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A general phase‐transfer catalyst (PTC) mediated enantioselective alkylation of N‐acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at −40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S‐(hetero)aryl and branched and unbranched S‐alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever‐increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free‐NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)‐sulfoximine stereoisomer. [ABSTRACT FROM AUTHOR]

It has been shown that the Pd(Acac)2–mod–H2 colloidal system, where mod denotes chiral stabilizers of molecular (8S,9R)-cinhonidine, (–)-Сin, and ionic (–)-Cin*HCl and (–)-Cin*2HCl types, exhibits catalytic activity in the asymmetric hydrogenation of N-acetyl-α-amidocinnamic acid (AACA) at room temperature and an H2 pressure of 5 atm. The esterification reaction of the product, N-acetylphenylalanine (N-APhA), occurs in the presence of protonated forms of cinchonidine. The excess of the R-(–)-enantiomer of N-acetylphenylalanine is as large as 78% for the Pd(Acac)2–(–)-Сin–H2 system at (–)-Сin/Pd = 1.5, while the protonated forms of the quinine alkaloid show lower efficiency as modifiers of the catalytic system with respect to chiral induction. The X-ray diffraction analysis and high-resolution transmission electron microscopy have been employed to show the formation of palladium nanoparticles with average sizes of 5.3 ± 0.8 and 4.2 ± 0.5 nm for the Pd(Acac)2–(–)-Cin–H2 and Pd(Acac)2–(–)-Сin *HCl–H2 systems, respectively. [ABSTRACT FROM AUTHOR]

Aim: Cinchonine (CN) and its isomer cinchonidine (CD), two of the common cinchona alkaloids, are wildly used as antimalarial drugs. However, the effects of CN and CD on the auditory system are unknown. Methods: Molecular docking and molecular dynamics (MD) simulation were used for predicting effective drugs. The CCK‐8 assay was conducted for assessing cell viability in House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells. MitoSox Red staining revealed reactive oxygen species (ROS) amounts. TMRM staining was used to assess the mitochondrial membrane potential (ΔΨm). Immunofluorescence staining of myosin 7a was used to examine hair cells (HCs) in cisplatin‐treated neonatal mouse cochlear explants, while TUJ‐1 immunostaining was used for the detection of spiral ganglion neurons (SGNs). Cleaved caspase‐3 and TUNEL immunostaining were utilized for apoptosis assessment. Immunoblot was carried out to detect PI3K‐AKT signaling effectors. Results: Pretreatment with CN or CD significantly increased cell viability and reduced mitochondrial dysfunction and ROS accumulation in cisplatin‐treated HEI‐OC1 cells. Immunofluorescent staining of cochlear explants showed that CN and CD attenuated cisplatin‐induced damage to SGNs and HCs. Immunoblot revealed that CN and CD downregulated the expression of cleaved caspase‐3 and activated PI3K‐AKT signaling in cisplatin‐injured HEI‐OC1 cells. Conclusion: CD and CN can reduce ototoxicity caused by cisplatin and might help treat cisplatin‐associated hearing loss. [ABSTRACT FROM AUTHOR]

A simple and rapid access to fluorinated dithioesters was developed by a one-pot sequence corresponding to a Grignard reaction—Mitsunobu type substitution. These activated dithioesters have shown excellent reactivity in an aminolysis reaction from simple or more complex primary amines such as cinchona alkaloids. A stoichiometric amount of amine was sufficient to prepare various thioamides, including a 4-styrenylthioamide cinchonidine monomer, under environmentally friendly conditions, at room temperature, and in a very short time. [ABSTRACT FROM AUTHOR]

A divergent, enantioselective synthetic strategy is reported to produce the non-proteinogenic, biologically active natural amino acids norvaline, 5-hydroxy-4-oxo-L-norvaline, and ɣ-oxonorvaline. These were synthesized in good yields (45–75%) from the common starting material (S)-allylglycine obtained by asymmetric transfer allylation of glycine Schiff base using the Corey catalyst derived from cinchonidine in more than 97% enantiomeric excess. [ABSTRACT FROM AUTHOR]

