- Ionic liquids: Efficient media for the lipase-catalyzed Michael addition
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Recently, ionic liquids (ILs) have been regarded as ideal media for non-aqueous bio-catalysis. In this work, the synthesis of warfarin by the lipase-catalyzed Michael addition in IL media and the parameters that affected the warfarin yield were investigated. Experimental results demonstrated that the chemical structures of the ILs were a major factor for influencing the warfarin yield. The ILs containing the NTf2– anion were suitable reaction media due to the high chemical stability of this anion. The incorporation of the hydroxyl group on the IL cation significantly improved the lipase activity due to the H2O-mimicking property of this group. The lipase activity decreased by increasing the alkyl chain length on the IL cation due to the non-polar domain formation of the IL cation at the active site entrance of lipase. The ILs and lipase could be reused no less than five times without reduction in the warfarin yield.
- Fan, Yunchang,Cai, Dongxu,Wang, Xin,Yang, Lei
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- Enzyme-catalyzed Michael addition for the synthesis of warfarin and its determination via fluorescence quenching of L-tryptophan
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A sensitive fluorescence sensor for warfarin was proposed via quenching the fluorescence of L-tryptophan due to the interaction between warfarin and L-tryptophan. Warfarin, as one of the most effective anticoagulants, was designed and synthesized via lipase from porcine pancreas (PPL) as a biocatalyst to catalyze the Michael addition of 4-hydroxycoumarin to α, β-unsaturated enones in organic medium in the presence of water. Furthermore, the spectrofluorometry was used to detect the concentration of warfarin with a linear range and detection limit (3σ/k) of 0.04–12.0?μmol?L??1 (R2?=?0.994) and 0.01?μmol?L??1, respectively. Herein, this was the first application of bio-catalytic synthesis and fluorescence for the determination of warfarin. The proposed method was applied to determine warfarin of the drug in tablets with satisfactory results.
- Yuan, Yusheng,Yang, Liu,Liu, Shaopu,Yang, Jidong,Zhang, Hui,Yan, Jingjing,Hu, Xiaoli
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- Hypervalent Iodine(III)-Mediated Tosyloxylation of 4-Hydroxycoumarins
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An efficient approach was developed for synthesis of 3-tosyloxy-4-hydroxycoumarins under mild conditions by using Koser's reagents. The reaction tolerated various functional groups, and the products served as useful aromatic building blocks. Additionally, a plausible mechanism via iodonium ylide was proposed, and the oral anticoagulant Warfarin was synthesized in good yield.
- Xu, Bowen,Gao, Yiping,Han, Jianwei,Xing, Zejing,Zhao, Sihan,Zhang, Ziyang,Ren, Runlin,Wang, Limin
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- Spectral assignments and structural studies of a warfarin derivative stereoselectively formed by tandem cyclization
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Abstract The structural elucidation of a Mannich condensation product of rac-Warfarin with benzaldehyde and methyl amine was carried out using IR, Mass, 1H NMR, 13C NMR, 1H-1H COSY, 1H-13C COSY, DEPT-135, HMBC, NOESY spectra and single crystal X-ray diffraction. Formation of a new pyran ring via a tandem cyclization in the presence of methyl amine was observed. The optimized geometry and HOMO-LUMO energy gap along with other important physical parameters were found by Gaussian 09 program using HF 6-31G (d, p) and B3YLP/DFT 6-31G (d, p) level of theory. The preferred conformation of the piperidine ring in solution state was found to be chair from the NMR spectra. Single crystal X-ray diffraction and optimized geometry (by theoretical study) also confirms the chair conformation in the solid state.
- Velayutham Pillai,Rajeswari,Vidhyasagar
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- Primary Amine Catalyzed Activation of Carbonyl Compounds: A Study on Reaction Pathways and Reactive Intermediates by Mass Spectrometry
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The field of organocatalysis is expanding at a fast pace. Its growth is sustained by major stimuli, such as the effort toward an understanding of the mechanisms of reaction and catalytic processes in general, the elucidation of basic properties leading to stereocontrol and the search for broad applicability and scalability of the synthetic methodology. This paper reports a thorough study based on ESI-MS spectrometry of amino-organocatalyzed model reactions under different experimental conditions. Off-line reaction monitoring of mixtures containing different catalytic systems, by ESI-MSn showed the presence of several putative intermediate species, either in their protonated or sodiated forms. In addition, enantioselective chromatography of crude reactions provides the stereochemical outcome of asymmetric reactions. The bulk of the data collected offers a clue of the intricate pathways occurring in solution for the studied reactions.
