Well‐controlled ring‐opening polymerization of cyclic esters catalyzed by aluminum amido complexes: Kinetics and mechanism

A series of aluminum dimethyl complexes 1 – 6 bearing N‐[2‐(pyrrolidinyl)benzyl]anilido ligands were synthesized and well characterized. The molecular structure of complex 1 determined by an X‐ray diffraction study indicates the bidentate chelating mode of the pyrrolidinyl‐anilido ligand. In the absence of a coinitiator, these complexes exhibited excellent control toward the polymerizations of ε‐caprolactone and rac‐lactide, affording polyesters with quite narrow molecular weight distributions (M_w/M_n = 1.04–1.26). The end group analysis of ε?CL oligomer via ¹H NMR and ESI‐TOF MS methods gave strong support to the hypothesis that the polymerization catalyzed by these aluminum complexes proceeds via a coordination‐insertion mechanism involving a unique Al? N (amido) bond initiation. Via ¹H NMR scale oligomerization studies, it is suggested that the insertion of the first lactide monomer into Al? N bond of the complex is much easier than the insertion of lactide monomer into the newly formed Al? O (lactate) bond and might also be easier than the insertion of the first ε?CL monomer into Al? N bond. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3096–3106     

ESI‐MS/MS analysis of protonated N‐methyl amino acids and their immonium ions

Methylation is one of the important posttranslational modifications of biological systems. At the metabolite level, the methylation process is expected to convert bioactive compounds such as amino acids, fatty acids, lipids, sugars, and other organic acids into their methylated forms. A few of the methylated amino acids are identified and have been proved as potential biomarkers for several metabolic disorders by using mass spectrometry–based metabolomics workstation. As it is possible to encounter all the N‐methyl forms of the proteinogenic amino acids in plant/biological systems, it is essential to have analytical data of all N‐methyl amino acids for their detection and identification. In earlier studies, we have reported the ESI‐MS/MS data of all methylated proteinogenic amino acids, except that of mono‐N‐methyl amino acids. In this study, the N‐methyl amino acids of all the amino acids ( 1 ‐ 21 ; including one isomeric pair) were synthesized and characterized by ESI‐MS/MS, LC/MS/MS, and HRMS. These data could be useful for detection and identification of N‐methyl amino acids in biological systems for future metabolomics studies. The MS/MS spectra of [M + H]⁺ ions of most N‐methyl amino acids showed respective immonium ions by the loss of (H₂O, CO). The other most common product ions detected were [MH‐(NH₂CH₃]⁺, [MH‐(RH)]⁺ (where R = side chain group) ions, and the selective structure indicative product ions due to side chain and N‐methyl group. The isomeric/isobaric N‐methyl amino acids could easily be differentiated by their distinct MS/MS spectra. Further, the MS/MS of immonium ions inferred side chain structure and methyl group on α‐nitrogen of the N‐methyl amino acids.     

Effect of β3‐Amino Acids on the Performance of the Peptidic Catalyst H‐dPro‐Pro‐Glu‐NH2

The effect of β³‐amino acids on the conformation and catalytic performance of the peptidic catalyst H‐d Pro‐Pro‐Glu‐NH₂ was investigated. Analogues of the peptidic catalyst bearing instead of the α‐amino acids the respective β³‐amino acids were prepared and their reactivity and stereoselectivity was investigated in conjugate addition reactions of aldehydes to nitroolefins. Additional computational studies provided insights into the preferred conformations of the peptidic catalysts. The results show that conformational flexibility at the N‐terminus has a severe effect on the stereoselectivity but is tolerated at the C‐terminus.     