Biological and synthetic molecular motors, fueled by various physical and chemical means, can perform asymmetric linear and rotary motions that are inherently related to their asymmetric shapes. Here, we describe silver-organic micro-complexes of random shapes that exhibit macroscopic unidirectional rotation on water surface through the asymmetric release of cinchonine or cinchonidine chiral molecules from their crystallites asymmetrically adsorbed on the complex surfaces. Computational modeling indicates that the motor rotation is driven by a pH-controlled asymmetric jet-like Coulombic ejection of chiral molecules upon their protonation in water. The motor is capable of towing very large cargo, and its rotation can be accelerated by adding reducing agents to the water. 'Molecular motors, fuelled by various physical and chemical means, can perform asymmetric linear and rotary motions that are inherently related to their asymmetric shapes. Here, the authors describe silver-organic micro-complexes of random shapes that exhibit macroscopic unidirectional rotation on water surface through the asymmetric release of cinchonine or cinchonidine chiral molecules. [ABSTRACT FROM AUTHOR]

The discovery of novel chiral selectors always fascinates us. This work describes the chiral separation performances of a new chiral selector (kasugamycin, KAS) in capillary electrophoresis (CE) for six pairs of stereoisomers, including ephedrine and pseudoephedrine, quinine and quinidine, cinchonine and cinchonidine, and amlodipine, promethazine and ofloxacin enantiomers. Kasugamycin, an aminoglycoside antibiotic in agriculture, shows significant biological activity against rice blast with low toxicity. As it turns out, this new chiral selector possesses good CE compatibility and stereoselectivity towards model analytes. In this work, we systematically investigated several separation parameters including kasugamycin concentration, buffer pH, separation voltage and the composition of the buffer solution. A detailed discussion about the chiral recognition mechanism was made based on Statistical Product and Service Solution (SPSS) analysis, NMR experiments (1D and 2D) and molecular modeling. This is the first time that kasugamycin is utilized as a chiral selector in CE, and the development of new chiral selectors from agricultural or veterinary antibiotics deserves more attention. [ABSTRACT FROM AUTHOR]

Alpha‐lipoic acid is a natural product that possesses distinct pharmacological properties. Lipoic acid is a short‐chain fatty acid containing an asymmetric carbon at five bonds of distance to the organic function. Herein, we developed a nuclear magnetic resonance protocol to access the chiral recognition of lipoic acid in a simple and rapid procedure employing cinchonidine as a cheap chiral solvation agent in deuterated chloroform. To optimize this method, a statistical design of the experimental model was performed to produce a clear understanding of the optimal concentration, temperature, and molar ratio parameters. Based on the obtained spectra, the cinchonidine H8‐H9 scalar coupling indicated a conformational preference in the chiral discrimination procedure. Density functional theory calculations established a proximity between the asymmetric center of lipoic acid and the aromatic moiety of cinchonidine, clarifying possible conformations in this ion‐pair interaction. The described protocol demonstrates how far is far enough to chiral discrimination using a chiral solvation agent, expanding the method to compounds that contain a remote stereocenter. [ABSTRACT FROM AUTHOR]

Enantioseparation of 3-hydroxycarboxylic acids via diastereomeric salt formation was demonstrated using 2-amino-1,2-diphenylethanol (ADPE) and cinchonidine as the resolving agents. Racemic 3-hydroxy-4-phenylbutanoic acid (rac-1), 3-hydroxy-4-(4-chlorophenyl)butanoic acid (rac-2), and 3-hydroxy-5-phenylpentanoic acid (rac-3) were efficiently resolved using these resolving agents. Moreover, the successive crystallization of the less-soluble diastereomeric salt of 1 and cinchonidine using EtOH yielded pure (R)-1 · cinchonidine salt in a high yield. The crystal structures of less-soluble diastereomeric salts were elucidated and it was revealed that hydrogen bonding and CH/π interactions play an important role in reinforcing the structure of the less-soluble diastereomeric salts. [ABSTRACT FROM AUTHOR]

