An N-protection free ligation of the peptide thioester and the peptide with an N-alkoxy- or N-aryloxyamino group at its N-terminus

Peptides with an N-alkoxy or N-aryloxy amino acid at their N-terminus were synthesized and successfully ligated with a peptide thioester by silver ion activation under a slightly acidic condition without requiring protection of the side chain amino groups. The N-methoxy group was easily cleaved by the SmI₂ reduction in CH₃OH aq. to obtain the desired peptide with a native peptide bond. This method was successfully applied to the synthesis of the human atrial natriuretic peptide showing the efficiency of the novel ligation.     

Deoxygenation of tertiary amine N-oxides under metal free condition using phenylboronic acid

A simple and efficient method for the deoxygenation of amine N-oxides to corresponding amines is reported using the green and economical reagent phenylboronic acid. Deoxygenation of N,N-dialkylaniline N-oxides, trialkylamine N-oxides and pyridine N-oxides were achieved in good to excellent yields. The reduction susceptible functional groups such as ketone, amide, ester and nitro groups are well tolerated with phenylboronic acid during the deoxygenation process even at high temperature. In addition, an indirect method for identification and quantification of tert-amine N-oxide is demonstrated using UV–Vis spectrometry which may be useful for drug metabolism studies.     

Measurements of the solubilities of derivatized amino acids in supercritical carbon dioxide

The solubilities of phenylalanine and tyrosine in supercritical carbon dioxide (SCCO₂) were measured after derivatization as the N-acetyl amino acid ethyl ester, N-carbobenzoxy amino acid and N-acetyl amino acid. Using an SCCO₂ flow system, a measuring method of the saturated solubilities of the derivatized amino acids was established in which the contact height of the extraction cell, i.e. a packed column, is increased till the concentration of a derivatized amino acid at the exit of the cell reaches a plateau. The solubilities of N-acetyl phenylalanine ethyl ester (APEE) exceeded 0.001 mole fraction, which is higher than those of caffeine produced in industrial SCCO₂ processes. A possible way of separating the amino acid mixtures using polarity differences in different amino acid side chains was demonstrated using the solubility data of the N-acetyl-amino acid ethyl esters in SCCO₂, as the solubilities of APEE are higher than those of N-acetyl tyrosine ethyl ester by two orders of magnitude.     

The use of an electrophile carrier to determine the number of intermediates in the chlorination of 1-methylpyrrole

A kinetic and product study of the dichloroacetic acid catalyzed chlorination of 1-methylpyrrole with 3- and 4-substituted N-chlorobenzamides was carried out. Protonated N-chlorobenzamides served as carriers of CI⁺. A Hammett correlation was obtained with ρ=−0.68 (r=0.98, n=8). General acid catalysis was observed with α=0.48 (r=0.99 and n=7). The yields of 2-chlorination (84±0.7%) and 3-chlorination (2.6±0.4%) were essentially constant (constant intramolecular selectivity) as the substituent on the N-chlorobenzamide was varied. Observation of constant intramolecular selectivity indicated that two intermediates were formed during the acid catalyzed chlorination of 1-methylpyrrole with N-chlorobenzamides. The carrier method is applicable to all types of aromatic systems and limited only by the availability of suitable carrier molecules.     

Evidence for a single minimum potential for hydrogen bonds of pyridine N-oxide complexes with dichloroacetic acid in dichloromethane

FTIR spectra of dichloracetic acid and its eight complexes with substituted pyridine N-oxides and N,N-dimethylaniline in dichloromethane-d₂ are reported. 4-N,N-dimethylaminopyridine N-oxides form two types of complexes with dichloroacetic acid; the acid interacts with NO or Me₂N groups. The shape of the second derivative of absorption in the carbonyl region implies that the hydrogen bonds are described by a strongly asymmetrical quasi-single minimum potential. The situation with regard to the observed carbonyl frequencies as related to conformational equilibria is reviewed.     

