Alkali metal ion binding to amino acids versus their methyl esters: affinity trends and structural changes in the gas phase

The relative alkali metal ion (M(+)) affinities (binding energies) between seventeen different amino acids (AA) and the corresponding methyl esters (AAOMe) were determined in the gas phase by the kinetic method based on the dissociation of AA-M(+)-AAOMe heterodimers (M=Li, Na, K, Cs). With the exception of proline, the Li(+), Na(+), and K(+) affinities of the other aliphatic amino acids increase in the order AAAAOMe is already observed for K(+). Proline binds more strongly than its methyl ester to all M(+) except Li(+). Ab initio calculations on the M(+) complexes of alanine, beta-aminoisobutyric acid, proline, glycine methyl ester, alanine methyl ester, and proline methyl ester show that their energetically most favorable complexes result from charge solvation, except for proline which forms salt bridges. The most stable mode of charge solvation depends on the ligand (AA or AAOMe) and, for AA, it gradually changes with metal ion size. Esters chelate all M(+) ions through the amine and carbonyl groups. Amino acids coordinate Li(+) and Na(+) ions through the amine and carbonyl groups as well, but K(+) and Cs(+) ions are coordinated by the O atoms of the carboxyl group. Upon consideration of these differences in favored binding geometries, the theoretically derived relative M(+) affinities between aliphatic AA and AAOMe are in good overall agreement with the above given experimental trends. The majority of side chain functionalized amino acids studied show experimentally the affinity order AAAAOMe. The latter ranking is attributed to salt bridge formation.     

Synthesis of new penicillin derivatives as drug-like molecules for biological screening

Chemical modification of penicillin β-lactam ring was made.Six thiazolidine amides were produced through N4-C7 β-lactam ring opening of penicillin V methyl ester with various aliphatic,aromatic,and heterocyclic primary amines.Five 8-hydroxypenillic acid derivatives with side chains of methyl,propyl,benzyl,and diethylaminoethyl groups were yielded via β-lactam ring rearrangement from6-aminopenicillanic acid(6-APA).Parallel synthetic methods were used for the alkylation of8-hydroxypenillic acid and β-lactam ring opening of penicillin V methyl ester.The biological activities of the compounds were evaluated.     

A convenient synthesis of amino acid methyl esters

A series of amino acid methyl ester hydrochlorides were prepared in good to excellent yields by the room temperature reaction of amino acids with methanol in the presence of trimethylchlorosilane. This method is not only compatible with natural amino acids, but also with other aromatic and aliphatic amino acids.     

β-Keto ester aminolysis of pheophorbide a methyl ester: a facile route for asymmetric chlorin ring substitution

A chemoselective aminolysis of the β-keto ester of pheophorbide a methyl ester is demonstrated opening a facile access to an asymmetric amide functionalization of a chlorin ring using a range of aromatic and aliphatic, primary and secondary amine nucleophiles. Aminolysis of pheophorbide a methyl ester with trans-1,2-diaminocyclohexane is shown to give a symmetric open face chlorin dimer.     

Stereoselective Synthesis of Unsaturated and Functionalized l-NHBoc Amino Acids, Using Wittig Reaction under Mild Phase-Transfer Conditions

The stereoselective synthesis of a new amino acid phosphonium salt was described by quaternization of melting triphenylphosphine with the γ-iodo NHBoc-amino ester, derived from l-aspartic acid. The deprotection of the carboxylic acid function to afford the phosphonium salt with a free carboxylic acid group was achieved by a palladium-catalyzed desallylation reaction. This phosphonium salt was used in the Wittig reaction with aromatic or aliphatic aldehydes and trifluoroacetophenone, under solid-liquid phase-transfer conditions in chlorobenzene and in the presence of K(3)PO(4) as weak base, to afford the corresponding unsaturated amino acids without racemization. Thus, the reaction with substituted aldehydes allows to graft various functionalized groups on the lateral chain of the amino acid, such as trifluoromethyl, cyano, nitro, ferrocenyl, boronato, or azido. In addition, the reaction of the amino acid Wittig reagent with α,β-unsaturated aldehydes leads to amino acids bearing a diene on the lateral chain. Finally, this amino acid phosphonium salt appears to be a new powerful tool for the preparation of unsaturated and non-proteinogenic α-amino acids, directly usable for the synthesis of customized peptides.     