An organocatalyzed α‐hydroxymethylation of α‐monoalkyl malonic diesters using 37% aqueous formaldehyde (formalin) as a one‐carbon electrophilic unit to generate all‐carbon substituted quaternary stereocenters has been developed. In the course of our exploration of catalytic methodologies, a metal‐free cooperative catalytic approach with cinchonidine and squaramide co‐catalysts was found to improve both reactivity and enantioselectivity in this transformation. Our organocatalytic method represents the first example of an enantioselective α‐hydroxymethylation of a malonic diester. The enantioenriched α‐hydroxymethyl products could be recrystallized with high recovery, yielding optically pure materials. Moreover, to demonstrate the utility of this methodology, the all‐carbon substituted α‐quaternary stereogenic malonate was converted to both (S)‐ and (R)‐4,4‐disubstituted oxazolidin‐2‐ones without loss of optical purity. [ABSTRACT FROM AUTHOR]

N-benzylcinchonidinium bromide, C26H29N2O+.Br-, with the systematic name (R)-[(2S,4S,5R)-1-benzyl-5-ethenyl-1-azoniabicyclo[2.2.2]octan-2-yl](quinolin-4-yl)methanol bromide, is a quaternary ammonium salt of the cinchona alkaloid cinchonidine. This salt is widely used as a chiral phase-transfer catalyst and chiral resolution agent. Both classical and non-classical hydrogen-bonding interactions, as well as anion effects have been shown to play key mechanistic roles in the catalysis of cinchona alkaloids. In an effort to understand the effects of water on these intermolecular interactions, the structures of anhydrous Nbenzylcinchonidinium bromide, (I), and the sesquihydrate, C26H29N2O+.Br-.-1.5H2O, (II), were determined. [ABSTRACT FROM AUTHOR]

Quinine- and cryptolepine-based antimalarials serve as valuable alternatives to artemisinin-based combination therapies (ACTs) in Ghana. Their use, however, is associated with adulteration and substandard quality challenges. An HPLC method targeting quinoline and indoloquinoline antimalarial alkaloids was developed, validated, and applied to evaluate herbal and pharmaceutical antimalarial formulations (HPAFs) and starting materials (APIs). The separation/quantitation of the alkaloids (including quinine, quinidine, cinchonine, cinchonidine, dihydroquinine, dihydroquinidine, and cryptolepine) was achieved on a Zorbax SB-CN column (250 mm × 4.6 mm, 5 μm), with an isocratic elution system of methanol: trifluoroacetic acid (0.1%, v/v) (15 : 85, v/v) at 1.5 mL/min and 223 nm. Method validation was according to ICH Q2(R1) guidelines. It was then used to assess the quality of APIs (n = 3) and HPAFs (n = 44) including quinine-based pharmaceutical antimalarial formulations (QBPAFs) (n = 23) and herbal antimalarial products (HAMPs). The method was found to be specific, selective, accurate, precise, and robust toward the alkaloids with linearity achieved within specified concentration ranges (r2 > 0.995 for all analytes). Analyte stability ranged between 6 and 12 hours. All the APIs contained quinine <99.0%–101.0%, with dihydroquinine and cinchonidine at levels compliant with the established acceptance criteria. The QBPAFs had quinine content ranging between 50.2% and 151.2%, with 43.5% (n = 10/23) of them complying with the acceptance criteria. The related alkaloids observed in the QBPAFs included quinidine (56.5%, n = 13/23), dihydroquinine (100%, n = 23/23), dihydroquinidine (21.7%, n = 5/23), cinchonine (17.4%, n = 4/23), and cinchonidine (95.7%, n = 22/23). For the HAMPs, 81.0% (n = 17/21) were adulterated with quinine (0.59 ± 0.04 mg/10 mL–86.03 ± 0.02 mg/10 mL). Cryptolepine was identified in 19% (n = 4/21) of the HAMPs with concentration ranging between 43.99 ± 0.43 μg/mL and 747.86 ± 0.34 μg/mL. In conclusion, the application of the ion-pair HPLC method targeting quinoline and indoloquinoline antimalarials has demonstrated the presence of quality and poor-quality HPAFs on the Ghanaian market. [ABSTRACT FROM AUTHOR]