Density and viscosity of α-amino acids in aqueous solutions of cetyltrimethylammonium bromide

The densities and viscosities of aqueous solution of cetyltrimethylammonium bromide (0.01 mol kg⁻¹) (CTAB) and solutions of CTAB containing amino acids, viz., glycine, l-serine, and l-valine (0.01–0.05 mol kg⁻¹), were determined in the temperature range 298.15—313.15 K. Apparent molar volumes of the amino acids were calculated from the density and viscosity values. The calculated apparent molar volumes were used to calculate standard partial molar volumes (-V ₂⁰) and standard partial molar volumes of transfer of amino acids from water to an aqueous solution of CTAB. The viscosity values were used for the calculation of the viscosity coefficients A and B in the Jones—Dole equation. The linear dependences of -V ₂⁰ and B on the number of carbon atoms in the alkyl chains of the amino acids were found. The results obtained were used in analysis of hydrophilic-hydrophilic, hydrophilic-hydrophobic, and hydrophobic-hydrophobic interactions that occur during dissolution of amino acids in an aqueous solution of CTAB.     

Strontium‐based initiator system for ring‐opening polymerization of cyclic esters

An amino isopropoxyl strontium (Sr‐PO) initiator, which was prepared by the reaction of propylene oxide with liquid strontium ammoniate solution, was used to carry out the ring‐opening polymerization (ROP) of cyclic esters to obtain aliphatic polyesters, such as poly(ε‐caprolactone) (PCL) and poly(L ‐lactide) (PLLA). The Sr‐PO initiator demonstrated an effective initiating activity for the ROP of ε‐caprolactone (ε‐CL) and L‐lactide (LLA) under mild conditions and adjusted the molecular weight by the ratio of monomer to Sr‐PO initiator. Block copolymer PCL‐b‐PLLA was prepared by sequential polymerization of ε‐CL and LLA, which was demonstrated by ¹H NMR, ¹³C NMR, and gel permeation chromatography. The chemical structure of Sr‐PO initiator was confirmed by elemental analysis of Sr and N, ¹H NMR analysis of the end groups in ε‐CL oligomer, and Fourier transform infrared (FTIR) spectroscopy. The end groups of PCL were hydroxyl and isopropoxycarbonyl, and FTIR spectroscopy showed the coordination between Sr‐PO initiator and model monomer γ‐butyrolactone. These experimental facts indicated that the ROP of cyclic esters followed a coordination‐insertion mechanism, and cyclic esters exclusively inserted into the Sr–O bond. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1934–1941, 2003     

Synthesis and Conformational Analysis of Hybrid α/β‐Dipeptides Incorporating S‐Glycosyl‐β2,2‐Amino Acids

We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α‐amino acid attached to a quaternary glyco‐β‐amino acid. In particular, we combined a S‐glycosylated β^2,2‐amino acid and two different types of α‐amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β‐dipeptides. The key step in the synthesis involved the ring‐opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur‐containing nucleophile by using 1‐thio‐β‐D ‐glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time‐averaged restraints (MD‐tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β‐amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α‐amino acids due to the presence of CH–π interactions between the phenyl or indole ring and the methyl groups of the β‐amino acid unit.     

Sequence determination of αs1‐casein isoforms from donkey by mass spectrometric methods

Four co‐eluting components, with experimentally measured M_r of 23 658, 23 786, 24 278 and 24 406 Da, were detected by reversed‐phase high‐performance liquid chromatography (RP‐HPLC) and matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) analysis in the dephosphorylated casein fraction of a milk sample collected at middle lactation stage from an individual donkey belonging to the Ragusano breed. By coupling RP‐HPLC, two‐dimensional polyacrylamide gel electrophoresis (2D‐PAGE), enzymatic digestions, MALDI‐TOF MS and capillary RP‐HPLC/nano‐electrospray ionization tandem mass spectrometry (nESI‐MS/MS) analyses, the four components were identified as donkey's α_s1‐CNs and their sequences completely characterized, using the known mare's α_s1‐CN (GenBank Acc. No. AAK83668; M_r 23750.7 Da) as reference. The proteins with M_r of 23 786 and 23 658 Da differ in the presence of a glutamine residue at position 83 in the full‐length component and present the amino acid substitutions Q⁸→H and H¹¹⁵→Y with respect to the mare's α_s1‐CN. The other two components with M_r 24 406 and 24 278 Da, which also differ in the presence of a glutamine residue at position 88 in the full‐length component, show the insertion of the pentapeptide HTPRE between Leu³³ and the Glu³⁴. The two α_s1‐CNs bearing the pentapeptide insertion were named variants A (202 amino acids; M_r 24 406) and A₁ (201 amino acids; M_r 24 278), whereas the two α_s1‐CNs without the pentapeptide were named variants B (197 amino acids; M_r 23 786) and B₁ (196 amino acids; M_r 23 658). Copyright © 2009 John Wiley & Sons, Ltd.     

