Bidentate Ligand Driven Intramolecularly Te O Bonded Organotellurium Cations from Synthesis, Stability to Catalysis.

A new series of unsymmetrical phenyl tellurides derived from 2-N-(quinolin-8-yl) benzamide ligand has been synthesized in a practical manner by the copper-catalyzed method by using diaryl ditelluride and Mg as a reductant at room temperature. In order to augment the Lewis acidity of these newly formed unsymmetrical monotellurides, these have been transformed into corresponding unsymmetrical 2-N-(quinolin-8-yl)benzamide tellurium cations. Subsequently, these Lewis acidic tellurium cations were used as chalcogen bonding catalysts, enabling the synthesis of various substituted 1,2-dihydroquinolines by activating ketones with anilines under mild conditions. Moreover, the synthesized 2-N-(quinolin-8-yl)benzamide phenyl tellurium cation has also catalyzed the formation of ß-amino alcohols in high regioselectivity by effectively activating epoxides at room temperature. Mechanistic insight by 1 H and 19 F NMR study, electrostatic surface potential (ESP map), control reaction in which tellurium cation reacted explosively with epoxide, suggested that the enhanced Lewis acidity of tellurium center seems responsible for efficient catalytic activities under mild conditions enabling ß-amino alcohols with excellent regioselectivity and 1,2-dihydroquinolines with trifluoromethyl, nitro, and pyridylsubstitution, which were difficult to access.

Interaction studies of water-soluble Zn(II) complex with calf thymus DNA using biophysical and molecular docking methods".

The binding between a fluorescent water-soluble Zn(II) complex of {2-[N-(2-hydroxyethylammonioethyl) imino methyl] phenol} and calf thymus DNA (ct-DNA) was investigated using spectroscopic techniques. The complex was prepared and identified by FT-IR, and 1H NMR spectroscopies. The significant changes in the absorption and the circular dichroism spectra of ct-DNA in the presence of the Zn(II) complex implied the interaction between the Zn(II) complex and ct-DNA. Upon addition of ct-DNA, the fluorescence emission intensity of the Zn(II) complex was increased and indicated the interaction between the Zn(II) complex and ct-DNA was occurred. The binding constant values (Kb) resulted from fluorescence spectra clearly showed the Zn(II) complex affinity to ct-DNA. The fluorescence studies also approved the static enhancement mechanism in the Zn(II) complex-DNA complexation process. The thermodynamic profile exhibited the exothermic and spontaneous formation of ct-DNA-Zn(II) complex system via hydrogen bonds and van der Waals forces. The competitive fluorescence investigation by methylene blue (MB), and Hoechst 33258 demonstrated that the Zn(II) complex could replace the DNA-bound Hoechst and bind to the minor groove binding site in ct-DNA. The viscosity changes were negligible, representing the Zn(II) complex binding to DNA via the groove binding mode. Molecular docking simulation affirmed that the Zn(II) complex is located in the minor groove of ct-DNA near the DG12, DA17, DA18, and DG16 nucleobases.

One-Pot Synthesis of Chiral 1-Aryl-2-Aminoethanols via Ir-Catalyzed Asymmetric Hydrogenation.

A straightforward synthesis approach to chiral 1-aryl-2-aminoethanols via the one-pot asymmetric hydrogenation catalyzed by Ir catalyst was developed. This tandem process involves the in situ generation of α-amino ketones via the nucleophilic substitution of α-bromoketones with amines and the Ir-catalyzed asymmetric hydrogenation of ketone intermediates to provide diverse enantiomerically enriched ß-amino alcohols. The excellent yields and enantioselectivities (up to 96 % yield and up to >99 % ee) with a wide substrate scope in this one-pot strategy were obtained.

Multicomponent Domino Cyclization of Ethyl Trifluoropyruvate with Methyl Ketones and Amino Alcohols as A New Way to γ-Lactam Annulated Oxazacycles.

A new route to bicyclic γ-lactams was found, which was proposed as a three-component cyclization of ethyl trifluoropyruvate with methyl ketones and 1,2-, 1,3-amino alcohols. As a result, a series of trifluoromethyl-substituted tetrahydropyrrolo [2,1-b]oxazol-5-ones and tetrahydropyrrolo[2,1-b][1,3]oxazine-6-ones was synthesized, in which the substituent at the nodal carbon atom was varied. The introduction of a twofold excess of ethyl trifluoropyruvate in reactions with amino alcohols and acetone made it possible to obtain the same bicycles, but functionalized with a hydroxyester fragment, which are formed due to four-component interactions of the reagents. Transformations with 2-butanone and aminoethanol lead predominantly to similar bicycles, while an analogous reaction with aminopropanol gives N-hydroxypropyl-2,3-dihydropyrrol-5-one. Almost all bicycles are formed as two diastereomers, the structure of which was determined using 1H, 19F, 13C NMR spectroscopy, including two-dimensional experiments and XRD analysis. A domino mechanism for the formation of tetrahydropyrrolo[2,1-b]oxazacycles was proposed, which was confirmed by their stepwise synthesis through the preliminary preparation of the aldol and bis-aldol from ethyl trifluoropyruvate and methyl ketones.