[Display omitted] The cobalt oxide-vanadium oxide (Co 3 O 4 -V 2 O 5) combined with reduced graphene oxide (rGO) having band gap of ∼ 3.3 eV appeared as a suitable photocatalyst for selective oxidation of 2-naphthol to BINOL. C 2-symmetric BINOL was achieved with good yield using hydrogen peroxide as the oxidant under UV-light irradiation. The same catalyst was chirally modified with cinchonidine and a newly synthesized chiral Schiff base ligand having a sigma-hole center. The strong interaction of the chiral modifiers with the cobalt-vanadium oxide was truly evident from various spectroscopic studies and DFT calculations. The chirally modified mixed metal oxide transformed the oxidative C C coupling reaction with high enantioselectivity. High enantiomeric excess upto 92 % of R -BINOL was obtained in acetonitrile solvent and hydrogen peroxide as the oxidant. A significant achievement was the formation of S -BINOL in the case of the cinchonidine modified catalyst and R -BINOL with the Schiff base ligand anchored chiral catalyst. The UV-light induced catalytic reaction was found to involve hydroxyl radical as the active reactive species. The spin trapping ESR and fluorescence experiment provided relevant evidence for the formation of such species through photodecomposition of hydrogen peroxide on the catalyst surface. The chiral induction to the resultant product was found to induce through supramolecular interaction like O H...π, H...Br interaction. The presence of sigma hole center was believed to play significant role in naphtholate ion recognition during the catalytic cycle. [ABSTRACT FROM AUTHOR]

Organocatalytic Friedel‐Crafts aminoalkylation reaction is demonstrated in this study for the construction of biologically important hybrid molecular architectures of carbazole containing 3‐amino oxindoles using bifunctional cinchonidine derived thiourea organocatalyst. The Friedel‐Crafts functionalization of 4‐hydroxy carbazole with isatin derived ketimines well performed with a wide range of substrates resulted in excellent yields (up to 95 %) and enantioselectivities (up to 99 % ee) of the desired products. A minimal catalyst loading (0.5 mol%) was utilized at ambient temperatures under mild reaction conditions. [ABSTRACT FROM AUTHOR]

The chiral ionic liquid CILTPT-MS [CH3(OCH2CH2)16CD]+[CH3SO3]− (CD = cinchonidine) is found to exhibit cloud point character. Due to this cloud point character, a CILTPT-MS-stabilized chiral nano-Pt catalyst is prepared and utilized to realize transfer in a H2O–1-pentanol biphasic system by simply changing the temperature. Therefore, a fluorine-free, thermoregulated phase-transfer catalysis system is developed and applied to the asymmetric hydrogenation of α-ketoesters with enantiomeric excess of >99% and excellent conversion. In addition, the chiral nano-Pt catalyst can be easily separated and reused efficiently. [ABSTRACT FROM AUTHOR]

Pharmaceutical multicomponent crystals (MCCs) including salts and co-crystals of active pharmaceutical ingredients (APIs), are an active focus of research to improve various physicochemical properties of drugs. In this work, we demonstrate that the pharmaceutical artesunate (AS), a derivative of artemisinin (ART), forms a 1 : 1 salt with two cinchona alkaloids: quinine (QN) and cinchonidine (CND), representing the first report of MCCs combining two major types of antimalarial drugs. [ABSTRACT FROM AUTHOR]

A small family of novel modular monofunctional epicinchonidine-1,2,3-triazole compounds was prepared in very good overall yield (3 steps from cinchonidine, 49–87% yield) using simple Cu(I) catalyzed click-chemistry. The objective of this study was to access their hitherto unknown catalytic role in some key organic reactions like: ketimine hydrosilylation, Michael-addition and the Biginelli reaction. This is the first report on the application of cinchonidine derived 1,2,3-triazoles in organocatalysis, and includes catalytic screening and preliminary Density Functional Theory (DFT) mechanistic studies. The new compounds were screened for antimalarial activity against Plasmodium falciparum (W2 strain), exhibiting IC50 values in the range 2.0–6.8 µM; and cholinesterase inhibition, showing activity against eqBuChE, but their main potential is for tumor anti-proliferation (showing a lowest GI50 of 8.1 µM). Gratifyingly, all our compounds were non-cytotoxic against the non-tumor healthy cell line, BJ-hTERT and they presented excellent simulated pharmacological properties. [ABSTRACT FROM AUTHOR]

