Chiral Amino Acids Research Articles

Asymmetric Conjugate Addition of Phosphine Sulfides to α-Substituted β-Nitroacrylates Using Cinchona Alkaloid Amide Catalysts.

Chiral phosphine-containing amino acids are useful motifs in pharmaceutical compounds. In this study, we developed the asymmetric conjugate addition of phosphine sulfides with α-substituted β-nitroacrylates to synthesize phosphine-containing amino acid precursors with chiral tetrasubstituted carbon centers. This method showed a wide substrate scope, and the obtained products were converted into various chiral compounds. The origin of the enantioselectivity was clarified by computational analysis.

Metabolic Engineering of Saccharomyces cerevisiae for High-Level Production of l-Pipecolic Acid from Glucose.

l-Pipecolic acid (L-PA), an essential chiral cyclic nonprotein amino acid, is gaining prominence in the food and pharmaceutical sectors due to its wide-ranging biological and pharmacological properties. Historically, L-PA has been synthesized chemically for commercial purposes. This study introduces a novel and efficient microbial production method for L-PA using engineered strain Saccharomyces cerevisiae BY4743. Initially, an optimized biosynthetic pathway was constructed within S. cerevisiae, converting glucose to L-PA with a yield of 0.60 g/L in a 250 mL shake flask in vivo. Subsequently, a multifaceted engineering strategy was implemented to enhance L-PA production: substrate-enzyme affinity modification, global transcription machinery engineering modification, and Kozak sequence optimization for enhanced L-PA production. Approaches above led to an impressive 8.6-fold increase in L-PA yield, reaching 5.47 g/L in shake flask cultures. Further scaling up in a 5 L fed-batch fermenter achieved a remarkable L-PA concentration of 74.54 g/L. This research offers innovative insights into the industrial-scale production of L-PA.

Fluorescence and Circular Dichroism Dual-Mode Probe for Chiral Recognition of Tyrosine and Its Applications in Bioimaging.

Chiral amino acids (AAs) are essential in metabolism and understanding physiological processes, and they could be used as biomarkers for the diagnosis of different diseases. In this study, chiral Cdots@Van were prepared by postmodifying an achiral Cdots core with vancomycin for recognizing and determining the enantiomeric excess (ee) of tyrosine (Tyr) enantiomers. The fluorescence response of Cdots@Van is based on an "on-off" strategy, with different quenching percentages for d- and l-tyrosine. Interestingly, the circular dichroism (CD) spectrum of Cdots@Van responded to only one form of Tyr enantiomer, specifically d-Tyr, and remained nearly unchanged upon the addition of l-Tyr. Quantum mechanical (QM) calculations were in excellent agreement with the experimental results, confirming the stronger binding affinity of Cdots@Van for d-Tyr compared to l-Tyr. We further investigated the chiral recognition ability of the interconnected vancomycin particles, which was synthesized using the EDC/NHS coupling reaction between vancomycin molecules without a Cdots core. Surprisingly, unlike free vancomycin molecules, interconnected vancomycin displayed an enantiomeric recognition ability by CD spectroscopy, similar to what was observed for Cdots@Van. Crucially, this chiral probe has been successfully utilized for cell imaging applications.

Synthesis of axially chiral biaryls via Pd(II)-catalyzed direct C(sp2)−H olefination

Herein, a protocol for the construction of axially chiral biaryls via Pd-catalyzed direct C–H olefination of 1-arylisoquinoline N-oxides through kinetic resolution have been uncovered. The atroposelective C–H olefination of 1-arylisoquinoline N-oxides is achieved with alkenes such as acrylates, styrenes, phenylvinyl sulfone, acrylonitrile, and maleimides. The commercially available, cost-effective, and bench-stable chiral mono-protected amino acid is successfully utilized as the chiral ligand to achieve atroposelective products via kinetic resolution. The high conformational stability of the axially chiral products observed from the DFT calculations, shows their excellent stability. A plausible mechanism has been proposed based on the preliminary mechanistic studies, which was further evidenced by the DFT calculations.

