(18-Crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent for determining the enantiomeric purity and absolute configuration of β-amino acids

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids and acyclic derivatives with aliphatic, aromatic, and heterocyclic aromatic moieties. The β-amino acids are mixed with the crown ether in methanol-d₄ in either their neutral or protonated form. Substantial enantiomeric discrimination typically occurs for the resonances of the α-methylene and β-methine hydrogen atoms. Resonances of the substituent group of the β-amino acid often exhibit enantiomeric discrimination. The enantiomeric discrimination of the α-methylene and β-methine resonances of specific groups of compounds shows consistent patterns that correlate with the absolute configuration.     

Synthesis of novel C2-symmetric chiral crown ethers and investigation of their enantiomeric recognition properties

A series of new C₂-symmetric chiral aza crown ether macrocycles 1–4 have been synthesized from (S)-3-aryloxy-1,2-propanediol and (S)-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These new macrocycles have been shown to be strong complexing agents for primary organic ammonium salts (with K up to 176.93 M^?1 and ΔG° up to 12.81 kJ mol^?1) by ¹H NMR titration. These macrocyclic host exhibited enantioselective bonding toward the d-enantiomer of phenylalanine methyl ester hydrochloride with K_D/K_L up to 6.87 in CDCl₃ with 0.25% CD₃OD.     

Investigation of Non-covalent Interactions of 18-Crown-6 with Amino Acids in Gas Phase by Mass Spectrometry

The non-covalent interactions between 18-Crown-6 (18c6) and 20 common types of protonated amino acids were explored by electrospray ionization mass spectrometry. The mass spectra showed that 18c6 could react with amino acids to form a non-covalent complexe in a stoichiometric ratio of 1:1. The calibration curves and linear equations for the complexes of L-Phe, L-Tyr, L-Lys and L-Asp with 18c6 were established by mass spectrometric titration and used as reference values for competitive ESI-MS. Through competitive equilibria, the binding constants for the complexes of 18c6 with other L-amino acids and their D-isomers were derived. It was found that, as a general trend, lgK_a for the complexes of 18c6 with the basic amino acid and the amino acid with alkyl side chain were larger than other complexes, and among the amino acid with alkyl side chain, Gly and Ala exhibited greater 18c6 binding affinities. As for Ser and Thr, the intramolecular hydrogen bond between the nitrogen atom from terminal –NH₂ and the oxygen atom from carboxyl might impede their protonated amino-group to attack the 18c6. Furthermore, Gln and Asn exhibited lower binding affinities to 18c6, probably due to effects of electron-withdrawing group of acylamide. Finally, the chiral selectivity of 18c6 for L-amino or D-amino acids were measured by ESI-MS, and the result showed that 18c6 could only recognize some neutral amino acid isomers.     

Enantioseparation of protonated primary arylalkylamines and amino acids containing an aromatic moiety on a pyridino-crown ether based new chiral stationary phase

This paper reports the preparation and testing of a new pyridino-18-crown-6 ether based chiral stationary phase (CSP). The chiral crown ether was covalently bound to silica gel. Circular dichroism (CD) spectroscopy was used for probing the complex formation of the chiral crown ether with the enantiomers of protonated primary arylalkylamines. The (S,S)-dimethylpyridino-18-crown-6 ether selector having a terminal double bond was first transformed to a triethoxysilyl derivative by regioselective hydrosilylation, and then heated with spherical HPLC quality silica gel to obtain the CSP. The discriminating power of the HPLC column filled with the above CSP was tested by using the hydrogenperchlorate salts of racemic α-(1-naphthyl)ethylamine (1-NEA), α-(2-naphthyl)ethylamine (2-NEA) and the hydrochloride salts of aromatic α-amino acids and α-amino acids containing different aromatic side-chain protecting groups.     