A V2O5@TiO2 catalyzed green and efficient protocol for the hydroxylation of boronic acid into phenol has been developed utilizing environmentally benign oxidant hydrogen peroxide. A wide range of electron‐donating and the electron‐withdrawing group‐containing (hetero)aryl boronic acids were transformed into their corresponding phenol. The methodology was also applied successfully to transform various natural and bioactive molecules like tocopherol, amino acids, cinchonidine, vasicinone, menthol, and pharmaceuticals such as ciprofloxacin, ibuprofen, and paracetamol. The other feature of the methodology includes gram‐scale synthetic applicability, recyclability, and short reaction time. [ABSTRACT FROM AUTHOR]

Bacterial resistance to antibiotics is an increasing threat to global healthcare systems. We therefore sought compounds with potential to reverse antibiotic resistance in a clinically relevant multi-drug resistant isolate of Escherichia coli (NCTC 13400). 200 natural compounds with a history of either safe oral use in man, or as a component of a traditional herb or medicine, were screened. Four compounds; ellagic acid, propyl gallate, cinchonidine and cepharanthine, lowered the minimum inhibitory concentrations (MICs) of tetracycline, chloramphenicol and tobramycin by up to fourfold, and when combined up to eightfold. These compounds had no impact on the MICs of ampicillin, erythromycin or trimethoprim. Mechanistic studies revealed that while cepharanthine potently suppressed efflux of the marker Nile red from bacterial cells, the other hit compounds slowed cellular accumulation of this marker, and/or slowed bacterial growth in the absence of antibiotic. Although cepharanthine showed some toxicity in a cultured HEK-293 mammalian cell-line model, the other hit compounds exhibited no toxicity at concentrations where they are active against E. coli NCTC 13400. The results suggest that phytochemicals with capacity to reverse antibiotic resistance may be more common in traditional medicines than previously appreciated, and may offer useful scaffolds for the development of antibiotic-sensitising drugs. [ABSTRACT FROM AUTHOR]

Cinchonidine-functionalized β-cyclodextrin was used as stabilizing agent for platinum nanoparticles dispersed in water, but also as chiral modifier for the asymmetric hydrogenation of ethyl pyruvate at 30 °C under 40 bar of hydrogen. This functionalized cyclodextrin allowed getting more stable, more catalytically active and also more enantioselective Pt nanoparticles compared to control catalytic systems. NMR and MALDI-MS analyses clearly showed the reduction of the vinyl group of the cinchonidine graft during the nanoparticles preparation. Under hydrogen pressure, the hydrogenation of the quinolinic moiety was also proven and can be responsible for the difficulties encountered during the recycling study.

Endeavor to discover biorational natural products-based insecticides, two series (27) of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine were prepared and assessed for their insecticidal activity against Mythimna separata in vivo by the leaf-dipping method at 1 mg/mL. Among all the compounds, especially derivatives 6l and 6o exhibited the best insecticidal activity with final mortality rates of 75.0% and 71.4%, respectively. Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9-substitution is well tolerated; the configuration of C8/9 position is important for insecticidal activity, and 9S-configuration is optimal; 6'-OCH3 moiety is not necessary, removal of it is also acceptable. [ABSTRACT FROM AUTHOR]

In order to prepare asymmetrically (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a), a key intermediate of dezocine, 17 cinchona alkaloid-derived catalysts were prepared and screened for the enantioselective alkylation of 1-methyl-7-methoxy-2-tetralone with 1,5-dibromopentane, and the best catalyst (C7) was identified. In addition, optimizations of the alkylation were carried out so that the process became practical and effective.

