Substituents R1 Research Articles

New Azo Derivative of β-Diketones and Its Cu(II), Co(II) Complexes: Synthesis, Theoretical Study and Biological Activity.

The paper is focused on biological activity and theoretical study of the structure and properties of a new azo derivative of β-diketones and its complexes with some metals. The aim of our work was to study the structure and properties of the newly synthesized compound as well as to theoretically determine the possibility of complex formation with the Cu(II) or Co(II) ions. A compound with the same substituents R1 =R2 =CH3 was chosen for the study. A synthesized azo compound based on 4-amino antipyrine and its complexes with Cu(II), Co(II) in solution and solid phase is reported. The structures of these compounds have been testified by X-ray, IR and NMR spectroscopy. The combined experimental and theoretical approach was used. To study the structure and properties of the synthesized compound, as well as its possible complex formation with the Cu(II), quantum-chemical calculations were carried out the 6-31G basis set and the electron density functional theory (DFT) method. These 3-(1-phenyl-2,3-dimethyl-pyrazolone-5) azopentadione-2,4 (PDPA) with Cu(II) and Co(II) complexes had effective inhibition against butyrylcholinesterase and acetylcholinesterase. IC50 values were found as 19.03, 3.64 μM for AChE and 28.47, 8.01 μM for BChE, respectively. Cholinesterase inhibitors work to slow down the acetylcholine's deterioration.

Mutation-driven resistance development in wastewater E. coli upon low-level cephalosporins: Pharmacophore contribution and novel mechanism

Cephalosporins have been widely applied in clinical and veterinary settings and detected at increasing concentrations in water environments. They potentially induce high-level antibiotic resistance at environmental concentrations. This study characterized how typical wastewater bacteria developed heritable antibiotic resistance under exposure to different cephalosporins, including pharmacophore-resistance correlation, resistance mechanism, and occurrence of resistance-relevant mutations in different water environments. Wastewater-isolated E. coli JX1 was exposed to eight cephalosporins individually at 25 µg/L for 60 days. Multidrug resistance developed and diverse mutations arose in selected mutants, where a single mutation in ATP phosphoribosyltransferase encoding gene (hisG) resulted in up to 128-fold increase in resistance to meropenem. Molprint2D pharma RQSAR analysis revealed that hydrogen-bond acceptors and hydrophobic groups in the R1 and R2 substituents of cephalosporins contributed positively to antibiotic resistance. Some of these pharmacophores may persist during bio- or photo-degradation in the environment. hisG mutation confers a novel resistance mechanism by inhibiting fatty acid degradation, and its variants were more abundant in water-related E. coli (especially in the effluent of wastewater treatment plants) compared with those in non-water environments. These results suggest that specific degradation of particular pharmacophores in cephalosporins could be useful for controlling resistance development, and mutations in previously unreported resistance genes (e.g., hisG) can lead to overlooked antibiotic resistance risks in water environments.

The use of multicomponent reactions in the development of bis-boronic acids for the detection of β-sialic acid.

Sialic acid (SA) is a naturally occurring monosaccharide found in glycoproteins and glycolipids. Changes in the expression of SA are associated with several diseases; thus, the detection of SA is of great significance for biological research, cancer diagnosis, and treatment. Boronic acid analogs have emerged as a promising tool for detecting sugars such as SA due to its reversible covalent bonding ability. In this study, 11 bis-boronic acid compounds and 2 mono-boronic acid compounds were synthesized via a highly efficient Ugi-4CR strategy. The synthesized compounds were subjected to affinity fluorescence binding experiments to evaluate their binding capability to SA. Compound A1 was shown to have a promising binding constant of 2602 ± 100 M-1 at pH = 6.0. Density Functional Theory (DFT) calculations examining the binding modes between A1 and SA indicated that the position of the boronic acid functional group was strongly correlated with its interaction with SA's α-hydroxy acid unit. The DFT calculations were consistent with the observations from the fluorescence experiments, demonstrating that the number and relative positions of the boronic acid functional groups are critical factors in enhancing the binding affinity to SA. DFT calculations of both S and R configuration of A1 indicated that the effect of the S/R configuration of A1 on its binding with β-sialic acid was insignificant as the Ugi-4CR generated racemic products. A fluorine atom was incorporated into the R2 substituent of A1 as an electron-withdrawing group to produce A5, which possessed a significantly higher capability to bind to SA (Keq = 7015 ± 5 M-1 at pH = 6.0). Finally, A1 and A5 were shown to possess exceptional binding selectivity toward β-sialic acid under pH of 6.0 and 6.5 while preferring to bind with glucose, fructose, and galactose under pH of 7.0 and 7.5.

Design of potential anti-cancer agents as COX-2 inhibitors, using 3D-QSAR modeling, molecular docking, oral bioavailability proprieties, and molecular dynamics simulation.

Modeling the structural properties of novel morpholine-bearing 1, 5-diaryl-diazole derivatives as potent COX-2 inhibitor, two proposed models based on CoMFA and CoMSIA were evaluated by external and internal validation methods. Partial least squares analysis produced statistically significant models with Q 2 values of 0.668 and 0.652 for CoMFA and CoMSIA, respectively, and also a significant non-validated correlation coefficient R² with values of 0.882 and 0.878 for CoMFA and CoMSIA, respectively. Both models met the requirements of Golbraikh and Tropsha, which means that both models are consistent with all validation techniques. Analysis of the CoMFA and CoMSIA contribution maps and molecular docking revealed that the R1 substituent has a very significant effect on their biological activity. The most active molecules were evaluated for their thermodynamic stability by performing MD simulations for 100 ns; it was revealed that the designed macromolecular ligand complex with 3LN1 protein exhibits a high degree of structural and conformational stability. Based on these results, we predicted newly designed compounds, which have acceptable oral bioavailability properties and would have high synthetic accessibility.

Design, Synthesis and Antifungal Activities of Novel Pyrazole Analogues Containing the Aryl Trifluoromethoxy Group.

On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF3 were designed and synthesized. Their chemical structures were characterized by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry. These compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi by the mycelium growth rate method. Most of the compounds showed some activity against each of the fungi at 100 μg/mL. Compounds 1t and 1v exhibited higher activity against all the tested fungi, and 1v displayed the highest activity against F. graminearum with an EC50 value of 0.0530 μM, which was comparable with commercial pyraclostrobin. Structure-activity relationship analysis showed that, with respect to the R1 substituent, the straight chain or cycloalkyl ring moiety was a key structural moiety for the activity, and the R2 substituent on the pyrazole ring could have significant effects on the activity. Simple and readily available pyrazoles with potent antifungal activity were obtained, which are ready for further elaboration to serve as a pharmacophore in new potential antifungal agents.

Genomic characterization of an NDM-9-producing Acinetobacter baumannii clinical isolate and role of Glu152Lys substitution in the enhanced cefiderocol hydrolysis of NDM-9.