Reactions of an aromatic σ,σ-biradical with amino acids and dipeptides in the gas phase

Gas-phase reactivity of a positively charged aromatic σ,σ-biradical (N-methyl-6,8-didehydroquinolinium) was examined toward six aliphatic amino acids and 15 dipeptides by using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR) and laser-induced acoustic desorption (LIAD). While previous studies have revealed that H-atom and NH₂ abstractions dominate the reactions of related monoradicals with aliphatic amino acids and small peptides, several additional, unprecedented reaction pathways were observed for the reactions of the biradical. For amino acids, these are 2H-atom abstraction, H₂O abstraction, addition — CO₂, addition — HCOOH, and formation of a stable adduct. The biradical reacts with aliphatic dipeptides similarly as with aliphatic amino acids, but undergoes also one additional reaction pathway, addition/C-terminal amino acid elimination (addition — CO — NHCHR_C). These reactions are initiated by H-atom abstraction by the biradical from the amino acid or peptide, or nucleophilic addition of an NH₂ or a HO group of the amino acid or peptide at the radical site at C-6 in the biradical. Reactions of the unquenched C-8 radical site then yield the products not observed for related monoradicals. The biradical reacts with aromatic dipeptides with an aromatic ring in N-terminus (i.e., Tyr-Leu, Phe-Val, and Phe-Pro) similarly as with aliphatic dipeptides. However, for those aromatic dipeptides that contain an aromatic ring in the C-terminus (i.e., Leu-Tyr and Ala-Phe), one additional pathway, addition/N-terminal amino acid elimination (addition — CO — NHCHR_N), was observed. This reaction is likely initiated by radical addition of the biradical at the aromatic ring in the C-terminus. Related monoradicals add to aromatic amino acids and small peptides, which is followed by Cα-Cβ bond cleavage, resulting in side-chain abstraction by the radical. For biradicals, with one unquenched radical site after the initial addition, the reaction ultimately results in the loss of the N-terminal amino acid. Similar to monoradicals, the C-S bond in amino acids and dipeptides was found to be especially susceptible to biradical attack.     

Resolution of non-protein amino acids via the microbial protease-catalyzed enantioselective hydrolysis of their N-unprotected esters

In the Aspergillus oryzae protease-catalyzed ester hydrolysis, substitution of N-unprotected amino acid esters for the corresponding N-protected amino acid esters resulted in a large enhancement of the hydrolysis rate, while the enantioselectivity was deteriorated strikingly when the substrates employed were the conventional methyl esters. This difficulty was overcome by employing esters bearing a longer alkyl chain such as the isobutyl ester. Utilizing this ester, amino acids carrying an aromatic side chain were resolved with excellent enantioselectivities (E=50 to >200). With amino acids bearing an aliphatic side chain also, good results in terms of the hydrolysis rate and enantioselectivity were obtained by employing such an ester as the isobutyl ester. Moreover, the enantioselectivity proved to be enhanced further by conducting the reaction at low temperature. This procedure was applicable to the case where the enantioselectivity was not high enough even by the use of the isobutyl ester.     

Stereoselective analysis of D and L dansyl amino acids as the mixed chelate copper(II) complexes by HPLC

This paper reviews the mixed chelation approach to resolution of the optical isomers of D and L dansyl amino acids by high performance liquid chromatography. The use of eluants containing Cu(II) complexes of L-proline, L-arginine, L-histidine, and L-histidine methyl ester effected the separation of many D and L amino acids, including those with aliphatic, polar, and aromatic substituents. The mechanism of separation, which is based on the preferential ternary complex formation of the analyte amino acid and the chiral chelate with Cu(II) in the mobile phase, is discussed. The stereoselectivity depends mainly on the different steric interactions between the alkyl side chains of the amino acid analytes and the chiral ligands coordinating around Cu(II), although such parameters as pH, temperature, organic modifier, and concentration of the chiral additive also affect the chromatographic separation. Among the chiral ligands studied, L-histidine methyl ester is unique in that it possesses both achiral selectivity for the dansyl amino acids and chiral selectivity for the respective D and L enantiomers. With a mobile phase gradient of acetonitrile in a buffer containing Cu(II) L-histidine methyl ester complex, a stereoselective procedure was devised for the analysis of D and L amino acid enantiomers, achieving the separation that the current amino acid analyzer could not perform. Finally, the use of the mixed chelation approach in two biomedical studies is described. In the first application, the histidine methyl ester gradient was adapted for analyzing amino acids in cerebrospinal fluid; in the second, an L-aspartame Cu(II) complex eluant was developed for measuring the urine concentration of D and L pipecolic acid (piperidine-2-carboxylic acid), a metabolite of lysine.     