- Bencivenni, Giorgio,Calcaterra, Andrea,Ciogli, Alessia,Iazzetti, Antonia,Mazzoccanti, Giulia,Righi, Paolo,Villani, Claudio
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supporting information
(2021/12/01)
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- Enantioseparation of mandelic acid on vancomycin column: Experimental and docking study
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So far, no detailed view has been expressed regarding the interactions between vancomycin and racemic compounds including mandelic acid. In the current study, a chiral stationary phase was prepared by using 3-aminopropyltriethoxysilane and succinic anhydride to graft carboxylated silica microspheres and subsequently by activating the carboxylic acid group for vancomycin immobilization. Characterization by elemental analysis, Fourier transform infrared spectroscopy, solid-state nuclear magnetic resonance, and thermogravimetric analysis demonstrated effective functionalization of the silica surface. R and S enantiomers of mandelic acid were separated by the synthetic vancomycin column. Finally, the interaction between vancomycin and R/S mandelic acid enantiomers was simulated by Auto-dock Vina. The binding energies of interactions between R and S enantiomers and vancomycin chiral stationary phase were different. In the most probable interaction, the difference in mandelic acid binding energy was approximately 0.2 kcal/mol. In addition, circular dichroism spectra of vancomycin interacting with R and S enantiomers showed different patterns. Therefore, R and S mandelic acid enantiomers may occupy various binding pockets and interact with different vancomycin functions. These observations emphasized the different retention of R and S mandelic acid enantiomers in vancomycin chiral column.
- Shahnani, Mostafa,Sefidbakht, Yahya,Maghari, Shokoofeh,Mehdi, Ahmad,Rezadoost, Hassan,Ghassempour, Alireza
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supporting information
p. 1289 - 1298
(2020/08/19)
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- Enantioselective Michael Addition Reaction Catalysed by Enantiopure Binuclear Nickel(II) Close-Ended Helicates
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The enantiopure Ni(II) helicates [Ni2L1RR.Cl2] (1), [Ni2L1SS.Cl2] (1′), [Ni2L2RR.Cl2] (2), [Ni2L2SS.Cl2] (2′) were synthesized by one-pot self-assembly technique from R-(+)- or S-(?)-1,1′-binaphthyl-2,2′-diamine, with 4-methyl-2,6-diformyl phenol or 4-tert-butyl-2,6-diformyl phenol and nickel salts. This binuclear double stranded Ni(II) helicates were characterized by ESI-MS, IR and single crystal X-ray structure wherever applicable. The extensive chiroptical studies suggest that the complexes are enantiopure in nature. The chirality transfer from ligand L1RR & L2RR to Ni(II) metal centre produced ΔΔ geometrical chirality, while their enantiomeric counterpart L1SS & L2SS produced ΛΛ chirality in their respective complexes.These enantiopure helicates were applied as catalysts in asymmetric Michael addition of 1,3-dicarbonyl compounds with β-nitrostyrene to produce nitroalkanes in good yield (96–98%) and ee (78–94%). (Figure presented.).
- Arunachalam, Rajendran,Chinnaraja, Eswaran,Natarajan, Ramalingam,Samanta, Krishanu,Subramanian, Palani S.
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- The Synthesis of Warfarin Using a Reconfigurable-Reactor Platform Integrated to a Multiple-Variable Optimization Tool
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Optimization of the asymmetric synthesis of warfarin, an important anticoagulant, has been evaluated using a reconfigurable reaction platform capable of performing batch, continuous flow, and plug-flow synthesis. Further, this platform has been integrated with a novel, multidimensional, multiple variable analysis tool that can evaluate multiple critical quality attributes (CQA), percent conversion and enantiomeric excess in this case, from a single injection that is repeatedly recycled in a closed loop of chromatography columns, a detector and a heart-cut valve. Further, the new, integrated analysis system also facilitates validation of each QA, providing a high-level of confidence in analytical measurements, which are obtained without operator intervention.
