Aliphatic Α-amino Acids Research Articles

Molecular Properties of Branched Aliphatic α-Amino Acids in Water.

Four branched-chain aliphatic α-amino acids─α-alanine, valine, leucine, and isoleucine (1-4)─were investigated by quantum-chemical calculations in water as a solvent by two methods. The B3LYP variant of DFT calculations was used to obtain the electronic structure and molecular descriptors of these species in their canonical amino acid form as well as the related zwitterionic form in three oxidation states (cation, neutral molecule, and anion). A total of 24 species were subjected to full geometry optimization and complete vibration analysis. Quantities related to ionization or affinity processes were evaluated under adiabatic conditions. The calculated standard reaction Gibbs energy facilitates evaluation of the absolute oxidation and reduction potential. The absolute reduction potential correlates with the electrophilicity index, and the absolute oxidation potential correlates with the adiabatic ionization energy. This finding makes it possible to skip the tedious vibrational analysis and use electronic properties to estimate the redox potentials. The molecular descriptors were compared with the calculated properties of four linear amino acids (glycine, β-alanine, GABA, and DAVA). Parallel calculations using the DLPNO-CCSD(T) method gave analogous results for 24 species. The absolute oxidation potential was related to the antioxidant activity index, which showed only a moderate antioxidant activity of 1-4.

Tandem mass spectrometry of homologous 3-hydroxyfurazan and nitrile amino acids: Analysis of cooperative interactions and fragmentation processes.

The assignment of structure by tandem mass spectrometry (MS/MS) relies on the interpretation of the fragmentation behavior of gas-phase ions. Mass spectra were acquired for a series of heterocyclic mimetics of acidic amino acids and a related series of nitrile amino acids. All amino acids were readily protonated or deprotonated by electrospray ionization (ESI), and distinctive fragmentation processes were observed when the ions were subjected to collision-induced dissociation (CID). The deprotonated heterocycles showed bond cleavages of the 3-hydroxyfurazan ring with formation of oxoisocyanate and the complementary deprotonated nitrile amino acid. Further fragmentation of the deprotonated nitrile amino acids was greatly dependent on the length of the alkyl nitrile side chain. Competing losses of CO2 versus HCN occurred from α-cyanoglycinate (shortest chain), whereas water was lost from 2-amino-5-cyanopentanoate (longest chain). Interestingly, loss of acrylonitrile by a McLafferty-type fragmentation process was detected for 2-amino-4-cyanobutanoate, and several competing processes were observed for β-cyanoalanate. In one process, cyanide ion was formed either by consecutive losses of ammonia, carbon dioxide, and acetylene or by a one-step decarboxylative elimination. In another, complementary ions were obtained from β-cyanoalanate by loss of acetonitrile or HN=CHCO2H. Fragmentation of the protonated 3-hydroxyfurazan and nitrile amino acids resulted in the cumulative loss (H2O + CO), a loss that is commonly observed for protonated aliphatic α-amino acids. Overall, the distinct fragmentation behavior of the multifunctional 3-hydroxyfurazan amino acids correlated with the charged site, whereas fragmentations of the deprotonated nitrile amino acids showed cooperative interactions between the nitrile and the carboxylate groups.

Synthesis of new Amides based on N-Phthaloyl-α-Amino Acids

N-phthaloyl derivatives of aliphatic α-amino acids were synthesized using phthalanhydride under standard conditions. The optimization reaction carried out by the thermal method to obtain the amides of these N-phthaloyl amino acids resulted in transimitted rather than amidation. The target amides of N-phthaloyl-α-amino acids were obtained by acylation of the amine with the corresponding acid chloroanhydrides in dichloromethane. These results were compared with the results of a similar acylation in a non-polar solvent (benzene). The dependence of the direction of the reaction on the duration of the acylation and the amount of amine used was established. The conditions for the formation of the corresponding N-phthaloyl-α-amino acid amides and asymmetric phthalic acid diamides were found. It is noteworthy that the formation of diamides is directly proportional to the equivalent amount of amine and the duration of the reaction, which makes it possible to purposefully control the synthesis in one reactor.