Reactivity of N-arylsulfonyl-1,4-benzoquinone imines. Reaction with hydrazoic acid

N-Arylsulfonyl-2-halo-1,4-benzoquinone imines react with hydrazoic acid in boiling acetic acid via two pathways: the 1,4-addition and nucleophilic replacement of the halogen atom by an azido group, followed by the 1,4-addition of HN₃. In the reaction of N-arylsulfonyl-2,6-dihalo-1,4-benzoquinone imines with hydrazoic acid, both halogen atoms are replaced by azido groups, while N-p-tolylsulfonyl-2-methyl-1,4-benzoquinone imine takes up HN₃ molecule according to the 1,4-addition pattern.     

Acid catalyzed monodehydro-2,5-diketopiperazine formation from N-α-ketoacyl amino acid amides

We have developed a new synthetic method for monodehydro-2,5-diketopiperazines (monodehydroDKPs), which is based on an acid catalyzed cyclization of N-α-ketoacyl amino acid amides. Using this cyclization reaction, monodehydroDKP was formed with no or slight racemization in case that N-α-ketoacyl amino acid amides with β-aliphatic-α-ketoacyl groups and sterically unhindered N-substituting groups at the C-terminal amide nitrogen were used in the presence of catalytic amount of p-TsOH (3-5 mol %) or 10% TFA. In the case of β-aryl-α-ketoacyl amino acid derivatives, in which an enol form predominantly exists by conjugation with the aromatic ring, racemization could be minimized by optimizing the reaction conditions (5 mol % p-TsOH, reflux for 6 h), although the chemical yield could not be dramatically improved. However, this reaction condition was successfully applied to the synthesis of a tubulin depolymerization agent, (−)-tert-butyl-oxa-phenylahistin, with no racemization.     

Description of the turbidity measurements near the phase transition temperature of poly(N-isopropyl acrylamide) copolymers: the effect of pH, concentration, hydrophilic and hydrophobic content on the turbidity

Absorbance values between 300 and 800 nm of aqueous solutions of poly(N-isopropyl acrylamide-co-itaconic acid-9.80), poly(N-isopropyl acrylamide-co-itaconic acid-52.05) and poly(N-isopropyl acrylamide)s containing Tegomer H-Si 2111 end groups and/or blocks were measured using a Shimadzu 160-A UV-visible spectrometer. Turbidities obtained from these absorbance values were used to interpret the macromolecular phase transition from a hydrophilic to a hydrophobic structure of the polymers. The effects of comonomer type and content, concentration of the solutions, pH and temperature on the coil-globule transition were discussed in terms of turbidity form factor, β related to size and shapes of particles and calculated by using the simplified form of Debye equation.The results presented in this work show that the presence of Tegomer H-Si 2111 (Si containing end groups and/or blocks) or high amount of itaconic acid (IA) in the chains prevent a collapse transition from hydrated extended coils to hydrophobic globules, which aggregate and form a separate phase (β<2). Furthermore, it was observed that in the case of concentrated solutions intermolecular hydrophobic interactions between isopropyl groups overcame the repulsive forces resulting from the ionized carboxylic acid groups of IA or surface active nature of Si containing hydrophobic groups (β>2). This stage of the transition corresponds to macroscopic phase separation after an intramolecular process.     

A novel method for the one-pot conversion of carboxylic acids to N,N-dimethylamides

A simple, efficient, and new method has been developed for the preparation of N,N-dimethylamides from carboxylic acids. As described below, treatment of a variety of aromatic carboxylic acids with N,N-dimethylsulfamoyl imidazole or N,N-dimethylsulfamoyl chloride in the presence of a mixture of methanesulfonic acid/phosphorus pentoxide (2:1, v/w) proceeded effectively to afford the corresponding N,N-dimethylamides in moderate to good yields. This method is easy, rapid, and good yielding for the synthesis of N,N-dimethylamides from carboxylic acids.     

Synthesis of N,N′-bis[4-(1H-1,2,3-triazol-1-yl)furazan-3-yl]-methylenediamine derivatives

[3+2] Cycloaddition of azide groups of N,N′-bis(4-azidofurazan-3-yl)methylenediamine to 1,3-dicarbonyl compounds and malonodinitrile was shown to proceed regioselectively with the formation of the corresponding N,N′-bis[4-(1H-1,2,3-triazol-1-yl)furazan-3-yl]methylenediamine derivatives. The reactions of N,N′-bis(4-azidofurazan-3-yl)methylenediamine with cyanoacetic acid ethyl ester and amide led to the formation of the product of transformation of the azide group in the starting compound to the amino groups.     