Here, we characterized the first French NDM-9-producing Acinetobacter baumannii isolate. A. baumannii 13A297, which belonged to the STPas25 (international clone IC7), was highly resistant to β-lactams including cefiderocol (MIC >32 mg/L). Whole genome sequencing (WGS) using both Illumina and Oxford Nanopore technologies revealed a 166-kb non-conjugative plasmid harboring a blaNDM-9 gene embedded in a Tn125 composite transposon. Complementation of E. coli DH5α and A. baumannii CIP70.10 strains with the pABEC plasmid carrying the blaNDM-1 or blaNDM-9 gene, respectively, resulted in a significant increase in cefiderocol MIC values (16 to >256-fold), particularly in the NDM-9 transformants. Interestingly, steady-state kinetic parameters, measured using purified NDM-1 and NDM-9 (Glu152Lys) enzymes, revealed that the affinity for cefiderocol was 3-fold higher for NDM-9 (Km = 53 μM) than for NDM-1 (Km = 161 μM), leading to a 2-fold increase in catalytic efficiency for NDM-9 (0.13 and 0.069 μM-1.s-1, for NDM-9 and NDM-1, respectively). Finally, we showed by molecular docking experiments that the residue 152 of NDM-like enzymes plays a key role in cefiderocol binding and resistance, by allowing a strong ionic interaction between the Lys152 residue of NDM-9 with both the Asp223 residue of NDM-9 and the carboxylate group of the R1 substituent of cefiderocol.

Spectroscopic, X-ray crystallographic and preliminary biological screening study of unsymmetrical diphosphinoamine (PNP’) and monodentate aminophosphine (PNH) ligands coordinated to Pt(II)

An efficient and simple synthetic route to a new class of unsymmetrical diphosphinoamine {PNP'=(o-Tol)2P'N(R1)P(R2)2} and monophosphinoamine {(o-Tol)2P(R1)NH} ligands are presented, which allowed the manipulation of the R1 substituents on the amine as well as the cyclic R2 substituents on the phosphorus atom. The unsymmetrical (o-Tol)2P'N(R1)P(R2)2 ligands {R1 = p-MePh (A), o-MePh (B), p-ClPh (C) or p-FPh (D)} and their coordination to a Pt(II) metal center as [Pt{κ2-(P,P')(PNP')}Cl2] (3N; N = A, C, D) type of complexes are presented. In addition, monophosphinoamine ligands {(o-Tol)2P(R1)NH} are described, yielding the cisplatin analogue cis-[Pt((o-Tol)2P(p-MePh)NH)2Cl2] (2A), and trans-[Pt((o-Tol)2P(o-MePh)NH)2Cl2] (2B). Five single crystal X-ray studies are reported (2A, 2B, 3A, 3C, 3D), together with a detailed 31P NMR spectroscopy study. The electrostatic and steric repulsions on the ortho-CH3 on these types of ligands induces restricted rotation as seen by solution NMR spectra of all free ligands. The presence of two stable conformers (syn,syn,anti) and (syn,syn,syn) for the free PNP' ligands is illustrated, both in solution and solid state (31P MAS NMR). Moreover, in the synthesis, a scrambling/disproportionation of the unsymmetrical PNP' ligand is observed, yielding some 20% of the corresponding symmetrical PNP nucleophiles. However, the (syn,syn,anti)-conformer disappear upon coordination to the Pt(II), as required by the cis-[Pt(PNP')Cl2] complexes. The two Pt-PN complexes cis-[Pt((o-Tol)2P(p-MePh)NH)2Cl2] (2A) and trans-[Pt((o-Tol)2P(o-MePh)NH)2Cl2] (2B) were evaluated for biological activity to ascertain whether the stereo chemistry on these would show more activity as analogous cisplatin and derivatives. Additionally, 2A and 2B were also screened for antimicrobial activity. Significant microbial inhibition against Gram-positive Staphylococcus aureus and two Fungi Cryptococcus neoformans and Candida albicans was found for complex trans-[Pt(p-MePh-PNH)2Cl2] (2A), while the cytotoxicity evaluation of 2A against HEK293 human embryonic kidney cells displayed a moderate activity CC50 of 18.1 μM.

Competition Between the Two σ-Holes in the Formation of a Chalcogen Bond.

A chalcogen atom Y contains two separate σ-holes when in a R1 YR2 molecular bonding pattern. Quantum chemical calculations consider competition between these two σ-holes to engage in a chalcogen bond (ChB) with a NH3 base. R groups considered include F, Br, I, and tert-butyl (tBu). Also examined is the situation where the Y lies within a chalcogenazole ring, where its neighbors are C and N. Both electron-withdrawing substituents R1 and R2 act cooperatively to deepen the two σ-holes, but the deeper of the two holes consistently lies opposite to the more electron-withdrawing group, and is also favored to form a stronger ChB. The formation of two simultaneous ChBs in a triad requires the Y atom to act as double electron acceptor, and so anti-cooperativity weakens each bond relative to the simple dyad. This effect is such that some of the shallower σ-holes are unable to form a ChB at all when a base occupies the other site.

Rational hapten design and establishment of broad-spectrum indirect competitive enzyme-linked immunosorbent assay for benzimidazoles monitoring in milk

AbstractObjectivesBenzimidazoles (BZs) are commonly used for the treatment of soil-transmitted helminth infections in veterinary clinics; however, misuse and overdosing of BZs will cause residual problems and have the potential to damage human health through the food chain. Thus, the existence of BZs in foods needs more attention. This study aims to establish a broad-spectrum immunoassay for rapid detection and to simultaneously monitor BZs in milk.Materials and MethodsBased on structure analysis, a ‘zero epitope loss’ strategy, which introduced a spacer arm into the imino group of the imidazole ring of albendazole, was first adopted for hapten modification to obtain an ultra-sensitive and broad-spectrum antibody. An indirect competitive enzyme-linked immunosorbent assay (icELISA) was established for the detection of 18 BZs in milk sample with a single-step pretreatment. A quantitative structure–activity relationship model was constructed to interpret and predict the recognition.ResultsThe antibody could recognize 20 BZs and the half-inhibitory concentrations ranged from 0.054 to 417.58 ng/mL, the limits of detection of icELISA ranged from 0.4 to 89.4 ng/mL, and the mean recovery rates ranged from 76.49% to 120.40%, with a coefficient of variation <20%. Substituent R1 of BZs was considered to be the main influencing factor for recognition, and the comparative molecular field analysis model (q2=0.724, r2=0.998) was finally chosen for further prediction.ConclusionsThe results indicated that the established icELISA could simultaneously identify 18 BZs, with good accuracy and precision, which was suitable for rapid detection of BZs in milk.

Expanding the Chemical Space of Drug-like Passerini Compounds: Can α-Acyloxy Carboxamides Be Considered Hard Drugs?

With their three points of diversity, α-acyloxy carboxamides, which are accessible with the Passerini reaction, provide heterogeneity for the preparation of libraries of putative active agents or intermediates used for the formation of more complex structures. If on the one hand the presence of a hydrolyzable ester function has been exploited to design both prodrugs and soft drugs, on the other hand medicinal chemists are reluctant to use this skeleton to prepare hard drugs. Herein we investigated whether the stability of the ester could be controlled, leading to the formation of hydrolytically stable α-acyloxy carboxamides. When the group directly attached to the ester moiety (R3) is an ortho-substituted or ortho,ortho'-disubstituted aromatic ring, α-acyloxy carboxamides are stable. In human liver but not in rodents, due to the different expression of esterases, the ester function is also stable toward hydrolysis when the R1 group is a bulky substituent regardless of the nature of the R3 substituent.