Enantiomeric discrimination of cyclic β-amino acids using (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids with cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, bicyclo[2.2.1]heptane, and bicyclo[2.2.1]heptene rings. The crown ether was added to the neutral β-amino acids in methanol-d₄. A neutralization reaction between the crown ether and β-amino acid forms the ammonium ion needed for favorable association. Enantiomeric discrimination of the two hydrogen atoms α to the amine and carboxylic acid moieties of the β-amino acid was observed with every substrate studied. Trends in the order of the enantiomeric discrimination of certain hydrogen atoms for substrates of similar structures correlate with the absolute configuration.     

o-Nitrobenzoyl group as a new amino protecting group for peptide synthesis and the synthesis of some anthranilyl peptides

N (o-nitrobenzoyl)amino acids can be coupled with other amino acids using DCC and the resulting product on hydrogenation gives peptides, containing the anthranilyl group as —NH₂ end group. N (anthranilyl)amino acids or peptides can also be obtained by reaction of isatoic anhydride on amino acids or peptides. The anthranilyl end group is easily cleaved by metal (Cu⁺²) catalysed hydrolysis to give α-amino acid peptides and the insoluble copper(II) anthranilate.     

Synthesis and preliminary studies on novel enantiopure crown ethers containing an alkyl diarylphosphinate or a proton-ionizable diarylphosphinic acid unit

This paper reports the synthesis, characterization and electronic circular dichroism (ECD) spectroscopic studies of a new type of crown ethers and their achiral analogues containing a tetrahedral phosphorous centre. The synthetic routes to the two chiral phosphinate derivatives [(R,R)-10 and (R,R)-11] were similar, starting from the earlier reported ethyl bis(2-hydroxyphenyl)phosphinate and the unreported methyl bis(2-hydroxyphenyl)phosphinate, respectively. The enantiopure crown ether containing phosphinic acid unit (R,R)-14 was obtained by hydrolysis of the phosphinates (R,R)-10 and (R,R)-11, respectively. ECD spectroscopy was used for investigation of the chiroptical properties as well as complex formation ability of the novel enantiopure ligands. Owing to the presence of the aryl substituents the ECD spectra are rich in bands in the ¹B_b, ¹L_a and ¹L_b regions (190-250 nm and 260-330 nm, respectively). In the case of (R,R)-14, a solvent dependent conformational behaviour was observed due to the strong dimer or aggregate forming ability of the POOH groups. This finding was supported by theoretical calculation of the monomer and the dimer forms. Phosphinates (R,R)-10 and (R,R)-11 form complexes with α-phenylethylammonium perchlorate (PEA) and α-(1-naphthyl)ethyl ammonium perchlorate (NEA) but do not discriminate between their enantiomers. All three chiral crown ethers bind strongly cations of ionic radii <∼1 Å.     

Synthesis and characterization of four new manganese(III) complexes and amino acid (L-aspartic acid, L-asparagine, L-glutamic acid, L-glutamine) Schiff bases

New series of manganese(III) complexes and amino acid Schiff bases have been prepared from 2-hydroxy-1-naphthaldehyde and α-amino acids [L-aspartic acid (Asp), L-asparagine (Asn), L-glutamic acid (Glu) and L-glutamine (Gln)]. The structures of the ligands and manganese complexes were identified using elemental analyses, i.r, electronic spectra, ¹H-n.m.r spectra, magnetic moment measurements and thermogravimetric analyses (t.g.a). The results suggest that H₂L¹: [N-(2-hydroxy-1-naphthylidene) aspartic acid] and H₂L³: [N-(2-hydroxy-1-naphthylidene)glutamic acid] Schiff bases behave as trianionic tetradentate species and coordinate to Mn(III) ion according to the general formula [MnL] · xH₂O complexes. But, H₂L²: [N-(2-hydroxy-1-naphthylidene) asparagine] and H₂L⁴: [N-(2-hydroxy-1-naphthylidene)glutamine] Schiff bases behave as dianionic tridentate and coordinate to Mn(III) ion in the general formula for [MnL(OOCH₃)] · xH₂O complexes.     