New isoxazolidinyl-based N-alkylethanolamines as new activators of human brain carbonic anhydrases.

Carbonic anhydrases (CAs) are widespread metalloenzymes which catalyse the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3-) and a proton, relevant in many physiological processes. In the last few years, the involvement of CA activation in different metabolic pathways in the human brain addressed the research to the discovery of novel CA activators. Here, a new series of isoxazoline-based amino alcohols as CA activators was investigated. The synthesis and the CA activating effects towards four human CA isoforms expressed in the human brain, that are hCAs I, II, IV and VII, were reported. The best results were obtained for the (methyl)-isoxazoline-amino alcohols 3 and 5 with KA values in the submicromolar range (0.52-0.86 µM) towards hCA VII, and a good selectivity over hCA I. Being hCA VII involved in brain function and metabolism, the newly identified CA activators might be promising hit compounds with potential therapeutic applications in ageing, epilepsy or neurodegeneration.

Engineering Enzyme Substrate Scope Complementarity for Promiscuous Cascade Synthesis of 1,2-Amino Alcohols.

Biocatalytic cascades are uniquely powerful for the efficient, asymmetric synthesis of bioactive compounds. However, high substrate specificity can hinder the scope of biocatalytic cascades because the constituent enzymes may have non-complementary activity. In this study, we implemented a substrate multiplexed screening (SUMS) based directed evolution approach to improve the substrate scope overlap between a transaldolase (ObiH) and a decarboxylase for the production of chiral 1,2-amino alcohols. To generate a promiscuous cascade, we engineered a tryptophan decarboxylase to act efficiently on ß-OH amino acids while avoiding activity on l-threonine, which is needed for ObiH activity. We leveraged this exquisite selectivity with matched substrate scope to produce a variety of enantiopure 1,2-amino alcohols in a one-pot cascade from aldehydes or styrene oxides. This demonstration shows how SUMS can be used to guide the development of promiscuous, C-C bond forming cascades.

Crystal structure and Hirshfeld surface analysis of 1-(tert-butyl-amino)-3-mesitylpropan-2-ol hemi-hydrate.

The title compound, 2C16H27NO·H2O, crystallizes in the monoclinic P21/c space group with two independent mol-ecules (A and B) in the asymmetric unit. In the crystal, mol-ecules A and B are linked through the water mol-ecules by inter-molecular O-H⋯O and O-H⋯N hydrogen bonds, producing chains along the b-axis direction. These chains are linked with neighboring chains parallel to the (103) plane via C-H⋯π inter-actions, generating ribbons along the b-axis direction. The stability of the mol-ecular packaging is ensured by van der Waals inter-actions between the ribbons. According to the Hirshfeld surface study, H⋯H inter-actions are the most significant contributors to the crystal packing (80.3% for mol-ecule A and 84.8% for mol-ecule B).

One-Step Biocatalytic Synthesis of Sustainable Surfactants by Selective Amide Bond Formation.

N-alkanoyl-N-methylglucamides (MEGAs) are non-toxic surfactants widely used as commercial ingredients, but more sustainable syntheses towards these compounds are highly desirable. Here, we present a biocatalytic route towards MEGAs and analogues using a truncated carboxylic acid reductase construct tailored for amide bond formation (CARmm-A). CARmm-A is capable of selective amide bond formation without the competing esterification reaction observed in lipase catalysed reactions. A kinase was implemented to regenerate ATP from polyphosphate and by thorough reaction optimisation using design of experiments, the amine concentration needed for amidation was significantly reduced. The wide substrate scope of CARmm-A was exemplified by the synthesis of 24 commercially relevant amides, including selected examples on a preparative scale. This work establishes acyl-phosphate mediated chemistry as a highly selective strategy for biocatalytic amide bond formation in the presence of multiple competing alcohol functionalities.

Synthesis, resolution, and absolute configuration determination of a vicinal amino alcohol with axial chirality. Application to the synthesis of new box and pybox ligands.

