Halo-substituted (S)-N-(2-benzoylphenyl)-1-benzylpyrolidine-2-carboxamides as new chiral auxiliaries for the asymmetric synthesis of (S)-α-amino acids

The synthesis of new chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(3,4-dichlorobenzyl)-pyrrolidine-2-carboxamide (1a), (S)-N-(2-benzoylphenyl)-1-(pentafluorobenzyl)pyrrolidine-2-carboxamide (1b), and (S)-N-(2-benzoylphenyl)-1-(4-isopropoxytetrafluorobenzyl)pyrrolidine-2-carboxamide (1c) and their application in the asymmetric synthesis of amino acids using Ni^II complexes of their Schiff"s bases with alanine and glycine are described. Compound 1a is particularly appropriate for highly stereoselective synthesis of -methyl--amino acids with high enatiomeric purity (ee >95%).     

Synthesis and In-Vitro Antimicrobial Activity of Novel Aminophosphinic Acids Containing Cyclobutane and 1,3-Thiazole

Abstract

The compounds {[4-(3-methyl-3-aryl(mesityl-phenyl-tetralino)cyclobutyl)-1,3-thiazol-2-yl]amino}(aryl)methyl-phosphinic acids 2a–l were prepared by condensation of 2-amino-4-(3-aryl(mesityl-phenyl-tetralino)-3-methylcyclobutyl) thiazoles 1a–c with various aromatic aldehydes and hypophosphorous acid through a one-pot reaction. The characterizations of these compounds were obtained by elemental analyses, infrared (IR) spectra, and ¹H, ¹³C, and ³¹P NMR (nuclear magnetic resonance) techniques. The synthesized compounds were tested in vitro against one Gram-positive and two Gram-negative bacterial strains, one mycobacterial strain, and a fungus Candida albicans. Compound 2f showed significant activity against Staphylococcus aureus, whereas the others had no remarkable activity on this strain. Compound 2g was found to be more active than the others against Mycobacterium fortuitum at an MIC (minimum inhibitory concentration) value of 32 μg/mL. The antibacterial and antifungal activities of 2a–l were also compared with various standard drugs.

[Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental resource: Biological Activities. Table S1. Figures S1–S6.]

GRAPHICAL ABSTRACT      

Molecular recognition on supramolecular systems (XXXV)

A novel β-cyclodextrin derivative4 bearing a pyridinio group on the primary side was synthesized by the reaction of 2-aminopyridine with 6-β-cyclodextrin monoaldehyde3, and its complexation stability constants with several aliphatic amino acids have been determined in phosphate buffer solution ( pH = 7.2, 0.1 mol·L⁻¹) at 25 °C by using spectrofluormetric titrations. The stoichiometry is 1:1 for the inclusion complexation of amino acids with compound4. Circular dichroism study indicates that the aromatic moiety was embedded shallowly into the cyclodextrin cavity. As a spectral probe, the pyridinio group in the modified cyclodextrin can recognize not only differences of the size and shape of amino acid molecules, but also theL/D-amino acid chiral isomer. As compared with mono-[6-(1-pyridinio)-6-deoxy]-β-cyclodextrin5, compound4 switched the enantiomer preference forL- toD-isomer, and showed the highest enantioselectivity of 5.4 forD/L-serine. These results are discussed from the viewpoints of geometric compensation, induced-fit concept and cooperation of several weak interactions.     

Novel 99mTc labeled σ receptor ligand as a potential tumor imaging agent

A novel ^99mTc labeled complex, [N-[2-((2-oxo-2-(4-(3-phenylpropyl)piperazin-1-yl)ethyl) (2-mercaptoethyl)amino)acetyl]-2-aminoethanethiolato]Technetium(V) oxide (PPPE-MAMA’-^99mTcO) ([ ^99m Tc]-2) has been designed and prepared based on the integrated approach. The corresponding rhenium complex (PPPE-MAMA’-ReO)(Re-2) has been prepared and characterized. In vitro competition binding assays show moderate affinity of Re-2 towards σ₁ and σ₂ receptors with K _i values of 8.67 ± 0.07 and 5.71 ± 1.88 μmol, respectively. Planar images obtained at 0.5 h, 4 h, 20 h after i.v. injection indicate the accumulation of [ ^99m Tc]-2 in MCF-7 human breast tumor bearing mice at 20 h. Furthermore, the accumulation of [ ^99m Tc]-2 has been inhibited at 20 h after co-injection of [ ^99m Tc]-2 plus haloperidol (1 mg/kg). Biodistribution studies of [ ^99m Tc]-2 display an in vivo tumor uptake of 0.14% ± 0.01% ID/g at 24 h post i.v. injection with a tumor/muscle ratio of 6.02 ± 0.87. The above results suggest that [ ^99m Tc]-2, derived from a previously published lead compound, retains certain tumor uptake and affinity for σ receptors. [ ^99m Tc]-2 may be used as a basis for further structural modifications to develop tumor imaging agents with high affinity for σ receptors.     