Tuning the diglycolamides for modifier-free minor actinide partitioning

The unsymmetrical diglycolamides (DGAs) such as N,N-dihexyl-N′,N′-dioctyl-3-oxapentane-1,5-diamide (DHDODGA), N,N-didecyl-N′,N′-dioctyl-3-oxapentane-1,5-diamide (D²DODGA), N,N-didodecyl-N′,N′-dioctyl-3-oxapentane-1,5-diamide (D³DODGA), were synthesized, and characterized by IR, NMR, and mass spectroscopic techniques. The extraction behaviour of Am(III), Eu(III), and Sr(II) by the solutions of these unsymmetrical DGAs in n-dodecane was studied as a function of concentration of nitric acid and DGA. The distribution ratio of Am(III) and Eu(III) increased with increase in the concentration of nitric acid; whereas, the distribution ratio of Sr(II) reached a maximum at 4 M nitric acid followed by decrease at higher acidities. The extraction of Am(III) and Eu(III) in 0.1 M DGA/n-dodecane decreased in the order DHDODGA > D²DODGA > D³DODGA. However, the order changed upon lowering the concentration of DGA. The third-phase formation behaviour of nitric acid and neodymium(III) in 0.1 M DGA/n-dodecane was studied as a function of concentration of nitric acid. The limiting organic concentration of nitric acid and neodymium increased with increase in the chain length of alkyl group attached to amidic nitrogen. Near stoichiometric amount of neodymium(III) was loaded in 0.1 M D³DODGA/n-dodecane without the formation of third-phase from 3 to 4 M nitric acid medium. The study revealed that the unsymmetrical diglycolamides D²DODGA and D³DODGA are superior candidates for partitioning the minor actinides from high-level liquid waste.     

Determination of alternative and conventional chelating agents as copper(II) complexes by capillary zone electrophoresis--the first use of didecyldimethylammonium bromide as a flow reversal reagent

A capillary zone electrophoresis (CZE) method for analyzing 11 chelating agents [β-alaninediacetic acid (β-ADA), trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CDTA), diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediamine-N,N′,N′-triacetic acid (HEDTA), N-(2-hydroxyethyl)iminodiacetic acid (HEIDA), iminodiacetic acid (IDA), methylglycinediacetic acid (MGDA), nitrilotriacetic acid (NTA), 1,3-diaminopropane-N,N,N′,N′-tetraacetic acid (PDTA) and triethylenetetraaminehexaacetic acid (TTHA)] as negatively charged copper(II) complexes has been established. Both conventional and alternative chelating agents were included in this study, because they are used side by side in industrial applications. In this study, didecyldimethylammonium bromide (DMDDAB) was successfully used as a flow reversal reagent for the first time in an aqueous CZE method based on phosphate BGE with UV spectrophotometric detection. In addition this new flow modifier was compared to common TTAB. Method development was done using a fused silica capillary (61 cm × 50 μm i.d.). The optimized BGE was a 105 mmol L⁻¹ phosphate buffer with TTAB or DMDDAB in the concentration 0.5 mmol L⁻¹ at pH 7.1. The measurements were done with −20 kV voltage using direct UV detection at 254 nm. In both CZE methods all 11 analyte zones were properly separated (resolutions ≥2.4), and the calibrations gave excellent correlation coefficients (≥0.998; linear range tested 0.5-2.0 mmol L⁻¹). The limits of detection were ≤34 and ≤49 μmol L⁻¹ with the method of DMDDAB and TTAB, respectively. A clear benefit of both methods was the short analysis time; all 11 complexes were detected in less than 6 and 5.5 min with the methods of TTAB and DMDDAB, respectively. The two methods were tested with dishwashing detergents and paper mill wastewater samples and proved to be suitable for practical use.     