New racemic vicinal amino alcohol derivatives with 4-benzylidenecyclohexane skeleton and axial chirality have been prepared. A preparatively easy and efficient protocol for resolution of the N-benzoylamino alcohol is described. Using a 250 × 20 mm (L × ID) Chiralpak® IA column, and the appropriate mixture of n-hexane/ethanol/chloroform as eluent, both enantiomers of N-benzoylamino alcohol 3 are obtained with >99% enantiomeric excess (ee) by successive injections of a solution of the racemic sample in chloroform. The obtained axially chiral vicinal amino alcohol is used to synthesize structurally novel bisoxazoline ligands in high yields.

Brønsted Acid-Catalysed Epoxide Ring-Opening Using Amine Nucleophiles: A Facile Access to ß-Amino Alcohols.

A mild, efficient, and metal-free synthetic protocol for the synthesis of ß-amino alcohols is reported. The reaction proceeds at room temperature with only 0.5 mol % catalyst loading and affords ß-amino alcohol derivatives in excellent yield. This protocol is well-tolerated by a wide range of styrene oxide and aniline derivatives. A notably efficacious gram-scale synthesis is also reported with a high TON=842. Further, the Hammett correlation study was also performed to identify the rate-determining step.

Eugenol ß-Amino/ß-Alkoxy Alcohols with Selective Anticancer Activity.

Eugenol, 4-allyl-2-methoxyphenol, is the main constituent of clove essential oil and has demonstrated relevant biological activity, namely anticancer activity. Aiming to increase this activity, we synthesized a series of eugenol ß-amino alcohol and ß-alkoxy alcohol derivatives, which were then tested against two human cancer cell lines, namely gastric adenocarcinoma cells (AGS) and lung adenocarcinoma cells (A549). An initial screening was performed to identify the most cytotoxic compounds. The results demonstrated that three ß-amino alcohol derivatives had anticancer activity that justified subsequent studies, having been shown to trigger apoptosis. Importantly, the most potent molecules displayed no appreciable toxicity towards human noncancer cells. Structure-activity relationships show that changes in eugenol structure led to enhanced cytotoxic activity and can contribute to the future design of more potent and selective drugs.

Asymmetric Synthesis of N-Substituted 1,2-Amino Alcohols from Simple Aldehydes and Amines by One-Pot Sequential Enzymatic Hydroxymethylation and Asymmetric Reductive Amination.

The chiral N-substituted 1,2-amino alcohol motif is found in many natural and synthetic bioactive compounds. In this study, enzymatic asymmetric reductive amination of α-hydroxymethyl ketones with enantiocomplementary imine reductases (IREDs) enabled the synthesis of chiral N-substituted 1,2-amino alcohols with excellent ee values (91-99 %) in moderate to high yields (41-84 %). Furthermore, a one-pot, two-step enzymatic process involving benzaldehyde lyase-catalyzed hydroxymethylation of aldehydes and subsequent asymmetric reductive amination was developed, offering an environmentally friendly and economical way to produce N-substituted 1,2-amino alcohols from readily available simple aldehydes and amines. This methodology was then applied to rapidly access a key synthetic intermediate of anti-malaria and cytotoxic tetrahydroquinoline alkaloids.

Hydrogen Bonding and Polymorphism of Amino Alcohol Salts with Quinaldinate: Structural Study.

Three amino alcohols, 3-amino-1-propanol (abbreviated as 3a1pOH), 2-amino-1-butanol (2a1bOH), and 2-amino-2-methyl-1-propanol (2a2m1pOH), were reacted with quinoline-2-carboxylic acid, known as quinaldinic acid. This combination yielded three salts, (3a1pOHH)quin (1, 3a1pOHH+ = protonated 3-amino-1-propanol, quin- = anion of quinaldinic acid), (2a1bOHH)quin (2, 2a1bOHH+ = protonated 2-amino-1-butanol), and (2a2m1pOHH)quin (3, 2a2m1pOHH+ = protonated 2-amino-2-methyl-1-propanol). The 2-amino-1-butanol and 2-amino-2-methyl-1-propanol systems produced two polymorphs each, labeled 2a/2b and 3a/3b, respectively. The compounds were characterized by X-ray structure analysis on single-crystal. The crystal structures of all consisted of protonated amino alcohols with NH3+ moiety and quinaldinate anions with carboxylate moiety. The used amino alcohols contained one OH and one NH2 functional group, both prone to participate in hydrogen bonding. Therefore, similar connectivity patterns were expected. This proved to be true to some extent as all structures contained the NH3+∙∙∙-OOC heterosynthon. Nevertheless, different hydrogen bonding and π∙∙∙π stacking interactions were observed, leading to distinct connectivity motifs. The largest difference in hydrogen bonding occurred between polymorphs 3a and 3b, as they had only one heterosynton in common.