Complexation of a Macrocycle Containing Thiopyrimidine and Uracil Moieties with Dicarboxylic and Amino Acids in Various Organic and Aqueous Organic Solutions

The complexation of a macrocycle containing thiopyrimidine and uracil moieties (M) with amino acids and some dicarboxylic acids was studied by pH-metric, UV-VIS, ¹H NMR spectroscopy methods in chloroform, methanol, aqueous 1,4-dioxane, and biphasic water–chloroform media. The complexation of M with acids is too weak to solubilize them from the solid state into chloroform solutions containing M. The ¹H NMR spectra and pH-metric data of aqueous 1,4-dioxane (80 vol.%) reveal the pH-dependent 1:1 binding between M and the acids studied. The protonation of M is not a prerequisite for binding of fumaric, succinic, o-phtalic acids and the series of amino acids, whereas binding of maleic acid requires the protonation of both thiopyrimidine moieties of M. Therefore,M·(H⁺)₂ exhibits strong selectivity towards maleic acid in aqueous 1,4-dioxane and in biphasic water–chloroform media.     

A New Approach to the Efficient Method for the Asymmetric Synthesis of (S)-O-, M-, P-Fluorophenylalanines and Their 2-Methyl-substituted Analogs

Abstract

The reactions of asymmetric C-alkylation of glycine and alanine in Ni^II complexes of their Schiff's bases with modified chiral auxiliaries (S)-2-N-[(N′-2-chlorobenzylprolyl)amino]benzophenone and (S)-2-N-[N′-(3,4-dimethylbenzylprolyl)amino]benzophenone by fluorine-substituted benzyl halogenides have been studied. As a result, a highly stereoselective and relatively rapid method for the asymmetric synthesis of (S)-o-, m-, p-fluorophenylalanines and their 2-methyl substituted analogs has been developed.     

Separation of polar antioxidants from Rhizoma Polygonatum Odorati by high-speed counter-current chromatography with a hydrophilic solvent system

Some highly polar compounds are quality control makers for medicinal herbs. However, investigation of them has been hampered because the existing fractionation steps are difficult and laborious to purify them. Similar situations happen to Rhizoma Polygonatum Odorati, a widely used food supplement and medicinal herb with strong antioxidant activity, and up to date, only ethyl acetate fraction of Rhizoma Polygonatum Odorati has been comprehensively investigated. Here, HSCCC using a hydrophilic solvent system composed of n-butanol–ethanol–2 M ammonium sulfate (1:1:2, v/v/v) was performed to isolate highly polar antioxidants in n–butanol fraction of Rhizoma Polygonatum Odorati, guided by DPPH–HPLC experiment. Afterward, Sephadex LH-20 column chromatography eluted by methanol was selected to eliminate ammonium sulfate and purify co-eluted compounds in HSCCC collected fractions. Finally, nine compounds, including four nucleosides, cytidine (1), uridine (4), guanosine (5), and adenosine (8); two nucleobases, guanine (3), and adenine (6); and three amino acids, tyrosine (2), phenylalanine (7), and tryptophan (9) with purities over 98% were achieved and identified by UV, MS, and ¹H NMR data. Notably, compounds 1–9 were first reported in genus Polygonatum. The results indicated that the proposed method was an efficient approach to isolate and purify highly polar compounds from complex extracts.     