Dl-Piperidinium-2-carboxyl-ate bis-(hydrogen peroxide): unusual hydrogen-bonded peroxide chains.

The title compound, C6H11NO2·2H2O2, is the richest (by molar ratio) in hydrogen peroxide among the peroxosolvates of aliphatic α-amino acids. The asymmetric unit contains a zwitterionic pipecolinic acid mol-ecule and two hydrogen peroxide mol-ecules. The two crystallographically independent hydrogen peroxide mol-ecules form a different number of hydrogen bonds: one forms two as donor and two as acceptor ([2,2] mode) and the other forms two as donor and one as acceptor ([2,1] mode). The latter hydrogen peroxide mol-ecule forms infinite hydrogen-bonded hydro-peroxo chains running along the c-axis direction, which is unusual for aliphatic α-amino acid peroxosolvates.

From Anodic Oxidation of Aliphatic α-Amino Acids to Polypeptides by Quantum Electrochemistry Approach: Beyond Miller-Urey Experiments.

For years, polypeptide formation has fascinated the scientific world because its understanding could lead to one of the possible explanations for the origin of life. Anodic oxidation of aliphatic α-amino acids in aqueous electrolytes can result either in their decomposition or in their polymerization into polypeptide. This behavior depends experimentally on both amino acid concentration and pH. The elucidation of the involved mechanisms remains a challenge because of the multitude of products which can be obtained. In this context, the electrochemical behavior of glycine and alanine on a biased platinum surface was examined at the nanoscale by quantum electrochemistry via the effective screening medium method. Several electrochemical systems with different concentrations and pH values have been explored. Simulations of the anodic oxidation of the amino acids have not only confirmed their electropolymerization and decomposition at high and low concentrations, respectively, but also have revealed unsuspected mechanisms at the origin of polypeptide formation. This sheds new light on electrochemistry of α-amino acids, on occurrence of polypeptides, and more generally on organic electrochemistry.

Synthesis and Cytotoxicity of N-(3,4-Dimethoxyphenyl)Ethylamides of N-Benzoyl-α-Amino Acids

Amides were synthesized from N-benzoyl aliphatic α-amino acids and homoveratrylamine and screened for cytotoxicity.

Comparative Study of Kinetic and Mechanistic Study of Oxidation of L-Alanine and L-Proline by Sodium Periodate Catalyzed by Osmium(VIII) in Micromolar Concentrations

The kinetics of oxidation of two aliphatic α-amino acids (AA), namely, alanine and proline by NaIO4 has been investigated in alkaline medium in the presence of osmium(VIII) catalyst at a constant ionic strength of 1.0 mol dm–3 and at 25°C. The reactions were very slow to be measured in the absence of the catalyst. The reactions have a first order with respect both to [Os(VIII)] and [NaIO4], and fractional order with respect to both [L-alanine] (Ala) and [L-proline](Pro). The reaction show negligible effect of dielectric constant and ionic strength of medium. Increasing [OH–] concentration was found to decrease the oxidation rates while mercuric acetate acts as scavenger for both the reactions. A plausible oxidation mechanism has been proposed and the rate law expression has been derived. Both spectral and kinetic evidences revealed formation of intermediate complexes between AA and Os(VIII) before the rate-controlling step. Kinetic investigations have revealed that the order of reactivity is Pro > Ala. The complex thus formed reacts with the oxidant [NaIO4] by an inner-sphere mechanism with formation of the oxidation products of the amino acids which were identified as the corresponding carboxylic compounds, ammonium ion and carbon dioxide. The activation parameters of the first order rate constants were evaluated and discussed.