Antifungal activity of amino-alcohols based cationic surfactants and in silico, homology modeling, docking and molecular dynamics studies against lanosterol 14-α-demethylase enzyme.

Fungi are being responsible for causing serious infections in humans and animals. The opportunistic microorganisms provoke environmental contaminations in health and storage facilities to represent a serious concern to health security. The present work investigates the antifungal activity of two amino-alcohols based cationic surfactants such as CnEtOH, CnPrOH (with n = 14 and 16 are the carbon numbers of alkyl chain and EtOH = Ethanol and PrOH = Propanol) against a collection of different Candida species (Candida tropicalis, Candida albicans, Candida auris, Cyberlindnera jadinii, Candida parapsilosis, Candida glabrata and Candida rugosa) respectively. The amino-alcohols based cationic surfactants exhibited good antifungal activity against all Candida strains tested with minimum inhibitory concentrations (MIC) ranging from 0.002 to 0.30 mM. The MIC evaluation shows an increase as a function of the hydrophobicity of all inhibitors against the majority of the Candida strains tested. The different location of the alcoholic OH function in the polar head shows the influence on the availability of N+ responsible for electrostatic interactions with the candidate's cell walls, which remains a very important step in the mode of action of quaternary ammonium cationic surfactants. Hence, a 3D structure of lanosterol 14-α-demethylase enzyme from C. auris was constructed by homology modeling using an online SWISS-MODEL server. The predicted model was analyzed by serval servers. Furthermore, a molecular docking study was carried out to better understand the binding mechanism of lanosterol homologous protein with surfactant ligands. Then, the docked complexes lanosterol-surfactants were refined by the molecular dynamic simulation to analyze their interaction behavior during the simulation.Communicated by Ramaswamy H. Sarma.

Experimental and Molecular Docking Studies on the Interaction of a Water-Soluble Pd(II) Complex Containing ß-Amino Alcohol with Calf Thymus DNA.

The interaction of water-soluble and fluorescent [Pd (HEAC) Cl2] complex, in which HEAC is 2-((2-((2-hydroxyethyl)amino)ethyl)amino) cyclohexanol, with calf thymus DNA (ct-DNA) has been studied. This study was performed using electronic absorption and fluorescence emission spectroscopies, cyclic voltammetry and circular dichroism analyses, dynamic viscosity measurements, and molecular docking theory. From hypochromic effect observed in ct-DNA absorption spectra, it was found that the Pd(II) complex could form a conjugate with ct-DNA strands through the groove binding mode. The Kb values obtained from fluorescence measurements clearly assert the Pd(II) complex affinity to ct-DNA. The fluorescence quenching of the DNA-Hoechst compound following the successive additions of the Pd(II) complex to the solution revealed that the Pd(II) complex is located in the ct-DNA grooves, and Hoechst molecules have been released into solution; moreover, the resulting measurements from relative viscosity authenticate the Pd(II) complex binding to the grooves. Negative quantities of thermodynamic parameters imply that the Pd(II) complex binds to ct-DNA mainly by the hydrogen bonds and van der Waals forces; also, the Gibbs-free energy changes show the exothermic and spontaneous formation of the Pd(II) complex-DNA system. The electrochemical behavior of the Pd(II) complex in the attendance of ct-DNA was investigated using the cyclic voltammetry method (CV). Several quasi-reversible redox waves were observed along with increasing the anodic/cathodic peak currents, as well as a shift in anodic/cathodic peak potentials. Circular dichroism (CD) observations suggested that the Pd(II)-DNA interaction could alter ct-DNA conformation. The results of molecular modeling confirmed that groove mechanism is followed by the Pd(II) complex to interact with ct-DNA.

Efficient preparation of stereopure amphiphilic 1,2-amino alcohols by using preparative enantioselective HPLC.