PHOSPHONOMETHYLATION OF AMINOALKANOLS PREPARATION OF 4-(PHOSPHONOMETHYL)-2-HYDROXY-2-OXO-1,4,2-OXAZAPHOSPHORINANES1

Abstract

Treatment of aminoalkanols 1 with phosphorous acid and formaldehyde in presence of conc. hydrochloric acid gave mixtures of [(2-hydroxy alkyl)imino] dimethylene diphosphonic acids 3 and 4-(phosphonomethyl)-2-hydroxy-2-oxo-1,4,2-oxazaphosphorinanes 2 from which 2 were isolated as crystalline solids. Similar treatment of 2-amino-2-methyl-1,3-propanediol 8 gave a complex mixture from which dimethylene diphosphonic acid of 5-amino-5-methyl-1,3-dioxane 9 was isolated. 2-Aminoethanethiol, when subjected to phosphonomethylation. gave an unexpected novel quarternary nitrogen product 11. N-Alkylaminoalkanols 4 on phosphonomethylation gave 3:1 mixtures of [N-alkyl-N-(2-hydroxyalkyl)amino] methane phosphonic acid 6 and N-alkyl-2-hydroxy-2-oxo-1,4,2-oxazaphosphorinane 5. Treatment of the crude mixtures of 5 and 6 with aqueous sodium hydroxide gave disodium salts of [N-alkyl-N-(2-hydroxyalkyl)amino] methanephosphonic acid 7. The ratio of the cyclic to the open chain structures obtained as well as the formation of any unexpected novel products is dependent on the structure of the aminoalkanol that is phosphonomethylated. The ¹H, ¹³C and ³¹P spectra are reported for all new compounds.     

Structure elucidation of acetylation products of 2-acyl-1,3-indanediones by correlation of infrared spectral data

Summary 2-(1-Acetoxyalkylidene)- and 2-(1-acetoxybenzylidene)-1,3-indanediones (1a–1e) were proven to be the products of acetylation of 2-acyl-1,3-indanediones (2a–2e) by ketene using a detailed investigation and correlation analysis of infrared spectral data as well as¹H-NMR and¹³C-NMR spectra. Study by means of CNDO/2 and MMPI methods also demonstrates that the structure1 is more stable as the alternative one of 2-acyl-3-acetoxy-2-indene-1-ones (5). It was shown that the recently proposed general correlations v(C=O)_s vs. v(C=O)_as and v(C=O) vs. X⁺(R) as well as the mechanical anharmonicities of asymmetric C=O stretching vibration can be successfully used as a tool of structural diagnostics of cyclic 1,3-dicarbonyl compounds.

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Strukturaufklärung von Acetylierungsprodukten von 2-Acyl-1,3-indandionen mittels Korrelation von Infrarot-Daten

Zusammenfassung 2-(1-Acetoxyalkyliden)- und 2-(1-Acetoxybenzyliden)-1,3-indandione (1a–1e) wurden mittels einer detaillierten infrarot-spektroskopischen Untersuchung (IR-Korrelation) und¹H-NMR und¹³C-NMR Spektroskopie als Acetylierungsprodukte von 2-Acyl-1,3-indandionen (2a–2e) mit Keten nachgewiesen. CNDO/2- und MMPI-Rechnungen zeigten auch, daß Struktur1 stabiler ist, als die der alternativen 2-Acyl-3-acetoxy-2-inden-1-one5. Es wird gezeigt, daß die kürzlich vorgeschlagenen allgemeinen Korrelationen v(C=O)_s gengen v(C=O)_as und v(C=O) gegen X ⁺(R) und auch die mechanischen Anharmonizitäten der asymmetrischen C=O Streckschwingung erfolgreich als Werkzeug zur Strukturaufklärung cyclischer 1,3-Dicarbonyl-Verbindungen eingesetzt werden können.

     

Tryptophan receptors containing acridine-based thiourea

Four derivatives of acridine and acridinium compounds (L1, L2, L1H and L2H) comprised thiourea-binding sites were synthesised. The binding abilities of receptors L1, L2, L1H and L2H towards amino acids (l-Trp, l-Phe, l-Leu, l-Ala and l-Gly) were studied by ¹H NMR spectroscopy, UV–vis and fluorescence spectrophotometry. Hydrogen bonding interactions between thiourea-binding site of the ligand and the carboxylate groups in zwitterionic amino acids were found to be the main interactions driving complexation to take place. The stoichiometry of 1:1 ligand to amino acid was observed in all cases. Neutral ligands L1 and L2 showed weak binding towards all studied amino acids. The cyclic ligand L1 showed better binding ability towards tryptophan (Trp) than the acyclic ligand L2 did (K for Trp is 307 and 266 M^? 1 for L1 and L2, respectively). Interestingly, binding abilities of the protonated ligands, L1H and L2H, towards studied amino acids, especially Trp (K for Trp is 3157 and 2873 M^? 1 for L1H and L2H, respectively), were increased due to R–COO^? …H…N⁺–acridinium interactions. Calculated structures of L1H·Trp and L2H·Trp showed that the polyglycol moiety in L1H provided a hydrophobic cavity for binding Trp resulting in a stronger binding affinity of L1H over L2H.     