Ag–Cu bimetallic nanoparticles were synthesised and used as cathode materials for the asymmetric electroreduction of ethyl benzoylformate. The reaction induced by cinchonidine was conducted in an undivided cell to produce the optically active ethyl mandelate. We obtained ethyl mandelate with 54% enantiomeric excess and 42% yield under the optimal conditions. [ABSTRACT FROM AUTHOR]

Among all the malaria parasites, P. falciparum is the most predominant species which has developed drug resistance against most of the commercial anti-malarial drugs. Thus, finding a new molecule for the inhibition of enzymes of P. falciparum is the pharmacological challenge in present era. Herein, ten novel molecules have been designed with an amalgamation of cinchonidine, carbohydrate moiety and triazole ring by utilizing copper-catalyzed click reaction of cinchonidine-derived azide and clickable glycosyl alkynes. The molecular docking of developed molecules showed promising results for plasmepsin inhibition in the form of effective binding with target proteins. [ABSTRACT FROM AUTHOR]

Each year about 250 million people around the world are infected with parasites from the Plasmodium group causing malaria. Although more than 50 antimalarials are currently being tested, cinchona tree alkaloids in the form of quinoline derivatives are still used to treat the disease. The objective of this work was to develop and apply a novel method for separation and determination of six biologically active alkaloids using isotachophoresis. The following derivatives were involved in the study: quinine, quinidine, cinchonine, cinchonidine, acetylcinchonine, and acetylquinidine. Successful application of isotachophoresis for the separation of these diastereoisomers required a new terminating electrolyte. The developed method allows for separation of the above-mentioned alkaloids in less than 33 minutes. Linear regression coefficients were high and ranged from 0.9995 to 0.9999. Relative standard deviation did not exceed 5%, and the standard measurement uncertainty was below 3 μgL−1. The new method was then successfully used to determine quinine content in selected products. [ABSTRACT FROM AUTHOR]

Full conformational space of cinchonine and cinchonidine has been investigated by means of statistical analysis of quantum chemical molecular dynamics simulations. Recently developed procedure comprising principal component analysis of molecular dynamics trajectories was applied on cinchonine and cinchonidine as well as on their protonated and methylated quaternary derivatives. The method for full conformational analysis includes Cartesian coordinates sampling through quantum chemical molecular dynamics simulations, reduction of dimensionality by principal component analysis, determination of probability distributions in a reduced space of Cartesian coordinates and search for all the strict extrema points in probability distribution functions. In order to gain crucial insight in the understanding of chirality induction of these alkaloids, comparison of the determined conformational spaces of pseudo-enantiomers has been made. It was shown that protonation of the quinuclidine nitrogen atom stabilizes the conformers with the intramolecular 1N-H···9O hydrogen bond whereas methylation on the same position results in the reduction of the domain of internal coordinates responsible for the conformational space. [ABSTRACT FROM AUTHOR]

Summary of main observation and conclusion: Described herein is an organocatalytic enantioselective protonation of monofluorinated silyl enol ethers, affording an array of optically active α‐secondary α‐fluoroketones in good to high yields and enantioselectivities, under the catalysis of bifunctional cinchonidine derived squaramide C4. It represents a rare example of facile synthesis of enantioenriched α‐secondary α‐fluoroketones. With D2O as the deuterium source and MeOD as the solvent, the first highly enantioselective preparation of chiral α‐deuterated α‐fluoroketones in >92% deuteration is developed. [ABSTRACT FROM AUTHOR]