- Bizarri, Nour,Kwak, Jee Seong,Mallik, Debasis,Organ, Michael G.,Sharif, Sepideh,Zhang, Wenyao Peter
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supporting information
p. 15505 - 15508
(2020/11/30)
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- A Silica-Supported Catalyst Containing 9-Amino-9-deoxy-9-epi-quinine and a Benzoic Acid Derivative for Stereoselective Batch and Flow Heterogeneous Reactions
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A heterogeneous, silica-based catalyst containing 9-amino-9-deoxy-epi-quinine (or quinidine) and a derivative of benzoic acid was synthesized through radical thiol-ene click reaction. The acid component allows the in situ activation of cinchona amino group, acting as a bifunctional catalyst. The heterogenized catalysts efficiently promoted the reaction of ketones with trans-β-nitrostyrene, with diastereo- and enantioselectivity comparable to those of the homogeneous counterparts (dr up to 90:10 and 90 % ee). In addition, the catalyst retained a constant activity for at least four cycles. Finally, the supported catalyst (9-amino-9-deoxy-epi-quinine/achiral acid) was employed under continuous-flow conditions. Two enantioselective Michael reactions were in sequence performed with the same homemade packed-bed reactor. The addition of cyclohexanone to trans-β-nitrostyrene provided the evaluation of optimal residence time with high level of stereoselection (2 μL/min flow rate, 83 % ee). Furthermore, the flow reactor well performed in the preparation of warfarin (isolated yield 95 %, 78 % ee. in 16 h at room temperature). The dual (chiral amine/achiral acid) solid supported system, making an even easier work-out, represents a valuable tool for green chemistry and is attractive for large scale applications.
- Ciogli, Alessia,Capitani, Donatella,Di Iorio, Nicola,Crotti, Simone,Bencivenni, Giorgio,Donzello, Maria Pia,Villani, Claudio
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p. 2020 - 2028
(2019/03/07)
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- 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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supporting information
p. 12233 - 12240
(2019/08/12)
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- Fe3O4?l-Proline/Pd nanocomposite for one-pot tandem catalytic synthesis of (±)-warfarin from benzyl alcohol: Synergistic action of organocatalyst and transition metal catalyst
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One-pot synthesis of (±)-warfarin, an anticoagulant, has been achieved from benzyl alcohol in a 'green way' by using a multicomponent catalyst. For the purpose, l-proline capped Fe3O4 nanoparticles (Fe3O4?l-proline NPs) were synthesized and metallic palladium was loaded on its surface (Fe3O4?l-proline/Pd NCs). The morphology, particle size and shape were studied by using FESEM and TEM analysis. The Pd present on the surface was responsible for oxidation of benzyl alcohol and its derivatives to the corresponding aldehyde in situ. This in turn, condensed with acetone to form the aldol condensation product, benzylideneacetone, at 70 °C due to the presence of the l-proline organocatalyst on the surface of Fe3O4 NPs. Later, 4-hydroxycoumarin was introduced to condense with in situ generated benzylideneacetone by a Michael addition to form the target product (±)-warfarin. It was established that benzyl alcohol can be converted into the final product, (±)-warfarin, with an overall 35% yield within 5 days in a single-pot process. This process requires a rise in temperature in stages to a maximum of 100 °C and 1 atm pressure of dioxygen gas. An important aspect of the developed process is the avoidance of loss of costly Pd by leaching and catalyst recovery by the use of a magnetic field. The use of a solvent like PEG-400 makes the process green in a true sense. The interaction of l-proline with Fe3O4 NPs and the presence of Pd on the surface were confirmed by the FTIR and XRD patterns, respectively. The present study hereby suggests a combined 3-step mechanism for the production of the target product warfarin. Pilot-scale one-pot production of (±)-warfarin was carried out and a flow diagram with various unit processes is presented.
- Tomer, Sanjiv O.,Soni, Hemant P.