Aldisin及其衍生物的合成和α-葡萄糖苷酶抑制活性研究

以三氯氧磷为环化试剂, 回流状态下, N-(2-吡咯甲酰基)-β-丙氨酸经分子内酰化环化反应, 合成了吡咯[2,3-c]氮杂二酮稠环化合物Aldisin及其衍生物1-Methylaldisin和3-Bromoaldisin, 通过¹H NMR, ¹³C NMR, IR, FABMS和元素分析对其结构进行了表征. 以X射线衍射法研究了3-Methylaldisin的晶体结构. 测定了三个化合物对α-葡萄糖苷酶的抑制作用.     

氨基糖衍生物二丁基锡配合物的合成、结构表征和生物活性

分别由2-[(2Z)-3-羧基-1-氧代-2-丙烯基]氨基-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖(1a), 2-[(2-羧基苯甲酰基)氨基]-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖(2a)和氧化二正丁基锡反应合成了两个新化合物双-{2-[(2Z)-3-羧基-1-氧代-2-丙烯基]氨基-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖}-二正丁基锡酯(1)和双-{2-[(2-羧基苯甲酰基)氨基]-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖}-二正丁基锡酯(2), 并经红外光谱、核磁共振(¹H, ¹³C NMR)、质谱初步确定了其结构. 体外抗肿瘤活性结果表明, 化合物1对人肺癌细胞株A-549和人肝癌细胞株BEL-7402的细胞毒活性显示为强效; 而对小鼠白血病细胞株P388和人白血病细胞株HL-60的细胞毒活性为弱效. 化合物2对肿瘤细胞株HL-60, A-549和BEL-7402具有强效的细胞毒活性; 而对肿瘤细胞株P388的作用则为弱效. 克隆基因分析表明化合物1和2在3.82×10^－6 和 3.02×10^－6 mol/L均具有造血细胞毒性.     

Facile synthesis of chiral <Emphasis Type="Italic">N</Emphasis>-glycosylated amino acids

Five designed chiral glycosylated amino acids have been synthesized for the first time by coupling of 1,3,4,6-tetra-O-acetyl-β-D-glucosamine sulfate (2), previously prepared by direct acetylation of D-glucosamine hydrochloride with acetic anhydride, with chiral Fmoc-protected amino acids and DIC, HOBt, and DIEA under mild conditions. The structures of these new compounds were characterized by IR, ¹H NMR, and ¹³C NMR spectroscopy and ESI MS.     

Synthesis and characterization of oxazine bearing pyridine scaffold as potential antimicrobial agents

A series of novel compounds 1-((1-(4-(2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)ethylidene)amino)-6-((benzylidene)amino)-2-oxo-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitriles (7a–o) were synthesized by a sequence of multistep reactions. IR, ¹H NMR, ¹³C NMR, and mass spectral techniques were used to confirm the structures newly synthesized compounds. Antimicrobial activity of the title compounds (7a–o) was studied against strains of bacteria (Staphylococcus aureus and Streptococcus pyogenes, Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger and Aspergillus clavatus) by serial dilution method. Compounds 7f and 7k exhibited significant antimicrobial activity.     

Preparation of a fluorescent sensor based on BODIPY-functionalized hydroxyapatite nanoparticles and spectroscopic study of the Cd2+ and Zn2+ complex formation

A new fluorescent chemosensor 1, which based on hydroxyapatite (HA) nanoparticles covalently functionalized with a difluoroboron dipyrromethene, has been prepared by nucleophilic substitution of the fluorescent dye 3-chloro-4,4-difluoro-8-(4-tolyl)-5-[bis(pyridine2-ylmethyl)amino]-4-bora-3a,4a-diaza-s-indacene (2) with surface-modified HA nanoparticles. The HA particles were prepared by using SiO₂ as templates (THA) with 3-(aminopropyl)triethoxysilane (THA-APTES). Substitution of the electron-withdrawing chlorine in 2 by an electron-donating amino group of HA changes the properties of the nanoparticles 1 and the corresponding fluorescent dye 2. Absorption and emission maxima of 1 in ethanol are red-shifted by 75 and 30?nm, respectively, in comparison with those of 2. In contrast to no selectivity of dye 2 for Cd²⁺ or Zn²⁺ in EtOH/H₂O (95/5?V/V) solutions, the nanofluorescent probe 1 forms 1?:?1 complexes with Cd²⁺ or Zn²⁺, producing an instant color change along with large hypsochromic shifts in the absorption and fluorescence spectra by 70 and 35?nm, respectively, and large cation-induced fluorescence amplifications.     