Electrogenerated-bases promoted electrochemical synthesis of N-bromoamino acids from imines and carbon dioxide

In this paper, the one-step synthesis of N-bromoamino acids has been developed by electrolyzing imines and carbon dioxide (4 MPa). The electrosynthesis was performed in an undivided cell with Ni cathode and Al sacrificial anode containing n-Bu₄NBr–DMF as supporting electrolyte with a constant current at room temperature. The N-bromoamino acids were afforded in moderate to good yields rather than traditional α-amino acids. To explore the truth, some influenced factors (cathode materials, supporting electrolyte, and electricity etc.) were investigated. The experimental results indicated that the NH group of the α-amino acid could be deprotonated by alkyl anion R⁻ (carbanion, a strong base), followed by the oxidation of hypobromous acid resulted from the two-step oxidation of the bromide ion at the anode, and produced the N-bromoamino acid. Finally, the reaction mechanism was briefly discussed.     

Protonation equilibria studies of the standard α-amino acids in NaNO3 solutions in water and in mixtures of water and dioxane

The protonation equilibria for 20 standard α-amino acids in solutions have been studied pH-potentiometrically. The dissociation constants (pK_a) of 20 amino acids and the thermodynamic functions (ΔG^∘, ΔH^∘, ΔS^∘, and δ) for the successive and overall protonation processes of amino acids have been derived at different temperatures in water and in three different mixtures of water and dioxane (mole fractions of dioxane were 0.083, 0.174, and 0.33). Titrations were also carried out in water ionic strengths of (0.15, 0.20, and 0.25) mol · dm⁻³ NaNO₃, and the resulting dissociation constants are reported. A detailed thermodynamic analysis of the effects of organic solvent (dioxane), temperature and ionic strength influencing the protonation processes of amino acids is presented and discussed to determine the factors which control these processes.     

Fluorescent detection of amidinium-carboxylate and amidinium formation using a 1,8-diphenylnaphthalene-based diamidine: dicarboxylic acid recognition with high fluorescence efficiency

A 1,8-diphenylnaphthalene-based diamidine (1) ‘turn-on’ fluorescent probe for the detection of dicarboxylic acids has been designed and synthesized. The fluorescence spectra of the diamidine 1 with carboxylic acids that showed two different fluorescence bands, which corresponded to the amidinium-carboxylate (λ_em=410–430 nm) and amidinium (λ_em=440–470 nm as a broad band, which consisted from two peaks) formation, were confirmed by DOSY NMR and TD-DFT calculations. The complexation of diamidine 1 with dicarboxylic acids, which have sufficient distances between the two carboxylic groups for binding to the diamidine 1 (dicarboxylic acids 3, 4, and α,ω-dicarboxylic acids 6 (C₆–C₂₀)), showed the formation of 1:1 complexes (i.e., amidinium-carboxylate formation). On the other hand, for the complexation with monocarboxylic acids and dicarboxylic acids having insufficient distances between the two carboxylic groups (benzoic acid 5, acetic acid 7, and α,ω-dicarboxylic acids 6 (C₃–C₅)), formation of the amidinium (1·2H⁺) was observed. Relatively similar binding constants (10⁻⁵) for the complexation of the diamidine 1 with dicarboxylic acids 6, which depend on their chain length (strain), were observed due to the flexibility of the 1,8-diphenylnaphthalene unit. Additionally, for the complexation of the diamidine 1 with dicarboxylic acids, higher fluorescence quantum yields (Φ_fl: up to 80%) were observed when compared to the binding of the diamidine 2 (Φ_fl: up to 35%).     

