- First aromatic amine organocatalysed activation of α,β-unsaturated ketones
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This work provides an unprecedented example of a chiral aromatic amine used to activate α,β-unsaturated ketones in asymmetric aminocatalysis. Chiral aromatic diamine VII has been efficiently employed, as a proof of concept, in the Michael addition reaction between benzylideneacetones (1a-f) and coumarins (2a-d). The reaction gives rise to warfarin derivatives 3 with promising results using this family of catalysts for the first time. The additional studies performed supported the bifunctional mode of activation of the chiral catalyst VII and the covalent nature of the interactions between the catalyst VII and benzylideneacetones 1.
- Sonsona, Isaac G.,Marqués-López, Eugenia,Gimeno, M. Concepción,Herrera, Raquel P.
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p. 12233 - 12240
(2019/08/12)
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- Green asymmetric synthesis of Warfarin and Coumachlor in pure water catalyzed by quinoline-derived 1,2-diamines
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Simple enantiomerically pure C2-symmetric quinoline (isoquinoline)-derived 1,2-diamines were synthesized from the corresponding aldehydes via stereospecific diaza-Cope rearrangement with 2,2′-(1,2-diaminoethane-1,2-diyl)diphenol (HPEN). Efficient green synthesis of both enantiomers of the anticoagulant Warfarin and rodenticide Coumachlor was achieved in an aqueous medium via the asymmetric iminium-type Michael reaction in the presence of the catalysts 8e and (ent)-8e in combination with (R)- or (S)-mandelic acid, respectively. This procedure provides high enantioselectivity (up to 91% ee), which has never been attained for these bioactive compounds with the known catalysts under aqueous conditions. Nearly optically pure Warfarin (~99% ee) was prepared via a green isolation procedure, which included acidic precipitation of the crude product from a basic aqueous solution followed by single recrystallization. Furthermore, unlike the known primary amine-derived organocatalysts, the developed aqueous catalytic system does not produce parasitic byproducts and can be recovered and reused in the asymmetric reaction.
- Kucherenko, Alexander S.,Kostenko, Alexey A.,Zhdankina, Galina M.,Kuznetsova, Olga Yu.,Zlotin, Sergei G.
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supporting information
p. 754 - 759
(2018/02/14)
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- Asymmetric synthesis of warfarin and its analogs catalyzed by C 2-symmetric squaramide-based primary diamines
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Novel C2-symmetric N,N′-bis(2-amino-1,2-diphenylethyl)squaramides with 1,2-di(pyridin-2-yl)ethane and 1,2-diphenylethane spacer groups were designed and applied as organocatalysts in asymmetric additions of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α,β-unsaturated ketones. Both enantiomers of the anticoagulant warfarin and its analogs were prepared in up to 96% yield and with 96% ee. Recyclability of the developed catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of potential chiral medications via acylation reactions were demonstrated.
- Kochetkov, Sergei V.,Kucherenko, Alexander S.,Zlotin, Sergei G.
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supporting information
p. 6423 - 6429
(2018/09/25)
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- Chiral primary amino amide alcohol organocatalyst for the asymmetric Michael addition of 4-hydroxycoumarin with α,β-unsaturated ketones
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Chiral primary amino amide organocatalysts were designed and synthesized as new organocatalysts for the enantioselective Michael addition of 4-hydroxycoumarin with α,β-unsaturated ketones to produce chiral warfarin (up to 56% ee with up to 92% yield).
