Protonation Of Enolates Research Articles

Crystal Structure and Toxicity of the Polymorphic Modifications of the Rodenticide Difenacin

Two new polymorphic forms (I and II) of 2-(diphenylacetyl)indanedione-1,3 (C23H16O3, difenacin, DF) were obtained by original methods. The crystal structures of the polymorphic forms, solved by X‑ray diffraction (XRD) analysis, were compared with those of the known modification III. The structure of the latter was re-determined and studied at a low temperature. The crystal parameters of the polymorphic forms of DF are: (I) Pna21: a = 8.549(2) Å, b = 35.323(7) Å, and c = 5.803(1) Å; Z = 4; (II) P21/c: a = 25.856(1) Å, b = 12.363(1) Å, and c = 16.081(1) Å; β = 94.00(1)°; Z = 12; (III) P21/n: a = 10.365(2) Å, b = 12.239(2) Å, and c = 13.227(2) Å; β = 95.83(1)°; Z = 4. For samples I and II, the recording was performed at room temperature; for III, at 173 K. The number of independent molecules in the polymorphs was found to be different: one molecule in I and III, and three in II. In difenacin crystals, the conformation of neutral C23H16O3 molecules is stabilized by intramolecular hydrogen bonding, with the enol proton localized near the oxygen atom of the keto group of the acyl fragment. The crystal packings contain various sets of C–H···O contacts and intermolecular π–π stacking interactions of indanedionate fragments, with interplanar distances varying from 3.50 to 3.65 Å. The C23H16O3 molecule does not contain a chiral center, but the phenyl groups in the acyl substituent in the crystals are nonequivalent, which should lead to optical activity (stereoisomers in equal amounts). The polymorphic forms proved equally efficient in the same dosage of 2.28 mg/kg for white rats.

Enantioselective enolate protonations: Evaluation of achiral templates with fluxional brønsted basic substituents in conjugate addition of malononitriles

Enoates derived from α−substituted acrylates containing 3-pyrazolidinone achiral template with Brønsted basic fluxional substituents were evaluated in chiral Lewis acid catalyzed enantioselective protonation reactions. The tandem 1,4-conjuagte addition/enantioselective protonation reaction catalyzed by chiral Lewis acids was found to depend on the fluxional group present on the achiral template. The enantioselectivity of the protonation step is highly dependent on the position of the Brønsted basic atom with respect to the pyrazolidinone nitrogen. A comparison of fluxional substituents without a Brønsted basic site and their impact on selectivity is also reported here. The results we detail here are in sharp contrast to our previous studies on enantioselective conjugate addition of malononitriles. The reaction showed reasonable substrate scope for varying α−substitution. The reactions gave conjugate adducts in good yields and good enantioselectivities up to 83 %.

Asymmetric Retro-Claisen Reaction Catalyzed by Chiral Aza-Bisoxazoline–Zn(II) Complex: Enantioselective Synthesis of α-Arylated Ketones

An asymmetric retro-Claisen reaction of α-monosubstituted β-diketones and quinones (or quinone imine) has been developed under the catalysis of a chiral aza-bisoxazoline-Zn(II) complex. The reaction proceeds via a sequence of conjugate addition, arylation, hemiketal anion-initiated C-C bond cleavage, and enantioselective protonation of enolate to provide various functionalized α-arylated ketones bearing a tertiary stereogenic center with high enantioselectivities. Notably, biologically important benzofuran and γ-butyrolactone derivatives could be synthesized by application of the developed protocol.

Curcumin-Based β-Diketo Ligands for Ga3+: Thermodynamic Investigation of Potential Metal-Based Drugs

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete 1H/13C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer.

Asymmetric Phenyl Substitution: An Effective Strategy to Enhance the Photosensitizing Potential of Curcuminoids.

Curcumin has been demonstrated to exhibit photosensitized bactericidal activity. However, the full exploitation of curcumin as a photo-pharmaceutical active principle is hindered by fast deactivation of the excited state through the transfer of the enol proton to the keto oxygen. Introducing an asymmetry in the molecular structure through acting on the phenyl substituents is expected to be a valuable strategy to impair this undesired de-excitation mechanism competing with the therapeutically relevant ones. In this study, two asymmetric curcumin analogs were synthesized and characterized as to their electronic-state transition spectroscopic properties. Fluorescence decay distributions were also reconstructed. Their analysis confirmed the substantial stabilization of the fluorescent state with respect to the parent compound. Nuclear magnetic resonance experiments were performed with the aim of determining the structural features of the keto–enol ring and the strength of the keto–enol hydrogen bond. Electronic structure calculations were also undertaken to elucidate the effects of substitution on the features of the keto–enol semi-aromatic system and the proneness to proton transfer. Finally, their singlet oxygen-generation efficiency was compared to that of curcumin through the 9,10-dimethylanthracene fluorescent assay.

