Modified cinchona alkaloid-catalysed enantioselective [4+4] annulations of cyclobutenones and 1-azadienes

Bacterial biofilms are resistant to most of the commonly available antibacterial chemotherapies. Thus, an enormous need exists to meet the demands of effective anti-biofilm therapy. In this study, a small library of cinchona alkaloids, including the naturally occurring compounds cinchonidine and cinchonine, as well as various synthetic derivatives and analogues was screened for antibacterial and anti-biofilm activity against the Staphylococcus aureus biofilm producing strain ATCC 25923. Two methods were used to evaluate activity against biofilms, namely crystal violet staining to measure biomass and resazurin assay to measure biofilms viability. Cinchonidine was found to be inactive, whereas a synthetic derivative, 11-triphenylsilyl-10,11-dihydrocinchonidine (11-TPSCD), was effective against planktonic bacteria as well as in preventing biofilm formation at low micromolar concentrations. Higher concentrations were required to eradicate mature biofilms.

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Formation and Structure of Cinchona Alkaloid (Bis-2,3-naphthalenediyl)orthoborate Salts

Zeitschrift für Naturforschung B ◽

10.1515/znb-2000-1115 ◽

2000 ◽

Vol 55 (11) ◽

pp. 1083-1088 ◽

Cited By ~ 1

Author(s):

Maciej Kubicki ◽

Teresa Borowiak ◽

Krystyna Gawrońska ◽

Jacek Gawroński

Keyword(s):

Crystal Structure ◽

Nitrogen Atom ◽

Hydrogen Bonds ◽

Cinchona Alkaloids ◽

Cinchona Alkaloid ◽

Cd Spectra ◽

Polar Solvents ◽

X Ray ◽

Solvent Molecules ◽

Additional Hydrogen

A series of (bis-2,3-naphthalenediyl)orthoborate salts of Cinchona alkaloids has been synthesized and characterized. The interactions between ions in the salts have been studied by means of circular dichroism spectroscopy and X-ray crystal structure determination. The CD spectra of the dihydroquinidine salt show that in non-polar solvents it exists as a tightly held ion pair. The crystal structure of the cinchonidine salt proves the existence of ions in the solid state. The protonation takes place at the quinuclidine nitrogen atom. The hydrogen bonds connect cation and anion into one recognizable unit. Additional hydrogen bonds (with hydroxy group as a hydrogen donor and quinoline nitrogen atom as an acceptor) form infinite chains of cations along the [001] direction. There are cavities in the crystal structure that are partially filled by solvent molecules (acetone).

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Liquid Chromatographic Analysis of Cinchona Alkaloids in Beverages

Journal of AOAC International ◽

10.1093/jaoac/89.4.1042 ◽

2006 ◽

Vol 89 (4) ◽

pp. 1042-1047 ◽

Cited By ~ 9

Author(s):

Masao Horie ◽

Mitsuo Oishi ◽

Fusako Ishikawa ◽

Tetsuya Shindo ◽

Akiko Yasui ◽

...

Keyword(s):

Solid Phase ◽

Potassium Dihydrogen Phosphate ◽

Ammonium Hydroxide ◽

Cinchona Alkaloids ◽

Cinchona Alkaloid ◽

Dihydrogen Phosphate ◽

Uv Detector ◽

Fluorescence Detector ◽

Beverage Samples ◽

Solid Phase Extraction Cartridge

Abstract A method for the determination of Cinchona extract (whose main components are the alkaloids cinchonine, cinchonidine, quinidine, and quinine) in beverages by liquid chromatography was developed. A beverage with an alcohol content of more than 10% was loaded onto an OASIS HLB solid-phase extraction cartridge, after it was adjusted to pH 10 with 28% ammonium hydroxide. Other beverages were centrifuged at 4000 rpm for 5 min, and the supernatant was loaded onto the cartridge. The cartridge was washed with water followed by 15% methanol, and the Cinchona alkaloids were eluted with methanol. The Cinchona alkaloids in the eluate were chromatographed on an L-column ODS (4.6 mm id × 150 mm) with methanol and 20 mmol/L potassium dihydrogen phosphate (3 + 7) as the mobile phase. Cinchona alkaloids were monitored with an ultraviolet (UV) detector at 230 nm, and with a fluorescence detector at 405 nm for cinchonine and cinchonidine and 450 nm for quinidine and quinine (excitation at 235 nm). The calibration curves for Cinchona alkaloids with the UV detector showed good linearity in the range of 2400 μg/mL. The detection limit of each Cinchona alkaloid, taken to be the concentration at which the absorption spectrum could be identified, was 2 μg/mL. The recovery of Cinchona alkaloids added at a level of 100 μg/g to various kinds of beverages was 87.6-96.5%, and the coefficients of variation were less than 3.3%. A number of beverage samples, some labeled to contain bitter substances, were analyzed by the proposed method. Quinine was detected in 2 samples of carbonated beverage.