Synthesis of 4-Pyrones by Formal Hydration of 1,3-Diynones Promoted by 1,4-Addition of Piperidine.

A new approach for the synthesis of 4-pyrones with broader substrate scope and functional group tolerance is described. The reaction proceeds via an initial 1,4-addition by piperidine, followed by nitrogen-assisted 6-endo-dig cyclization and hydrolysis. 1,3-Diynones with nonenolizable electron-withdrawing ketones and nonpropargylic H provide relatively high yields. For substrates with particular R2 substituents, 1,4- or 1,6-adducts were isolated, suggesting that steric and electronic factors of the R2 substituent should have a strong impact on the 6-endo-dig cyclization.

In silico design of novel quinazoline-based compounds as potential Mycobacterium tuberculosis PknB inhibitors through 2D and 3D-QSAR, molecular dynamics simulations combined with pharmacokinetic predictions

Serine/threonine protein kinase B (PknB) is essential to Mycobacterium tuberculosis (M. tuberculosis) cell division and metabolism and a potential anti-tuberculosis drug target. Here we apply Hologram Quantitative Structure Activity Relationship (HQSAR) and three-dimensional QSAR (Comparative Molecular Similarity Indices Analysis (CoMSIA)) methods to investigate structural requirements for PknB inhibition by a series of previously described quinazoline derivatives. PknB binding of quinazolines was evaluated by molecular dynamics (MD) simulations of the catalytic domain and binding energies calculated by Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) methods. Evaluation of a training set against experimental data showed both HQSAR and CoMSIA models to reliably predict quinazoline binding to PknB, and identified the quinazoline core and overall hydrophobicity as the major contributors to affinity. Calculated binding energies also agreed with experiment, and MD simulations identified hydrogen bonds to Glu93 and Val95, and hydrophobic interactions with Gly18, Phe19, Gly20, Val25, Thr99 and Met155, as crucial to PknB binding. Based on these results, additional quinazolines were designed and evaluated in silico, with HQSAR and CoMSIA models identifying sixteen compounds, with predicted PknB binding superior to the template, whose activity spectra and physicochemical, pharmacokinetic, and anti-M. tuberculosis properties were assessed. Compound, D060, bearing additional ortho- and meta-methyl groups on its R2 substituent, was superior to template regarding PknB inhibition and % caseum fraction unbound, and equivalent in other aspects, although predictions identified hepatotoxicity as a likely issue with the quinazoline series. These data provide a structural basis for rational design of quinazoline derivatives with more potent PknB inhibitory activity as candidate anti-tuberculosis agents.

Luminescent cyclometalated alkynylplatinum(II) complexes with 1,3-di(pyrimidin-2-yl)benzene ligands: synthesis, electrochemistry, photophysics and computational studies.

In this article, we report on a series of cyclometalated chloro- and alkynyl-platinum(II) complexes bearing various tridentate N^C^N-cyclometalated ligands derived from 1,3-bis(pyrimidin-2-yl)benzene. The X-ray crystal structures of two alkynyl-platinum(II) complexes were determined and other structures were DFT-calculated. Electrochemical and DFT-computational studies suggest a ligand-centred reduction on the R1-substituted N^C^N ligand, whereas oxidation likely occurs either on the Pt-phenylacetylide moiety and/or the cyclometalated ligand. In CH2Cl2 solution at room temperature, the complexes show phosphorescent emissions ranging from green to orange, depending on the R1 and R2 substituents on the ligands. In KBr solid state matrix, excluding complexes bearing a trifluoromethyl substituted ligand, all compounds exhibit red emission. The presence of an alkynyl ancillary ligand has limited influence on absorption and emission spectra except in the case of the complex with the strongly electron-donating diphenylamino R2 substituent on the alkynyl ligand, for which a significant red-shift was observed. The alkynyl Pt(II) complex with OMe groups as both R1 and R2 substituents shows the best emission quantum yield (0.81 in CH2Cl2 solution) in this series. The full series of DFT calculated band gaps correlated generally well with the electrochemical and absorption data and reasonably model the impact of the substituents on the electronics of these complexes.

A Diastereoselective Catalytic Approach to Pentasubstituted Pyrrolidines by Tandem Anionic‐Radical Cross‐Over Reactions

AbstractPentasubstituted pyrrolidines are ubiquitous constituents of natural products and drugs, however the access options to them especially with respect to absolute and relative stereochemistry are not well developed. We report an asymmetric synthesis of N,2,3,4,5‐pentasubstituted pyrrolidines by oxidative single‐electron transfer‐catalyzed tandem aza‐Michael addition/radical 5‐exo cyclization/oxygenation reactions. The absolute stereochemistry is set by applying readily accessible chiral allylamines in asymmetric conjugate additions to various β‐substituted‐α,β‐unsaturated esters, which dependent on the substituent R2 sets the configuration of the two stereocenters next to the amine function, whereas two more are diastereoselectively generated by the radical 5‐exo cyclization step. This allows the diastereodivergent single‐step synthesis of pyrrolidines with four contiguous stereogenic centers. The stereoselectivity is rationalized by a predictive model.magnified image

Yellow–green luminescence of four-coordinate copper(I) complexes bearing N–heterocyclic carbene (NHC) ligands: Synthesis, photophysical and computational studies

The synthesis and photophysical investigation of a series of six copper(I) complexes bearing benzimidazolylidene–type N–heterocyclic carbene (NHC) ligands with different groups are reported. Their photophysical properties can be tuned by adjusting the groups at the R1/R2 positions of the pyridine ring. The lowest-lying metal–to–ligand (MLCT) absorption bands at 325–437 nm can be observed for all the complexes. Upon excitation with UV light all the complexes emit bright yellow-green light (λem = 540–573 nm) with higher emission quantum yields of 21.1–55.6% and excited state lifetimes on the microsecond scale (τ = 30.6–62.1 μs) in PMMA films. The substituents (R2 = COCH3, F, Br, CH3, or OCH3) on R2–position of the pyridine ring were shown to have effects on the emission wavelengths of these complexes, while the introduction of R1 substituents (R1 = CH3) shows negligible effects on the emission wavelength but allow the enhancement of photoluminescence quantum yield (Φ) of the complexes. Additionally, the electronic properties, absorption and emission profiles of these complexes were further explored using DFT/TDDFT methods.

Leishmanicidal and cytotoxic activities and 4D-QSAR of 2-arylidene indan-1,3-diones.