Exploring molecular interactions of aliphatic α-amino acids glycine, l-alanine, l-valine in aqueous potassium oxalate solutions from 288.15 K to 318.15 K through thermo-acoustical analysis

In the present communication, the densities and speeds of sound of aliphatic α-amino acids of homologous series i.e. glycine, l-alanine and l-valine in (0.2, 0.4, 0.6, 0.8) mol·kg−1 potassium oxalate (KOX) solutions at different temperatures ranging from 288.15K to 318.15K having interval of 10K and experimental pressure p=0.1MPa. Density measurements are used to evaluate apparent molar volumes (Vϕ), partial molar volumes (Vϕο), partial molar volume of transfer (ΔVϕο) from water to aqueous potassium oxalate, expansion coefficients. Apparent molar isentropic compression (Kϕ,s), partial molar isentropic compression (Kϕ,sο) and partial molar isentropic compression of transfer (ΔKϕ,sο) from water to aqueous potassium oxalate are attained from ultrasonic data. Using McMillan-Mayer theory of solutions, the interaction coefficients have also been achieved from the experimental data. These parameters are discussed in terms of solute-cosolute interactions and serve to distinguish the structure making or breaking tendency of studied compounds.

Design, Synthesis, and Application of an Optimized Monofluorinated Aliphatic Label for Peptide Studies by Solid-State 19 F NMR Spectroscopy.

A conformationally restricted monofluorinated α-amino acid, (3-fluorobicyclo[1.1.1]pentyl)glycine (F-Bpg), was designed as a label for the structural analysis of membrane-bound peptides by solid-state 19 F NMR spectroscopy. The compound was synthesized and validated as a 19 F label for replacing natural aliphatic α-amino acids. Calculations suggested that F-Bpg is similar to Leu/Ile in terms of size and lipophilicity. The 19 F NMR label was incorporated into the membrane-active antimicrobial peptide PGLa and provided information on the structure of the peptide in a lipid bilayer.

A Comparative Kinetic Study of Silver(I)-Catalyzed Oxidations of Alanine and Valine by Platinum (IV) in Perchloric and Sulfuric Acids Solutions

The kinetics of oxidations of two aliphatic α-amino acids (AA), namely, alanine and valine by platinum (IV) has been investigated spectrophotometrically in perchloric and sulfuric acids solutions in the presence of silver (I) catalyst at a constant ionic strength of 1.0 mol dm-3 and at 25°C. The reactions were very slow to be measured in the absence of the catalyst. The reactions in both acids showed a first order dependence on both [PtIV] and [AgI], and less than unit order dependences with respect to both [AA] and [H+]. Increasing ionic strength was found to decrease the oxidation rates. Under comparable experimental conditions, the oxidation rates of alanine and valine in perchloric acid solutions were found to be about five times higher than those obtained in sulfuric acid solutions and the oxidation rates of alanine in both acids were found to be higher than those recorded with respect to valine. A plausible oxidations mechanism has been proposed and the rate law expression has been derived. Both spectral and kinetic evidences revealed formation of 1:1 intermediate complexes between AA and AgI in both acids before the rate-controlling step. Then the formed complexes react with the oxidant (PtIV) by an inner-sphere mechanism to give rise to the oxidation products of the amino acids which were identified as the corresponding aldehyde, ammonium ion and carbon dioxide. The activation parameters of the second order rate constants were evaluated and discussed.

Kinetics and Mechanistic Approach to Palladium (II)-Catalyzed Oxidative Deamination and Decarboxylation of Leucine and Isoleucine by Anticancer Platinum (IV) Complex in Perchlorate Solutions

Oxidations of two aliphatic α-amino acids (AA), namely, leucine and isoleucine by hexachloroplatinate (IV) as an anticancer platinum (IV) complex has been studied using a spectrophotometric technique in perchlorate solutions in the presence of palladium (II) catalyst at a constant ionic strength of 1.0 mol dm-3 and at 25°C. The reactions did not proceed in the absence of the catalyst. The reactions of both amino acids showed a first order dependence on both [PtIV] and [PdII], and less than unit order dependences with respect to both [AA] and [H+]. Increasing ionic strength and dielectric constant of the reactions medium increased the rates of the reactions. A probable oxidations mechanism has been suggested and the rate law expression has been derived. Both spectral and kinetic evidences revealed formation of 1:1 intermediate complexes between AA and PdII before the rate-controlling step. The oxidation products of the investigated amino acids were identified as the corresponding aldehyde, ammonium ion and carbon dioxide. The activation parameters of the second order rate constants were evaluated and discussed

