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Journal of Organic Chemistry | 2008

TiCl4/Et3N-promoted three-component condensation between aromatic heterocycles, aldehydes, and active methylene compounds.

Andrea Renzetti; Emmanuel Dardennes; Antonella Fontana; Paolo De Maria; Janos Sapi; Stéphane Gérard

A one-pot methodology for the synthesis of polyfunctionalized indole derivatives by a TiCl4/Et3N-promoted trimolecular condensation of aldehydes, indole heterocycles, and various activated carbonyl compounds is reported. Rationalization of these reactions and extension to other heterocyclic systems is also described.


Chemistry: A European Journal | 2009

Condensation of β‐Diester Titanium Enolates with Carbonyl Substrates: A Combined DFT and Experimental Investigation

Alessandro Marrone; Andrea Renzetti; Paolo De Maria; Stéphane Gérard; Janos Sapi; Antonella Fontana; Nazzareno Re

The condensation of dialkyl beta-diesters with various aldehydes promoted by TiCl4 has been studied by DFT approaches and experimental methods, including NMR, IR and UV/Vis spectroscopy. Various possible reaction pathways have been investigated and their energy profiles evaluated to find out a plausible mechanism of the reaction. Theoretical results and experimental evidence point to a three-step mechanism: 1) Ti-induced formation of the enolate ion; 2) aldol reaction between the enolate ion and the aldehyde, both coordinated to titanium; and 3) intramolecular elimination that leads to a titanyl complex. The presented mechanistic hypothesis allows one to better understand the pivotal role of titanium(IV) in the reaction.


Journal of Organic Chemistry | 2012

Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (−)-, and (±)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one via Reductive Domino Transformations of 3-β-Carbomethoxyethyl-Substituted Six-Membered Cyclic Nitronates

Alexey Yu. Sukhorukov; Yaroslav D. Boyko; Yulia V. Nelyubina; Stéphane Gérard; S. L. Ioffe; V. A. Tartakovsky

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKlines highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed.


Molecules | 2016

Radical Smiles Rearrangement: An Update.

Ingrid Allart-Simon; Stéphane Gérard; Janos Sapi

Over the decades the Smiles rearrangement and its variants have become essential synthetic tools in modern synthetic organic chemistry. In this mini-review we summarized some very recent results of the radical version of these rearrangements. The selected examples illustrate the synthetic power of this approach, especially if it is incorporated into a domino process, for the preparation of polyfunctionalized complex molecules.


Tetrahedron Letters | 2000

Synthesis of 3-trialkylsilyl pyrazoles from β-oxo acylsilanes

Stéphane Gérard; Richard Plantier-Royon; Jean-Marc Nuzillard; Charles Portella

Abstract The synthesis of β-oxo acylsilanes via cyclic sulfates is described and applied to carbohydrates. These compounds are used for the synthesis of new silylated pyrazoles linked to a carbohydrate moiety by the addition of hydrazines. The regiochemistry of the reaction was determined by NMR analyses ( 1 H/ 13 C and 1 H/ 15 N correlations).


RSC Advances | 2014

Yonemitsu-type condensations catalysed by proline and Eu(OTf)3

Andrea Renzetti; Emanuela Boffa; Marco Colazzo; Stéphane Gérard; Janos Sapi; Tak-Hang Chan; Hiroshi Nakazawa; Claudio Villani; Antonella Fontana

We report a Yonemitsu-type trimolecular condensation of aromatic heterocycles, aldehydes, and active methylene compounds to afford polyfunctionalised heterocycles. The reaction is catalysed by L-proline and Eu(OTf)3, takes place in methanol at room temperature, and in some cases is highly diastereoselective (d.e. >90%). The reaction offers two advantages with respect to the previously reported Ti(IV)-promoted condensation: (1) it adheres to some principles of green chemistry, and (2) it provides access to compounds that cannot be obtained by classical methodology.


Molecules | 2014

Photochemical Aryl Radical Cyclizations to Give (E)-3-Ylideneoxindoles

Michael Gurry; Ingrid Allart-Simon; Patrick McArdle; Stéphane Gérard; Janos Sapi; Fawaz Aldabbagh

(E)-3-Ylideneoxindoles are prepared in methanol in reasonable to good yields, as adducts of photochemical 5-exo-trig of aryl radicals, in contrast to previously reported analogous radical cyclizations initiated by tris(trimethylsilyl)silane and azo-initiators that gave reduced oxindole adducts.


European Journal of Medicinal Chemistry | 2018

Synthesis and biological evaluation of pyridazinone derivatives as potential anti-inflammatory agents

Chantal Barberot; Aurélie Moniot; Ingrid Allart-Simon; Laurette Malleret; Tatiana Yegorova; Marie Laronze-Cochard; Abderrazzaq Bentaher; Maurice Médebielle; Jean-Philippe Bouillon; Eric Henon; Janos Sapi; Frédéric Velard; Stéphane Gérard

Cyclic nucleotide phosphodiesterase type 4 (PDE4), that controls intracellular level of cyclic nucleotide cAMP, has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases. Here we describe the development of two families of pyridazinone derivatives as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4,5-dihydropyridazinone representatives possess promising activity, selectivity towards PDE4 isoenzymes and are able to reduce IL-8 production by human primary polymorphonuclear cells.


Chirality | 2015

Diastereomer Interconversion via Enolization: A Case Study

Andrea Renzetti; Antonello Di Crescenzo; Feilin Nie; Andrew D. Bond; Stéphane Gérard; Janos Sapi; Antonella Fontana; Claudio Villani

The three-component reaction of indole, isobutyraldehyde, and methyl acetoacetate affords methyl 2-(acetyl)-3-(1H-indol-3-yl)-4-methylpentanoate as a single diastereomer. To investigate the origin of the observed diastereoselectivity, the thermodynamics and kinetics of interconversion of diastereomers 1 and 2 in solution were studied by a combination of (1)H nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography (HPLC), mass spectrometry, and deuteration experiments. The results indicate that interconversion is both acid- and base-catalyzed, and that the alpha carbon is the only stereolabile center in the molecule. The evidence points to an enolization mechanism for the interconversion process. The selective precipitation of 1 in the presence of the equilibrium 1⇆2 eventually results in the exclusive formation of 1 (crystallization-induced asymmetric transformation).


ChemMedChem | 2013

Cyclopropyl-tryptamine Analogues: Synthesis and Biological Evaluation as 5-HT6 Receptor Ligands

Claude Szalata; Jan Szymoniak; Frédéric Fabis; Sabrina Butt-Gueulle; Sylvain Rault; Philippe Bertus; Stéphane Gérard; Janos Sapi

Conformational restrictions: Based on the pharmacophore model for 5-HT(6) receptor ligands (shown), tryptamine analogues bearing a cyclopropyl ring on the α-position of the tryptamine side chain were synthesized and evaluated against 5-HT receptors. N,N-Dimethyl-1-arylsulfonyltryptamine derivatives exhibited promising selectivity for 5-HT(6) over 5-HT(1a) and 5-HT(4) receptors and interesting activity against 5-HT(6) (K(i) =∼0.15 μM; IC(50) =∼0.20 μM).

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