The indan-1,3-dione and its derivatives are important building blocks in organic synthesis and present important biological activities. Herein, the leishmanicidal and cytotoxicity evaluation of 16 2-arylidene indan-1,3-diones is described. The compounds were evaluated against the leukemia cell lines HL60 and Nalm6, and the most effective ones were 2-(4-nitrobenzylidene)-1H-indene-1,3(2H)-dione (4) and 4-[(1,3-dioxo-1H-inden-2(3H)-ylidene)methyl]benzonitrile (10), presenting IC50 values of around 30 µmol/L against Nalm6. The leishmanicidal activity was assessed on Leishmania amazonensis, with derivative 4 (IC50 = 16.6 µmol/L) being the most active. A four-dimensional quantitative structure-activity analysis (4D-QSAR) was applied to the indandione derivatives, through partial least-squares regression. The statistics presented by the regression models built with the selected field descriptors of Coulomb (C) and Lennard-Jones (L) nature, considering the activities against L. amazonensis, HL60, and Nalm6 leukemia cells, were, respectively, R2 = 0.88, 0.92, and 0.98; Q2 = 0.83, 0.88, and 0.97. The presence of positive Coulomb descriptors near the carbonyl groups indicates that these polar groups are related to the activities. Besides, the presence of positive Lennard-Jones descriptors close to substituents R3 or R1 indicates that bulky nonpolar substituents in these positions tend to increase the activities. This study provides useful insights into the mode of action of indandione derivatives for each biological activity involved.

Experimental and computational structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles

Four compounds (1–4) reported in our previous work as potential antipsychotics with affinity for dopamine D2 and serotonin 5-HT1A and 5-HT2A receptors, were now subjected to detailed structural characterization. The X-ray analysis conducted for studied compounds proved that interatomic distances and bond angles in their crystal structures lie within normal values. The indole group in all compounds is planar, whereas tetrahydropyridine moiety exhibits almost ideal or close to half-chair conformation and is slightly or significantly rotated in relation to the indole group plane by 9.49(1)°, 30.24(11)°, 7.43(6)° and 15.98(18)° in compounds 1–4, respectively. The R1 substituents of tetrahydropyridine group in all cases form a dihedral angle with the indole moiety with value ranging from 66.57(14)° (2) to 86.73(17)° (4). The crystal structure of 1 is stabilized by N–H···N hydrogen bonds and C–H···π interactions. The intermolecular C(12)−H(12B)···Cg(2) interactions form a supramolecular two-dimensional network. The molecules in the crystal of 2 are linked by N–H···N. The formed chains are additionally stabilized with C–H···S hydrogen bonds. In case of compound 3, molecule chains are formed by N–H···N hydrogen bonds and are further linked via C–H···O hydrogen bonds into layer. The crystal structure is also stabilized by intermolecular C–H···π interactions. The molecules of compound 4 are linked by N–H···N hydrogen bonds and further stabilized by intermolecular C–H···π interactions. Crystallographic analysis was complemented with computational studies, such as Frontier Molecular Orbital analysis, which indicated that all four compounds display similar chemical reactivity, regardless of different R1 and R2 substituents. In addition, the most reactive parts of the compounds appear to be the indole and double bond located in tetrahydropyridine moiety. Lastly, the calculations of electrostatic potential and non-covalent interactions have been performed.

Biochemical characterization of OXA-244, an emerging OXA-48 variant with reduced β-lactam hydrolytic activity.

OXA-48-producing Enterobacterales have widely disseminated globally with an increasing number of variants identified. Among them, OXA-244 is increasingly reported, despite detection difficulties. To determine the steady-state kinetic parameters of OXA-244. The blaOXA-244 gene was amplified, cloned into plasmids p-TOPO and pET41b+, and transformed into Escherichia coli TOP10 for MIC determination and E. coli BL21 DE3 for purification. Steady-state kinetic parameters and IC50s of clavulanic acid, tazobactam and NaCl were determined using purified OXA-244. Molecular modelling was also performed. A reduction in MICs of temocillin and carbapenems was observed in E. coli expressing OXA-244 as compared with OXA-48. The kinetic parameters revealed a reduced carbapenemase activity of OXA-244 as compared with OXA-48, especially for imipenem, which was 10-fold lower. Similarly, catalytic efficiency (kcat/Km) was reduced by 4-fold and 20-fold for ampicillin and temocillin, respectively. Kinetic parameters for cephalosporins were, however, similar. Molecular modelling studies evidenced the key role of R214 in OXA-48, establishing salt bridges with D159 and with the carboxylate group of the R1 substituent of temocillin. These interactions are not possible with G214 in OXA-244, explaining the reduced affinity of temocillin for this enzyme. The R214G mutation in OXA-244 is also likely to induce changes in the active site's water network that would explain the decrease in the hydrolysis rate of carbapenems. Our data confirm that the R214G mutation (present in OXA-244) results in reduced carbapenem- and temocillin-hydrolysing activity, confirming the crucial role of residue 214 in the hydrolysis of these substrates by OXA-48-like β-lactamases.

Using Bases as Initiators to Isomerize Allylic Alcohols: Insights from Density Functional Theory Studies.

Allylic alcohols, as common and readily available building blocks, could be converted into many widely used carbonyl compounds through isomerization reactions. However, these processes often involve expensive transition metal (TM) complexes as the catalyst. What is the bottleneck in the mechanism when no TM is used? In this study, density functional theory (DFT) was employed to explore the mechanistic patterns of allylic alcohols catalyzed using bases, such as KOH, NaOH, LiOH, tBuOK, tBuONa, tBuOLi, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. Our results show that bases containing metal cations follow the metal cation-assisted (MCA) mechanism, whereas organic bases without metal cations follow the ion pair-assisted (IPA) mechanism. The catalytic efficiency of bases containing metal cations is higher than that of bases without metal cations, indicating that metal cations play an important role in the reaction. Additionally, the modulation of substituents R1 and R2 in the substrate reveals that electron-withdrawing groups are favorable for C-H bond cleavage, and electron-donating groups are favorable for hydrogen transfer. To better understand these patterns, we applied the DFT and information-theoretic approach (ITA) to examine the impact of bases and substrate substituents on the reactivity of allylic alcohol isomerization. This work should provide a much-needed theoretical guidance to design better non-TM catalysts for the isomerization of allylic alcohols and their derivatives.