Innovative Bacterial Removal Technique Using Green Synthetic Nano Curcumin Zinc (II) Complex for Sustainable Water Resource Management

Sustainable management of water resources is a daunting challenge, especially with respect to microbes. This study primarily focused on the development of a novel application for the removal of specific bacterial groups in different water types using a green synthetic nano Cur-Zn(II) complex. The results of UV and FT-IR spectroscopic techniques suggested the formation of a chelation complex. Proton NMR showed that the main enolic proton peak with a chemical shift of 16.45 nm identified in curcumin was missed, indicating the contribution of carbonyl oxygen of enol in the formation of the complex. The crystalline nature of the complex and Wurtzite structure of annealed products was inferred from the XRD analysis data. SEM results confirmed the complex’s morphology as spherical and clustered with a rough surface, having an average particle size of 68.2 nm. In addition, the complex was observed to be stable up to 300 °C without any decomposition from STA. Being acidic in nature with a pH of 5.36, the complex penetrates into the cell membrane and inhibit microbial growth. Intrinsically, no studies have been reported for the removal of microbes from water using natural materials embedded with inorganic metals, particularly in nano form. Therefore, the study is the first, innovative, eco-friendly, and economical method to use nano Cur-Zn(II) for removing targeted bacteria in real water samples with 100% efficiency by using optimized amounts (0.025–0.2 g/L) of the complex at a contact time interval between 4 and 24 h. The complex developed is toxic-free and can be applied in situ.

Stereoselective protonation of 2-methyl-1-tetralone lithium enolate catalyzed by salan-type diamines

Asymmetric protonation of ketone enolates is a convenient alternative to asymmetric alkylation of enolates that allows to convert racemic ketones into their optically active form. Here, we have reported an efficient enantioselective protonation of 2-methyl-1-tetralone lithium enolate catalyzed by salan-type diamines. A broad series of salan-type catalysts were synthesized, including several previously unknown, and subsequently tested in the title reaction. For the first time, a chiral amine used as organocatalyst has shown better results than as stoichiometric protonating agent. Application of only 10 mol% of salan allows to obtain the title ketone with high yield and enantiomeric excess up to 75%. The DFT calculations of the structure of the catalyst and its complex with lithium enolate were conducted, which makes it possible to propose a likely reaction mechanism.

Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion.

Carbohydrates are synthetically challenging molecules with vital biological roles in all living systems. Selective synthesis and functionalization of carbohydrates provide tremendous opportunities to improve our understanding on the biological functions of this fundamentally important class of molecules. However, selective functionalization of seemingly identical hydroxyl groups in carbohydrates remains a long-standing challenge in chemical synthesis. We herein describe a practical and predictable method for the site-selective and stereoselective alkylation of carbohydrate hydroxyl groups via Rh(II)-catalyzed insertion of metal carbenoid intermediates. This represents one of the mildest alkylation methods for the systematic modification of carbohydrates. Density functional theory (DFT) calculations suggest that the site selectivity is determined in the Rh(II)-carbenoid insertion step, which prefers insertion into hydroxyl groups with an adjacent axial substituent. The subsequent intramolecular enolate protonation determines the unexpected high stereoselectivity. The most prevalent trans-1,2-diols in various pyranoses can be systematically and predictably differentiated based on the model derived from DFT calculations. We also demonstrated that the selective O-alkylation method could significantly improve the efficiency and stereoselectivity of glycosylation reactions. The alkyl groups introduced to carbohydrates by OH insertion reaction can serve as functional groups, protecting groups, and directing groups.