One‐Pot Biocatalytic Conversion of Chemically Inert Hydrocarbons into Chiral Amino Acids through Internal Cofactor and H2O2 Recycling

Chemically inert hydrocarbons are the primary feedstocks used in the petrochemical industry and can be converted into more intricate and valuable chemicals. However, two major challenges impede this conversion process: selective activation of C‐H bonds in hydrocarbons and systematic functionalization required to synthesize complex structures. To address these issues, we developed a multi‐enzyme cascade conversion system based on internal cofactor and H2O2 recycling to achieve the one‐pot deep conversion from heptane to chiral (S)‐2‐aminoheptanoic acid under mild conditions. First, a hydrogen‐borrowing‐cycle‐based NADH regeneration method and H2O2in situ generation and consumption strategy were applied to realize selective C‐H bond oxyfunctionalization, converting heptane into 2‐hydroxyheptanoic acid. Integrating subsequent reductive amination driven by the second hydrogen‐borrowing cycle, (S)‐2‐aminoheptanoic acid was finally accumulated at 4.57 mM with eep > 99%. Hexane, octane, 2‐methylheptane, and butylbenzene were also successfully converted into the corresponding chiral amino acids with eep > 99%. Overall, the conversion system employed internal cofactor and H2O2 recycling, with O2 as the oxidant and ammonium as the amination reagent to fulfill the enzymatic conversion from chemically inert hydrocarbons into chiral amino acids under environmentally friendly conditions, which is a highly challenging transformation in traditional organic synthesis.

One-Pot Biocatalytic Conversion of Chemically Inert Hydrocarbons into Chiral Amino Acids through Internal Cofactor and H2O2 Recycling.

Chemically inert hydrocarbons are the primary feedstocks used in the petrochemical industry and can be converted into more intricate and valuable chemicals. However, two major challenges impede this conversion process: selective activation of C-H bonds in hydrocarbons and systematic functionalization required to synthesize complex structures. To address these issues, we developed a multi-enzyme cascade conversion system based on internal cofactor and H2O2 recycling to achieve the one-pot deep conversion from heptane to chiral (S)-2-aminoheptanoic acid under mild conditions. First, a hydrogen-borrowing-cycle-based NADH regeneration method and H2O2in situ generation and consumption strategy were applied to realize selective C-H bond oxyfunctionalization, converting heptane into 2-hydroxyheptanoic acid. Integrating subsequent reductive amination driven by the second hydrogen-borrowing cycle, (S)-2-aminoheptanoic acid was finally accumulated at 4.57 mM with eep > 99%. Hexane, octane, 2-methylheptane, and butylbenzene were also successfully converted into the corresponding chiral amino acids with eep > 99%. Overall, the conversion system employed internal cofactor and H2O2 recycling, with O2 as the oxidant and ammonium as the amination reagent to fulfill the enzymatic conversion from chemically inert hydrocarbons into chiral amino acids under environmentally friendly conditions, which is a highly challenging transformation in traditional organic synthesis.

Simultaneous determination of free DL-amino acids in human hair with a novel DBD-M-Pro derivatization by UHPLC-HRMS: An application in diabetes patients

