RESUMEN
BACKGROUND: 2-Aminochromene derivatives display important pharmacological properties, including mainly antibiotic and anticancer activities. OBJECTIVE: The study aims to synthesize new chromene derivatives via a new approach using Grignard reagents, for the evaluation of their antibiotic and antifungal properties. METHOD: A series of novel 3-cyano-4-aminochromene derivatives bearing alkyl substituents at the 4-position was prepared for biological evaluation. RESULTS: These compounds were obtained by the addition of various Grignard reagents into Nethoxycarbonyl- 3-cyanoiminocoumarines in moderate to good yields (72-96%). The reaction is completely regioselective. The new chromene derivatives were screened for their in vitro antimicrobial activities against a panel of six bacterial and three fungal strains using agar dilution method. CONCLUSION: The antibacterial activity of the chromene derivatives was more pronounced on Gram-positive bacteria than on Gram-negative bacteria with a significant activity observed against Staphylococcus aureus. An interesting antifungal activity against Fusarium sp. and Fusarium oxysporum was also noticed.
Asunto(s)
Carbamatos/química , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Fusarium/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Análisis Espectral/métodos , Relación Estructura-ActividadRESUMEN
The successive addition of two different Grignard reagents to acyl cyanohydrins was performed with success by taking advantage of the low reactivity of alkynyl Grignard reagents. The experimental conditions were adjusted so that they were not reactive during the first addition step, but reactive only in the second one. The synthetic utility of the prepared compounds was validated by the preparation of chiral quaternary α-amino acids.
RESUMEN
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) =â¼0.15â µM; IC(50) =â¼0.20â µM).
Asunto(s)
Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Triptaminas/química , Triptaminas/farmacología , Animales , Ciclopropanos/síntesis química , Ciclopropanos/química , Ciclopropanos/farmacología , Humanos , Antagonistas de la Serotonina/síntesis química , Relación Estructura-Actividad , Triptaminas/síntesis químicaRESUMEN
The double addition of Grignard (alkyl, aryl, alkenyl, alkynyl) reagents to acyl cyanohydrins was performed under unusually smooth conditions with a concomitant O-N acyl transfer, providing a very simple and general access to α,α,α-trisubstituted amides.
RESUMEN
An organotin reagent supported on an ionic liquid was used as a highly effective catalyst (down to 0.1 mol%) for the direct reductive amination of aldehydes and ketones using PhSiH3; this solvent-free method facilitates purification of the products, thus minimizing the contamination by tin.
Asunto(s)
Aldehídos/química , Cetonas/química , Estaño/química , Aminación , Catálisis , Líquidos Iónicos/química , Oxidación-ReducciónRESUMEN
Nitrogen-in-the-ring analogues of l-fucose and l-rhamnose were prepared, which feature a spirocyclopropyl moiety in place of the methyl group of the natural sugar. The synthetic route involved a titanium-mediated aminocyclopropanation of a glycononitrile as the key step. Four new spirocyclopropyl iminosugar analogues were generated, which displayed some activity towards l-fucosidase and l-rhamnosidase.
Asunto(s)
Ciclopropanos/síntesis química , Inhibidores Enzimáticos/síntesis química , Fucosa/análogos & derivados , Ramnosa/análogos & derivados , Compuestos de Espiro/síntesis química , Ciclopropanos/química , Ciclopropanos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Fucosa/síntesis química , Fucosa/química , Fucosa/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Glicósido Hidrolasas/metabolismo , Cinética , Espectroscopía de Resonancia Magnética , Rotación Óptica , Ramnosa/síntesis química , Ramnosa/química , Ramnosa/farmacología , Espectrometría de Masa por Ionización de Electrospray , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , alfa-L-Fucosidasa/antagonistas & inhibidores , alfa-L-Fucosidasa/metabolismoRESUMEN
The copper-catalyzed carbomagnesiation (or hydrometalation) reaction of chiral cyclopropenylcarbinol derivatives, obtained by means of a kinetic resolution of secondary allylic alcohols, leads to an easy and straightforward preparation of enantiomerically pure alkylidenecyclopropane derivatives. The reaction mechanism is composed of a syn-carbometalation followed by a syn-elimination reaction. To gain further insight into the reaction mechanism of the carbometalation, the diastereoselective formation of cyclopropylcarbinol was also achieved and was found to be very sensitive to the nature of the organometallic species used for the addition reaction. Cyclopropylcarbinol could also be prepared through a diastereoselective reduction of cyclopropenylcarbinol derivatives. Finally, functionalization of enantiomerically enriched cyclopropenylcarbinols into the corresponding acetate or phosphinite derivatives leads, under mild conditions, to various enantiomerically pure heterosubstituted alkylidenecyclopropanes.