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p. 6517 - 6531
(2019/11/20)
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- Warfarin hapten and artificial antigen, preparation method and application thereof
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The invention relates to warfarin hapten and artificial antigen, a preparation method and an application thereof. The structure of the warfarin hapten is shown in the formula (I) which is as shown inthe specification, wherein the warfarin artificial antigen is obtained by coupling hapten shown in the formula (I) with carrier protein. By using the warfarin artificial antigen to immunize animals, aspecific antibody with high titer and sensitivity can be obtained. The warfarin hapten and the antibody prepared by the warfarin hapten provide a new method for establishing a rapid, simple, cheap, sensitive and specific warfarin detection method.
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Paragraph 0060; 0061-0063
(2019/06/30)
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- Diquats with Robust Chirality: Facile Resolution, Synthesis of Chiral Dyes, and Application as Selectors in Chiral Analysis
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Diquats with extremely high racemization barriers with ΔG≠theor of 233 kJ mol?1 at 180 °C are described. Reported configurational robustness is due to a combination of two structural features: the rigid o-xylylene tether connecting the nitrogen atoms and the presence of two substituents in the bay region of the bipyridinium scaffold. The straightforward synthesis of diquats, plus facile resolution and derivatization make them attractive for chiral application studies. This is demonstrated by: 1) synthesis of the first non-racemic diquat dyes with pronounced chiroptical properties, and 2) capability of diquats to interact stereospecifically with chiral molecules. This suggests potential for diquat derivatives to be used as chiral selectors in separation methods.
- Talele, Harish R.,Koval, Du?an,Severa, Luká?,Reyes-Gutiérrez, Paul E.,Císa?ová, Ivana,Sázelová, Petra,?aman, David,Bednárová, Lucie,Ka?i?ka, Václav,Teply, Filip
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supporting information
p. 7601 - 7604
(2018/06/11)
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- A protein-based mixed selector chiral monolithic stationary phase in capillary electrochromatography
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A new mixed selector chiral stationary phase (CSP) was prepared with co-immobilized human serum albumin and cellulase on a poly(glycidylmethacrylate-co-ethylene glycol dimethacrylate) (poly(GMA-co-EDMA)) monolith and the evaluation of its usefulness in chiral separation research was presented. For comparison, two single selector chiral stationary phases (CSPs) were also fabricated with the corresponding proteins. The enantioseparation ability of these CSPs was investigated by capillary electrochromatography (CEC) with various racemates. The mixed selector CSP exhibited a broader range of enantioselectivities than the single selectors and it could separate 10 chiral analytes while the two single selector CSPs resolved 3 and 8 respectively. Moreover, for (±)-warfarin, the enantioresolution was improved on the mixed selector CSP. Meanwhile, compared with the single selector CSPs, no additional preparation stage or reagent consumption was required in the simultaneous immobilization of different proteins, which is more favorable from economical and practical points of view. Consequently, by mixing HSA and cellulase together, the composite column combines the enantioselectivities of both individual proteins, thus expanding their application range practically.
- Xu, Shujuan,Wang, Yuying,Tang, Yixia,Ji, Yibing
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p. 13520 - 13528
(2018/08/21)
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- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
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A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
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p. 1067 - 1078
(2018/08/01)
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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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- 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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- 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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p. 577 - 587
(2018/02/10)
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- Ultrafast chiral separations for high throughput enantiopurity analysis
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Recent developments in fast chromatographic enantioseparations now make high throughput analysis of enantiopurity on the order of a few seconds achievable. Nevertheless, routine chromatographic determinations of enantiopurity to support stereochemical investigations in pharmaceutical research and development, synthetic chemistry and bioanalysis are still typically performed on the 5-20 min timescale, with many practitioners believing that sub-minute enantioseparations are not representative of the molecules encountered in day to day research. In this study we develop ultrafast chromatographic enantioseparations for a variety of pharmaceutically-related drugs and intermediates, showing that sub-minute resolutions are now possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed phase liquid chromatography (RP-LC). Examples are provided illustrating how such methods can be routinely developed and used for ultrafast high throughput analysis to support enantioselective synthesis investigations.
- Barhate, Chandan L.,Joyce, Leo A.,Makarov, Alexey A.,Zawatzky, Kerstin,Bernardoni, Frank,Schafer, Wes A.,Armstrong, Daniel W.,Welch, Christopher J.,Regalado, Erik L.