Acetocatechol functionalized viologen as polyfunctional material that responds to anion, cation and reductant in aqueous and organic solvents

Both viologen and catechol have been studied extensively. However, the stability of catechol-Fe(III) without additional oxidant is still not well understood. In this paper, we introduced acetocatechol into viologen to investigate its interactions with anion, cation, and reductant, as well as the stability of its Fe(III) complexes. This acetocatechol functionalized viologen, 1,1′-bis(2-(3,4-dihydroxyphenyl)-2-oxoethyl)- [4,4′-bipyridine]-1,1′-diium chloride (H6V·Cl2) exists in central symmetric ketone cation form in solid state. Viologen cation increased the acidity of the aceto group and deprotonated the enolic proton to form monodeprotonated enolic H5V+ in the presence of anion/base, which had the deepest color in organic solvents. The absorbance maximum of H5V+ increased with the decrease of solvent polarity. It also interacted with B4O72− and MoO42− by forming catechol ester in DMSO solution. The catechol moiety can coordinate to metal ion, especially Fe(III), in both aqueous and DMSO solution. In particular, it coordinated to Fe(III) much more readily in aqueous solution than in DMSO. Green monocatecholato Fe(III) and red-brown bis-catecholato Fe(III) complex also formed in aqueous solution. The monocatecholato Fe(III) complex first-order dimerized in aqueous solution at room temperature but underwent second-order decomposition to Fe(II) complex at 60 °C. The biscatecholato Fe(III) complex also transferred to other Fe(III) complexes at first- and second-order at room-temperature and 60 °C respectively. The t1/2 varied from several hours at room-temperature and several minutes at 60 °C at 10−4 M concentration. The interactions of Fe(III) in DMSO is much more complex than that of acetocatecholate without viologen. Fe(III) can also be reduced to free viologen radicals in the presence of sodium Na2S2O4, but not N2H4. In conclusion, this polyfunctional compound responds to anion via aceto and catechol, metal ion via catechol hydroxyl, while reductant via viologen.

Excited state dynamics of bis-dehydroxycurcumin tert-butyl ester, a diketo-shifted derivative of the photosensitizer curcumin.

Bis-dehydroxycurcumin tert-butyl ester (K2T23) is a derivative of the natural spice curcumin. Curcumin is widely studied for its multiple therapeutic properties, including photosensitized cytotoxicity. However, the full exploitation of curcumin phototoxic potential is hindered by the extreme instability of its excited state, caused by very efficient non radiative decay by means of transfer of the enolic proton to the nearby keto oxygen. K2T23 is designed to exhibit a tautomeric equilibrium shifted toward the diketo conformers with respect to natural curcumin. This property should endow K2T23 with superior excited-state stability when excited in the UVB band, i.e., in correspondence of the diketo conformers absorption peaks, making this compound an interesting candidate for topical photodynamic therapy of, e.g., skin tumors or oral infections. In this work, the tautomeric equilibrium of K2T23 between the keto-enolic and diketo conformers is assessed in the ground state in several organic solvents by UV-visible absorption and by nuclear magnetic resonance. The same tautomeric equilibrium is also probed in the excited-state in the same environments by means of steady-state fluorescence and time-correlated single-photon counting measurements. These techniques are also exploited to elucidate the excited state dynamics and excited-state deactivation pathways of K2T23, which are compared to those determined for several other curcuminoids characterized in previous works of ours. The ability of K2T23 in photosensitizing the production of singlet oxygen is compared with that of curcumin.

Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine

The asymmetric syntheses of pyrrolizidine, indolizidine and quinolizidine alkaloids have been achieved using the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to α-alkenyl-α,β-unsaturated esters followed by diastereoselective protonation of the resultant enolates as the key stereodefining steps. The azabicyclic scaffolds were then efficiently constructed upon sequential oxidative cleavage of the olefinic units within the resultant β-amino esters and hydrogenolytic N-debenzylation of the corresponding dialdehydes, which occurs with concomitant double reductive cyclisation. Subsequent reduction of the ester moieties with LiAlH4 gave (+)-trachelanthamidine, (+)-tashiromine, (1S,8aR)-1-(hydroxymethyl)octahydroindolizine and (+)-epilupinine in 4.9, 4.1, 3.0 and 5.9% overall yield, respectively, in only six steps from commercially available starting materials.