Fluorescent detection of amidinium-carboxylate and amidinium formation using anthracene-based diamidine: an application for the analysis of dicarboxylic acid binding

An anthracene-based diamidine (1) ‘turn-on’ fluorescent probe for the detection of dicarboxylic acids has been designed and synthesized. The fluorescence spectra of the diamidine 1 with carboxylic acids that showed two different fluorescence bands, which corresponded to the amidinium-carboxylate (λ_em=430-440 nm), and amidinium (λ_em=460-470 nm as a broad band) formation, were confirmed by DOSY NMR and TD-DFT calculations. These different fluorescence bands showed the binding mode of carboxylic acids and the stability of formed complexes toward diamidine 1. The fluorescent detection of amidinium-carboxylate formation using diamidine 1 was applicable to the detection of α,ω-dicarboxylic acids (C₆-C₁₃) and succeeded in the detection of α,ω-dicarboxylic acid (adipic acid) in human urine.     

Enhanced activity of α-chymotrypsin in organic media using designed molecular staples

We report the enhancement of α-chymotrypsin activity in organic solvents using modified peptides bearing two crown ethers. The transesterification of N-acetyl-l-phenylalanine ethyl ester with 1-propanol was used as model reaction. Co-lyophilization of crown ether modified peptides with α-chymotrypsin prior to use resulted in an increase of enzyme catalytic activity in non-aqueous media. The efficiency of enzyme activation is dependent on the amino acid sequence of peptidic additives and on the positions of the amino acids bearing the crown ligand.     

Chiral calix[4]azacrowns for enantiomeric recognition of amino acid derivatives

In this study the synthesis of novel chiral calix[4]azacrown derivatives has been reported. The enantioselectivity of chiral receptors was investigated by using UV-vis spectroscopy. All the chiral calix[4]arene derivatives exhibited certain chiral recognition toward the enantiomers of phenylalanine (Phe-OMe·HCl) and alanine methyl ester hydrochlorides (Ala-OMe·HCl). As a chiral receptor, the furfuryl-armed calix[4]azacrown ether 7 has the best enantiomeric discriminating ability for α-amino acid ester hydrochlorides (up to K_L/K_D=2.08, ΔΔG₀=−1.82 kJ mol⁻¹) in CHCl₃. The enantiomeric recognition abilities for guests are also discussed from a thermodynamic point of view.     

A simple method for determining the absolute configuration of α-amino acids

Chiral α-amino acids react with 2-methoxy - 2,4 - diphenyl - 3 (2H) - furanone 1 to afford N-substituted 3,5 - diphenyl - 5 - hydroxy - 2 - pyrrolin - 4 - ones 2. The characteristic cotton effects given by these chromophoric derivatives provide a means for the determination of the absolute configuration of the parent amino acids. The longest wavelength(first) extremum in the chiroptical spectra (ORD and CD) of the l-amino acid derivatives is always positive, while it is negative for the d-amino acid derivatives.     

Investigation of the effects of various parameters on the synthesis of oligopeptides in aqueous solution

Oligomerization efficiency of amino acids in aqueous solution has been compared under different conditions (temperature, activating agent, etc.) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1,1^′-carbonyldiimidazole (CDI) as coupling agents. Glycine (H₂N-CH₂-COOH) and α-alanine (H₂N-CH(CH₃)-COOH) were chosen as α-amino acids and β-alanine (H₂N-CH₂-CH₂-COOH) as the β-amino acid. The coupling reaction between EDC and glycine was shown to occur but does not go to completion either at ambient temperature or at 70 °C. The presence of a carboxylic activating agent such as N-hydroxysuccinimide improves the EDC-mediated coupling reaction, and the amino acid structure (α- or β-) was shown to have an influence on the oligomerization efficiency, with β-alanine polymerisation being more efficient. These findings are explained by reference to the reaction mechanism.     

Ring closing metathesis of α- and β-amino acid derived dienes

Three new classes of conformationally constrained peptidomimetics, derived from modified α- and β-amino acids, have been prepared by ring closing metathesis (RCM). The first involves C_α–N′ cyclisation of the peptidic diene (23, 24, 26), the second C_β2–N′ cyclisation (27, 28, 29), and the third N–C_β2 cyclisation (30). The key C-centred olefin of the dienes was introduced by stereoselective α-allylation of either an α- or β-amino acid. The normal favourable influence of a tertiary amide linker in the diene towards RCM is negated by significant steric congestion, and the combination of a secondary amide linker and α,α-disubstitution promotes ring contraction on RCM.     