L‐Valine assisted distinction between the stereo‐isomers of D‐hexoses by positive ion ESI tandem mass spectrometry

The binary mixtures of 7 hexoses and 20 amino acids were investigated by electrospray ionization ion trap mass spectrometry (ESI‐ITMS). The adduct ions of the amino acid and the hexose were detected for 12 amino acids but not for the other 8 amino acids which are basic acidic amino acids and amides. The ions of amino acid–hexose complexes were further investigated by tandem mass spectrometry (MS/MS), and some of them just split easily into two parts whereas the others gave rich fragmentation, such as the complex ions of isoleucine, phenylalanie, tyrosine, and valine. We found that hexoses could be complexed by two molecules of valine but only by one molecule of the other amino acids. Among seven kinds of valine–hexose complexes coordinated by potassium ion, the MS² spectra of the ion at m/z 453 yielded unambiguous differentiation. And the fragmentation ions are sensitive to the stereochemical differences at the carbon‐4 of hexoses in the complexes, as proved by the MS². Copyright © 2010 John Wiley & Sons, Ltd.     

Heteroleptic Tin(II) Initiators for the Ring‐Opening (Co)Polymerization of Lactide and Trimethylene Carbonate: Mechanistic Insights from Experiments and Computations

The tin(II) complexes {LO^x}Sn(X) ({LO^x}^?=aminophenolate ancillary) containing amido ( 1 – 4 ), chloro ( 5 ), or lactyl ( 6 ) coligands (X) promote the ring‐opening polymerization (ROP) of cyclic esters. Complex 6 , which models the first insertion of L ‐lactide, initiates the living ROP of L ‐LA on its own, but the amido derivatives 1 – 4 require the addition of alcohol to do so. Upon addition of one to ten equivalents of iPrOH, precatalysts 1 – 4 promote the ROP of trimethylene carbonate (TMC); yet, hardly any activity is observed if tert‐butyl (R)‐lactate is used instead of iPrOH. Strong inhibition of the reactivity of TMC is also detected for the simultaneous copolymerization of L ‐LA and TMC, or for the block copolymerization of TMC after that of L ‐LA. Experimental and computational data for the {LO^x}Sn(OR) complexes (OR=lactyl or lactidyl) replicating the active species during the tin(II)‐mediated ROP of L ‐LA demonstrate that the formation of a five‐membered chelate is largely favored over that of an eight‐membered one, and that it constitutes the resting state of the catalyst during this (co)polymerization. Comprehensive DFT calculations show that, out of the four possible monomer insertion sequences during simultaneous copolymerization of L ‐LA and TMC: 1) TMC then TMC, 2) TMC then L ‐LA, 3) L ‐LA then L ‐LA, and 4) L ‐LA then TMC, the first three are possible. By contrast, insertion of L ‐LA followed by that of TMC (i.e., insertion sequence 4) is endothermic by +1.1 kcal mol^?1, which compares unfavorably with consecutive insertions of two L ‐LA units (i.e., insertion sequence 3) (?10.2 kcal mol^?1). The copolymerization of L ‐LA and TMC thus proceeds under thermodynamic control.     