- Kumagai, Jun,Kohari, Yoshihito,Seki, Chigusa,Uwai, Koji,Okuyama, Yuko,Kwon, Eunsang,Nakano, Hiroto
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p. 1124 - 1134
(2015/04/27)
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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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- Atom-economic synthesis of optically active warfarin anticoagulant over a chiral mof organocatalyst
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A novel chiral metal-organic framework (MOF) organocatalyst has been developed, based on readily available MIL-101 and the chiral primary diamine (1R,2R)-1,2-diphenylethylenediamine, by the post-synthetic modification. Over the developed chiral heterogeneous catalyst the asymmetric synthesis of (S)-warfarin with high enantioselectivity can be fulfilled on a gram-scale (2.8 g) with excellent yield (92%) at low cost, making the synthesis method an ideal alternative to existing methods. Copyright
- Shi, Tao,Guo, Zhiwei,Yu, Huixian,Xie, Jianwu,Zhong, Yijun,Zhu, Weidong
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supporting information
p. 2538 - 2543
(2013/10/21)
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- Gas phase retro-Michael reaction resulting from dissociative protonation: Fragmentation of protonated warfarin in mass spectrometry
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A mass spectrometric study of protonated warfarin and its derivatives (compounds 1 to 5) has been performed. Losses of a substituted benzylideneacetone and a 4-hydroxycoumarin have been observed as a result of retro-Michael reaction. The added proton is initially localized between the two carbonyl oxygens through hydrogen bonding in the most thermodynamically favorable tautomer. Upon collisional activation, the added proton migrates to the C-3 of 4-hydroxycoumarin, which is called the dissociative protonation site, leading to the formation of the intermediate ion-neutral complex (INC). Within the INC, further proton transfer gives rise to a proton-bound complex. The cleavage of one hydrogen bond of the proton-bound complex produces the protonated 4-hydroxycoumarin, while the separation of the other hydrogen bond gives rise to the protonated benzylideneacetone. Theoretical calculations indicate that the 1, 5-proton transfer pathway is most thermodynamically favorable and support the existence of the INC. Both substituent effect and the kinetic method were utilized for explaining the relative abundances of protonated 4-hydroxycoumarin and protonated benzylideneacetone derivative. For monosubstituted warfarins, the electron-donating substituents favor the generation of protonated substituted benzylideneacetone, whereas the electron-withdrawing groups favor the formation of protonated 4-hydroxycoumarin. Copyright
- Zhang, Jia,Chai, Yunfeng,Jiang, Kezhi,Yang, Huameng,Pan, Yuanjiang,Sun, Cuirong
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p. 1059 - 1064
(2012/11/07)
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- Chiral primary amine tagged to ionic group as reusable organocatalyst for asymmetric Michael reactions of C-nucleophiles with α,β-unsaturated ketones
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The first primary amine-derived organocatalyst modified with an ionic group for asymmetric Michael reactions of C-nucleophiles with α,β- unsaturated ketones was synthesized. In the presence of this catalyst and an acidic co-catalyst (AcOH), hydroxycoumarin and its sulfur-containing analogue reacted with benzylideneacetone derivatives or cyclohexenone to afford the corresponding Michael adducts in high yields (up to 97%) and with reasonable enantioselectivity (up to 80%). The catalyst could be easily recovered and efficiently reused three times, afterwards, its activity and stereodifferentiating ability gradually declined. The analysis of recovered catalyst samples by ESI-MS allowed us to detect undesirable side reactions that poisoned the catalyst, and propose an approach for its reactivation. Copyright
- Kucherenko, Alexander S.,Siyutkin, Dmitry E.,Nigmatov, Albert G.,Chizhov, Alexander O.,Zlotin, Sergei G.
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supporting information
p. 3078 - 3086
(2013/01/15)
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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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- Highly enantioselective synthesis of warfarin and its analogs by means of cooperative LiClO4/DPEN-catalyzed Michael reaction: Enantioselectivity enhancement and mechanism
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The highly enantioselective synthesis of warfarin and its analogs was reported in this manuscript. And a cooperative catalysis was observed in asymmetric primary amine-catalyzed Michael reaction for the enantioselective synthesis of warfarin and its analogs, which led to the finding of several cooperative catalyst systems combined with Lewis acid and primary amine, such as LiClO4/DPEN. In this Michael reaction of 4-hydrocoumarin, the cooperative catalyst system (LiClO4/DPEN) resulted in higher levels of stereoselectivity (up to 94%ee). Additionally, the mechanism of the enantioselectivity enhancement in the cooperative catalytic Michael reaction has been investigated by using of ESI-MS and the study of nonlinear effect.