Copper‐Catalyzed 1,5‐Addition of Grignard reagents to Enantioenriched Donor–Acceptor Cyclopropanes with Inversion

AbstractA highly regioselective and stereoselective 1,5‐addition of alkyl groups to enantioenriched donor–acceptor cyclopropanes 1 and bicyclic cyclopropanes such as 6‐aryl‐1‐methoxycarbonyl‐3‐oxabicyclo[3.1.0]hexan‐2‐ones 4 using a Grignard reagent with a catalytic amount of Cu(OTf)2 (0.1 equivalent) afforded optically active diesters 2 or trans‐α,β‐disubstituted γ‐butyrolactones 5 with an excellent level of stereoinduction. An excess of the Grignard reagent is necessary to perform the 1,5‐alkylation with high yields. In the reaction of the enantioenriched bicyclic lactone 4, a highly stereoselective 1,5‐addition and subsequent highly trans‐selective protonation of the magnesium enolate via keto‐enol isomerization furnished the trans‐α,β‐disubstituted‐γ‐lactones with three contiguous chiral centers with excellent enantioselectivity. Based on the results, we also proposed the mechanism through cluster ion pairs or a simple ion pair to rationalize the high stereoselectivity of the reaction.

Asymmetric Cooperative Catalysis in a Three-Component Reaction: Mechanism and Origin of Enantio- and Diastereoselectivities.

Mechanistic insights gained through density functional theory (DFT M06 and B3LYP) computations on a three-component cooperative asymmetric catalytic reaction between a diazo ester, a carbamate, and an imine, catalyzed by dirhodium acetate and chiral phosphoric acid (Brønsted acid), are presented. The addition of the dirhodium-bound enol to the imine yielding an α,β-diamino ester is energetically more preferred over a potentially competitive protonation of the same enol leading to an α-amino ester.

Asymmetric Syntheses of (+)-Preussin B, the C(2)-Epimer of (-)-Preussin B, and 3-Deoxy-(+)-preussin B.

Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (-)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding β-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied by diastereoselective reductive cyclization in situ; reductive N-methylation then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product. Meanwhile, the same conjugate addition but followed by enolate oxidation with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-β-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to the corresponding syn-α-hydroxy-β-amino ester. Homologation of both of these diastereoisomeric α-hydroxy-β-amino esters gave the corresponding β-hydroxy-γ-amino ketones. N-Debenzylation and concomitant diastereoselective reductive cyclization, followed by reductive N-methylation, provided the C(2)-epimer of (-)-preussin B and (+)-preussin B as the major diastereoisomeric products, respectively. The overall yields (from phenylacetaldehyde) were 19% for 3-deoxy-(+)-preussin B over seven steps, 8% for the C(2)-epimer of (-)-preussin B over nine steps, and 7% for (+)-preussin B over eleven steps.

Quantum Chemical and Docking Insights into Bioavailability Enhancement of Curcumin by Piperine in Pepper.

We combine quantum chemical and molecular docking techniques to provide new insights into how piperine molecule in various forms of pepper enhances bioavailability of a number of drugs including curcumin in turmeric for which it increases its bioavailability by a 20-fold. We have carried out docking studies of quantum chemically optimized piperine structure binding to curcumin, CYP3A4 in cytochrome P450, p-Glycoprotein and UDP-glucuronosyltransferase (UGT), the enzyme responsible for glucuronosylation, which increases the solubility of curcumin. All of these studies establish that piperine binds to multiple sites on the enzymes and also intercalates with curcumin forming a hydrogen bonded complex with curcumin. The conjugated network of double bonds and the presence of multiple charge centers of piperine offer optimal binding sites for piperine to bind to enzymes such as UDP-GDH, UGT, and CYP3A4. Piperine competes for curcumin's intermolecular hydrogen bonding and its stacking propensity by hydrogen bonding with enolic proton of curcumin. This facilitates its metabolic transport, thereby increasing its bioavailability both through intercalation into curcumin layers through intermolecular hydrogen bonding, and by inhibiting enzymes that cause glucuronosylation of curcumin.

Quantum chemical insights into Alzheimer's disease: Curcumin's chelation with Cu(II), Zn(II), and Pd(II) as a mechanism for its prevention

We provide quantum chemical insights into curcumin's prevention of Alzheimer' disease through curcumin's scavenging of neurotoxic Cu(II), Zn(II), and Pd(II) transition metal ions that catalyze polymerization of amyloid-β and promote misfolding of amyloid into neurotoxic conformations. We have employed high level quantum chemical computations to study the chelate complexes of curcumin with Cu(II), Zn(II), and Pd(II). Quantum chemically derived structures, IR spectra, and UV-visible spectra of these complexes corroborate with the observed spectra, confirming that the primary site of chelation is the β-diketone bridge through the loss of an enolic proton of curcumin. We have also obtained the various structural parameters such as the Mulliken charges on various centers, highest occupied, lowest unoccupied molecular orbitals—all of which confirm that curcumin forms chelate complexes and thus acts as a scavenger of these neurotoxic metal ions preventing Alzheimer's disease. We find that the open-d-shell Cu(II) and Pd(II) form nearly square planar complexes while the closed-d-shell Zn(II) forms a tetrahedral complex with curcumin. © 2016 Wiley Periodicals, Inc.

