Cinchona Alkaloid Derivatives Research Articles

Enantiospecific Analysis of Carboxylic Acids Using Cinchona Alkaloid Dimers as Chiral Solvating Agents.

Cinchona alkaloid derivatives as Brønsted base catalysts have attracted considerable attention in the field of asymmetric catalysis. However, their potential application as chiral solvating agents has not been described. In this research, we investigated the use of the Cinchona alkaloid dimer, namely, (DHQ)2PHAL, as a chiral solvating agent for discerning various mandelic acid derivatives through 1H NMR spectroscopy. The addition of catalytic amounts of DMAP facilitated this process. Our experimental results demonstrate that dimeric (DHQ)2PHAL exhibits remarkable chiral discrimination properties regarding the diagnostic split protons of 1H NMR signals (including 24 examples, up to 0.321 ppm). Furthermore, it serves as an excellent chiral discriminating agent and provides good resolution for racemic chiral phosphoric acid as determined by 31P NMR spectroscopy. The quality of enantiodifferentiation has also been evaluated by means of the parameter "resolution (Rs)". Significantly, this class of CSAs based on (alkaloid)2linker systems with an azaaromatic linker can be directly employed, which is commercially available in an enantiopure form at very low cost and exhibits promising potential in determining the enantiopurity of α-hydroxy acids by chemoselective and biocatalytic reactions.

Synthesis, Anti-Oomycete and Anti-fungal Activities of Novel Cinchona Alkaloid Derivatives Containing Sulfonate Moiety.

Using cinchona alkaloid as the lead compound, twenty-four cinchona alkaloid sulfonate derivatives (1 a-l, 2 a-c, 3 a-c, 4 a-c, and 5 a-c) were designed and prepared by modifying their C9 position, and structurally confirmed by 1 H-NMR, 13 C-NMR, HR-MS and melting points. Moreover, the stereochemical configurations of compounds 1 f and 1 l were unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we determined the anti-oomycete and anti-fungal activities of these target compounds against Phytophthora capsici and Fusarium graminearum in vitro. The results showed that two compounds 4 b and 4 c exhibited prominent anti-oomycete activity, and the median effective concentration (EC50 ) values of 4 b and 4 c against P. capsici were 22.55 and 16.32 mg/L, respectively. This study suggested that when the C9 position of cinchona alkaloid sulfonate derivatives is in the S configuration and the 6'-position methoxy group is not present, the anti-oomycete activity is superior. In addition, five compounds 1 e, 1 f, 1 k, 3 c and 4 c displayed significant anti-fungal activity, with EC50 values of 43.64, 45.07, 80.18, 48.58 and 41.88 mg/L against F. graminearum, respectively. This result indicates that only when a specific substituent is introduced into the structural framework of the target compound, the corresponding compound exhibits significant inhibitory activity against fungi.

Synthesis, anti-oomycete and anti-fungal activities of novel cinchona alkaloid derivatives bearing carbamate moiety

In order to explore novel natural product-based anti-oomycete and anti-fungal agents, twenty cinchona alkaloid carbamate derivatives (1a-d, 2a-d, 3a-d, 4a-d, and 5a-d) were designed and prepared, and structurally confirmed by 1H NMR, 13C NMR, HRMS, and melting point. The stereochemical configuration of compound 1a was unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we evaluated the anti-oomycete and anti-fungal activities of these target compounds against Phytophthora capsici and Fusarium graminearum in vitro. The results showed that five compounds 1d, 2d, 3d, 4d, and 5d exhibited prominent anti-oomycete and anti-fungal activities, and the median effective concentration (EC50) values of 1d, 2d, 3d, 4d, and 5d against P. capsici and F. graminearum were 21.1, 16.6, 22.4, 14.4, 13.9 mg/L and 38.2, 19.8, 36.6, 30.3, 27.7 mg/L, respectively. This study suggested that when a specific substituent is introduced into the cinchona alkaloid skeleton, i.e. R1/R2 = Ph/Ph, the corresponding derivatives exhibit significant anti-oomycete and anti-fungal activities. And the configuration of the C8/9 position of the target compound is crucial for its anti-oomycete and anti-fungal activities, and 9S-configuration is optimal.