Chiral amphiphiles are useful for controlling the structures and properties of supramolecular assemblies, but their stereocontrolled synthesis is generally difficult, because their long alkyl chains tend to bring unfavorable effects on the solubility, reactivity, and crystallinity of molecules. Typical examples are amphiphilic 1,2-amino alcohols (S)-1 and (1S,2S)-2 developed by our group, which were known to serve as chiral reaction media for controlling the stereochemistry of asymmetric photoreactions. We previously developed synthetic schemes for these 1,2-amino alcohols, but their synthetic efficiencies were unsatisfactory (13 steps with 2% overall yield for (S)-1; eight steps with 8% yield for (1S,2S)-2). As the main reason of such low efficiencies, the stereocontrolling methods we previously employed (diastereomer-salt crystallization for (S)-1; stereoselective reactions for (1S,2S)-2) were not ideal. Here, we report highly improved synthetic schemes for (S)-1 and (1S,2S)-2 based on the enantioselective high performance liquid chromatography (HPLC) separation of intermediates in preparative scales. Compared with the previous schemes, the new schemes are advantageous in fewer number of steps, higher overall yield, and lower risk of racemization (seven steps with 15% overall yield for (S)-1; seven steps with 26% overall yield for (1S,2S)-2).

Kukhtin-Ramirez-Reaction-Inspired Deprotection of Sulfamidates for the Synthesis of Amino Sugars.

Herein, we present a mild strategy for deprotecting cyclic sulfamidates via the Kukhtin-Ramirez reaction to access amino sugars. The method features the removal of the sulfonic group of cyclic sulfamidates, which occurs through an N-H insertion reaction that implicates the Kukhtin-Ramirez adducts, followed by a base-promoted reductive N-S bond cleavage. The mild reaction conditions of the protocol enable the formation of amino alcohols including analogs that bear multiple functional groups.

Rh(III)-catalyzed Intra- and Intermolecular 3,4-Difunctionalization of 1,3-Dienes via Rh(III)-π-allyl Amidation with 1,4,2-Dioxazolones.

We herein report a modular strategy, which enables Rh(III)-catalyzed diastereoselective 3,4-amino oxygenation and diamination of 1,3-dienes using different O- and N-nucleophiles in combination with readily available 3-substituted 1,4,2-dioxazolones (78 examples, 37-91% yield). Previous attempts to functionalize the internal double bond rested on the use of plain alcoholic solvents as nucleophilic coupling partners thus dramatically limiting the scope of this transformation. We have now identified hexafluoroisopropanol as a non-nucleophilic solvent which allows the use of diverse nucleophiles and greatly expands the scope, including an unprecedented amino hydroxylation to selectively install valuable, unprotected ß-amino alcohols across 1,3-dienes. Moreover, various elaborate alcohols prove to be compatible providing unique access to complex organic molecules. Finally, this method is employed in a series of intramolecular reactions to deliver valuable nitrogen heterocycles as well as γ- and δ-lactones.

Amino Alcohols from Eugenol as Potential Semisynthetic Insecticides: Chemical, Biological, and Computational Insights.

A series of ß-amino alcohols were prepared by the reaction of eugenol epoxide with aliphatic and aromatic amine nucleophiles. The synthesized compounds were fully characterized and evaluated as potential insecticides through the assessment of their biological activity against Sf9 insect cells, compared with a commercial synthetic pesticide (chlorpyrifos, CHPY). Three derivatives bearing a terminal benzene ring, either substituted or unsubstituted, were identified as the most potent molecules, two of them displaying higher toxicity to insect cells than CHPY. In addition, the most promising molecules were able to increase the activity of serine proteases (caspases) pivotal to apoptosis and were more toxic to insect cells than human cells. Structure-based inverted virtual screening and molecular dynamics simulations demonstrate that these molecules likely target acetylcholinesterase and/or the insect odorant-binding proteins and are able to form stable complexes with these proteins. Encapsulation assays in liposomes of DMPG and DPPC/DMPG (1:1) were performed for the most active compound, and high encapsulation efficiencies were obtained. A thermosensitive formulation was achieved with the compound release being more efficient at higher temperatures.

Chiral Arylated Amines via C-N Coupling of Chiral Amines with Aryl Bromides Promoted by Light.

The Buchwald-Hartwig C-N coupling reaction has found widespread applications in organic synthesis. Over the past two decades or so, many improved catalysts have been introduced, allowing various amines and aryl electrophiles to be readily used nowadays. However, there lacks a protocol that could be used to couple a wide range of chiral amines and aryl halides, without erosion of the enantiomeric excess (ee). Reported in this article is a method based on molecular Ni catalysis driven by light, which enables stereoretentive C-N coupling of optically active amines, amino alcohols, and amino acid esters with aryl bromides, with no need for any external photosensitizer. The method is effective for a wide variety of coupling partners, including those bearing functional groups sensitive to bases and nucleophiles, thus providing a viable alternative to accessing synthetically important chiral N-aryl amines, amino alcohols, and amino acids esters. Its viability is demonstrated by 92 examples with up to 99 % ee.