Elucidation of the relationships between H-bonding patterns and excited state dynamics in cyclovalone.

Cyclovalone is a synthetic curcumin derivative in which the keto-enolic system is replaced by a cyclohexanone ring. This modification of the chemical structure might in principle result in an excited state that is more stable than that of curcumin, which in turn should produce an enhanced phototoxicity. Indeed, although curcumin exhibits photosensitized antibacterial activity, this compound is characterized by very fast excited-state dynamics which limit its efficacy as a photosensitizer. In previous works we showed that the main non-radiative decay pathway of keto-enolic curcuminoids is through excited-state transfer of the enolic proton to the keto-oxygen. Another effective deactivation pathway involves an intermolecular charge transfer mechanism occurring at the phenyl rings, made possible by intramolecular H-bonding between the methoxy and the hydroxyl substituent. In this paper we present UV-Vis and IR absorption spectra data with the aim of elucidating the intramolecular charge distribution of this compound and its solvation patterns in different environments, with particular focus on solute-solvent H-bonding features. Moreover, we discuss steady state and time-resolved fluorescence data that aim at characterizing the excited-state dynamics of cyclovalone, and we compare its decay photophysics to that of curcumin. Finally, because during the characterization procedures we found evidence of very fast photodegradation of cyclovalone, its photostability in four organic solvents was studied by HPLC and the corresponding relative degradation rates were calculated.

ChemInform Abstract: Amino Alcohol‐Mediated Enantioselective Syntheses of α‐Substituted Indanones and Tetralones, Ammonium Enolates as Key Intermediates

AbstractReview: [40 refs.

Curcumin derivatives as metal-chelating agents with potential multifunctional activity for pharmaceutical applications

Curcuminoids represent new perspectives for the development of novel therapeutics for Alzheimer's disease (AD), one probable mechanism of action is related to their metal complexing ability. In this work we examined the metal complexing ability of substituted curcuminoids to propose new chelating molecules with biological properties comparable with curcumin but with improved stability as new potential AD therapeutic agents. The K2T derivatives originate from the insertion of a -CH2COOC(CH3)3 group on the central atom of the diketonic moiety of curcumin. They retain the diketo-ketoenol tautomerism which is solvent dependent. In aqueous solution the prevalent form is the diketo one but the addition of metal ion (Ga3+, Cu2+) causes the dissociation of the enolic proton creating chelate complexes and shifting the tautomeric equilibrium towards the keto–enol form. The formation of metal complexes is followed by both NMR and UV–vis spectroscopy. The density functional theory (DFT) calculations on K2T21 complexes with Ga3+ and Cu2+ are performed and compared with those on curcumin complexes. [Ga(K2T21)2(H2O)2]+ was found more stable than curcumin one. Good agreement is detected between calculated and experimental 1H and 13C NMR data. The calculated OH bond dissociation energy (BDE) and the OH proton dissociation enthalpy (PDE), allowed to predict the radical scavenging ability of the metal ion complexed with K2T21, while the calculated electronic affinity (EA) and ionization potential (IP) represent yardsticks of antioxidant properties. Eventually theoretical calculations suggest that the proton-transfer-associated superoxide-scavenging activity is enhanced after binding metal ions, and that Ga3+ complexes display possible superoxide dismutase (SOD)-like activity.

ChemInform Abstract: Asymmetric Synthesis of the Marine Alkaloid (‐)‐(S)‐Nakinadine C.

Abstract The first asymmetric synthesis of the marine alkaloid (−)-(S)-nakinadine C is described. This synthesis employs the conjugate addition of lithium dibenzylamide to an N-α-phenylacryloyl SuperQuat derivative followed by diastereoselective protonation of the intermediate enolate using 2-pyridone as the key step to introduce the stereochemistry. (−)-(S)-Nakinadine C was isolated in 13% yield over 9 steps from commercially available atropic acid, 98:2 dr [(Z):(E) ratio] and >99% ee.