Partial Molar Volumes of Some of α-Amino Acids in Binary Aqueous Solutions of MgSO4·7H2O at 298.15 K

The apparent molar volume, V ^o _{φ, 2}, of glycine, alanine, α-amino-n-butyric acid, valine and leucine have been determined in aqueous solutions of 0.25, 0.5 and 1.0 mol⋅dm⁻³ magnesium sulfate, and the partial specific volume from density measurements at 298.15 K. These data have been used to calculate the infinite dilution apparent molar volume, V ^o _2,m , group contribution of amino acids and partial molar volume of transfer, Δ_tr V _2,m ^o, from water to aqueous magnesium sulfate solutions. The linear correlation of V _2,m ^o for a homologous series of amino acids has been utilized to calculate the contributions of charged end groups (NH₃ ⁺, COO⁻), CH₂ - groups and other alkyl chains of amino acids to V _2,m ^o. The results for Δ_tr V _2,m ^o of amino acids from water to aqueous magnesium sulfate solutions have been interpreted in terms of ion-ion, ion-polar, hydrophilic-hydrophilic and hydrophobic-hydrophobic group interactions. The values of the standard partial molar volume of transfer for the amino acids with different hydrophobic contents, from water to aqueous MgSO₄ are in general positive, indicating the predominance of the interactions of zwitterionic/hydrophilic groups of amino acids with ions of the salt. The hydration number decreases with increasing concentration of salt. The number of water molecules hydrated to amino acids decreases, further strengthening the predominance of ionic/hydrophilic interactions in this system.     

Characterization of N‐methylated amino acids by GC‐MS after ethyl chloroformate derivatization

Methylation is an essential metabolic process in the biological systems, and it is significant for several biological reactions in living organisms. Methylated compounds are known to be involved in most of the bodily functions, and some of them serve as biomarkers. Theoretically, all α‐amino acids can be methylated, and it is possible to encounter them in most animal/plant samples. But the analytical data, especially the mass spectral data, are available only for a few of the methylated amino acids. Thus, it is essential to generate mass spectral data and to develop mass spectrometry methods for the identification of all possible methylated amino acids for future metabolomic studies. In this study, all N‐methyl and N,N‐dimethyl amino acids were synthesized by the methylation of α‐amino acids and characterized by a GC‐MS method. The methylated amino acids were derivatized with ethyl chloroformate and analyzed by GC‐MS under EI and methane/CI conditions. The EI mass spectra of ethyl chloroformate derivatives of N‐methyl ( 1–18 ) and N,N‐dimethyl amino acids ( 19–35 ) showed abundant [M‐COOC₂H₅]⁺ ions. The fragment ions due to loss of C₂H₄, CO₂, (CO₂ + C₂H₄) from [M‐COOC₂H₅]⁺ were of structure indicative for 1–18 . The EI spectra of 19–35 showed less number of fragment ions when compared with those of 1–18 . The side chain group (R) caused specific fragment ions characteristic to its structure. The methane/CI spectra of the studied compounds showed [M + H]⁺ ions to substantiate their molecular weights. The detected EI fragment ions were characteristic of the structure that made easy identification of the studied compounds, including isomeric/isobaric compounds. Fragmentation patterns of the studied compounds ( 1–35 ) were confirmed by high‐resolution mass spectra data and further substantiated by the data obtained from ¹³C₂‐labeled glycines and N‐ethoxycarbonyl methoxy esters. The method was applied to human plasma samples for the identification of amino acids and methylated amino acids. Copyright © 2016 John Wiley & Sons, Ltd.     