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supporting information
p. 509 - 512
(2017/01/13)
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- Inhibition of platelet activation, aggregation and/or adhesion by hypothermia
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A method for treating acute coronary syndromes (i.e., unstable angina or non-Q-wave MI) or transient ischemic attacks in a human or animal patient by placing a heat exchange apparatus in the patient's vasculature and using that heat exchange apparatus to cool the patient to a temperature (e.g. 30-36 degrees C.) at which platelet inhibition (i.e., inhibition of platelet activation and/or aggregation and/or adhesion) occurs. Anti-shivering drugs or anesthesia may be administered to patients whose body temperature is cooled below that patient's shivering threshold (typically approximately 35.5 degrees C.). If it is determined that platelet inhibition is no longer desirable, such as when the patient is about to undergo a surgical or interventional procedure wherein bleeding could be problematic, the hypothermia-induced platelet inhibition may be rapidly reversed by using the intravascular heat exchange apparatus to re-warm the patient's body to normothermia or near normothermia.
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- Photochemically immobilized 4-methylbenzoyl cellulose as a powerful chiral stationary phase for enantioselective chromatography
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A process to immobilize para-methylbenzoyl cellulose (PMBC) on silica gel has been developed and applied to prepare chiral stationary phases (CSPs) for enantioselective chromatography. The immobilization was achieved by simple irradiation of the polysaccharide derivative with ultraviolet light after coating on a silica gel support. The influence of parameters such as irradiation time and solvent on immobilization effectiveness were investigated. The performance of the prepared immobilized phases were evaluated by injection of a series of racemic compounds onto the packed columns and determination of their chiral recognition ability. By contrast to the classical coated phase, the immobilized CSP can be used under various chromatographic conditions without limitation of organic solvent types as the mobile phase. This extended applicability permits to improve selectivity and to resolve chiral compounds which are not or only poorly soluble in the mobile phases which are compatible with the non-immobilized PMBC stationary phase.
- Francotte, Eric,Huynh, Dan,Zhang, Tong
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- Stereoselective organocatalysed reactions in deep eutectic solvents: Highly tunable and biorenewable reaction media for sustainable organic synthesis
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Three distinct stereoselective reactions, catalysed by using a chiral primary amine through different activation methods, have been successfully carried out for the first time in bio-based eutectic mixtures, thereby affording functionalised molecules in very high enantioselectivity. The use of these unconventional and biorenewable reaction media also provides opportunities for facilitating the recovery and the recycling of the chiral catalyst.
- Massolo, Elisabetta,Palmieri, Silvia,Benaglia, Maurizio,Capriati, Vito,Perna, Filippo M.
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supporting information
p. 792 - 797
(2016/02/12)
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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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- NMR and DFT Insight into the Synergistic Role of Bovine Serum Albumin–Ionic Liquid for Multicomponent Cascade Aldol/Knoevenagel–thia-Michael/Michael Reactions in One Pot
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The synergistic combination of two catalysts is an emerging strategy towards the formation of unprecedented complex molecules, and herein bovine serum albumin (BSA) and the neutral ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br) are used together for the first time towards multiple C?C and C?S bond-formation reactions in one pot under metal-free, acid-free, and base-free conditions by merging two classical named reactions, that is, aldol condensation (AC) and thia-Michael addition (TMA) for the cascade chemoselective generation of β-aryl-β-sulfido carbonyl compounds from aliphatic ketones, aromatic aldehydes, and thiols. NMR spectroscopy and DFT calculations studies provided insight into the synergism, progress, and mechanism of the reaction, and control experiments highlighted that the single catalysts (BSA or IL) alone did not allow even the first AC step to proceed. Moreover this synergistic BSA–[bmim]Br catalytic system offers the step-economical synthesis of the anticoagulant warfarin through sequential aldol–Michael addition reactions and potent pyridine analogues through a Knoevenagel–Michael route. Besides, the recyclability of the catalytic system (up to 5 times) with the generation of water as a byproduct makes our one-pot protocol more economically efficient and synthetically attractive than traditional methods.