One water molecule stabilizes the cationized arginine zwitterion

Singly hydrated clusters of lithiated arginine, sodiated arginine, and lithiated arginine methyl ester are investigated using infrared action spectroscopy and computational chemistry. Whereas unsolvated lithiated arginine is nonzwitterionic, these results provide compelling evidence that attachment of a single water molecule to this ion makes the zwitterionic form of arginine, in which the side chain is protonated, more stable. The experimental spectra of lithiated and sodiated arginine with one water molecule are very similar and contain spectral signatures for protonated side chains, whereas those of lithiated arginine and singly hydrated lithiated arginine methyl ester are different and contain spectral signatures for neutral side chains. Calculations at the B3LYP/6-31++G** level of theory indicate that solvating lithiated arginine with a single water molecule preferentially stabilizes the zwitterionic forms of this ion by 25-32 kJ/mol and two essentially isoenergetic zwitterionic structure are most stable. In these structures, the metal ion either coordinates with the N-terminal amino group and an oxygen atom of the carboxylate group (NO coordinated) or with both oxygen atoms of the carboxylate group (OO coordinated). In contrast, the OO-coordinated zwitterionic structure of sodiated arginine, both with and without a water molecule, is clearly lowest in energy for both ions. Hydration of the metal ion in these clusters weakens the interactions between the metal ion and the amino acid, whereas hydrogen-bond strengths are largely unaffected. Thus, hydration preferentially stabilizes the zwitterionic structures, all of which contain strong hydrogen bonds. Metal ion size strongly affects the relative propensity for these ions to form NO or OO coordinated structures and results in different zwitterionic structures for lithiated and sodiated arginine clusters containing one water molecule.     

An Easy Access to Construct Some Fused 1,2,4‐Triazines with Ring Junction Nitrogen Systems and Their Biological Evaluation

The chemical reactivity of 4‐amino‐6‐benzyl‐3‐mercapto‐1,2,4‐triazine‐5(4H )‐one ( 1 ) towards various aliphatic or/and mono and bis aromatic carboxylic acid derivatives to give the corresponding fused heterocyclic systems, 1,3,4‐thiadiazoles 4 , 5 , 6 , which incorporating 1,2,4‐triazine nucleus was achieved. Moreover, compound 1 was subjected to react either with halo acetic acids or bromo ester to afford the respective fused nitrogen ring junction systems, thiadiazole 2 and 3 , or thiadiazine 7 . However, the tetracyclic ring system 9 was furnished through condensation reaction of isatine with triazine 1 . In addition, some of the new synthesized compounds were evaluated as an antioxidant and antitumor agents.     

An Easy Access to Construct Some New Fused 1,2,4‐Triazines with Ring Junction Nitrogen Systems and Their Biological Evaluation

The chemical reactivity of 4‐amino‐6‐benzyl‐3‐mercapto‐1,2,4‐triazine‐5(4H )‐one ( 1 ) towards various aliphatic or/and mono and bis aromatic carboxylic acid derivatives to give the corresponding fused heterocyclic systems, 1,3,4‐thiadiazoles 4 , 5 , 6 , which incorporating 1,2,4‐triazine moiety was achieved. Moreover, compound 1 was subjected to reaction either with halo acetic acids or bromo ester to afford the respective fused nitrogen ring junction systems, thiadiazole 2 and 3 or thiadiazine 7 . However, while the tetracyclic ring system 9 was furnished through condensation reaction of isatine with triazine 1 . In addition, some of the new synthesized compounds were evaluated as an antioxidant and antitumor agents.     

Samarium(II)-promoted radical spirocyclization onto an aromatic ring

Samarium(II)-mediated spirocyclization onto an aromatic ring was achieved by the reaction of methyl 4-(4-oxoalkyl)benzoates with SmI(2) in the presence of i-PrOH and HMPA, yielding methyl 1-alkyl-1-hydroxyspiro[4.5]dec-6-ene-8-carboxylates in moderate to high yields. Utilizing this chemistry, spiro[3.5] and -[5.5] systems, and sterically congested spiro[4.5] systems, were easily synthesized. For the successful conversion, appropriate activation of the aromatic ring has proven to be extremely important: while an ester or amide functionality on the aromatic ring can promote the spirocyclization, a sulfonamide substituent causes ortho cyclization.     

Homogeneous ion-exchange membranes of improved flexibility

Poly(styrenesulfonic acid) ion-exchange membranes having various degrees of porosity and flexibility have been prepared by using aliphatic and aromatic esters of p-styrenesulfonic acid. The membranes formed from the aliphatic ester monomers were found to exhibit an increase in water uptake, permeability, and flexibility with increase in the size of the alcohol group of the ester monomer. With membranes formed from the phenyl and β-naphthyl ester monomers the reverse trend was indicated. The flexibility of the membranes formed from the aromatic ester monomers was much greater than that obtained with the aliphatic esters.     