RESUMEN
1,3-Dicarbonyl derivatives, such as 1,3-diketones, beta-ketoaldehydes, beta-ketoesters, beta-ketoamides, beta-ketophosphonates and beta-ketosulfones were efficiently converted to the corresponding Z vinyl triflates with high stereoselectivity. Precoordination with lithium triflate in dichloromethane and enolization with mild bases such as trialkylamines or DBU followed by trapping with triflic anhydride probably accounted for such high selectivity, achieved even at 0 degrees C. This method offers the first direct route to vinyl triflates from beta-ketoamides, beta-ketophosphonates and beta-ketosulfones.
RESUMEN
The synthesis of carbohydrate-based glycogen phosphorylase inhibitors is attractive for potential applications in the treatment of type 2 diabetes. A titanium-mediated synthesis led to a benzoylated C-glucosylated cyclopropylamine intermediate, which underwent a benzoyl migration to afford the corresponding 2-hydroxy-C-glycoside. X-ray crystallographic studies revealed a unit cell composed of four molecules as pairs of dimers connected through two hydrogen bonds. The deprotection of the benzoate esters under Zemplén conditions afforded a glycogen phosphorylase inhibitor candidate displaying weak inhibition toward glycogen phosphorylase (16% at 2.5mM).
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Glucógeno Fosforilasa de Forma Muscular/antagonistas & inhibidores , Glucógeno/metabolismo , Animales , Cristalografía por Rayos X , Dimerización , Evaluación Preclínica de Medicamentos , Glucósidos/síntesis química , Glucósidos/farmacología , Glucógeno Fosforilasa de Forma Hepática/antagonistas & inhibidores , Glucógeno Fosforilasa de Forma Hepática/metabolismo , Glucógeno Fosforilasa de Forma Muscular/metabolismo , Glicosilación , ConejosRESUMEN
It has been shown that diene-titanium complexes exhibit substrate-dependent 1,2- or 1,4-dicarbanion reactivity. On this basis, 3-cyclopentenylamines and spiro-vinylcyclopropane lactams were easily prepared by using homoallylic Grignard reagents, Ti(O-i-Pr)4, and nitriles or cyanoesters, respectively.
RESUMEN
We report a straightforward synthesis of 1-azaspirocyclopropane lactams from imides. Following the described procedure, polycyclic nitrogen heterocycles containing a cyclopropane unit could be obtained from unsaturated imides. [reaction: see text].
RESUMEN
Polyhydroxy 4-azaspiro[2.4]heptane derivatives (spirocyclopropyl iminosugars) were prepared in four to six steps from readily available protected aldoses. The key step of the reaction sequence involves a titanium-mediated aminocyclopropanation of glycononitriles with subsequent cyclization. Five new polyhydroxypyrrolidines so-obtained have been evaluated for their ability to inhibit 16 glycosidases. One of them exhibits selective inhibition of alpha-L-fucosidase from bovine kidney (Ki=1.6 microM, competitive).
Asunto(s)
Inhibidores Enzimáticos/farmacología , Pirrolidinas/farmacología , Compuestos de Espiro/química , alfa-L-Fucosidasa/antagonistas & inhibidores , Animales , Bovinos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Riñón/enzimología , Conformación Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The Ti-mediated reaction of Grignard reagents with nitriles was investigated with sub-stoichiometric amounts of titanium isopropoxide. Cyanoesters were converted to spirocyclopropanelactams in good yields using as low as 0.05 eq of Ti(O(i)Pr)4. Under similar conditions, cyanocarbonates led to spirocyclopropane oxazolidinones and/or aminocyclopropylcarbinols. A very short synthesis of the naturally occurring aminocyclopropanecarboxylic acid illustrates the usefulness of this methodology.
RESUMEN
In the presence of Ti(OiPr)4 and iPrMgCl, dienes couple with nitriles to afford the title products in good yields.
RESUMEN
The reaction of various aromatic nitriles with 1.1 equiv of Ti(Oi-Pr)(4) and 2.2 equiv of EtMgBr followed by addition of a Lewis acid gave 1-aryl cyclopropylamines in 43-76% yields. Under similar conditions, conjugated alkenenitriles afford 1-alkenylcyclopropylamines (42-65%).
RESUMEN
Alpha-alkoxy, amino-, and thio nitriles undergo a Ti(II)-mediated coupling with Grignard reagents to afford heterofunctionalized cyclopropylamines. A chelation effect appears to be generally responsible for the spontaneous contraction of the intermediate azatitanacycle leading to cyclopropane. By using the described reaction, 1-aminocyclopropanecarboxylic acids were prepared in four steps, in good overall yields, from the readily available benzyloxyacetonitrile.