Ultra‐Fast Continuous‐Flow Photo‐Thiol‐Ene Functionalization of Conformation‐Controlled Cinchona Alkaloids

AbstractIn this work, we describe ultra‐fast continuous flow photo‐thiol‐ene reactions on cinchona alkaloids derivatives through a control of the reactive conformation in solution. Flow thiol‐ene reactions proceed at 32 °C under light irradiation at 365 nm and require only 2.5 minutes of residence time to reach completion. The short path length of the tubular flow photochemical reactor, which maximizes and homogenizes the photon flux, associated to the fine tuning of the reactive conformation of cinchona alkaloids in solution are the main reasons for the high rates observed. The predominant conformation in solution of cinchona alkaloids was adjusted through the substitution of the hydroxyl group at C9 by a phenyl carbamate function.

Synthesis, Biological Evaluation and Machine Learning Prediction Model for Fluorinated Cinchona Alkaloid-Based Derivatives as Cholinesterase Inhibitors.

A series of 46 Cinchona alkaloid derivatives that differ in positions of fluorine atom(s) in the molecule were synthesized and tested as human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. All tested compounds reversibly inhibited AChE and BChE in the nanomolar to micromolar range; for AChE, the determined enzyme-inhibitor dissociation constants (Ki) ranged from 3.9–80 µM, and 0.075–19 µM for BChE. The most potent AChE inhibitor was N-(para-fluorobenzyl)cinchoninium bromide, while N-(meta-fluorobenzyl)cinchonidinium bromide was the most potent BChE inhibitor with Ki constant in the nanomolar range. Generally, compounds were non-selective or BChE selective cholinesterase inhibitors, where N-(meta-fluorobenzyl)cinchonidinium bromide was the most selective showing 533 times higher preference for BChE. In silico study revealed that twenty-six compounds should be able to cross the blood-brain barrier by passive transport. An extensive machine learning procedure was utilized for the creation of multivariate linear regression models of AChE and BChE inhibition. The best possible models with predicted R2 (CD-derivatives) of 0.9932 and R2(CN-derivatives) of 0.9879 were calculated and cross-validated. From these data, a smart guided search for new potential leads can be performed. These results pointed out that quaternary Cinchona alkaloids are the promising structural base for further development as selective BChE inhibitors which can be used in the central nervous system.

Synthesis of Sulfonylated Cinchona Alkaloids via Zinc-Mediated Sulfonylation of the N-Oxides of the Quinoline Groups

AbstractA general and practical method for the synthesis of sulfonylated cinchona alkaloids is presented. The reactions are carried out via Zn-mediated nucleophilic aromatic substitution of the N-oxides of the quinoline core in cinchona alkaloids with a range of sulfonyl chlorides. By careful optimization of the reaction parameters and the procedure, both aromatic and aliphatic sulfonyl chlorides react efficiently with the N-oxides to afford the corresponding sulfonylated products in high yields. In addition, the reaction can be reliably scaled up to gram level. As a result, this method provides a practical route for the synthesis of new cinchona alkaloid derivatives that might be potentially useful compounds, particularly in asymmetric catalysis.

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

: 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 have 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.

Cinchona Alkaloid-Inspired Urea-Containing Autophagy Inhibitor Shows Single-Agent Anticancer Efficacy.

Autophagy is upregulated in response to metabolic stress, a hypoxic tumor microenvironment, and therapeutic stress in various cancers and mediates tumor progression and resistance to cancer therapy. Herein, we identified a cinchona alkaloid derivative containing urea (C1), which exhibited potential cytotoxicity and inhibited autophagy in hepatocellular carcinoma (HCC) cells. We showed that C1 not only induced apoptosis but also blocked autophagy in HCC cells, as indicated by the increased expression of LC3-II and p62, inhibition of autophagosome-lysosome fusion, and suppression of the Akt/mTOR/S6k pathway in the HCC cells. Finally, to improve its solubility and efficacy, we encapsulated C1 into PEGylated lipid-poly(lactic-co-glycolic acid) (PLGA) nanoscale drug carriers. Systemic administration of nanoscale C1 significantly suppressed primary tumor growth and prevented distant metastasis while maintaining a desirable safety profile. Our findings demonstrate that C1 combines autophagy modulation and apoptosis induction in a single molecule, making it a promising therapeutic option for HCC.

Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems

AbstractChiral halogenated substances have many applications in pharmaceuticals, agrochemicals, and materials, such as polymers, liquid crystals and as intermediates in synthesis. The presence of a halogen atom in a molecule can have a large effect in its properties; for instance, halogens are used in drugs to improve lipophilicity, membrane permeability and absorption, and even the blood‐brain barrier permeability. As highlighted in this review, there are nowadays a range of highly selective, versatile halogenating reagents, electrophilic, nucleophilic or radical in nature, which operate under mild conditions, allowing late‐stage functionalization of complex molecules in cascade reactions. Recent developments in organocatalyst design revealed novel Cinchona alkaloids derivatives, chiral phosphoric acids, amines, phosphines and several bifunctional catalysts, mostly thiourea‐ or squaramide‐based, which introduced chirality, with high levels of enantio‐ and diastereoselection, in the formation of one or multiple chiral centers in a single synthetic operation, as shown. In this review we survey the literature published in this field from 2014 to 2020.

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

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.

C2‐Symmetric Cinchona Alkaloid Derivatives: Versatile Catalysts for the Enantioselective C−C Bond Forming Conjugate Addition of Nucleophiles to Simple α,β‐Unsaturated Acyl Pyrazoles

AbstractA single C2‐symmetric squaramide catalyst system allows the facile addition of either malononitrile or benzyl nitroacetate to simple pyrazole‐based Michael acceptors with excellent enantiocontrol and at lower catalyst loadings than previously possible. The latter reactions are not diastereoselective, however facile hydrogenolysis leads to decarboxylation and formation of the formal adduct from the addition of nitromethane (a very recalcitrant nucleophile in this chemistry) with excellent yield and enantiocontrol.

Diastereodivergent Synthesis of Bridged Tetrahydroisoquinoline Derivatives Catalyzed by Modularly Designed Organocatalysts

AbstractThe diastereodivergent synthesis of bridged 1,2,3,4‐tetrahydroisoquinoline derivatives has been achieved by using appropriate modularly designed organocatalysts (MDOs) that are self‐assembled in situ from amino acids and cinchona alkaloid derivatives. The domino Mannich/aza‐Michael/aldol reaction between (E)‐2‐[2‐(3‐aryl‐3‐oxoprop‐1‐en‐1‐yl)phenyl]acetaldehydes and ethyl or benzyl (E)‐2‐[(4‐methoxyphenyl)imino]acetates catalyzed by MDOs gives two different diastereomers of the desired bridged tetrahydroisoquinolines in good yields and excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to >99% ee). The diastereodivergence was achieved in the aldol reaction step.magnified image

Enantioselective Ammonium Ylide Mediated One‐Pot Synthesis of Highly Substituted γ‐Butyrolactones

AbstractAn ammonium ylide mediated access towards trans‐β,γ‐disubstituted, all‐trans‐α,β,γ‐trisubstituted, and α,α,β,γ‐tetrasubstituted γ‐butyrolactones bearing a broad variety of functionalities was developed. Starting from widely accessible benzylidene Meldrum's acid derivatives and α‐bromo carbonyl compounds, γ‐butyrolactones were obtained in yields between 32–99% with up to excellent diastereoselectivities (>95:5) via a DABCO‐mediated [2+1] annulation. Utilization of enantiomerically pure cinchona alkaloid derivatives enables the first asymmetric ammonium ylide mediated method to provide (3R, 4R)‐β,γ‐disubstituted and (2R, 3R, 4R)‐α,β,γ‐trisubstituted γ‐butyrolactones in moderate to good yields with up to very good enantiomeric ratios (97:3). The scalability of the transformation was proven while determining the absolute configuration.magnified image

Highly activity asymmetric hydrogenation of enones catalyzed by iridium complexes with chiral diamines and achiral phosphines

A selective asymmetric hydrogenation of enones has been well established by using an iridium complex composed of cheap phosphine ligands and cinchona alkaloids derivatives as catalyst. A wide range of allylic alcohol products could be obtained in high chemoselectivities (up to 99.6%), enantioselectivities (70.1% ee) and high activities (up to 3.64 × 104(1/h) TOF). This catalytic system opens a new way of selective asymmetric hydrogenation and the method can be of practical value.