Phosgene‐free synthesis of polypeptides: Useful synthesis for hydrophobic polypeptides through polycondensation of activated urethane derivatives of α‐amino acids

We report a useful synthetic method of polypeptides using a series of urethane derivative of α‐amino acids (l ‐leucine, l ‐phenylalanine, l ‐valine, l ‐alanine, l ‐isoleucine, l ‐methionine), which are readily synthesized by N‐carbamoylation of tetrabutylammonium salts of α‐amino acids with diphenyl carbonate. Heating these urethane derivatives in N,N‐dimethylacetamide in the presence of n‐butylamine successfully gave the corresponding polypeptides with well‐defined structures through polycondensation with the elimination of phenol and CO₂. The matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry investigation showed that the resulting polypeptides had an n‐BuNH₂‐incorporated initiating end and an amino group at propagating end. These results strongly indicated that primary amines served as an initiator in this polycondensation system. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3726–3731     

Chiral differentiation of some cyclic β‐amino acids by kinetic and fixed ligand methods

Differentiation of β ‐amino acid enantiomers with two chiral centres was investigated by kinetic method with trimeric metal‐bound complexes. Four enantiomeric pairs of β ‐amino acids were studied: cis‐(1R,2S)‐, cis‐(1S,2R)‐, trans‐(1R,2R)‐ and trans‐(1S,2S)‐2‐aminocyclopentanecarboxylic acids (cyclopentane β ‐amino acids), and cis‐(1R,2S)‐, cis‐(1S,2R)‐, trans‐(1R,2R)‐, and trans‐(1S,2S)‐2‐aminocyclohexanecarboxylic acids (cyclohexane β ‐amino acids). The results showed that the choice of metal ion (Cu²⁺, Ni²⁺) and chiral reference compound (α‐ and β ‐amino acids) had an effect on the enantioselectivity. Especially, aromaticity of the reference compound was noted to enhance the enantioselectivity. The fixed‐ligand kinetic method, a modification of the kinetic method, was then applied to the same β ‐amino acids, with dipeptides used as fixed ligands. With this method, dipeptide containing an aromatic side chain enhanced the enantioselectivity. Copyright © 2009 John Wiley & Sons, Ltd.     

Sensor Array Based Determination of Edman Degradated Amino Acids Using Poly(p-phenyleneethynylene)s

A cross-reactive optical sensor array based on poly(p-phenyleneethynylene)s (PPEs) determines Edman degraded amino acids. We report a sensor array composed of three anionic PPEs P1–P3 , and their electrostatic complexes with metal ions (Fe²⁺, Cu²⁺, Co²⁺). We recorded distinct fluorescence intensity response patterns as “fingerprints” of this chemical tongue toward standard phenylthiohydantoin (PTH) amino acids—degradation products of the Edman process. These “fingerprints” were converted into canonical scores by linear discrimination analysis (LDA), which differentiates all of the PTH-amino acids. This array discriminates PTH-amino acid residues degraded from an oligopeptide through Edman sequencing. This approach is complementary to chromatography approaches which rely on mass spectrometry; our array offers the advantage of simplicity.     

Hexabenzocoronene Graphitic Nanocoils Appended with Crown Ethers: Supramolecular Chirality Induced by Host–Guest Interaction

We have designed and synthesized two new achiral hexa-peri-hexabenzocoronene (HBC) derivatives, HBC^CE and HBC^TEG-CE , which bear the crown ether as the pendant for the amino acid binding site. The HBC^CE self-assembled into a racemic mixture of P- and M-handed helical nanocoils, however, in the presence of chiral amino acid guests, it formed helical nanocoils with one-handed screw sense. The effects of the concentration, type and configuration of the guests on the induced circular dichroism (ICD) during the co-assembly of HBC^CE with chiral amino acids were also investigated. Additionally, after complete removal of the chiral guests, the optically active nanocoils did not racemize, even in the presence of excess amino acids with the opposite configuration. In contrast, HBC^TEG-CE with a long triethylene glycol (TEG) chain between the crown ether group and the HBC unit did not exhibit ICD during the co-assembly with chiral amino acids.     