N-磷酰化肽酯及小肽与溶菌酶相互作用的ESI-MS研究

用ESI-MS研究了一系列结构具有可比性的N-磷酰化肽酯及小肽和溶菌酶的非共价相互作用, 比较了磷酰化肽酯及小肽分子中的不同基团对相互作用的影响. 结果表明—OH对其与溶菌酶的相互作用有较大贡献; 芳香环由于位阻原因, 对相互作用有促进和阻碍双重效应; 当—OH与芳香环相连时会发生协同效应, 可使相互作用显著增强. 磷酰化肽酯及小肽的体积大小、空间位阻对相互作用亦有显著影响. 磷酰化二肽中氨基酸残基的构型、顺序、碳链长短的变化(增加1～2个C)对其与蛋白溶菌酶之间的相互作用在质谱中没有表现出影响. 分子结构较为伸展、分子柔顺性好、空间位阻较小的磷酰化小肽更容易使蛋白在溶液中的构象趋于收缩, 而构象较为收缩的蛋白分子更易结合空间位阻较小的磷酰化小肽分子.     

The synthesis of cyclodopa (Leukodopachrom)

The synthesis of the methylester of cyclodopa (5.6-dihydroxy-indoline-2-carboxylic acid) is achieved by oxidative conversion of dopa methyl ester to dopachrome methyl ester and its subsequent reduction at pH 8, using respectively potassium hexacyanoferrate(III) and sodium dithionite. The efficiency of the oxidation step was found to be dependent on the rather low concentration of the reactants and the very short reaction time involved. After its production cyclodopa methyl ester was stabilized by immediate protonation followed by acetylation leading in a high yield to O,O,N-triacetyl cyclodopa methyl ester. By partial hydrolysis this derivative gives an O,N-diacetyl cyclodopa methyl ester and further N-acetyl cyclodopa methyl ester. Cyclodopa methyl ester and cyclodopa are obtained by prolonged anaerobic hydrolysis. Micro-separation procedures, nmr-, uv-spectra and chiral-optical properties of cyclodopa and its derivatives are reported and discussed. It is shown by nmr evidence that under acidic conditions the aromatic proton on C(7) of cyclodopa slowly exchanges with deuterium. When an alcoholic solution of cyclodopa methyl ester and semicarbazide is allowed to oxidize in the air, the semicarbazone of dopachrome methyl ester forms.     

Synthesis of 3‐Ω‐aminohydantoins

Several 3‐Ω‐amino monosubstituted hydantoins have been obtained in the reaction of isocyanate of glycine ethyl ester with the appropriate aliphatic or aromatic diamine. It was found, that the 3‐(aminoaryl) monosubstituted hydantoins may be diazotized and their diazonium salts may be coupled and hydrolysed without changes in the hydantoin ring.     

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.     

Asymmetric aza Diels-Alder reactions of amino acid ester imines with Brassard's diene

Imines 1 obtained from aromatic, aliphatic or functionalized aldehydes and valine tert-butyl ester undergo Lewis acid catalyzed hetero Diels-Alder reactions with Brassard's diene 2. The cycloadducts are formed in good to high yields and with diastereomer ratios of 92:8 – 97:3. For the removal of the chiral auxiliary group a new method was developed whose principle consists in the conversion of the amino acid -C-atom into an acetalic center employing a Curtius rearrangement as the key step.     

Asymmetric Pictet-Spengler Reactions：Synthesis of Tetrahydroisoquinoline Derivatives from L-DOPA

The cis-l-substituted-6,7-dihydroxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid esters 3 can be obtained in a highly diastereoselective fashion through 1,3-induction Pictet- Spengler(P-S) cyclization of the L-DOPA (3,4-dihydroxyphenylalanine) methyl ester with aromatic or aliphatic aldehydes under acidic conditions. Their epimers 4 are also obtained as minor products.     

Phenacyl esters as a new photocleavable linker in liquid-phase chemistry

PEG-supported 2-methylphenacyl ester as a new photocleavable linker is reported. The photocleavage based on an efficient intramolecular hydrogen abstraction was carried out with 280-366 nm UV irradiation in benzene or methanol to give the corresponding carboxylic acid in high yields and purities. The linker was suitable for aliphatic and aromatic carboxylic acids as well as protected amino acids.