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

•Enantiotopic differentiation of dinitrile to all-carbon quaternary centers•Atom economic synthesis of enantioenriched densely substituted pyridines•Zinc-promoted hetero-cyclometallation of nickel with alkyne and nitrile•Broad scope, good enantioselectivity, and excellent regioselectivity Pyridines are among the most significant heterocycles not only prevalently found in pharmaceuticals, natural products, and materials, but also widely applied as ligands or catalysts in organic synthesis. State-of-the-art methods to access enantioenriched and densely functionalized pyridines are rather limited due to great challenges to selectively install devise substitution patterns. In this article, we report a zinc-promoted nickel-catalyzed enantioselective [2 + 2 + 2] cycloaddition of alkynes with alkyne-tethered malononitriles for the construction of densely substituted pyridines from chemical feedstocks. The nitrile-containing all-carbon quaternary stereocenter is efficiently introduced by desymmetrization of dinitrile in good yield, regioselectivity, and enantioselectivity. We believe that the established strategy and its underlying mechanism will provide new opportunities in asymmetric catalysis and organic synthesis and find applications in broad research fields. Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step. Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step. The incorporation of stereogenic centers to enhance the three-dimensional complexity of privileged molecules is of great importance in drug discovery.1Lovering F. Bikker J. Humblet C. Escape from flatland: increasing saturation as an approach to improving clinical success.J. Med. Chem. 2009; 52: 6752-6756Crossref PubMed Scopus (1807) Google Scholar,2Liu Y. Han S.J. Liu W.B. Stoltz B.M. Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules.Acc. Chem. Res. 2015; 48: 740-751Crossref PubMed Scopus (431) Google Scholar As one of the most common heterocycles, densely substituted pyridines with varying substituents on the pyridine nucleus feature prominently in bioactive small molecules (Scheme 1A).3Pozharskii A.F. Soldatenkov A.T. Katritzky A.R. Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry, Biochemistry and Applications.2nd Edition. Wiley, 2011Crossref Scopus (267) Google Scholar,4Altaf A.A. Shahzad A. Gul Z. Rasool N. Badshah A. Lal B. Khan E. A review on the medicinal importance of pyridine derivatives.J. Drug. Des. Med. Chem. 2015; 1: 1-11Google Scholar Moreover, optically pure pyridines have been ubiquitously employed as ligands or catalysts in asymmetric synthesis.5Kwong H.-L. Yeung H.-L. Yeung C.-T. Lee W.-S. Lee C.-S. Wong W.-L. Chiral pyridine-containing ligands in asymmetric catalysis.Coord. Chem. Rev. 2007; 251: 2188-2222Crossref Scopus (177) Google Scholar, 6Yang G. Zhang W. Renaissance of pyridine-oxazolines as chiral ligands for asymmetric catalysis.Chem. Soc. Rev. 2018; 47: 1783-1810Crossref PubMed Google Scholar, 7Wurz R.P. Chiral Dialkylaminopyridine catalysts in asymmetric synthesis.Chem. Rev. 2007; 107: 5570-5595Crossref PubMed Scopus (248) Google Scholar Thus, methods to enantioselectively synthesize novel pyridines containing an adjacent all-carbon quaternary center can potentially expand the accessible chemical and biological space of this privileged motif, as well as offer new opportunities in asymmetric catalysis.8Allais C. Grassot J.M. Rodriguez J. Constantieux T. Metal-free multicomponent syntheses of pyridines.Chem. Rev. 2014; 114: 10829-10868Crossref PubMed Scopus (325) Google Scholar, 9Hill M.D. Recent strategies for the synthesis of pyridine derivatives.Chem. Eur. J. 2011; 16: 12052-12062Crossref Scopus (363) Google Scholar, 10Gulevich A.V. Dudnik A.S. Chernyak N. Gevorgyan V. Transition metal-mediated synthesis of monocyclic aromatic heterocycles.Chem. Rev. 2013; 113: 3084-3213Crossref PubMed Scopus (790) Google Scholar Conventional methods to access such structures include enantioselective 1,2-addition/reduction of pyridyl ketones, imines, and alkenes,11Liu Y. Chen F. He Y.M. Li C. Fan Q.H. Enantioselective synthesis of tunable chiral pyridine–aminophosphine ligands and their applications in asymmetric hydrogenation.Org. Biomol. Chem. 2019; 17: 5099-5105Crossref PubMed Google Scholar, 12Komanduri V. Krische M.J. Enantioselective reductive coupling of 1,3-enynes to heterocyclic aromatic aldehydes and ketones via rhodium-catalyzed asymmetric hydrogenation: mechanistic insight into the role of Brønsted acid additives.J. Am. Chem. Soc. 2006; 128: 16448-16449Crossref PubMed Scopus (211) Google Scholar, 13Friel D.K. Snapper M.L. Hoveyda A.H. Aluminum-catalyzed asymmetric alkylations of pyridyl-substituted alkynyl ketones with dialkylzinc reagents.J. Am. Chem. Soc. 2008; 130: 9942-9951Crossref PubMed Scopus (64) Google Scholar, 14Yin Y. Dai Y. Jia H. Li J. Bu L. Qiao B. Zhao X. Jiang Z. Conjugate addition−enantioselective protonation of N-aryl glycines to α-branched 2-vinylazaarenes via cooperative photoredox and asymmetric catalysis.J. Am. Chem. Soc. 2018; 140: 6083-6087Crossref PubMed Scopus (133) Google Scholar, 15Qiao B. Li C. Zhao X. Yin Y. Jiang Z. Enantioselective reduction of azaarene-based ketones via visible light-driven photoredox asymmetric catalysis.Chem. Commun. 2019; 55: 7534-7537Crossref PubMed Google Scholar, 16Yin Y. Li Y. Gonçalves T.P. Zhan Q. Wang G. Zhao X. Qiao B. Huang K.W. Jiang Z. All-carbon quaternary stereocenters α to azaarenes via radical-based asymmetric olefin difunctionalization.J. Am. Chem. Soc. 2020; 142: 19451-19456Crossref PubMed Scopus (30) Google Scholar transition-metal-catalyzed arylation using 2-pyridyl halides17Ge S. Hartwig J.F. Nickel-catalyzed asymmetric α-arylation and heteroarylation of ketones with chloroarenes: effect of halide on selectivity, oxidation state, and room-temperature reactions.J. Am. Chem. Soc. 2011; 133: 16330-16333Crossref PubMed Scopus (130) Google Scholar, 18Ghosh A. Walker J.A. Ellern A. Stanley L.M. Coupling catalytic alkene hydroacylation and α-arylation: enantioselective synthesis of heterocyclic ketones with α-chiral quaternary stereocenters.ACS Catal. 2016; 6: 2673-2680Crossref Scopus (23) Google Scholar, 19Friis S.D. Pirnot M.T. Buchwald S.L. Asymmetric hydroarylation of vinylarenes using a synergistic combination of CuH and Pd catalysis.J. Am. Chem. Soc. 2016; 138: 8372-8375Crossref PubMed Scopus (144) Google Scholar and boronic acids,20Schäfer P. Palacin T. Sidera M. Fletcher S.P. Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates.Nat. Commun. 