Rhodium nanoparticles (Rh NPs) stabilized by natural cinchona alkaloids were synthesized in imidazolium-based ionic liquids using H2 as the reductant. Characterization showed well-dispersed Rh NPs of about 1.96 nm (TEM and HRTEM) and confirmed the ionic liquid and cinchona alkaloid stabilization to the Rh(0) NPs (XPS). When modified by chiral diamine, including (1R,2R)-diphenylethylenediamine ((1R,2R)-DPEN) or cinchona alkaloid derivatives, the Rh NPs catalysts exhibited good activity, chemoselectivity and enantioselectivity in the heterogeneous enantioselective hydrogenation of aromatic ketones. Synergistic effect between (1R,2R)-DPEN and cinchonidine was also observed, which significantly accelerated the reaction rate and enhanced the enantioselectivity. 63.0% enantioselectivity and 98.9% chemoselectivity could be achieved in the acetophenone enantioselective hydrogenation; up to 70.2% enantioselectivity and 100% chemoselectivity was obtained in the isobutyrylbenzene catalytic enantioselective hydrogenation. Catalytic system could be reused several times without significant loss in activity, chemoselectivity as well as enantioselectivity. This catalytic protocol opens the door to heterogeneous enantioselective hydrogenation of aromatic ketones with metal Rh NPs immobilized in ionic liquid. [ABSTRACT FROM AUTHOR]

New efficient catalysts based on electrophilic N‐fluoro quaternary ammonium salts are reported for catalytic allylation of (E)‐N,1‐diphenylmethanimine. The chiral version of the catalyst based on cinchonidine (F‐CD‐BF4) shows high catalytic activity with approximately 94% ee and TOF (>800 h−1). The F‐CD‐BF4 is prepared from cinchonidine and Selectfluor by one‐step transfer fluorination. [ABSTRACT FROM AUTHOR]

A new family of copolymers based on styrene and a polymerizable cinchonidine thioamide derivative was synthesized by conventional radical polymerization. The copolymers were tested as homogeneous supported organocatalysts in the enantioselective decarboxylative protonation (EDP) of α-aminomalonate hemiesters giving access to α-amino acids under very mild conditions. These macromolecular catalysts could be prepared on a large scale and outperformed their unsupported analogues providing the desired products in high yield and enantioselectivity. Furthermore, recycling experiments were conducted which showed good enantioselectivities. A new styrenic thioamide-bearing cinchonidine was synthesized over several grams and used in a conventional radical polymerization with different ratios of styrene as comonomer. The copolymers were tested as homogeneous supported organocatalysts in the enantioselective decarboxylative protonation (EDP) reaction of α-aminomalonate hemiesters (MAHOs) giving access to phenylalanine derivatives in high yield and enantioselectivity. [Display omitted] • Synthesis of a styrenic monomer from cinchonidine with a thioamide function. • Macromolecular catalysts were obtained by radical copolymerizations with styrene. • Decarboxylative protonation reactions were performed with macromolecular catalysts. • Products were obtained in high yield and enantioselectivity. • Recycling experiments were conducted which good enantioselectivities. [ABSTRACT FROM AUTHOR]

Abstract: The development of efficient syntheses of complex natural products has long been a major challenge in synthetic chemistry. Designing cascade reactions and employing bioinspired transformations are an important and reliable means of achieving this goal. Presented here is a combination of these two strategies, which allow efficient asymmetric synthesis of the cinchona alkaloid (+)‐cinchonidine. The key steps of this synthesis are a controllable, visible‐light‐induced photoredox radical cascade reaction to efficiently access the tetracyclic monoterpenoid indole alkaloid core, as well as a practical biomimetic cascade rearrangement for the indole to quinoline transformation. The use of stereoselective chemical transformations in this work makes it an efficient synthesis of (+)‐cinchonidine. [ABSTRACT FROM AUTHOR]

An organocatalytic enantioselective allylic alkylation of 5 H -oxazol-4-ones with Morita-Baylis-Hillman carbonates has been developed. With 10 mol% of commercially available cinchonidine, a wide range of substituted 5 H -oxazol-4-one derivatives were constructed in good-to-excellent yields with high diastereo- and enantioselectivities. The allylic alkylation adducts obtained are valuable precursors for the synthesis of chiral α-alkyl α-hydroxycarboxylic acid derivatives, which represent a series of versatile building blocks in many biologically active compounds. [ABSTRACT FROM AUTHOR]

The cinchonidine squaramide catalyzed enantioselective 1,6‐Michael addition reaction between pyrazolin‐5‐ones and 3‐methyl‐4‐nitro‐5‐alkenylisoxazoles has been developed. This method successfully afforded various chiral heterocyclic compounds that containing both pyrazole and isoxazole moieties in good yields (up to 91 %) with high enantiomeric ratios (er up to 91:9). [ABSTRACT FROM AUTHOR]

