Réaction de kulinkovich sur des esters dérivés d'aminoacides naturels et non naturels

Cette thèse est consacrée à l'étude de la cyclopropanation intramoléculaire de Kulinkovich des esters préparés à partir des acides aminés naturels et non naturels. Les réactions ont été effectuées avec des réactifs de Grignard en présence des quantités catalytiques ou stoechiométriques de tétraisopropylate de titane. Le premier chapitre montre la portée de la réaction de Kulinkovich ce qui permet la transformation des esters en cyclopropanols. Les réactions ont été effectuées en modes inter et intramoléculaires et sont applicables aux dérive s carboxyliques cycliques tels que des lactones, des anhydrides, etc Dans le deuxième chapitre, nous étudions la régio et la stéréoselectivité de la réaction de cyclopropanation pour des composés possédant deux fonctions ester et une double liaison terminale. Le dérivé du glutamate a fourni les cyclopropanols prévus tandis que le dérivé de l aspartate a donné directement les pyrrolidinones imprévues. Dans le troisième chapitre, la cyclopropanation intramoléculaire a été appliquée sur d'autres alpha-aminoesters pour conduire aux cyclopropanols bicycliques attendus sous forme d un mélange de deux diastéréoisomères, fournissant ainsi un accès aux azabicyclo[3.1.0]hexanols énantiomériquement purs. Le quatrième chapitre étudie l ouverture des composés cyclopropaniques préparés précédemment. Les différents azabicyclo[3.1.0]hexanols ont été transformés en dihydropyridinones, pyrrolidinones, pipéridinones ou pyridinols, éventuels précurseurs de produits bioactifs. La préparation de la (S) - 2-phénylpipéridin-3-one (antagoniste de la substance P) a été réalisée.This thesis is devoted to the study of the intramolecular Kulinkovich cyclopropanation of esters prepared from natural and unnatural aminoacids. The reactions were performed with Grignard reagents in the presence of catalytic or stoechiometric amounts of titanium isopropoxide. The first chapter shows the scope of the Kulinkovich reaction which allows the transformation of esters into cyclopropanols. The reactions were carried out in both inter and intramolecular modes and are extended to cyclic carboxylic derivatives such as lactones, anhydrides, etc In the second chapter, we study the regio and stereoselectivity of the cyclopropanation reaction when the starting materials possess two ester functions and a terminal double bond. The glutamate derivative furnished expected fused cyclopropanols while the aspartate derivative only gave unexpected pyrrolidinones. In the third chapter, the intramolecular cyclopropanation applied on other alpha aminoesters afforded expected bicyclic cyclopropanols as a mixture of diastereomers, thus providing an access to enantiomerically pure azabicyclo[3.1.0]hexanols. The fourth chapter concerns the reactivity of these alcohols under ring opening conditions. The different azabicyclo[3.1.0]hexanols were transformed into dihydropyridinones, pyrrolidinones, piperidones or pyridinols , possible precursors of bioactive products. Application of this methodology allowed the preparation of the (S)-2-phenylpiperidin-3-one , a potent intermediate in the synthesis of pharmacologically significant products (substance P antagonists).ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Solvent-free microwave-assisted Meyers’ lactamization

International audienceMicrowave solvent-free conditions developed for Meyers’ lactamization, a typical bielectrophile-binucleophile reaction that produces quaternary centers in a stereoselective manner, give access to Meyers’ chiral lactams in good yield and high diastereoselectivity in short times

Highly Diastereoselective Synthesis of 1‑Carbamoyl-4-aminoindoloazepinone Derivatives via the Ugi Reaction

A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-<i>c</i>]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component reaction (Ugi-3CR) was developed to present trisubstituted indoloazepinones in good yields and excellent diastereomeric excess

Pharmacomodulation of the antimalarial plasmodione: synthesis of biaryl- and N-arylalkylamine analogues, antimalarial activities and physicochemical properties

With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -N(Me)2 or -N(Et)2 in different positions (ortho, meta and para) on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo in Plasmodium berghei-infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization

T3P-Promoted, Mild, One-Pot Syntheses of Constrained Polycyclic Lactam Dipeptide Analogues via Stereoselective Pictet–Spengler and Meyers Lactamization Reactions

A new convenient, mild, one-pot procedure is described for the diastereoselective synthesis of constrained 7,5- and 7,6-fused azabicycloalkanes. Using 2-formyl-L-tryptophan and 2-formyl-l-phenylalanine as bielectrophilic building blocks, T3P-mediated Pictet–Spengler and Meyers lactamization reactions were developed to present chiral and polycyclic aminoindolo- and aminobenzazepinone compounds in excellent yields. The conformationally constrained compounds can serve as templates for peptidomimetic research or polyheterocyclic privileged scaffolds

A Redox-Active Fluorescent pH Indicator for Detecting Plasmodium falciparum Strains with Reduced Responsiveness to Quinoline Antimalarial Drugs

Mutational changes in the Plasmodium falciparum chloroquine resistance transporter (<i>Pf</i>CRT) have been associated with differential responses to a wide spectrum of biologically active compounds including current and former quinoline and quinoline-like antimalarial drugs. <i>Pf</i>CRT confers altered drug responsiveness by acting as a transport system, expelling drugs from the parasite’s digestive vacuole where these drugs exert, at least part of, their antiplasmodial activity. To preserve the efficacy of these invaluable drugs, novel functional tools are required for epidemiological surveys of parasite strains carrying mutant <i>Pf</i>CRT variants and for drug development programs aimed at inhibiting or circumventing the action of <i>Pf</i>CRT. Here we report the synthesis and characterization of a pH-sensitive fluorescent chloroquine analogue consisting of 7-chloro-<i>N</i>-{2-[(propan-2-yl)­amino]­ethyl}­quinolin-4-amine functionalized with the fluorochrome 7-nitrobenzofurazan (NBD) (henceforth termed Fluo-CQ). In the parasite, Fluo-CQ accumulates in the digestive vacuole, giving rise to a strong fluorescence signal but only in parasites carrying the wild type <i>Pf</i>CRT. In parasites carrying the mutant <i>Pf</i>CRT, Fluo-CQ does not accumulate. The differential handling of the fluorescent probe, combined with live cell imaging, provides a diagnostic tool for quick detection of those P. falciparum strains that carry a <i>Pf</i>CRT variant associated with altered responsiveness to quinoline and quinoline-like antimalarial drugs. In contrast to the accumulation studies, chloroquine (CQ)-resistant parasites were observed cross-resistant to Fluo-CQ when the chemical probe was tested in various CQ-sensitive and -resistant parasite strains. NBD derivatives were found to act as redox cyclers of two essential targets, using a coupled assay based on methemoglobin and the NADPH-dependent glutathione reductase (GRs) from P. falciparum. This redox activity is proposed to contribute to the dual action of Fluo-CQ on redox equilibrium and methemoglobin reduction via <i>Pf</i>CRT-mediated drug efflux in the cytosol and then continuous redox-dependent shuttling between food vacuole and cytosol. Taking into account these physicochemical characteristics, a model was proposed to explain Fluo-CQ antimalarial effects involving the contribution of <i>Pf</i>CRT-mediated transport, methemoglobin reduction, hematin binding, and NBD reduction activity catalyzed by <i>Pf</i>GR in CQ-resistant versus CQ-sensitive parasites. Therefore, introduction of NBD fluorophore in drugs is not inert and should be taken into account in drug transport and imaging studies