- Thopate, Yogesh,Singh, Richa,Sinha, Arun K.,Kumar, Vikash,Siddiqi, Mohammad Imran
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p. 3050 - 3056
(2016/10/11)
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- Comparison of different polymer- and silica-supported 9-amino-9-deoxy-epi-quinines as recyclable organocatalysts
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9-Amino-9-deoxy-epi-quinine, properly modified by suitable linkers, was anchored on highly cross-linked polystyrene, poly(ethylene glycol), and silica. The resulting species were characterized by NMR spectroscopy and tested as supported organocatalysts in the reaction between isobutyric aldehyde and trans-β-nitrostyrene. Polystyrene- and poly(ethylene glycol)-supported catalysts outperformed their nonsupported counterpart affording the desired product in high yield and ee (>90 % ee). Silica-supported catalysts proved to be less efficient in terms of both chemical yield and enantioselectivity. Polystyrene- and poly(ethylene glycol)-supported 9-amino-9-deoxy-epi-quinine were then used in the same reaction with different substrates, leading to the desired products in high yield and ee, as well as in three other reactions operating with different mechanism. An investigation of the recyclability of the polystyrene- and poly(ethylene glycol)-supported systems showed that these could be recovered and recycled with no loss of stereochemical activity but with a marked erosion of chemical efficiency occurring at the fifth reaction cycle. This was ascribed to chemical degradation of the alkaloid occurring during the reaction.
- Porta, Riccardo,Coccia, Francesca,Annunziata, Rita,Puglisi, Alessandra
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p. 1490 - 1499
(2015/08/05)
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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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- Lipase-supported metal-organic framework bioreactor catalyzes warfarin synthesis
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A green and sustainable strategy synthesizes clinical medicine warfarin anticoagulant by using lipasesupported metal-organic framework (MOF) bioreactors (see scheme). These findings may be beneficial for future studies in the industrial production of chemical, pharmaceutical, and agrochemical precursors
- Liu, Wan-Ling,Yang, Ni-Shin,Chen, Ya-Ting,Lirio, Stephen,Wu, Cheng-You,Lin, Chia-Her,Huang, Hsi-Ya
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supporting information
p. 115 - 119
(2015/10/12)
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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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- Primary amine attached to an N-(carboxyalkyl)imidazolium cation: A recyclable organocatalyst for the asymmetric Michael reaction
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A (1S,2S)-1,2-diphenylethane-1,2-diamine derivative modified with an N-(4-carboxybutyl)imidazolium cation and PF6- anion has been developed and applied as a recyclable organocatalyst of the asymmetric 1,4-conjugate addition of 4-hydroxy-2H-chromen-2-one to 1-substituted buten-3-ones or cyclohexen-3-one to afford corresponding Michael adducts in high yields (up to 97-%) and enantioselectivities (up to 90-% ee). The most active (S) enantiomer of the clinically useful anticoagulant warfarin was prepared in this way. The catalyst exhibited better recyclability than its known analog, which does not contain a carboxy group: it could be recycled 5 times in the reaction without a significant decrease in product yield or ee values. Gradual deactivation of the catalyst was caused by leaching during workup rather than by off-cycle reactions between the catalyst and reagents. The sustainability of ionic-liquid-supported primary-amine-derived recyclable chiral organocatalyst of practical important in asymmetric Michael reactions has been improved by incorporating a peripheral carboxylic group that suppresses undesirable off-cycle reactions during the catalytic process. Copyright
- Kucherenko, Alexandr S.,Lisnyak, Vladislav G.,Chizhov, Alexandr O.,Zlotin, Sergei G.
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supporting information
p. 3808 - 3813
(2014/06/24)
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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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- Predictability of enantiomeric chromatographic behavior on various chiral stationary phases using typical reversed phase modeling software
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Pharmaceutical companies worldwide tend to apply chiral chromatographic separation techniques in their mass production strategy rather than asymmetric synthesis. The present work aims to investigate the predictability of chromatographic behavior of enantiomers using DryLab HPLC method development software, which is typically used to predict the effect of changing various chromatographic parameters on resolution in the reversed phase mode. Three different types of chiral stationary phases were tested for predictability: macrocyclic antibiotics-based columns (Chirobiotic V and T), polysaccharide-based chiral column (Chiralpak AD-RH), and protein-based chiral column (Ultron ES-OVM). Preliminary basic runs were implemented, then exported to DryLab after peak tracking was accomplished. Prediction of the effect of % organic mobile phase on separation was possible for separations on Chirobiotic V for several probes: racemic propranolol with 97.80% accuracy; mixture of racemates of propranolol and terbutaline sulphate, as well as, racemates of propranolol and salbutamol sulphate with average 90.46% accuracy for the effect of percent organic mobile phase and average 98.39% for the effect of pH; and racemic warfarin with 93.45% accuracy for the effect of percent organic mobile phase and average 99.64% for the effect of pH. It can be concluded that Chirobiotic V reversed phase retention mechanism follows the solvophobic theory. 2013 Wiley Periodicals, Inc.