Enantioseparation of ß-carboline, tetrahydroisoquinoline and benzazepine analogues of pharmaceutical importance: Utilization of chiral stationary phases based on polysaccharides and sulfonic acid modified Cinchonaalkaloids in high-performance liquid and subcritical fluid chromatography

High-performance liquid chromatographic (HPLC) and subcritical fluid chromatographic (SFC) separations of the enantiomers of structurally diverse, basic ß-carboline, tetrahydroisoquinoline and benzazepine analogues of pharmacological interest were performed applying chiral stationary phases (CSPs) based on (i) neutral polysaccharides- and (ii) zwitterionic sulfonic acid derivatives of Cinchona alkaloids. The aim of this work was to reveal the influence of structural peculiarities on the enantiorecognition on both types of CSP through the investigation of the effects of the composition of the bulk solvent, the structures of the chiral analytes (SAs) and chiral selectors (SOs) on retention and stereoselectivity. As a general tendency, valid for all polysaccharide SOs studied, the increase of the concentration of the apolar component in the mobile phase (n-hexane for LC or liquid CO2 for SFC) was found to significantly increase retention, which in most cases, was accompanied with increased selectivity and resolution. In a way, similar behaviour was registered for the zwitterionic SOs. In polar ionic mode employing eluent systems composed of methanol and acetonitrile with organic acid and base additives, moderate increases in retention factor, selectivity and resolution were observed with increasing acetonitrile content. However, under SFC conditions, an extremely high increase in retention was observed with increased CO2 content, while selectivity and resolution changed only slightly. Thermodynamic parameters derived from temperature dependence studies revealed that separations are controlled by enthalpy.

Cinchona-based zwitterionic stationary phases: Exploring retention and enantioseparation mechanisms in supercritical fluid chromatography with a fragmentation approach

Chiralpak ZWIX(+) and ZWIX(-), are brush-type bonded-silica chiral stationary phases (CSPs), based on complex diastereomeric Cinchona alkaloids derivatives bearing both a positive and a negative charge. In the present study, we aimed to improve the understanding of retention and enantioseparation mechanisms of these CSPs employed in supercritical fluid chromatography (SFC). For this purpose, 9 other stationary phases were used as comparison systems: two of them are commercially available and bear only a positive charge (Chiralpak QN-AX and QD-AX) and the 7 others were designed purposely to be structurally similar to the parent ZWIX phases, but miss some portion of the complex ligand. First, cluster analysis was employed to identify similar and dissimilar behavior among the 11 stationary phases, where ionic interactions appeared to dominate the observed differences. Secondly, the stationary phases were characterized with linear solvation energy relationships (LSER) based on the SFC analysis of 161 achiral analytes and a modified version of the solvation parameter model to include ionic interactions. This served to compare the interaction capabilities for the 11 stationary phases and showed in particular the contribution of attractive and repulsive ionic interactions. Then the ZWIX phases were characterized for their enantioseparation capabilities with a set of 58 racemic probes. Discriminant analysis was applied to explore the molecular structural features that are useful to successful enantioseparation on the ZWIX phases. In particular, it appeared that the presence of positive charges in the analyte is causing increased retention but is not necessarily a favorable feature to enantiorecognition. On the opposite, the presence of negative charges in the analyte favors early elution and enantiorecognition. Finally, a smaller set of 30 pairs of enantiomers, selected by their structural diversity and different enantioseparation values on the ZWIX phases, were analyzed on all chiral phases to observe the contribution of each structural fragment of the chiral ligand on enantioselectivity. Molecular modelling of the ligands also helped in understanding the three-dimensional arrangement of each ligand, notably the intra-molecular hydrogen bonding or the possible contribution of ionic interactions. In the end, each structural element in the ZWIX phases appeared to be a significant contributor to successful enantioresolution, whether they contribute as direct interaction groups (ion-exchange functions) or as steric constraints to orientate the interacting groups towards the analytes.

