. Thus, a primary allylic halide or phosphate reacts with Grignard or diorganozinc reagents to afford the SN' product (or ?-product) in high regio- and enantioselectivities. Besides the results of the authors, we present also other, different approaches to this reaction, with emphasis on the organo-metallic and the type of chiral ligand used