Aliphatic α-Amino Acids by Rhodium-Catalyzed Asymmetric Hydrogenation

Key words asymmetric catalysis - hydrogenation - amino acids - rhodium

Electrochemical and Spectrophotometric Study of the Hydration of Orthophthalaldehyde and Its Reaction with Amines and Aminoacids

Reactions of orthophthalaldehyde (OPA) with aliphatic α-amino acids and with aliphatic primary amines were studied in buffered aqueous solution and in non-aqueous acetonitrile. For comparison lysine and glycine ethyl ester were used. The role of the substitution on the α-carbon was discovered and the effect of OPA hydration on the course of the reaction was also investigated. In contrary to the published information, the dialdehydic unhydrated form is not the primary reactive species and for the successful reaction of OPA with amines, the presence of water is necessary.

Efficient synthesis of α-amino acid derivatives via phase-transfer-catalyzed directed reductive amination

An efficient phase-transfer-catalyzed directed reductive amination of α-keto esters was described using simple substituted benzyl amines as nitrogen source and K2CO3 as base at room temperature, giving a series of aliphatic α-amino acid derivatives in moderate to high yields(up to 99%). Preliminary study on this asymmetric process showed that cinchona-derived phase transfer catalyst was effective, affording the corresponding product in 13% e.e. and 40% yield.

Highly enantioselective synthesis of non-natural aliphatic α-amino acids via asymmetric hydrogenation.

By employing a rhodium-Duanphos complex as the catalyst, β-alkyl (Z)-N-acetyldehydroamino esters were smoothly hydrogenated in a highly efficient and enantioselective way. Excellent enantioselectivities together with excellent yields were achieved for a series of substrates. An efficient approach for the synthesis of the intermediate of the orally administered anti-diabetic drugs Alogliptin and Linagliptin in the DPP-4 inhibitor class was also developed.

Benzo[d]imidazole and Aliphatic α-Amino Acid Derived Primary Amines in Asymmetric Aldol Reactions

Starting from essential α-amino acids, four new benzo[ d ]imidazole and alkyl-chain-substituted primary amines were synthesized. The reaction sequence involves activation of the Boc-amino acid carboxylic acid, reaction with o -phenylenediamine, and subsequent cyclization to benzo[ d ]imidazole. N-Methylation and final Boc group removal afforded four new primary amines. The synthesized amines were preliminarily applied as organocatalysts in an asymmetric version of the aldol reaction between 4-nitrobenzaldehyde and acetone/cyclohexanone, achieving chemical yields of 40–64% and ee and de values up to 65 and 96%, respectively.

Synthesis and chemical properties of new derivatives of 3a',6a'-dihydro-2'H-spiro- [indole-3,1'-pyrrolo[3,4-c]pyrrole]-2,4',6'(1H,3'H,5'H)-trione

A series of new 3a',6a'-dihydro-2'H-spiro[indole-3,1'-pyrrolo[3,4-c]pyrrole]-2,4',6'(1H,3'H,5'H)- triones has been synthesized by cycloaddition of azomethine ylides, obtained from isatins and acyclic aliphatic and sulfur-containing α-amino acids, to maleimides. The direction of the cycloaddition was determined and the chemical properties of the obtained spiro products were examined.