- Wagdy, Hebatallah A.,Hanafi, Rasha S.,El-Nashar, Rasha M.,Aboul-Enein, Hassan Y.
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p. 506 - 513
(2013/09/12)
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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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- Development of a novel method for warfarin synthesis via lipase-catalyzed stereoselective michael reaction
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Stereoselective synthesis of warfarin by promiscuous lipase-catalyzed Michael reaction of 4-hydroxycoumarin to benzylideneacetone has been developed. The best result was obtained using lipase AS as a catalyst in anhydrous DMSO with 1:3 molar ratio of 4-hydroxycoumarin to benzylideneacetone at 20 °C for 7 days. The yield and enantiomeric excess were 85% and 45% ee (R-form), respectively.
- Sano, Kaoru,Saito, Shun-Ichi,Hirose, Yoshihiko,Kohari, Yoshihito,Nakano, Hiroto,Seki, Chigusa,Tokiwa, Michio,Takeshita, Mitsuhiro,Uwai, Koji
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p. 1269 - 1278
(2013/07/05)
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- Metal-mediated aminocatalysis provides mild conditions: Enantioselective Michael addition mediated by primary amino catalysts and alkali-metal ions
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Four catalysts based on new amides of chiral 1,2-diamines and 2-sulfobenzoic acid have been developed. The alkali-metal salts of these betaine-like amides are able to form imines with enones, which are activated by Lewis acid interaction for nucleophilic attack by 4-hydroxycoumarin. The addition of 4-hydroxycoumarin to enones gives ee's up to 83% and almost quantitative yields in many cases. This novel type of catalysis provides an effective alternative to conventional primary amino catalysis were strong acid additives are essential components.
- Leven, Matthias,Neudoerfl, Joerg M.,Goldfuss, Bernd
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p. 155 - 165
(2013/03/28)
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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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- C2-symmetric proline-derived tetraamine as highly effective catalyst for direct asymmetric Michael addition of ketones to chalcones
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A C2-symmetric tetraamine catalyst was developed for the asymmetric Michael addition of ketones to chalcones. The corresponding adducts 1,5-dicarbonyl compounds were obtained in good chemical yields with high levels of diastereo- and enantioselectivities (up to >99:1 dr and 93% ee) under mild conditions. By studying the ESI-MS of the intermediates, a proposed mechanism was disclosed.
- Ma, Shijun,Wu, Lulu,Liu, Ming,Wang, Yongmei
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experimental part
p. 3721 - 3729
(2012/05/20)
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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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- Enantioselective synthesis of coumarin derivatives by PYBOX-DIPH-Zn(II) complex catalyzed Michael reaction
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A potential pharmacologically active chiral 3-substituted 4-hydroxy-2-oxo-2H-chromene skeleton has been synthesized by enantioselective Michael addition catalyzed by PYBOX-DIPH-Zn(OTf)2 complex. The methodology has successfully been employed in the synthesis of (R)-Warfarin and another related compounds.
- Ray, Sumit K.,Singh, Pradeep K.,Singh, Vinod K.,Molleti, Nagaraju
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p. 8802 - 8808,7
(2012/12/12)
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- Enantioselective synthesis of coumarin derivatives by PYBOX-DIPH-Zn(II) complex catalyzed Michael reaction
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A potential pharmacologically active chiral 3-substituted 4-hydroxy-2-oxo-2H-chromene skeleton has been synthesized by enantioselective Michael addition catalyzed by PYBOX-DIPH-Zn(OTf)2 complex. The methodology has successfully been employed in
- Ray, Sumit K.,Singh, Pradeep K.,Molleti, Nagaraju,Singh, Vinod K.