Several synthetic strategies were developed for the preparation of chiral dendrimer-encapsulated Pt nanoparticle (Pt DEN) catalysts. In one approach, regular OH-terminated polyamidoamine (PAMAM) dendrimers were first derivatized with cinchonidine using “click” chemistry and sebacic acid as a linker. As many as half of the 64 terminal OH groups in a 4th generation PAMAM dendrimer could be modified this way, and the overall cinchonidine content could be tuned by controlling the CD:PAMAM ratio during synthesis. Platinum nanoparticles were then added to these cinchonidine-modified dendrimers. In an alternative route, regular Pt DENs were made first using PAMAM, and the resulting material was then derivatized with cinchonidine. The two synthetic routes proved successful, but led to materials with different spectroscopic and catalytic properties, presumably because the metal nanoparticles in the first case are made near the cinchonidine functionality, in the outside of the dendrimer structure rather than in its inside, as believed to be the case with the second procedure. A potential complication related to the poisoning of the Pt nanoparticle surface during synthesis was also identified in the second protocol. The catalytic performance of these catalysts for the hydrogenation of α-ketoesters proved to be poor in all cases, presumably because of a number of problems associated with mass transport limitations inside the dendrimer structures and restricted flexibility of the outer chiral branches, which may not be able to interact with the catalytic surfaces. Nevertheless, interesting synthetic lessons were derived from our work with potential value for other applications. [ABSTRACT FROM AUTHOR]

Abstract: A site‐divergent stereoselective Michael reaction system is developed based on the identification of two distinct catalysts. Cinchonidine‐derived thiourea catalyzes the 1,4‐addition of prochiral azlactone enolates to enynyl N‐acyl pyrazoles in a highly diastereo‐ and enantioselective manner to give stereochemically defined alkynes, while P‐spiro chiral triaminoiminophosphorane catalytically controls the stereoselective 1,6‐addition and the consecutive γ‐protonation of the vinylogous enolate intermediate to afford Z,E‐configured conjugated dienes. This 1,6‐adduct serves as a valuable precursor for the synthesis of a 2‐amino‐2‐deoxy sugar. [ABSTRACT FROM AUTHOR]

Hydrogenation of acetophenone and esters of ketoacids with molecular hydrogen in the presence of the Pd(acac)2-(-)-cinchonidine-H2 catalytic system has been studied. The dependence of the molar ratio of (-)-cinchonidine/Pd on size and shape of palladium nanoparticles, formed in the system, also on reaction rate and enantioselectivity has been established. The nature of the regularities observed for the Pd(acac)2-(-)-cinchonidine-H2 catalytic system was discussed. [ABSTRACT FROM AUTHOR]

Cinchonidine and Theophylline vitrification abilities have been investigated by differential and fast scanning calorimetry. These active pharmaceutical compounds are known in the literature to have a very high tendency to crystallize which has been confirmed by classical differential scanning calorimetry. Due to the growing interest in amorphous pharmaceutical compounds, their possible vitrifications have been investigated by fast scanning calorimetry. This work shows the high potential of this advanced thermal analysis technique to investigate the vitrification of active pharmaceutical compounds by melt-quenching protocol. For the first time, glass transitions of Cinchonidine and Theophylline were measured. From Cinchonidine, it has been shown that complete glassy state can be obtained by cooling from the melt at 2000 K/s. Crystallization has also been suppressed by cooling down from the melt at 2 K/s. However, such rate does not avoid the formation of nuclei. Theophylline crystallization process has been suppressed by a melt-quenching protocol carried out with a cooling rate of 4000 K/s. However, the phenomenon of nuclei formation upon cooling seems unavoidable at this cooling rate. For both active pharmaceutical compounds, physical aging has been observed to play a role on the nuclei formation below the glass transition leading to modify the subsequent crystallization. [ABSTRACT FROM AUTHOR]