- Yang, Hua-Meng,Li, Li,Jiang, Ke-Zhi,Jiang, Jian-Xiong,Lai, Guo-Qiao,Xu, Li-Wen
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supporting information; experimental part
p. 9708 - 9713
(2011/02/24)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 52
(2010/12/31)
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- Organocatalytic enantioselective michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones: a simple synthesis of warfarin
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A type of C2-symmetric secondary amine amide catalysts were developed for the asymmetric Michael addition of Ahydroxycoumarin to α,ss-unsaturated ketones. A series of important biologically and pharmaceutically active compounds were obtained in
- Dong, Zhenhua,Wang, Lijia,Chen, Xiaohong,Liu, Xiaohua,Lin, Lili,Feng, Xiaoming
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experimental part
p. 5192 - 5197
(2010/01/11)
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- Development of new HPLC chiral stationary phases based on native and derivatized cyclofructans
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An unusual class of chiral selectors, cyclofructans, is introduced for the first time as bonded chiral stationary phases. Compared to native cyclofructans (CFs), which have rather limited capabilities as chiral selectors, aliphatic-and aromatic-functionalized CF6s possess unique and very different enantiomeric selectivities. Indeed, they are shown to separate a very broad range of racemic compounds. In particular, aliphatic-derivatized CF6s with a low substitution degree baseline separate all tested chiral primary amines. It appears that partial derivatization on the CF6 molecule disrupts the molecular internal hydrogen bonding, thereby making the core of the molecule more accessible. In contrast, highly aromaticfunctionalized CF6 stationary phases lose most of the enantioselective capabilities toward primary amines, however they gain broad selectivity for most other types of analytes. This class of stationary phases also demonstrates high "loadability" and therefore has great potential for preparative separations. The variations in enantiomeric selectivity often can be correlated with distinct structural features of the selector. The separations occur predominantly in the presence of organic solvents.
- Sun, Ping,Wang, Chunlei,Breitbach, Zachary S.,Zhang, Ying,Armstrong, Daniel W.
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experimental part
p. 10215 - 10226
(2010/05/01)
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- Highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to α,β-unsaturated ketones
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The highly enantioselective Michael addition of 1,3-cyclic dicarbonyl compounds to α,β-unsaturated ketones was reported to be catalyzed by an organic primary amine derived from quinine. A chiral anticoagulant drug, (S)-warfarin, was directly prepared in 96% ee, and other related important adducts were also obtained in excellent enantioselectivity (89-99% ee).
- Xie, Jian-Wu,Yue, Lei,Chen, Wei,Du, Wei,Zhu, Jin,Deng, Jin-Gen,Chen, Ying-Chun
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p. 413 - 415
(2008/02/12)
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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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- Retention and selectivity of teicoplanin stationary phases after copper complexation and isotopic exchange
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Teicoplanin is a macrocyclic glycopeptide that is highly effective as a chiral selector for LC enantiomeric separations. Two possible interaction paths were investigated and related to solute retention and selectivity: (1) interactions with the only teicoplanin amine group and (2) role of hydrogen bonding interactions. Mobile phases containing 0.5 and 5 mM copper ions were used to try to block the amine group. In the presence of copper ions, it was found that the teicoplanin stationary phase has a decreased ability to separate most underivatized racemic amino acids. However, it maintained its ability to separate enantiomers that were not α - amino acids. It is established that there is little copper - teicoplanin complex formation. The effect of Cu2+ on the enantioseparation of some α - amino acids appears to be due to the fact that these solutes are good bidentate ligands and form complexes with copper ions in the mobile phase. Isotopic exchange with deuterium oxide was performed using acetonitrile - heavy water mobile phases. It was found that the retention times of all amino acids were lower with deuterated mobile phases. The retention times of polar or apolar molecules without amine groups were higher with deuterated mobiles phases. In all cases, the enantio-selectivity factors were unaffected by the deuterium exchange. It is proposed that the electrostatic interactions are decreased in the deuterated mobile phases and the solute-accessible stationary-phase volume is somewhat swollen by deuterium oxide. The balance of these effects is a decrease in the amino acid retention times and an increase in the apolar solute retention time. The enantio-selectivity factors of all of the molecules remain unchanged because all of the interactions are changed equally. We propose a new global quality criterion (the E factor) for comparing and evaluating enantiomeric separations.
- Berthod,Valleix,Tizon,Leonce,Caussignac,Armstrong
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p. 5499 - 5508
(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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- Synthesis, toxicological and pharmacological assessment of some 4-hydroxycoumarin derivatives
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The synthesis of seven coumarin derivatives from 4-hydroxycoumarin and different unsaturated ketones is described. The structures of the synthesized compounds were proved by IR, 1H-NMR and mass-spectral data. Acute toxicity studies of the compounds were performed on mice by oral and intraperitoneal administration. A comparative pharmacological study of the in vivo anticoagulant effects of the derivatives with respect to Warfarin showed that the new compounds have different anticoagulant activities. 4-Acetoxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2- one 2 showed slight acute toxicity and a higher anticoagulant effect than Warfarin.
- Manolov,Danchev
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p. 531 - 535
(2007/10/02)
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