Human hair is a non-invasive biological sample that is easy to collect and store and can reflect long-term body health. However, the correlation between DL-amino acids and metabolic diseases in hair samples has not been studied. Therefore, we propose a novel UHPLC-HRMS method for analyzing seven free chiral amino acids (DL-Thr, DL-Glu, DL-Ala, DL-Val, DL-Pro, DL-Leu, and DL-Phe) simultaneously in hair samples by derivatization of chiral probe 4-(N,N-dmethylaminosulfonyl)-2,1,3-benzoxadiazole-trans-2-methyl-L-proline (DBD-M-Pro) labeled with targeted amino functional groups. Gradient elution was carried out using an ACQUITYTM BEH C18 (100×2.1 mm,1.7 μm) column with a mobile phase of 0.15 % formic acid (FA) in 10 mM ammonium acetate (CH3-COONH4) and 0.2 % FA in acetonitrile. The labelled DL-amino acid diastereoisomers could be completely separated, with a resolution (Rs) of 1.59–11.44. These amino acids show a strong linear correlation within the range of 3.1–99.2 pmol (R2 ≥ 0.9990). Intraday and interday precision was 1.87 %–14.87 %. The average recovery was 96.12 %–105.33 %. The limit of detection (LOD) ranged from 0.29 to 2.11 pmol. We then employed the method to determine the concentration of free chiral amino acids in hair samples from 30 healthy volunteers (HVs) and 30 diabetes patients (DPs). Male diabetes patients had significantly higher levels of L-Thr, L-Val, L-Leu (p < 0.05), and D-Ala (p < 0.01) in their hair samples than male healthy volunteers and female diabetes patients had significantly higher levels of D-Ala (p < 0.05) in their hair samples than female healthy volunteers. This is the first study to confirm the feasibility of using free DL-amino acids in human hair as potential biomarkers for diabetes.

Complexes of Hydrogen Peroxide, the Simplest Chiral Molecule, with L- and D-Serine Enantiomers and Their Clusters: MP2 and DFT Calculations.

The interaction between natural amino acids and hydrogen peroxide is of paramount importance due to the widespread use of hydrogen peroxide in biological and environmentally significant processes. Given that both amino acids and hydrogen peroxide occur in nature in two enantiomeric forms, it is crucial to investigate the formation of complexes between them, considering the role of molecular chirality. In this work, we report a theoretical study on the hydrogen peroxide enantiomers and their interactions with L- and S-serine and their clusters. We aimed to evaluate the non-covalent interactions between each hydrogen peroxide enantiomer and the L- and D-enantiomers of the non-essential amino acid serine and their clusters. First, the potential energy surfaces (PES) of transitions between enantiomers of the simplest chiral molecule, hydrogen peroxide, in the gas phase and in aqueous solution were studied using the Møller-Plesset theory method MP2/aug-cc-pVDZ. The activation energies of such transitions were calculated. The interactions of both hydrogen peroxide enantiomers (P and M) with L- and D-serine enantiomers were analyzed by density functional theory (DFT) with ωb97xd/6-311+G**, B3Lyp/6-311+G**, B3P86/6-311+G**, and M06/6-311+G** functionals. We found that both enantiomers of hydrogen peroxide bind more strongly to L-serine and its clusters than to D-serine, especially highlighting that the L form is the predominant natural form of this and other chiral amino acids. The optimized geometric parameters, interaction energies, and HOMO-LUMO energies for various complexes were estimated. Furthermore, circular dichroism (CD) spectra, which are optical chirality characteristics, were simulated for all the complexes under study.

Heat of Dilution and Racemization of Chiral Amino Acid Solutions

Heat of Dilution and Racemization of Chiral Amino Acid Solutions

Urinary D-asparagine level is decreased by the presence of glioblastoma

Gliomas, particularly glioblastomas (GBMs), pose significant challenges due to their aggressiveness and poor prognosis. Early detection through biomarkers is critical for improving outcomes. This study aimed to identify novel biomarkers for gliomas, particularly GBMs, using chiral amino acid profiling. We used chiral amino acid analysis to measure amino acid L- and D-isomer levels in resected tissues (tumor and non-tumor), blood, and urine from 33 patients with primary gliomas and 24 healthy volunteers. The levels of D-amino acid oxidase (DAO), a D-amino acid-degrading enzyme, were evaluated to investigate the D-amino acid metabolism in brain tissue. The GBM mouse model was created by transplanting GBM cells into the brain to confirm whether gliomas affect blood and urine chiral amino acid profiles. We also assessed whether D-amino acids produced by GBM cells are involved in cell proliferation. D-asparagine (D-Asn) levels were higher and DAO expression was lower in glioma than in non-glioma tissues. Blood and urinary D-Asn levels were lower in patients with GBM than in healthy volunteers (p < 0.001), increasing after GBM removal (p < 0.05). Urinary D-Asn levels differentiated between healthy volunteers and patients with GBM (area under the curve: 0.93, sensitivity: 0.88, specificity: 0.92). GBM mouse model validated the decrease of urinary D-Asn in GBM. GBM cells used D-Asn for cell proliferation. Gliomas induce alterations in chiral amino acid profiles, affecting blood and urine levels. Urinary D-Asn emerges as a promising diagnostic biomarker for gliomas, reflecting tumor presence and severity.