Kinetics and Mechanism of Oxidation of Tryptophan by Ferrate(VI)

Kinetics of the oxidation of tryptophan (Trp) and kynurenine (Kyn), precursors of nitrogenous disinfection byproducts (N-DBP), by ferrate(VI) (Fe(VI)O4(2-), Fe(VI)) were investigated over the acidic to basic pH range. The second-order rate constants decreased with increase in pH, which could be described by the speciation of Fe(VI) and Trp (or Kyn). The trend of pH dependence of rates for Trp (i.e., aromatic α-amino acid) differs from that for glycine (i.e., aliphatic α-amino acid). A nonlinear relationship between transformation of Trp and the added amount of Fe(VI) was found. This suggests that the formed intermediate oxidized products (OPs), identified by LC-PDA and LC-MS techniques, could possibly compete with Trp to react with Fe(VI). N-Formylkynurenine (NFK) at pH 7.0 and 4-hydroxyquinoline (4-OH Q) and kynurenic acid (Kyn-A) at pH 9.0 were the major OPs. Tryptophan radical formation during the reaction was confirmed by the rapid-freeze quench EPR experiments. The oxygen atom transfer from Fe(VI) to NFK was demonstrated by reacting Fe(18)O4(2-) ion with Trp. A proposed mechanism explains the identified OPs at both neutral and alkaline pH. Kinetics and OPs by Fe(VI) were compared with other oxidants (chlorine, ClO2(•), O3, and (•)OH).

Proton and potassium affinities of aliphatic and N-methylated aliphatic α-amino acids: Effect of alkyl chain length on relative stabilities of K+ bound zwitterionic complexes

The relative and absolute K+ affinities of a full series of aliphatic amino acids (Gly, Ala, Val, Leu, Ile and α-amino-isobutyric acid (α-AiB)) and N-methylated aliphatic amino acids (N-Me-(Gly/Ala/α-AiB/Val/Leu)) were investigated theoretically by density functional theory calculations at the B3–LYP/6-311+G(3df,2p)//B3-LYP/6-31G(d) level, and experimentally measured by the standard mass spectrometric kinetic method. Very good quantitative agreement was found between the theoretical and experimental results. The experimental K+ affinities were found to be consistent with the most stable charge-solvated CS1 binding mode (bidentate form with K+ bonded between two carboxylic oxygens, OC, OH) for aliphatic amino acids, and the zwitterionic ZW1 binding mode (bidentate form with K+ bonded between two carboxylate oxygens, COO−) for the N-methylated aliphatic amino acids. A steeper rising trend in ZW1 stabilities (affinities) relative to that of CS1 was found in the smaller aliphatic amino acids (Gly/Ala/α-AiB), but leveling off among the larger aliphatic amino acids (Val/Leu/Ile). This observed trend was rationalized in terms of greater deformation energy, Edef, found for the smaller Gly/Ala, and the leveling off of stabilizing ion-induced dipole (molecular polarizability) contributions from the non-interacting alkyl side chain in the larger aliphatic amino acids. The leveling off effect is aided by the relatively large size and soft, not so polarizing nature of the potassium cation. A good linear correlation (r2≥0.95) was found between the proton affinities (PA) and the ZW1/CS1K+ affinities, but because of the leveling off effect, the cross over or transition from CS1 to ZW1K+ binding mode was not found for isoleucine.

The Singular Gas-Phase Structure of 1-Aminocyclopropanecarboxylic Acid (Ac3c)

The natural nonproteinogenic α-amino acid 1-aminocyclopropanecarboxylic acid (Ac(3)c) has been vaporized by laser ablation and studied in the gas phase by molecular-beam Fourier transform microwave spectroscopy. Comparison of the experimental rotational and (14)N nuclear quadrupole coupling constants with the values predicted ab initio for these parameters has allowed the unambiguous identification of three Ac(3)c conformers differing in the hydrogen bonding pattern. Two of them resemble those characterized before for the coded aliphatic α-amino acids. Remarkably, a third conformer predicted to be energetically accessible for all of these amino acids but never observed (the so-called "missing conformer") has been found for Ac(3)c, close in energy to the global minimum. This is the first time that such a conformer, stabilized by an N-H···O(H) hydrogen bond, is detected in the rotational spectrum of a gaseous α-amino acid with a nonpolar side chain. The conjugative interaction established between the cyclopropane ring and the adjacent carbonyl group seems to be responsible for the unique conformational properties exhibited by Ac(3)c.