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p. 8802 - 8808
(2013/01/15)
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- Dehydrative C-H alkylation and alkenylation of phenols with alcohols: Expedient synthesis for substituted phenols and benzofurans
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A well-defined cationic Ru-H complex catalyzes the dehydrative C-H alkylation reaction of phenols with alcohols to form ortho-substituted phenol products. Benzofuran derivatives are efficiently synthesized from the dehydrative C-H alkenylation and annulation reaction of phenols with 1,2-diols. The catalytic C-H coupling method employs cheaply available phenols and alcohols, exhibits a broad substrate scope, tolerates carbonyl and amine functional groups, and liberates water as the only byproduct.
- Lee, Dong-Hwan,Kwon, Ki-Hyeok,Yi, Chae S.
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supporting information; experimental part
p. 7325 - 7328
(2012/06/16)
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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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- Enantioselective synthesis of polycyclic coumarin derivatives catalyzed by an in situ formed primary amine-imine catalyst
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A facile in situ formed primary amine-imine organocatalyst was developed in the asymmetric Michael addition of substituted 4-hydroxycoumarins to cyclic enones. A series of optically active polycyclic coumarin derivatives were obtained in high yields with excellent enantioselectivities up to 97% ee.
- Zhu, Xi,Lin, Aijun,Shi, Yan,Guo, Jingyu,Zhu, Chengjian,Cheng, Yixiang
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supporting information; experimental part
p. 4382 - 4385
(2011/10/08)
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- Highly effective and enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts
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Highly asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by chiral primary amine thiourea bifunctional catalysts was developed and a series of Michael adducts were obtained in excellent yields (up to 97%) and enantioselectivities (up to 95% ee). Optically pure S-warfarin was easily obtained in 99% ee after single recrystallization.
- Mei, Ren-Qiang,Xu, Xiao-Ying,Li, Yan-Chun,Fu, Ji-Ya,Huang, Qing-Chun,Wang, Li-Xin
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supporting information; experimental part
p. 1566 - 1568
(2011/05/05)
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- Efficient "on water" organocatalytic protocol for the synthesis of optically pure warfarin anticoagulant
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The present development leads to an efficient protocol for the "on water" formation of one of the most widely used anticoagulants warfarin: the presented scalable and environmentally friendly organocatalytic approach affords the target drug in optically pure form.
- Rogozinska, Maria,Adamkiewicz, Anna,Mlynarski, Jacek
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scheme or table
p. 1155 - 1157
(2011/06/26)
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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; 57
(2010/12/31)
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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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- Iron-catalyzed Michael reactions revisited: A synthetically useful process for the preparation of tri-carbonyl compounds and chiral warfarin
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The LBAs (Lewis acid-assisted Br?nsted acid catalysis) is proposed as possible mechanistic process in the simple FeCl3-catalyzed Michael reactions of chalcones with active methylene compounds in organic solvents. And iron salts were found to be effective promoters in the asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketone, which resulted in excellent yield and high level of enantioselectivity (up to 91% ee) in the presence of low catalytic amount of iron and simple chiral primary amine.
- Yang, Hua-Meng,Gao, Yue-Hua,Li, Li,Jiang, Zhen-Yu,Lai, Guo-Qiao,Xia, Chun-Gu,Xu, Li-Wen
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experimental part
p. 3836 - 3839
(2010/08/20)
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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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- New phenylglycine-derived primary amine organocatalysts for the preparation of optically active warfarin
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In this work we present new, fully synthetic phenylglycinederived primary amine organocatalysts useful, for the onestep preparation, of optically active warfarin, an. important anticoagulant. Both enantiomeric forms of the catalysts are equally available and can be prepared by robust procedures without recourse to chromatographic purification. Together with a co-catalyst, particularly acetic acid or2,4-dinitrophen- ol, they can furnish warfarin in approximately 80 % ee and represent inexpensive alternatives to other primary amine organocatalysts such as the chiral diamines and. Cinchona-derived primary amines.
- Kristensen, Tor E.,Vestli, Kristian,Hansen, Finn K.,Hansen, Tore
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experimental part
p. 5185 - 5191
(2010/01/11)
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