Selective Chiral Interactions between Hydrophilic/Hydrophobic Amino Acids and Growing Gypsum Crystals.

In nature, selective interactions between chiral amino acids and crystals are important for the formation of chiral biominerals and provide insight into the mysterious origin of homochirality. Here, we show that chiral amino acids with different hydrophilicities/hydrophobicities exhibit different chiral selectivity preferences in the dynamically growing gypsum [001] steps. Hydrophilic amino acids show a chiral selectivity preference for their d-isomers, whereas hydrophobic amino acids prefer their l-isomers. These differences in chiral recognition can be attributed to the different stereochemical matching between the hydrophilic and hydrophobic amino acids on the [001] steps of growing gypsum. These different chiral selectivities resulting from the amino acid hydrophilicity/hydrophobicity are confirmed by the experimental crystallization investigations from nano regulation on dynamic steps, to microscopic modification of gypsum morphology, and to macroscopic precipitation. Furthermore, as the hydrophilicity of amino acids increases, the disparity in chiral selection rises; conversely, the increase in the hydrophobicity of amino acids results in a decline in chiral selection. These insights improve our understanding of the interaction mechanism between amino acids and crystals and provide insights into the formation process of chiral biominerals and the origin of homochirality in nature.

LC-MS analysis of chiral amino acids in human urine reveals D-amino acids as potential biomarkers for colorectal cancer

Colorectal cancer (CRC) is a common malignant tumor in the gastrointestinal tract. Changes in amino acid metabolites have been implicated in tumorigenesis and disease progression. Biomarkers on the basis of chiral amino acids, especially D-amino acids, have not been established for early diagnosis of CRC. Quantification of chiral amino acids, especially very low concentrations of endogenous D-amino acids, is technically challenging. We report here the quantification of L- and D-amino acids in urine samples collected from 115 CRC patients and 155 healthy volunteers, using an improved method. The method of chiral labeling, liquid chromatography, and tandem mass spectrometry enabled separation and detection of 28 amino acids (14 L-amino acids, 13 D-amino acids and Gly). Orthogonal partial least squares discriminant analysis identified 14 targeted variables among these chiral amino acids that distinguished the CRC from the healthy controls. Binary logistic regression analysis revealed that D-α-aminobutyric acid (D-AABA), L-alanine (L-Ala), D-alanine (D-Ala), D-glutamine (D-Gln) and D-serine (D-Ser) could be potential biomarkers for CRC. A receiver operating characteristic curve analysis of combined multi-variables contributed to an area under the curve (AUC) of 0.995 with 98.3 % sensitivity and 96.8 % specificity. A model constructed with D-AABA, D-Ala, D-Gln, and D-Ser achieved an AUC of 0.988, indicating important contributions of D-amino acids to the association with CRC. Further analysis also demonstrated that the metabolic aberration was associated with age and the development of CRC, D-methionine (D-Met) was decreased in CRC patients with age over 50, and D/L-Gln in patients at stage IV was higher than patients at stage I. This study provides the signature of D-amino acids in urine samples and offers a promising strategy for developing non-invasive diagnosis of CRC.