Dinuclear ruthenium(I) complexes of the type [Ru2(CO)4L2] with carboxylate or 2-pyridonate ligands: Evaluation as catalysts for olefin cyclopropanation with diazoacetates

Dinuclear ruthenium(I,I) carboxylate complexes [Ru₂(CO)₄(μ-OOCR)₂]_n (R = CH₃ (1a), C₃H₇ (1b), H (1c), CF₃ (1d)) and 2-pyridonate complex [Ru₂(CO)₄(μ-2-pyridonate)₂]_n (3) catalyze efficiently the cyclopropanation of alkenes with methyl diazoacetate. High yields are obtained with terminal nucleophilic alkenes (styrene, ethyl vinyl ether, α-methylstyrene), medium yields with 1-hexene, cyclohexene, 4,5-dihydrofuran and 2-methyl-2-butene. The E-selectivity of the cyclopropanes obtained from the monosubstituted alkenes and the cycloalkenes decreases in the order 1b > 1a > 1d > 1c. The cyclopropanation of 2-methyl-2-butene is highly syn-selective. Several complexes of the type [Ru₂(CO)₄(μ-L¹)₂]₂ (4) and (5), [Ru₂(CO)₄(μ-L¹)₂L²] (L² = CH₃OH, PPh₃) (6)–(9) and [Ru₂(CO)₄(CH₃CN)₂(μ-L¹)₂] (10) and (11), where L¹ is a 6-chloro- or 6-bromo-2-pyridonate ligand, are also efficient catalysts. Compared with catalyst 3, a halogen substituent at the pyridonate ligand affects the diastereoselectivity of cyclopropanation only slightly.     

Synthesis and Cation Recognition Study of Novel Benzo Crown Ether Functionalized Enamine Derivatives

A novel series of benzo crown ether (dibenzo 18-crown-6 ether, benzo 18-crown-6 ether, and benzo 15-crown-5 ether) functionalized enamines derivatives from amino benzo crown ether (4-amino dibenzo 18-crown-6 ether, 4-amino benzo 18-crown-6 ether, 4-amino benzo 15-crown-5 ether) and substituted 3-(dimethylamino)-1-phenylprop-2-en-1-one compounds have been synthesized. All the synthesized compounds were characterized by infrared, ¹H NMR, ¹³C NMR, distortionless enhancement polarization transfer, and mass and elemental analysis techniques. The cation recognition property for benzo crown ether enamine 8a was studied by absorption and fluorescence spectroscopy.     

Synthesis and decarboxylation of N-acyl-α-triphenylphosphonio-α-amino acids: a new synthesis of α-(N-acylamino)alkyltriphenylphosphonium salts

4-Phosphoranylidene-5(4H)-oxazolones 1 undergo hydrolysis in THF in the presence of HBF₄ at room temperature to give N-acyl-α-triphenylphosphonioglycines 3 (R² = H) in very good yields. 4-Alkyl-4-triphenylphosphonio-5(4H)-oxazolones 2 react with water in CH₂Cl₂/THF solution without any acidic catalyst at 0-5 °C in a few days yielding N-acyl-α-triphenylphosphonio-α-amino acids 3 (R² = Me) or α-(N-acylamino)alkyltriphenylphosphonium salt 4 (R² = CH₂OMe). α-Triphenylphosphonio-α-amino acids 3, on heating up to 105-115 °C under reduced pressure (5 mmHg) or on treatment with diisopropylethylamine in CH₂Cl₂ at 20 °C undergo decarboxylation to give the corresponding α-(N-acylamino)alkyltriphenylphosphonium salts 4, usually in very good yields.