Investigation for the cyclization efficiency of linear tetrapeptides: Synthesis of tentoxin B and dihydrotentoxin

Investigation of the cyclization efficiency of N-methyl linear tetrapeptides using a molecular modeling study and chemical synthesis is described. The linear peptide with two N-methyl groups, MeAla-Leu-MePhe-Gly, forms γ-turn like conformation with the amine at N-terminus and the carbonyl at C-terminus in closer proximity to give the desired cyclic tetrapeptide, dihydrotentoxin. In addition, synthesis of tentoxin B by the combination of Fmoc solid-phase peptide synthesis and cyclization in solution phase has been reported. An unusual amino acid, an L-N-methyl-β-hydroxyphenylalanine derivative, which was assembled on solid support, was prepared from ethyl cinnamate. Cyclic tetrapeptide formation and cleavage of benzyl ether were optimized with DIPCI/HOBt/DIPEA and Et₃SiH/Pd(OH)₂, respectively.     

Di-ionizable calix[4]arene-1,2-crown-5 and -crown-6 ethers in cone conformations: synthesis and divalent metal ion extraction

Two series of di-ionizable calix[4]arene-1,2-crown-5 and -crown-6 ethers in cone conformations are synthesized. The ionizable groups are oxyacetic acid moieties and N-(X)sulfonyl oxyacetamide units with X=methyl, phenyl, 4-nitrophenyl, and trifluoromethyl, which ‘tunes’ their acidity. For competitive solvent extraction of alkaline earth metal cations from aqueous solutions into chloroform, the new ligands with N-(X)sulfonyl carbamoyl groups are efficient extractants with Ba²⁺ selectivity. On the other hand, the dicarboxylic acid analogues exhibit little selectivity in extraction of alkaline earth metal cations. For single species extractions of Pb²⁺, the ligands with both types of ionizable groups show very good extractions abilities. In single species extractions of Hg²⁺, the N-(X)sulfonyl carboxamide ligands are highly efficient, in contrast to the dicarboxylic acid compounds. Influences of the ionizable group identity, the crown ether ring size, and the presence of upper-rim p-tert-butyl groups on divalent metal ion extraction are explored.     

Intramolecular electrophilic cyclization of functional derivatives of unsaturated compounds: III. Reaction of N,4-Diarylbut-3-enamides with arenesulfenyl chlorides. Synthesis of 5-aryl-4-arylsulfanyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-ones

N-Aryl-4-phenylbut-3-enamides reacted with arenesulfenyl chlorides in chloroform to give N,4-diaryl-3-arylsulfanyl-4-chlorobutanamides, whereas in acetic acid in the presence of lithium perchlorate N-[4-arylsulfanyl-5-phenyltetrahydrofuran-2-ylidene]arenaminium perchlorates were obtained. Reactions of arenesulfenyl chlorides with N,4-diarylbut-3-enamides having strong electron-donating groups in positions 3 and 4 of the N-aryl substituent afforded 5-aryl-4-arylsulfanyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-ones.     

Extraction of metal ions by N-phenyl-, N-methyl-, and N-unsubstituted hydroxamic acid resins

Procedures are described for preparing macroreticular chelating resins with hydroxamic acid or N-methylhydroxamic acid functional groups. The chelating properties of the resins are compared with each other and with an N-phenylhydroxamic acid resin reported earlier. The extraction of 19 metal ions was studied as a function of pH for the N-methylhydroxamic acid resin. Several analytical applications of this resin have been demonstrated including the purification of chemical reagents, concentration of trace metal ions, and chromatographic separation of metal-ion mixtures.     

FT-IR study of the interaction of oxygen,argon, helium,nitrogen and xenon with hydroxyl groups in H-Y zeolite at low temperatures

Adsorptions of O₂, Ar, He, N₂ and Xe on H-Y zeolite at low temperatures were studied by transmission Fouriertransform infrared spectroscopy. For the O₂ adsorption, a weak v(OO) band was observed at 1550 cm⁻¹. The formation of a weak hydrogen-bonding of O₂ and Ar with the bridging OH-groups in the supercage was observed, while these molecules did not interact chemically nor physically with the bridging OH-groups in the small cavities. These results indicate that O₂ and Ar can approach the acid sites in the supercages, but cannot approach those in the small cavities. However, a slight physical interaction (not the H-bonding) of He with the OH groups in the small cavities was observed, suggesting that He would be able to approach near the sites. N₂ adsorption gave two v(NN) bands at 2353 and 2338 cm⁻¹, which have been attributed to the N2 species adsorbed on Lewis acid sites and on Br0nsted acid sites, respectively. It was observed that N₂ and Xe interact strongly with the bridging OH-groups in the supercages as well as weakly with the silanol groups. On the basis of the IR-spectroscopic data on the strength of the interaction with the small and nonpolar gases, the acidic properties of H-Y was compared with those of H-MOR and H-ZSM-5.     