Astrochemistry and Astrobiology over the last 20 years

A review of the achievements of astrochemistry and astrobiology over the past 20 years is given. Advances in astrochemistry in understanding the processes of emergence and survival high molecular weight chemical compounds are directly related to the conditions of prebiomolecules origin, like -amino acids and complex hydrocarbons. And if on the case of amino acids and hydrocarbons synthesis , the astrophysical picture seems quite clear, then on the case of the emergence of chiral amino acids, of which the proteins of living organisms are composed, there is no generally accepted point of view. Probably they occurred in certain photochemical transformations under the influence of circularly polarized radiation in the conditions of star formation regions of molecular clouds.

Synthesis of Chiral L2/Z-Type Ligands Featuring a Bis-Oxazoline Framework and their Application to Palladium-Catalyzed Asymmetric Allylic Alkylation

Chiral L2/Z*-type ligands featuring a bis-oxazoline framework have been successfully synthesized and applied in asymmetric allylic alkylation. These ligands, designed based on an oxazoline skeleton and derived from chiral amino acid derivatives, incorporate antimony and bismuth as Z-type ligands. Ligands with bulky, electron-withdrawing groups on antimony and bismuth showed enhanced catalytic performance. This research highlights the potential of these novel chiral L2/Z*-type ligands to improve asymmetric catalysis.

Integrating a Copper-Histidine Brace in a Mimetic Nanozyme Streamlines the Tyrosinase Recognition Moiety to Achieve Chiral Differentiation.

Designing artificial mimetic enzymes with high activity/selectivity to replace chiral bioenzymes is of great interest in the development of chiral materials consisting of molecules, enantiomers, that exist in two forms as mirror images of one another but cannot be superimposed. In this study, the chiral catalytic structural unit was streamlined from tyrosinase to integrate a mimetic nanozyme. The chiral amino acid l-histidine, as the chiral binding/recognition site, and the active metal site Cu were coupled (Cu@l-His) to create a copper-histidine brace with enantioselective catalytic ability to tyrosinol enantiomers. Results of kinetic parameters and activation energies confirmed the excellent peroxidase-like activity with a preference of Cu@l-His to l-tyrosinol. Such a preference could be attributed to the structurally oriented copper-histidine brace with a stronger affinity and catalytic activity to l-tyrosinol. By accurately evaluating chiral recognition units derived from bioenzymes, stable and superior chiral mimetic nanoenzymes could be constructed in a more straightforward and simplified manner, and they could also be extended to the reconstruction of diverse chiral enzymes.

Pick and Choose the Coordinated Metal Ion to Tune the Porphyrin Supramolecular Chirogenesis

AbstractThe solvent‐driven aggregation of metalloporphyrin derivatives, bearing an L‐ or D‐prolinate appendage, results in the stereospecific formation of chiral species that are strictly influenced by the aminoacid chirality and, above all, by the metal axial coordination capability. The Pd porphyrin derivatives self‐assemble in hydroalcoholic mixtures in fractal‐like suprastructures, displaying intense, specular dichroic bands and peculiar UV‐Vis spectral features, accounting for the formation of J‐type aggregates of complex morphology. Spectroscopic and kinetic studies gave important information on the aggregation process, allowing for a comparison with previously reported systems achieved from the free base and Zn derivatives in the same aggregative conditions. Analyzing the self‐aggregation process for the three porphyrin derivatives highlights the remarkable influence of porphyrin inner core features on the chirogenesis of the final systems, revealing an easy tunability of the asymmetry of the assemblies upon metal choosing.

β-CD@AgNPs with peroxisase-like activity for colorimetric determination of chiral tryptophan

Different enantiomer forms of amino acids play different roles in multifarious fields, and improper use will cause irreversible effects. Therefore, the identification of chiral amino acids is a vital issue in the field of pharmaceutical analysis. Herein, a chiral sensing system of β-cyclodextrin coated silver nanoparticle (β-CD@AgNPs) with peroxidase-like activity was designed for the fast and efficient colorimetric identification of tryptophan (Trp) enantiomers based on the difference in binding capacity between D/L-Trp and β-CD. The results showed the satisfactory linearity for detecting D/L-Trp over the concentration range from 0.2 to 4 mM with a LOD of 0.16 and 0.18 mM, respectively. Moreover, the absorbance increased linearly with the rise of D-Trp concentration percentage in the Trp enantiomer mixture. The proposed method avoided the use of natural enzymes and improved the stability due to the protective effect of cyclodextrin, which provided a new idea for selective colorimetric recognition and detection of D/L-Trp based on cyclodextrin.