2017; 8: 15762Crossref PubMed Scopus (65) Google Scholar and allylation of 2-substituted pyridines21Trost B.M. Thaisrivongs D.A. Palladium-catalyzed Regio-, Diastereo-, and enantioselective benzylic allylation of 2-substituted pyridines.J. Am. Chem. Soc. 2009; 131: 12056-12057Crossref PubMed Scopus (98) Google Scholar, 22Liu X.J. Jin S. Zhang W.Y. Liu Q.Q. Zheng C. You S.L. Sequence-dependent Stereodivergent allylic alkylation/fluorination of acyclic ketones.Angew. Chem. Int. Ed. Engl. 2020; 59: 2039-2043Crossref PubMed Scopus (36) Google Scholar, 23Motaleb A. Rani S. Das T. Gonnade R.G. Maity P. Phosphite catalyzed C–H allylation of azaarenes via an enantioselective [2,3]-Aza-Wittig rearrangement.Angew. Chem. Int. Ed. Engl. 2019; 58: 14104-14109Crossref PubMed Scopus (6) Google Scholar (Scheme 1B). However, these methods require the use of prefunctionalized pyridines. Recently, remarkable advances of direct enantioselective C–H functionalization of pyridines have been achieved by utilizing dual photoredox/Brønsted acid catalysis24Proctor R.S.J. Davis H.J. Phipps R.J. Catalytic enantioselective Minisci-type addition to heteroarenes.Science. 2018; 360: 419-422Crossref PubMed Scopus (234) Google Scholar,25Zheng D. Studer A. Asymmetric synthesis of heterocyclic γ-amino-acid and diamine derivatives by three-component radical cascade reactions.Angew. Chem. Int. Ed. Engl. 2019; 58: 15803-15807Crossref PubMed Scopus (56) Google Scholar and scandium catalysis26Song G. O W.W. Hou Z. Enantioselective C–H bond addition of pyridines to alkenes catalyzed by chiral half-sandwich rare-earth complexes.J. Am. Chem. Soc. 2014; 136: 12209-12212Crossref PubMed Scopus (161) Google Scholar (Scheme 1C). Although these are efficient methods, enantioselective access to enantioenriched pyridines with dense core substitutions is still limited. By contrast, transition-metal-catalyzed [2+ 2+ 2] cycloaddition of alkynes with nitriles represents a fascinating and atom-economical tool for the construction of pyridines, utilizing feedstock chemicals as starting materials to build diverse substitution patterns in a single synthetic step.27Heller B. Hapke M. The fascinating construction of pyridine ring systems by transition metal-catalysed [2+2+2] cycloaddition reactions.Chem. Soc. Rev. 2007; 36: 1085-1094Crossref PubMed Scopus (427) Google Scholar, 28Shaaban M.R. El-Sayed R. Elwahy A.H.M. Construction of fused heterocycles by metal-mediated [2+2+2] cyclotrimerization of alkynes and/or nitriles.Tetrahedron. 2011; 67: 6095-6130Crossref Scopus (118) Google Scholar, 29Tanaka K. Hara H. Nishida G. Hirano M. Synthesis of perfluoroalkylated benzenes and pyridines through cationic Rh(I)/modified BINAP-catalyzed chemo- and regioselective [2+2+2] cycloaddition.Org. Lett. 2007; 9: 1907-1910Crossref PubMed Scopus (66) Google Scholar, 30Kashima K. Ishii M. Tanaka K. Synthesis of pyridylphosphonates by rhodium-catalyzed [2+2+2] cycloaddition of 1,6- and 1,7-diynes with diethyl phosphorocyanidate.Eur. J. Org. Chem. 2015; 2015: 1092-1099Crossref Scopus (18) Google Scholar, 31Wada A. Noguchi K. Hirano M. Tanaka K. Enantioselective synthesis of C2-symmetric spirobipyridine ligands through cationic Rh(I)/modified-BINAP catalyzed double [2 + 2 + 2] cycloaddition.Org. Lett. 2007; 9: 1295-1298Crossref PubMed Scopus (86) Google Scholar, 32Wang C. Li X. Wu F. Wan B. A simple and highly efficient iron catalyst for a [2+2+2] cycloaddition to form pyridines.Angew. Chem. Int. Ed. Engl. 2011; 50: 7162-7166Crossref PubMed Scopus (151) Google Scholar, 33Tan J.F. Bormann C.T. Perrin F.G. Chadwick F.M. Severin K. Cramer N. Divergent synthesis of densely substituted arenes and pyridines via cyclotrimerization reactions of alkynyl triazenes.J. Am. Chem. Soc. 2019; 141: 10372-10383Crossref PubMed Scopus (32) Google Scholar, 34Onodera G. Shimizu Y. Kimura J.N. Kobayashi J. Ebihara Y. Kondo K. Sakata K. Takeuchi R. Iridium-catalyzed [2+2+2] cycloaddition of α,ω-diynes with nitriles.J. Am. Chem. Soc. 2012; 134: 10515-10531Crossref PubMed Scopus (92) Google Scholar Correspondingly, an asymmetric catalytic version to assemble enantioenriched pyridines is a conceptually straightforward yet largely unsolved route.35Link A. Sparr C. Stereoselective arene formation.Chem. Soc. Rev. 2018; 47: 3804-3815Crossref PubMed Google Scholar There are a handful of examples reported but primarily limited to the construction of atropisomers of arylpyridines (Scheme 1D).36Gutnov A. Heller B. Fischer C. Drexler H.J. Spannenberg A. Sundermann B. Sundermann C. Cobalt(I) catalyzed asymmetric [2+2+2] cycloaddition of alkynes and nitriles: synthesis of enantiomerically enriched atropoisomers of 2-arylpyridines.Angew. Chem. Int. Ed. Engl. 2004; 43: 3795-3797Crossref PubMed Scopus (220) Google Scholar, 37Hapke M. Kral K. Fischer C. Spannenberg A. Gutnov A. Redkin D. Heller B. Asymmetric synthesis of axially chiral 1-aryl-5,6,7,8-tetrahydroquinolines by cobalt-catalyzed [2+2+2] cycloaddition reaction of 1-aryl-1,7-octadiynes and nitriles.J. Org. Chem. 2010; 75: 3993-4003Crossref PubMed Scopus (111) Google Scholar, 38Kashima K. Teraoka K. Uekusa H. Shibata Y. Tanaka K. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of ortho-substituted phenyl diynes with nitriles: effect of ortho substituents on regio- and enantioselectivity.Org. Lett. 2016; 18: 2170-2173Crossref PubMed Scopus (24) Google Scholar Seminal contributions to create central chirality were elegantly conducted by Tanaka group employing a rhodium catalyst with 67:33–82:18 er achieved, albeit two substrates were included (Scheme 1E).39Tanaka K. Suzuki N. Nishida G. Cationic rhodium(I)/modified-BINAP catalyzed [2+2+2] cycloaddition of alkynes with nitriles.Eur. J. Org. Chem. 2006; 2006: 3917-3922Crossref Scopus (125) Google Scholar The reaction was proposed involving an oxidative coupling of the diynes with the rhodium complex to form a metallacyclopentadiene species (int I) and a subsequent nitrile insertion. The induction of enantioselectivity is likely from desymmetrizing the dinitrile in the intermolecular nitrile insertion step. Pioneering studies by the Louie group have demonstrated the capability of nickel catalysis in coupling diynes and nitriles to construct pyridines.40McCormick M.M. Duong H.A. Zuo G. Louie J. A nickel-catalyzed route to pyridines.J. Am. Chem. Soc. 2005; 127: 5030-5031Crossref PubMed Scopus (202) Google Scholar, 41Kumar P. Prescher S. Louie J. A serendipitous discovery: nickel catalyst for the cycloaddition of diynes with unactivated nitriles.Angew. Chem. Int. Ed. Engl. 2011; 50: 10694-10698Crossref PubMed Scopus (92) Google Scholar, 42Stolley R.M. Duong H.A. Thomas D.R. Louie J. The discovery of [Ni(NHC)RCN]2 species and their role as cycloaddition catalysts for the formation of pyridines.J. Am. Chem. Soc. 2012; 134: 15154-15162Crossref PubMed Scopus (60) Google Scholar, 43Stolley R.M. Duong H.A. Louie J. Mechanistic evaluation of the Ni(IPr)2-catalyzed cycloaddition of alkynes and nitriles to afford pyridines: evidence for the formation of a key η1-Ni(IPr)2(RCN) intermediate.Organometallics. 