Peptide thioester preparation based on an N-S acyl shift reaction mediated by a thiol ligation auxiliary

Formation of peptide thioesters, based on an N to S acyl shift mediated by an auxiliary, N-4,5-dimethoxy-2-mercaptobenzyl (Dmmb) group, under acidic conditions, is described. The protected peptide was assembled on a hydroxymethylphenylacetamidomethyl resin via an N-Dmmb-amino acid residue according to standard Fmoc solid-phase peptide synthesis following treatment with trifluoroacetic acid. The peptide α-thioester was released from the resin by reaction with 2-mercaptoethanesulfonic acid in the presence of N,N-diisopropylethylamine.     

Synthesis and characterization of new soluble and thermally stable aromatic poly(amide-imide)s based on N-[3,5-bis(N-trimellitoyl)phenyl]phthalimide

A new dicarboxylic acid, N-[3,5-bis(N-trimellitoyl)phenyl]phthalimide (1a), bearing three preformed imide rings was synthesized from the condensation of N-(3,5-diaminophenyl)phthalimide and trimellitic anhydride in glacial acetic acid at 1:2 molar ratio. For study of structure-properties relationship 1,3-bis(N-trimellitoyl)benzene (1b, as a reference) was also synthesized in a similar manner. 1a and 1b were characterized by spectroscopic methods and elemental analyses.A series of wholly aromatic poly(amide-imide)s with inherent viscosities of 0.63-1.09 dl g⁻¹ was prepared by triphenyl phosphite-activated polycondensation from the triimide-dicarboxylic acid 1a and the reference monomer 1b with various aromatic diamines. All of the polymers were fully characterized by FT-IR and ¹H NMR spectroscopy. The effects of the phthalimide pendent group on the polymers properties such as solubility, crystallinity, and thermal stability were investigated by comparison of the polymers. The polymers obtained from triimide-dicarboxylic acid 1a exhibited excellent solubility in a variety of solvents such as N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, and dimethylsulfoxide. These poly(amide-imide)s possessed glass-transition temperatures from 334 to 403 °C and exhibited excellent thermal stabilities and had 10% weight losses from 541 to 568 °C under a nitrogen atmosphere. Poly(amide-imide)s containing phthalimide pendent groups showed higher solubility, higher T_g and T_d10% values than those having no phthalimide pendent groups.     

Antiallergic Activity of 6-Deoxy-2-O-methyl-6-(N-hexadecanoyl)amino-l-ascorbic Acid

Allergy is an excessive immune response to a specific antigen. Type I allergies, such as hay fever and food allergies, have increased significantly in recent years and have become a worldwide problem. We previously reported that an ascorbic acid derivative having palmitoyl and glucosyl groups, 2-O-α-d-glucopyranosyl-6-O-hexadecanoyl-l-ascorbic acid (6-sPalm-AA-2G), showed inhibitory effects on degranulation in vitro and on the passive cutaneous anaphylaxis (PCA) reaction in mice. In this study, several palmitoyl derivatives of ascorbic acid were synthesized and a structure–activity relationship study was performed to discover more potent ascorbic acid derivatives with degranulation inhibitory activity. 6-Deoxy-2-O-methyl-6-(N-hexadecanoyl)amino-l-ascorbic acid (2-Me-6-N-Palm-AA), in which a methyl group was introduced into the hydroxyl group at the C-2 position of ascorbic acid and in which the hydroxyl group at the C-6 position was substituted with an N-palmitoyl group, exhibited much higher inhibitory activity for degranulation in vitro than did 6-sPalm-AA-2G. 2-Me-6-N-Palm-AA strongly inhibit the PCA reaction in mice at lower doses than those of 6-sPalm-AA-2G. These findings suggest that 2-Me-6-N-Palm-AA may be a promising therapeutic candidate for allergic diseases.