- New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling
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In this work, a serie of cyclocoumarol derivatives was designed, synthesized, characterized and studied for their potentialities as selective inhibitors of COX-2. All target compounds have been screened for their anti-inflammatory activity by the assay of PGE2 production. Among them, compound 5d exhibited the most potent inhibitory activity with a PGE2 inhibition compared to NS-398 (79% and 88% respectively) and showed non-inhibitory activity towards the COX-1 enzyme. Docking studies revealed the capacity of this compound to occupy the selective COX-2 cavity establishing additional hydrogen bonds between the oxygen of the methoxy group and the His90 and Arg513 of the binding site of the enzyme.
- Rayar, Anita Marie,Lagarde, Nathalie,Martin, Frederique,Blanchard, Florent,Liagre, Bertrand,Ferroud, Clotilde,Zagury, Jean-Fran?ois,Montes, Matthieu,Sylla-Iyarreta Veitía, Maité
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supporting information
p. 577 - 587
(2018/02/10)
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- A bis-Lewis basic 2-aminoDMAP/prolinamide organocatalyst for application to the enantioselective synthesis of Warfarin and derivatives
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A new chiral sec-amine/amidine-base hybrid catalyst, 2-aminoDMAP/prolinamide, is reported, which is able to catalyze conjugate addition of 4-hydroxycoumarin and various benzylideneacetones, a reaction that directly gives anticoagulant Warfarin and its analogues, with good yields (70-87%) and enantioselectivities (58-72%).
- I?ik, Murat,Akkoca, H. Ufuk,Akhmedov, I. Mecido?lu,Tanyeli, Cihangir
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p. 384 - 388
(2016/05/19)
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- Helical-Peptide-Catalyzed Enantioselective Michael Addition Reactions and Their Mechanistic Insights
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Helical peptide foldamer catalyzed Michael addition reactions of nitroalkane or dialkyl malonate to α,β-unsaturated ketones are reported along with the mechanistic considerations of the enantio-induction. A wide variety of α,β-unsaturated ketones, including β-aryl, β-alkyl enones, and cyclic enones, were found to be catalyzed by the helical peptide to give Michael adducts with high enantioselectivities (up to 99%). On the basis of X-ray crystallographic analysis and depsipeptide study, the amide protons, N(2)-H and N(3)-H, at the N terminus in the α-helical peptide catalyst were crucial for activating Michael donors, while the N-terminal primary amine activated Michael acceptors through the formation of iminium ion intermediates.
- Ueda, Atsushi,Umeno, Tomohiro,Doi, Mitsunobu,Akagawa, Kengo,Kudo, Kazuaki,Tanaka, Masakazu
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p. 6343 - 6356
(2016/08/16)
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- Asymmetric synthesis of warfarin and its analogues on water
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The asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones on water without organic co-solvents is reported to be catalysed by organic primary amines. The application of enantiomerically pure (S,S)-diphenylethylenediamine affords a series of important pharmaceutically active compounds in good to excellent yields (73-98%) and with good enantioselectivities (up to 76% ee) via reactions accelerated by ultrasound. In particular, our developments led to an efficient protocol for the 'solids on water' formation of the anticoagulant warfarin in both enantiomeric forms. The presented scalable and environmentally friendly organocatalytic approach affords the target drug in enantiomerically pure form.
- Rogozińska-Szymczak, Maria,Mlynarski, Jacek
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p. 813 - 820
(2014/06/23)
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- Synthesis and characterization of novel polystyrene-supported TBD catalysts and their use in the Michael addition for the synthesis of Warfarin and its analogues
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In the search for efficient and polymeric supports for organic bases to be used in environmentally friendly media and conditions, novel polystyrene-bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) has been prepared and characterized. Their catalytic properties have been tested in the Michael additions of 4-hydroxycoumarin to α,β-unsaturated ketones as a representative useful process for the syntheses of 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H- chromen-2-one (Warfarin), 4-hydroxy-3-(1-(4-nitrophenyl)-3-oxobutyl)-2H- chromen-2-one (Acenocumarol), 4-hydroxy-3-(1-(4-chlorophenyl)-3-oxobutyl) -2H-chromen-2-one (Coumachlor), and 4-hydroxy-3-(1-(4-methoxyphenyl)-3- oxobutyl)-2H-chromen-2-one. Products were obtained in high to quantitative conversion yields. The novel catalytic systems showed promising catalytic properties, and they could be all easily recovered by filtration and have been reused for three representative consecutive runs without any significant lowering of their activity.
- Alonzi, Matteo,Bracciale, Maria Paola,Broggi, Alessandra,Lanari, Daniela,Marrocchi, Assunta,Santarelli, Maria Laura,Vaccaro, Luigi
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p. 260 - 267
(2014/04/03)
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- Highly enantioselective synthesis of Warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalysts
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An efficient enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones catalysed by primary amine-phosphinamide bifunctional catalysts has been developed. This reaction afforded Warfarin and its analogs in moderate to excellent yie
- Dong, Juan,Du, Da-Ming
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p. 8125 - 8131
(2012/11/06)
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- Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-Dicarbonyl Compounds and α,β-Unsaturated Ketones - A Highly Atom-Economic Catalytic One-Step Formation of Optically Active Warfarin Anticoagulant
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A broad range of Michael adducts 3 were obtained by the organocatalytic asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds 1 to α,β-unsaturated ketones 2. The reaction allows a one-step synthesis of the optically active anti-coagulant warfarin and several analogues 3 on a kilogram scale in up to 99% yield with 88% ee (>99.9% ee after a single recrystallization).
- Halland, Nis,Hansen, Tore,Jorgensen, Karl Anker
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p. 4955 - 4957
(2007/10/03)
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- An asymmetric approach to coumarin anticoagulants via hetero-Diels-Alder cycloaddition
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We have developed a general, two-step protocol for the synthesis of chiral non-racemic coumarin anticoagulants (e.g. warfarin, coumachlor and acenocoumarol). This approach features a one-pot three-component tandem Knoevenagel-hetero-Diels-Alder reaction between in situ generated 3-arylidene-2,4-chromanediones and iso-propenyl ether derived from (-)-menthol.
- Cravotto, Giancarlo,Nano, Gian Mario,Palmisano, Giovanni,Tagliapietra, Silvia
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p. 707 - 709
(2007/10/03)
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