2013; 32: 4952-4960Crossref PubMed Scopus (37) Google Scholar, 44Thakur A. Louie J. Advances in nickel-catalyzed cycloaddition reactions to construct carbocycles and heterocycles.Acc. Chem. Res. 2015; 48: 2354-2365Crossref PubMed Scopus (76) Google Scholar, 45Clevenger A.L. Stolley R.M. Staudaher N.D. Al N. Rheingold A.L. Vanderlinden R.T. et al.Comprehensive study of the reactions between chelating phosphines and Ni(cod)2.Organometallics. 2018; 37: 3259-3268Crossref Scopus (19) Google Scholar, 46Takahashi T. Tsai F.Y. Li Y. Wang H. Kondo Y. Yamanaka M. Nakajima K. Kotora M. Selective preparation of pyridines, pyridones, and iminopyridines from two different alkynes via azazirconacycles.J. Am. Chem. Soc. 2002; 124: 5059-5067Crossref PubMed Scopus (192) Google Scholar Inspired by their mechanistic studies44Thakur A. Louie J. Advances in nickel-catalyzed cycloaddition reactions to construct carbocycles and heterocycles.Acc. Chem. Res. 2015; 48: 2354-2365Crossref PubMed Scopus (76) Google Scholar and in line with our interest in desymmetrization,47Lu Z. Hu X.D. Zhang H. Zhang X.W. Cai J. Usman M. Cong H. Liu W.B. Enantioselective assembly of cycloenones with a nitrile-containing all-carbon quaternary center from malononitriles enabled by Ni catalysis.J. Am. Chem. Soc. 2020; 142: 7328-7333Crossref PubMed Scopus (20) Google Scholar,48Zeng X.P. Cao Z.Y. Wang Y.H. Zhou F. Zhou J. Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters.Chem. Rev. 2016; 116: 7330-7396Crossref PubMed Scopus (379) Google Scholar we envisaged that an intramolecular hetero-cyclometallation of an alkyne-tethered malononitrile 1 with a nickel complex could form an aza-nickelacyclopentadiene (int II), followed by an alkyne insertion (int III) and reductive elimination to deliver enantioenriched fully substituted pyridines (Scheme 1F). We anticipated that the formation of the rigid five-membered ring-fused int II could facilitate the discrimination of the two CN groups efficiently. However, to realize this hypothesis, there are several potential challenges to address. First, the oxidative hetero-coupling of nickel between a sterically bulky and unactivated alkyl nitrile and an alkyne is generally sluggish.41Kumar P. Prescher S. Louie J. A serendipitous discovery: nickel catalyst for the cycloaddition of diynes with unactivated nitriles.Angew. Chem. Int. Ed. Engl. 2011; 50: 10694-10698Crossref PubMed Scopus (92) Google Scholar Second, undesired competition reactions such as cyclotrimerization of alkynes49Bhatarah P. Smith E.H. Nickel(0)-promoted synthesis of tetralin lactones from the co-cyclisation of monoynes and octa-1,7-diynes terminally substituted with ester or amide groups.J. Chem. Soc. Perkin Trans. 1. 1992; 1992: 2163-2168Crossref Google Scholar,50Sato Y. Nishimata T. Mori M. Asymmetric synthesis of isoindoline and isoquinoline derivatives using nickel(0) catalyzed [2+2+2] cocyclization.J. Org. Chem. 1994; 59: 6133-6135Crossref Scopus (163) Google Scholar or cleavage of the C–CN bond under nickel catalysis51Mills L.R. Graham J.M. Patel P. Rousseaux S.A.L. Ni-catalyzed reductive cyanation of aryl halides and phenol derivatives via transnitrilation.J. Am. Chem. Soc. 2019; 141: 19257-19262Crossref PubMed Scopus (34) Google Scholar, 52Nakao Y. Yada A. Ebata S. Hiyama T. A dramatic effect of Lewis-acid catalysts on nickel-catalyzed carbocyanation of alkynes.J. Am. Chem. Soc. 2007; 129: 2428-2429Crossref PubMed Scopus (241) Google Scholar, 53Zhang T. Luan Y.X. Zheng S.J. Peng Q. Ye M. Chiral aluminum complex controls enantioselective nickel-catalyzed synthesis of indenes: C-CN bond activation.Angew. Chem. Int. Ed. Engl. 2020; 59: 7439-7443Crossref PubMed Scopus (16) Google Scholar would be problematic. Third, enantiotopic differentiation among the two nitrile groups is extremely challenging and rarely explored due to their minuscule steric size54Eliel E.L. Wilen S.H. Mander L.N. Stereochemistry of Organic Compounds. Wiley, 1994Google Scholar and their binding affinity, which might poison the catalyst.55Rach S.F. Kühn F.E. Nitrile ligated transition metal complexes with weakly coordinating counteranions and their catalytic applications.Chem. Rev. 2009; 109: 2061-2080Crossref PubMed Scopus (118) Google Scholar Therefore, the identification of a catalytic system that can accelerate the aza-metallacycle forming process while creating a chiral environment to control the enantioselectivity is key to achieving this transformation. Notably, the products provided by our strategy are valuable not only due to the importance of pyridine itself but also because of the nitrile group as a pharmacophore in drug discovery.56Wang Y. Du Y. Huang N. A survey of the role of nitrile groups in protein–ligand interactions.Future Med. Chem. 2018; 10: 2713-2728Crossref PubMed Scopus (27) Google Scholar, 57Fleming F.F. Yao L. Ravikumar P.C. Funk L. Shook B.C. Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore.J. Med. Chem. 2010; 53: 7902-7917Crossref PubMed Scopus (955) Google Scholar, 58Fleming F.F. Nitrile-containing natural products.Nat. Prod. Rep. 1999; 16: 597-606Crossref Scopus (394) Google Scholar The adjacent quaternary carbon center to the nitrile moiety plays an important role in preventing toxic cyanide liberation.56Wang Y. Du Y. Huang N. A survey of the role of nitrile groups in protein–ligand interactions.Future Med. Chem. 2018; 10: 2713-2728Crossref PubMed Scopus (27) Google Scholar Here, we disclose a nickel-catalyzed desymmetric [2 + 2 + 2] cycloaddition of readily available disubstituted malononitriles 1 and alkynes to generate densely substituted pyridines 2 bearing an α-nitrile-containing all-carbon quaternary center. This reaction operates under mild conditions and uses an eco-friendly solvent, 2-MeTHF.59Pace V. Hoyos P. Castoldi L. Domínguez de María P. Alcántara A.R. 2-methyltetrahydrofuran (2-MeTHF): a biomass-derived solvent with broad application in organic chemistry.ChemSusChem. 2012; 5: 1369-1379Crossref PubMed Scopus (388) Google Scholar The addition of Lewis acid is also crucial to the reactivity. Investigations of the reaction conditions were carried out using 2-benzyl-2-phenylbutynyl-malononitrile 1a and 6-dodecyne as the model substrates, as highlighted in Figure 1 (see Tables S1–S5 for details). Previous remarkable observations by Liu et al. revealed that the addition of Lewis acids could promote the cycloaddition of nitriles with alkynes.60You X. Xie X. Wang G. Xiong M. Sun R. Chen H. et al.Nickel-catalyzed [2+2+2] cycloaddition of alkyne-nitriles with alkynes assisted by Lewis acids: efficient synthesis of fused pyridines.Chem. Eur. J. 2016; 22: 16765-16769Crossref PubMed Scopus (20) Google Scholar,61Wang G. You X. Gan Y. Liu Y. Synthesis of δ- and α-carbolines via nickel-catalyzed [2+2+2] cycloaddition of functionalized alkyne-nitriles with alkynes.Org. Lett. 2017; 19: 110-113Crossref PubMed Scopus (50) Google Scholar Inspired by this, we first examined the effect of ligands using ZnCl2 