Amide-Based Cinchona Alkaloids as Phase-Transfer Catalysts: Synthesis and Potential Application.

Herein we present a library of simple amide derivatives of Cinchona alkaloids in the form of quaternary ammonium salts. The obtained derivatives can be generated very easily and efficiently from inexpensive and commercially available substrates. We tested this class of alkaloids in the alkylation of glycine derivative, carried out under phase-transfer catalyst conditions. The presented hybrid catalysts offer both high reaction yields (up to 97%) and high enantioselectivities of the obtained product (up to 94% ee).

4-Plex Chemical Labeling Strategy Based on Cinchona Alkaloid-Derived Primary Amines for the Analysis of Chiral Carboxylic Acids by Liquid Chromatography-Mass Spectrometry.

Chiral carboxylic acids play important roles in energy metabolism and signal transduction in the human body. These enantiomers usually possess different bioactivities and are also associated with the development of some diseases. Therefore, simultaneous determination of multiple chiral carboxylic acids is vital for study of the pathogenesis of related diseases. However, it is still challenging to simultaneously detect the enantiomers of multiple chiral carboxylic acids in biological samples. Here, we developed a novel 4-plex chemical labeling strategy based on 4 analogues of cinchona alkaloid-derived primary amines (CAPAs) for simultaneous determination of 16 enantiomers of 8 chiral carboxylic acids by liquid chromatography-mass spectrometry (LC-MS). To achieve high-throughput analysis, one CAPA analogue was used to label chiral carboxylic acid standards and served as internal standards (ISs), while the other 3 CAPA analogues were used to label endogenous chiral carboxylic acids in 3 different biological samples. After CAPAs labeling, the 16 chiral carboxylic acid enantiomers could be detected by LC-MS, and their detection sensitivity was greatly enhanced by up to 3 orders of magnitude compared to intact analytes. Further, the developed method for the determination of 16 chiral carboxylic acid enantiomers was validated in human serums and mammalian cells. Finally, the proposed method was applied to the determination of chiral carboxylic acids in the serum samples from type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC) patients. We found that 5 chiral carboxylic acid enantiomers in T2DM serum samples and 4 chiral carboxylic acid enantiomers in CRC serum samples exhibited significant change compared to the healthy control (HC).

Diastereodivergent Synthesis of Hexahydro-6H-benzo[c]chromen-6-one Derivatives Catalyzed by Modularly Designed Organocatalysts.

The diastereodivergent synthesis of hexahydro-6H-benzo[c]chromen-6-one derivatives with good to high diastereoselectivities (up to 98:2 d.r.) and enantioselectivities (up to >99 % ee) has been achieved by using a domino Michael/Michael/hemiacetalization reaction between trans-2-hydroxy-β-nitrostyrenes and trans-7-oxo-5-heptenals followed by oxidation. With use of appropriate modularly designed organocatalysts (MDOs) that are self-assembled in situ from amino acid derivatives and cinchona alkaloid derivatives, two different diastereomers of the desired hexahydro-6H-benzo[c]chromen-6-ones are obtained from the same substrates.

Asymmetric Catalysis Using Modularly Designed Organocatalysts: Synthesis of Fused Tricyclic Pyrano‐Pyrano[2,3‐c]pyrrol Derivatives

AbstractA highly enantioselective organocatalytic Michael addition‐acetalation/oxa‐Michael reaction involving aldehydes and dioxopyrrolidines has been discovered. The asymmetric reaction is mediated by modularly designed organocatalysts (MDOs) self‐assembled from cinchona alkaloid derivatives and amino acids providing a range of optically active tricyclic hexahydro‐2H‐pyrano[3′,2′:5,6]pyrano[2,3‐c]pyrrol derivatives in high yields (up to 99%) with good to excellent enantioselectivities (up to 99% ee) under mild reaction conditions.magnified image