Neue Reagentien zum papierchromatographischen Nachweis von Aminosäuren, 4. Mitt.: Zur Chemie der “Ninhydrin-Reaktion”

Zusammenfassung Es wird gezeigt, daß bei der Umsetzung von vic. Triketoverbindungen mit Aminosäuren (Ninhydrin-Reaktion) intermediär die entsprechende Aminoverbindung, als wichtige Komponente für die Farbstoffbildung, entsteht. Die Reaktion von Aminosäuren mit 1,8-Trimethylen-chinisatinhydrat (TMCH) in Gegenwart von Eisessig/Ac ₂O führt zum 3-Acetamido-4-hydroxy-1,8-trimethylencarbostyril (5).

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A study of the reaction of vic. trioxo compounds with amino acids (ninhydrin reaction) shows that the corresponding amino compound is the important intermediate of dye formation. The reaction of amino acids with 1.8-trimethylene-quinisatinhydrate (TMCH) in the presence of acetic acid and acetic anhydride yields 3-acetamido-4-hydroxy-1.8-trimethylene-carbostyril (5).

     

Chemiluminescence Detection of Amino Acids,Peptides, and Proteins Using Tris-2,2′-Bipyridine Ruthenium (III)

Abstract

The feasibility of using the tris-2-2′-bipyridine ruthenium (III) (Ru(bpy)₃ ^{3 +}) chemiluminescent (CL) reaction for the detection of amino acids, peptides, and proteins has been studied.

Detection limits of the amino acids as determined by flow injection analysis (FIA) ranged from 20 pmol of proline to 50 nmol of asparagine. In general, amino acids containing secondary amine groups yielded the strongest responses. A reaction mechanism for Ru (bpy)₃ ^{3 +} chemiluminescence of aliphatic amines has been proposed. Studies of peptide molecules and poly-prolines showed that the peptide bond barely contributes to the detection signals. The separation of hydroxyproline and proline in synthetic collagen by HPLC with Ru (bpy)₃ ^{3 +} chemiluminescence detection has been shown to be possible.     

Novel Synthesis of 2-(2-(3-Hydroxy-5-oxo-4-phenylthiophen-2(5H)-ylidene)-2-phenylacetamido)propanoic Acid Analogues and Their Anti-Inflammatory Properties

This article describes the reaction of 3,6-diphenyl-thieno[3,2-b]furan-2,5-dione 1 with different amino acids 2a–j in glacial acetic acid which afforded the 2-(2-(3-hydroxy-5-oxo-4-phenylthiophen-2(5H)-ylidene)-2-phenylacetamido)propanoic acid analogues 3a–j and also describes the reaction of 3,6-diphenyl-thieno[3,2-b]thiophene-2,5-dione 4 with different amino acids 5a–e in acidic medium to give 2-(2-(3-mercapto-5-oxo-4-phenylthiophen-2(5H)-ylidene)-2-phenylacetamido)propanoic acid analogues 6a–e. All the compounds have been screened for their anti-inflammatory activity against the carrageenan induced rat paw edema in albino rats. In the primary screening, some of the compounds exhibited appreciable activity.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Synthesis,characterization, and cytotoxicity of complexes of platinum(II) with 2,2′-bipyridine and N-benzoyl-L-amino acid dianion

Four new platinum(II) complexes (1–4) with N-benzoyl-L-amino acid and bipy were synthesized and characterized by elemental analysis, IR, UV, ¹H NMR, and mass spectra. The crystal structure of 1 was determined by X-ray diffraction analysis. Cytotoxicities were measured by MTT and SRB assays. Complexes 1–4 exert cytotoxicity with selectivity against HL-60, Bel-7402, BGC-823, and KB cell lines. This suggests that amino acids and acylated groups have important effects on cytotoxicity; the cytotoxicity is also related to the species of tumor cells, but the IC₅₀ values do not show definite correlation with the variation of amino acids and acylated groups.