Catalytic Asymmetric Synthesis of Unnatural Axially Chiral Biaryl δ-Amino Acid Derivatives via a Chiral Phenanthroline-Potassium Catalyst-Enabled Dynamic Kinetic Resolution.

Axially chiral biaryl δ-amino acids possess significantly different conformational properties and chiral environment from centrally chiral amino acids, therefore, have drawn considerable attention in the fields of synthetic and medicinal chemistry. Herein, a novel chiral phenanthroline-potassium catalyst has been developed by constructing a well-organized axially chiral ligand composed of one 1,10-phenanthroline unit and two axially chiral 1,1'-bi-2-naphthol (BINOL) units. In the presence of this catalyst, good to excellent yields and enantioselectivities (up to 99 % yield, 98 : 2 er) have been achieved in the ring-opening alcoholytic dynamic kinetic resolution of a variety of biaryl lactams, thereby providing an efficient protocol for catalytic asymmetric synthesis of unnatural axially chiral biaryl δ-amino acid derivatives.

Catalytic Asymmetric Synthesis of Unnatural Axially Chiral Biaryl δ‐Amino Acid Derivatives via a Chiral Phenanthroline‐Potassium Catalyst‐Enabled Dynamic Kinetic Resolution

AbstractAxially chiral biaryl δ‐amino acids possess significantly different conformational properties and chiral environment from centrally chiral amino acids, therefore, have drawn considerable attention in the fields of synthetic and medicinal chemistry. Herein, a novel chiral phenanthroline‐potassium catalyst has been developed by constructing a well‐organized axially chiral ligand composed of one 1,10‐phenanthroline unit and two axially chiral 1,1′‐bi‐2‐naphthol (BINOL) units. In the presence of this catalyst, good to excellent yields and enantioselectivities (up to 99 % yield, 98 : 2 er) have been achieved in the ring‐opening alcoholytic dynamic kinetic resolution of a variety of biaryl lactams, thereby providing an efficient protocol for catalytic asymmetric synthesis of unnatural axially chiral biaryl δ‐amino acid derivatives.

Chiral gypsum with high‐performance mechanical properties induced by self‐assembly of chiral amino acid on an amorphous mineral

AbstractFunctional chiral suprastructures are common in biology, including in biomineralization, and they are frequently found in many hardened structures of both marine and terrestrial invertebrates, and even in pathologic human otoconia of the inner ear. However, the biological processes by which they form remain unclear. Here, we show that chiral hierarchical suprastructures of calcium sulfate dihydrate (gypsum) can be induced by the chiral Aspartic acid (Asp). Left‐handed (clockwise) morphology of gypsum is induced by the d‐enantiomer of Asp, while right‐handed (counterclockwise) morphology is induced by the l‐enantiomer. A layer‐by‐layer, oriented inclination mineral growth model controlled by continuous self‐assembly of chiral Asp enantiomers on an amorphous calcium sulfate mineral surface of gypsum platelet layers is postulated to produce these chiral architectures. This hybrid amorphous‐crystallized chiral and hierarchical suprastructure of gypsum displays outstanding mechanical properties, including high‐performance strength and toughness. Furthermore, the induction of chiral gypsum suprastructures can be more generally extended from specific acidic amino acids to other (nonamino acid) molecules. These findings contribute to our understanding of the molecular mechanisms by which biomineral‐associated enantiomers exert structural control over chiral architectures commonly seen in biominerals and in biomimetically synthesized functional materials.