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ADMET Polymerization of Dimeric Cinchona Squaramides for the Preparation of a Highly Enantioselective Polymeric Organocatalyst

Catalysts ◽

10.3390/catal10050591 ◽

2020 ◽

Vol 10 (5) ◽

pp. 591

Author(s):

Mohammad Shahid Ullah ◽

Sadia Afrin Chhanda ◽

Shinichi Itsuno

Keyword(s):

Second Generation ◽

Michael Reaction ◽

Cinchona Alkaloids ◽

Cinchona Alkaloid ◽

Acyclic Diene Metathesis ◽

Chiral Polymers ◽

Admet Polymerization ◽

Reaction Condition ◽

High Yields ◽

Asymmetric Michael Reaction

Under the acyclic diene metathesis (ADMET) reaction condition, the C3-vinyl groups of cinchona alkaloids readily react with each other to form a C-C bond. A novel type of cinchona alkaloid polymers was synthesized from dimeric cinchona squaramides using the Hoveyda-Grubbs’ second-generation catalysts (HG2) by means of ADMET reaction. The chiral polymers, containing cinchona squaramide moieties in their main chains, were subsequently employed as catalysts for the enantioselective Michael reaction to give the corresponding chiral adducts in high yields with excellent enantioselectivity and diastereoselectivity. Both enantiomers from the asymmetric Michael reaction were distinctively prepared while using the polymeric catalysts, possessing pseudoenantiomeric structures. The catalysts were readily recovered from the reaction mixture and recycled several times due to the insolubility of the cinchona-based squaramide polymers.

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Antimicrobial Activity of Quasi-Enantiomeric Cinchona Alkaloid Derivatives and Prediction Model Developed by Machine Learning

Antibiotics ◽

10.3390/antibiotics10060659 ◽

2021 ◽

Vol 10 (6) ◽

pp. 659

Author(s):

Alma Ramić ◽

Mirjana Skočibušić ◽

Renata Odžak ◽

Ana Čipak Gašparović ◽

Lidija Milković ◽

...

Keyword(s):

Machine Learning ◽

Antimicrobial Activity ◽

Potential Energy ◽

Potential Energy Surfaces ◽

Bacterial Infections ◽

Cinchona Alkaloids ◽

Cinchona Alkaloid ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Energy Surfaces

Bacterial infections that do not respond to current treatments are increasing, thus there is a need for the development of new antibiotics. Series of 20 N-substituted quaternary salts of cinchonidine (CD) and their quasi-enantiomer cinchonine (CN) were prepared and their antimicrobial activity was assessed against a diverse panel of Gram-positive and Gram-negative bacteria. All tested compounds showed good antimicrobial potential (minimum inhibitory concentration (MIC) values 1.56 to 125.00 μg/mL), proved to be nontoxic to different human cell lines, and did not influence the production of reactive oxygen species (ROS). Seven compounds showed very strong bioactivity against some of the tested Gram-negative bacteria (MIC for E. coli and K. pneumoniae 6.25 μg/mL; MIC for P. aeruginosa 1.56 μg/mL). To establish a connection between antimicrobial data and potential energy surfaces (PES) of the compounds, activity/PES models using principal components of the disc diffusion assay and MIC and data towards PES data were built. An extensive machine learning procedure for the generation and cross-validation of multivariate linear regression models with a linear combination of original variables as well as their higher-order polynomial terms was performed. The best possible models with predicted R2(CD derivatives) = 0.9979 and R2(CN derivatives) = 0.9873 were established and presented. This activity/PES model can be used for accurate prediction of activities for new compounds based solely on their potential energy surfaces, which will enable wider screening and guided search for new potential leads. Based on the obtained results, N-quaternary derivatives of Cinchona alkaloids proved to be an excellent scaffold for further optimization of novel antibiotic species.