Convenient and useful synthesis of N‐carboxyanhydride monomers through selective cyclization of urethane derivatives of α‐amino acids

A new convenient synthesis of N‐carboxyanhydrides (NCAs) of α‐amino acids was achieved by selective cyclization of urethane derivatives of α‐amino acids. The urethanes were readily synthesized via N‐carbamoylation of α‐amino acids by bis(4‐nitrophenyl)carbonate quantitatively. These urethanes having 4‐nitrophenoxy moiety were tolerant to air and moisture to allow their facile purification and storage. When the obtained urethanes were heated in 2‐butanone at 60 °C, they underwent the selective cyclization via intramolecular nucleophilic attack of the carboxyl moiety to the urethane moiety with releasing 4‐nitrophenol, leading to the successful formation of the corresponding NCAs. Addition of carboxylic acids remarkably stabilized the formed NCAs during the reaction, allowing their isolation in high yields. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3839–3844, 2009     

Synthesis of Ureido-Linked Glycosylated Amino Acids from N α-Fmoc-Asp/Glu-5-oxazolidinones and Their Application to Neoglycopeptide Synthesis

A simple route for the synthesis of ureido-linked glycosylated amino acids has been described. The key step involves the reaction of isocyanates derived from N ^α-Fmoc-Asp/Glu-5-oxazolidinones 1 with glycosyl amines followed by hydrolysis. The resulting ureido-linked glycosylated amino acids have been incorporated into peptides. The overall procedure is simple, high-yielding, and involves fewer steps.     

Synthesis of a new 2‐amino‐glycan,poly‐(1→6)‐α‐D‐mannosamine,by ring‐opening polymerization of 1,6‐anhydro‐mannosamine derivatives

A stereoregular 2‐amino‐glycan composed of a mannosamine residue was prepared by ring‐opening polymerization of anhydro sugars. Two different monomers, 1,6‐anhydro‐2‐azido‐mannose derivative ( 3 ) and 1,6‐anhydro‐2‐(N, N‐dibenzylamino)‐mannose derivative ( 6 ), were synthesized and polymerized. Although 3 gave merely oligomers, 6 was promptly polymerized into high polymers of the number‐average molecular weight (M_n) of 2.3 × 10⁴ to 2.9 × 10⁴ with 1,6‐α stereoregularity. The differences of polymerizability of 3 and 6 from those of the corresponding glucose homologs were discussed. It was found that an N‐benzyl group is exceedingly suitable for protecting an amino group in the polymerization of anhydro sugars of a mannosamine type. The simultaneous removal of O‐ and N‐benzyl groups of the resulting polymers was achieved by using sodium in liquid ammonia to produce the first 2‐amino‐glycan, poly‐(1→6)‐α‐D ‐mannosamine, having high molecular weight through ring‐opening polymerization of anhydro sugars.© 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

High-Performance Liquid Chromatographic Analysis of Amino Acids in Edible Seaweeds after Derivatization with Phenyl Isothiocyanate

Summary A reversed-phase high-performance liquid-chromatographic method has been used for analysis of the amino acids in edible seaweed. Sample proteins were hydrolysed with hydrochloric acid and the amino acids produced were derivatized with phenyl isothiocyanate. The resulting phenylthiocarbamyl amino acids were chromatographed on an ODS2 column with UV detection at 254 nm. The mobile phase was a mixture of 0.14 M ammonium acetate buffer, pH 6.4, containing 0.05% triethylamine (A) and 60:40 (v/v) acetonitrile–water (B), at a flow rate of 1.1 mL min^–1; the elution gradient (min:A%) was: 0:90, 8:90, 10:70, 12:70, 18:52, 20:0, 25:0, 28:90, 35:90. Method precision for the different amino acids was between 1.33 and 3.88% (relative standard deviation); detection limits were between 6.9 and 14.3 ng mL^–1. The amino acid content of the algae analysed ranged from 22.4 ± 1.9 to 138.0 ± 5.6 mg g^–1 d.w. The amino acids present at highest concentrations were glutamic acid, alanine, and phenylalanine.