as an additive. Bisphosphine ligands with a biaryl backbone showed moderate reactivity and selectivity in general (Table S1). For instance, BINAP (L1) and TolBINAP (L2) delivered the desired product 2a with moderate enantioselectivity (75:25 er, entries 1 and 2), while XylBINAP (L3) resulted in an increased er (83:17, entry 3). By screening solvents, we were delighted to find that the reaction in bio-renewable 2-MeTHF provided a better yield and enantioselectivity (entries 3–5 and Table S2), which is probably due to its weak coordination ability to transition metals and high solubility of zinc halides.62Aycock D.F. Solvent applications of 2-methyltetrahydrofuran in organometallic and biphasic reactions.Org. Process Res. Dev. 2007; 11: 156-159Crossref Scopus (325) Google Scholar The addition of 4 Å molecular sieves (MS) slightly improved the yield and er (entry 6 and Table S3). Lowering the temperature diminished the yield but enhanced the enantioselectivity, and an increased yield was obtained at a higher concentration of 1a with 3 equivalents of 6-dodecyne (entry 7 and Table S4). Our further evaluation of the additives led to a better balance of yield and enantioselectivity (97:3 er) by using 1 equivalent of ZnBr2 (entry 8 and Table S5). The zinc halide plays a substantial role in this cycloaddition process (vide infra) and virtually no desired product was observed in the control experiment without its presence (entry 9). We also conducted the reaction using a rhodium/BINAP catalyst,39Tanaka K. Suzuki N. Nishida G. Cationic rhodium(I)/modified-BINAP catalyzed [2+2+2] cycloaddition of alkynes with nitriles.Eur. J. Org. Chem. 2006; 2006: 3917-3922Crossref Scopus (125) Google Scholar but resulted in no product formation (Scheme S1). With optimal reaction conditions established, we turned our attention to elucidate the scope of the substrates (Scheme 2). Substituents on the aryl group of the tethered alkyne moiety were first examined (Scheme 2A). Substrates with electron-donating substituents, including 4-methyl (2b), 4-methoxy (2c), and 3-methoxy (2j), delivered the corresponding products in 53%–79% yields with 95:5–97:3 er. Substrates bearing halides and electron-withdrawing groups generally provided the desired pyridines (2d–2h, 2k–2m) in increased yields (67%–90%) with a slightly lower er (92:8–95:5). It is notable that valuable functional groups, including aldehyde, ketone, and ester, were compatible with the cycloaddition reaction. Importantly, 2-thienyl alkyne-tethered malononitrile afforded the corresponding pyridine (2i) with good enantioselectivity (97:3 er), albeit in moderate yield. A 2-naphthyl-substituted substrate was also tested, resulting in 75% yield with 95:5 er (2n). Next, malononitriles with a range of substituents (R2) attached to the α-prochiral center were explored (Scheme 2B). Substituents with varying electronic nature on the benzylic moiety, such as methyl (2o, 2p), methoxy (2q), and trifluoromethyl (2r), delivered acceptable yields (70%–75%) and good enantioselectivities. The reactions of a substrate with 1-naphthyl group led to product 2s in 69% yield with 95:5 er. Remarkably, heterocycle-containing malononitriles, for instance, 2-furyl (2t), 2-thienyl (2u), and 3-indolyl (2v), are all well tolerated, giving 61%–76% yields and 93.5:6.5–94:6 er. It is noted that the enantioselectivity decreases with a smaller size of R2 substituents. For instance, the reaction with cyclohexylmethyl substrate (2w) resulted in 97:3 er, while methyl-substituted substrate (2x) provided only 86:14 er. The reaction with an allyl substituted substrate was also carried out, leading to 76% yield and decreased enantioselectivity (2y). An array of alkynes, including internal and terminal, as a cycloaddition partner were also investigated (Scheme 2C). Besides the 6-dodecyne and 2-butyne demonstrated in Scheme 2A, the cycloaddition of 1a with other aliphatic alkynes, including 3-hexyne, 4-octyne, and 5-decyne, delivered the corresponding pyridines 2z–2ab in moderate yields (54%–57%) with good enantioselectivities (95:5 er). When diaryl acetylenes were employed, slightly increased yields (63%–73%) but diminished enantioselectivities (92:8–94:6 er) were obtained (2ac–2ae). The absolute configuration of the enantiopure product 2ac (>99.5:0.5 er) was determined by X-ray analysis. With unsymmetrical 1-phenyl-1-propyne, the reaction resulted in 3.4:1 of regioselectivity and 91:9 er for the major isomer 2af. Remarkably, tetrasubstituted pyridines were also accessed by employing terminal alkynes as the substrates. Alkyl and aryl-substituted terminal alkynes were converted into the corresponding 2,3,4,5-tetrasubstituted pyridines (2ag–2aj) with good enantioselectivities (95:5–96:4) and perfect regioselectivities (>20:1 for all except 2aj). Moreover, ethynylcyclopropane, enyne, trimethylsilylacetylene, and nitrile- and benzyloxy-containing acetylenes were subjected to the transformation to form pyridines 2ak–2ap in good yields, enantioselectivities, and regioselectivities. The regioselectivities using terminal alkynes are consistent with previous observations in the non-enantioselective nickel-catalyzed cycloadditions.61Wang G. You X. Gan Y. Liu Y. Synthesis of δ- and α-carbolines via nickel-catalyzed [2+2+2] cycloaddition of functionalized alkyne-nitriles with alkynes.Org. Lett. 2017; 19: 110-113Crossref PubMed Scopus (50) Google Scholar Additional examples demonstrated the compatibility of chloro- and bromo-substituted aryl groups (2aq and 2ar), and heteroaryl (2as and 2at) on the pendent alkyne of malononitriles. Our preliminary bioactivity assay showed that pyridines 2d and 2ap were able to inhibit glucagon activity in cultured primary hepatocytes.63For an example of using substituted pyridines for inhibition of the glucagon receptor, see: Schmidt, G., Angerbauer, R., Brandes, A., Muller-Gliemann, M., Bischoff, H., Schmidt, D., Wohfeil, S., Schoen, W.R., Ladouceur, G.H., Cook, J.H.II, et al. (1996). Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents. WO9804528, filed, 29 July 1997, and published, 5 February 1998.Google Scholar We further expanded the scope of R1 substituent beyond aromatics. The reactions with enyne-tethered malononitriles were examined resulting in good enantioselectivities, albeit in lower yields (2au and 2av). The pendent alkyne substituted by alkyl groups (e.g., cyclopropyl, 2aw; methyl, 2ax) were also compatible, providing the corresponding pyridines in moderate yields with slightly decreased er. Specific limitations of this chemistry in terms of unsuccessful substrates that we tried are included in Scheme S2. No reaction occurred with propynyl chloride, amine, and benzoate. Ethynyl borate was also proven unreactive. The tether between the alkyne and malononitrile has a profound influence on the reactivity, as no reaction was observed with either one carbon lo