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New α- and β-cyclodextrin derivatives with cinchona alkaloids used in asymmetric organocatalytic reactions

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.15.80 ◽

2019 ◽

Vol 15 ◽

pp. 830-839

Author(s):

Iveta Chena Tichá ◽

Simona Hybelbauerová ◽

Jindřich Jindřich

Keyword(s):

Click Reaction ◽

Enantiomeric Excess ◽

Cinchona Alkaloids ◽

Cinchona Alkaloid ◽

Cyclodextrin Derivatives ◽

Allylic Amination ◽

Asymmetric Syntheses ◽

Wide Range ◽

Enantioselective Reactions ◽

Organocatalytic Reactions

The preparation of new organocatalysts for asymmetric syntheses has become a key stage of enantioselective catalysis. In particular, the development of new cyclodextrin (CD)-based organocatalysts allowed to perform enantioselective reactions in water and to recycle catalysts. However, only a limited number of organocatalytic moieties and functional groups have been attached to CD scaffolds so far. Cinchona alkaloids are commonly used to catalyze a wide range of enantioselective reactions. Thus, in this study, we report the preparation of new α- and β-CD derivatives monosubstituted with cinchona alkaloids (cinchonine, cinchonidine, quinine and quinidine) on the primary rim through a CuAAC click reaction. Subsequently, permethylated analogs of these cinchona alkaloid–CD derivatives also were synthesized and the catalytic activity of all derivatives was evaluated in several enantioselective reactions, specifically in the asymmetric allylic amination (AAA), which showed a promising enantiomeric excess of up to 75% ee. Furthermore, a new disubstituted α-CD catalyst was prepared as a pure AD regioisomer and also tested in the AAA. Our results indicate that (i) the cinchona alkaloid moiety can be successfully attached to CD scaffolds through a CuAAC reaction, (ii) the permethylated cinchona alkaloid–CD catalysts showed better results than the non-methylated CDs analogues in the AAA reaction, (iii) promising enantiomeric excesses are achieved, and (iv) the disubstituted CD derivatives performed similarly to monosubstituted CDs. Therefore, these new CD derivatives with cinchona alkaloids effectively catalyze asymmetric allylic aminations and have the potential to be successfully applied in other enantioselective reactions.

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Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of β-ketoesters

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.8.138 ◽

2012 ◽

Vol 8 ◽

pp. 1233-1240 ◽

Cited By ~ 15

Author(s):

Wen-Bin Yi ◽

Xin Huang ◽

Zijuan Zhang ◽

Dian-Rong Zhu ◽

Chun Cai ◽

...

Keyword(s):

Solid Phase Extraction ◽

Solid Phase ◽

Cinchona Alkaloids ◽

Cinchona Alkaloid ◽

Phase Extraction

A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of β-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from the reaction mixture by simple fluorous solid-phase extraction (F-SPE) and used for the next round of reaction without further purification.

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The Use of cinchona Alkaloid Derivatives as Chiral Ligands and Organocatalysts in Asymmetric Catalysis

Mini-Reviews in Organic Chemistry ◽

10.2174/1570193x18666210428133120 ◽

2021 ◽

Vol 18 ◽

Author(s):

Minghua Li ◽

Wei He ◽

Sheng-Yong Zhang

Keyword(s):

Asymmetric Catalysis ◽

Organic Synthesis ◽

Cinchona Alkaloids ◽

Cinchona Alkaloid ◽

Chiral Induction ◽

Design And Synthesis ◽

The Past ◽

Oxidation Reduction ◽

Induction Process ◽

New Ideas

: Cinchona alkaloids are natural products extracted from cinchona plants, which contain quinine, quinidine, cinchonine, and cinchonidine. During the past 30 years, due to their attractive structural properties, these compounds have been used as chiral skeletons and organocatalysts in asymmetric organic synthesis. In this review, we summarize the applications of cinchona alkaloids derivatives in asymmetric catalysis recently developed by our group, including oxidation, reduction, and C-C bonds formation. These studies solved some of the problems with the various asymmetric reactions discussed, while also enriching alkaloids chemistry, providing new ideas for the design and synthesis of chiral catalysts, and providing abundant experimental data for the chiral induction process.

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