ABSTRACT
The potential of copper(I)-zeolite catalysis was evaluated in the three-component KA2-coupling mediated synthesis of α-tertiary propargylamines. Our archetypal copper(I)-doped zeolite CuI-USY proved to be efficient under ligand- and solvent-free conditions at 80 °C. Usable up to four times, this catalytic material enables the coupling of diverse ketones, alkynes, and amines with a broad functional group tolerance. A decarboxylative and a desilylative version, respectively, involving an alkynoic acid and trimethylsilylacetylene as alkyne surrogates, was also set up to bypass selectivity issues and/or to access α-tertiary propargylamines that are unattainable under standard KA2 conditions. Interestingly, the KA2-type coupling reactions were successfully linked to other CuI-catalyzed reactions, thus resulting in sequential one-pot processes under full CuI-USY catalysis.
ABSTRACT
The copper(I)-doped zeolite CuI-USY proved to be a versatile, efficient, and recyclable catalyst for various Ullmann-type coupling reactions. Easy to prepare and cheap, this catalytic material enables the arylation and heteroarylation of diverse O-, N-, S-, and C-nucleophiles under ligand-free conditions while exhibiting large functional group compatibility. The facility of this catalyst to promote C-O bond formation was further demonstrated with the total synthesis of 3-methylobovatol, a naturally occurring diaryl ether of biological relevance. From a mechanistic viewpoint, two competitive pathways depending on the nature of the nucleophile and consistent with the obtained results have been proposed.
ABSTRACT
Similarly to polymer-supported assisted synthesis (PSAS), organic synthesis could be envisaged being performed by using zeolites, native or metal-doped, as heterogeneous catalysts. To illustrate this unprecedented Zeolite-Based Organic Synthesis (ZeoBOS), the total synthesis of acortatarin A was achieved through a novel strategy and using five out of eleven synthetic steps catalyzed by H- or metal-doped zeolites as catalysts. Notably, the formation of an yne-pyrrole intermediate with a copper-doped zeolite and the spiroketalization of an alkyne diol with a silver-doped zeolite have been developed as key steps of the synthesis.
ABSTRACT
Silver and gold have become incredibly versatile and mild catalysts for numerous transformations, especially in heterocycle synthesis. For the most prominent of them, i.e. furans, silver and gold, with their unique reactivity and mildness, allow numerous possible routes to highly substituted and/or functionalized furans from a large variety of starting materials. Silver and gold catalysis provide thus the most flexible way to this important family of compounds. The present review describes these silver and gold-catalyzed routes, with some emphasis on mechanistic aspects, and proposes a comparison of both the silver and the gold-catalyzed syntheses of furans.
ABSTRACT
The Diels-Alder reaction between isoprene and methyl acrylate over several zeolites was thoroughly investigated. ZSM-5 zeolites provided the highest productivity in methyl 4-methylcyclohex-3-enecarboxylate isomer, achieving 0.219â mmol product per mmolâ H+ in 1â hour. In addition, this study highlights the influence of ZSM-5 zeolite's Brønsted acidity and crystal size on its performance in the Diels-Alder reaction. An optimal configuration between the two reactants within the medium-pore-sized ZSM-5 framework is obtained, thus suggesting the presence of a confinement effect.
ABSTRACT
We here report the synthesis and biological evaluation of new 3-[(2-indolyl)]-5-phenyl-3,5-pyridine, 3-[(2-indolyl)]-5-phenyl-2,4-pyridine and 3-[(2-indolyl)]-5-phenyl-2,6-pyrazine derivatives designed as potential CDK inhibitors. Indoles and phenyls were used to generate several substitutions of the pyridine and pyrazine rings. The synthesis included Stille or Suzuki type reactions, which were carried out on the 3,5-dibromopyridine, 2,4-dichloropyridine and 2,6-dichloro-1-4-pyrazine moieties. Cell effects of the V-shaped family were in the micromolar range. Kinase assays were conducted and showed that compound 11 inhibited CDK5 with an inhibitory concentration of 160 nM with a moderate selectivity over GSK3 compared to the reference C which exhibited a slightly lower activity on CDK5 (1.5 µM). Compound 11 was also found to be the most potent compound in the series and was identified as a new lead for DYRK1A inhibitor discovery (IC(50) = 60 nM). Docking studies were carried out in order to investigate the inhibition of DYRK1A.
Subject(s)
Chemistry Techniques, Synthetic , Indoles/chemical synthesis , Indoles/pharmacology , Protein Kinases/metabolism , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Catalysis , Cell Line, Tumor , Humans , Indoles/chemistry , Microwaves , Models, Molecular , Molecular Conformation , Palladium/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinases/chemistry , Pyrazines/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
We report the synthesis and biological evaluation of new oxophenylarcyriaflavins designed as potential anticancer agents. An efficient synthesis involving palladium-catalyzed Suzuki and Stille reactions is presented, without any indolic protective group. The central ring closure of the scaffold was performed through an electrophilic reaction on the position C-2 of the indole ring. The use of indole and 5-benzyloxyindole, along with substituted phenyl rings, generated three different scaffolds, which were successively exploited to modulate the structure. The cytotoxicity of the newly designed compounds on four cancer cell lines and activities against three kinases (CDK1, CDK5 and GSK3) were evaluated. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range, and induced important cell cycle perturbations, with a G2/M arrest. Some compounds revealed DNA binding properties and were found to inhibit topoisomerase-mediated DNA relaxation of supercoiled DNA, but these properties are not mandatory for a cytotoxic action. A novel lead compound () has been identified and warrants further investigations.