Preparation of amino acid chiral ionic liquid and visual chiral recognition of glutamine and phenylalanine enantiomers.

In this paper, the amino acid chiral ionic liquid (AACIL) was prepared with L-phenylalanine and imidazole. It was characterized by CD, FT-IR, 1H NMR, and 13C NMR spectrum. The chiral recognition sensor was constructed with AACIL and Cu(II), which exhibited different chiral visual responses (solubility or color difference) to the enantiomers of glutamine (Gln) and phenylalanine (Phe). The effects of solvent, pH, time, temperature, metal ions, and other amino acids on visual chiral recognition were optimized. The minimum concentrations of Gln and Phe for visual chiral recognition were 0.20 mg/ml and 0.28 mg/ml, respectively. The mechanism of chiral recognition was investigated by FT-IR, TEM, SEM, TG, XPS, and CD. The location of the host-guest inclusion or molecular placement has been conformationally searched based on Gaussian 09 software.

A Proline-Based Artificial Enzyme That Favors Aldol Condensation Enables Facile Synthesis of Aliphatic Ketones via Tandem Catalysis.

A proline-based artificial enzyme is prepared by grafting the l-proline moieties onto the surface of bovine serum albumin (BSA) protein through atom transfer radical polymerization (ATRP). The artificial enzyme, the BSA-PolyProline conjugate, prefers to catalyze the formation of unsaturated ketones rather than ß-hydroxy ketones in the reaction between acetone and aldehydes, which is difficult to achieve in free-proline catalysis. The altered reaction selectivity is ascribed to the locally concentrated l-proline moieties surrounding the BSA molecule, indicating a microenvironmental effect-induced switching of the reaction mechanism. Taking advantage of this selectivity, we used this artificial enzyme in conjunction with a natural enzyme, old yellow enzyme 1 (OYE1), to demonstrate a simple synthesis of different aliphatic ketones from acetone and aldehydes via tandem catalysis.

Enantioselective Detection of Gaseous Odorants with Peptide-Graphene Sensors Operating in Humid Environments.

Replicating the sense of smell presents an ongoing challenge in the development of biomimetic devices. Olfactory receptors exhibit remarkable discriminatory abilities, including the enantioselective detection of individual odorant molecules. Graphene has emerged as a promising material for biomimetic electronic devices due to its unique electrical properties and exceptional sensitivity. However, the efficient detection of nonpolar odor molecules using transistor-based graphene sensors in a gas phase in environmental conditions remains challenging due to high sensitivity to water vapor. This limitation has impeded the practical development of gas-phase graphene odor sensors capable of selective detection, particularly in humid environments. In this study, we address this challenge by introducing peptide-functionalized graphene sensors that effectively mitigate undesired responses to changes in humidity. Additionally, we demonstrate the significant role of humidity in facilitating the selective detection of odorant molecules by the peptides. These peptides, designed to mimic a fruit fly olfactory receptor, spontaneously assemble into a monomolecular layer on graphene, enabling precise and specific odorant detection. The developed sensors exhibit notable enantioselectivity, achieving a remarkable 35-fold signal contrast between d- and l-limonene. Furthermore, these sensors display distinct responses to various other biogenic volatile organic compounds, demonstrating their versatility as robust tools for odor detection. By acting as both a bioprobe and an electrical signal amplifier, the peptide layer represents a novel and effective strategy to achieve selective odorant detection under normal atmospheric conditions using graphene sensors. This study offers valuable insights into the development of practical odor-sensing technologies with potential applications in diverse fields.

Linear dichroism reveals the perpendicular orientation of DNA bases in the RecA and Rad51 recombinase filaments: A possible mechanism for the strand exchange reaction.

Linear dichroism spectroscopy is used to investigate the structure of RecA family recombinase filaments (RecA and Rad51 proteins) with DNA for clarifying the molecular mechanism of DNA strand exchange promoted by these proteins and its activation. The measurements show that the recombinases promote the perpendicular base orientation of single-stranded DNA only in the presence of activators, indicating the importance of base orientation in the reaction. We summarize the results and discuss the role of DNA base orientation.

[Deep eutectic solvents synergistic with carboxymethyl -ß-cyclodextrin on the improvement of chiral separation of metoprolol by capillary electrophoresis].

The physical and chemical properties of chiral drugs are very similar. However, their pharmacological and toxicological effects vary significantly. For example, one enantiomer may have favorable properties whereas the other may be ineffective or even have toxic side effects. Hence, exploring innovative strategies to improve enantiomeric resolution is of great importance. Metoprolol (MET) is a ß-receptor blocker used to treat hypertension, stable angina pectoris, and supraventricular tachyarrhythmia. Establishing chiral separation and analysis methods of MET enantiomers is important for enhancing the quality of chiral drugs. Capillary electrophoresis (CE) has the advantages of a small sample size, simple operation, high separation efficiency, and many alternative modes; therefore it is widely used in the field of chiral drug separation. The chiral selectors commonly used for CE-based chiral separation include cyclodextrin (CD) and its derivatives, polysaccharides, proteins, and macrocyclic antibiotics. CD is one of the most commonly used and effective chiral selectors for CE. The relatively hydrophobic structure inside the cavity and the relatively hydrophilic structure outside the cavity of CD enable it and chiral molecules to form inclusion compounds with different binding constants, thus achieving chiral separation. However, the use of CD alone as a chiral selector does not always yield satisfactory separation results. Hence, the addition of other additives, such as ionic liquids and deep eutectic solvents (DESs) to assist CD-based chiral separation systems has received extensive attention. Previous studies on the enantiomeric separation of MET by CE have focused on the addition of CD and its derivatives alone for separation. Few studies have been conducted on the synergistic addition of auxiliary additives to CD to improve the enantiomeric resolution of MET. In this study, three DESs, namely, choline chloride-D-glucose, choline chloride-D-fructose, and lactate-D-glucose, were used for the CE-based chiral separation of MET for the first time, and the synergistic effect of the DESs on the separation of MET enantiomers by CD-based capillary zone electrophoresis was speculated. For this purpose, an uncoated fused silica capillary with inner diameter of 50 µm, total length of 50 cm and effective length of 41.5 cm was used as the separation column. First, the effects of CD type, CD concentration, buffer pH, and buffer concentration on MET separation were investigated, and the optimal conditions (15 mmol/L carboxymethyl-ß-cyclodextrin (CM-ß-CD), pH=3.0, and 40 mmol/L phosphate buffer) were obtained. Other CE conditions were as follows: UV detection at 230 nm, applied voltage of 25 kV. All operations were carried out at 20 ℃. Next, three types of DESs were prepared as auxiliary additives via a mixed-heating method. The DESs were mixed in a 50 mL round-bottomed flask at a certain molar ratio and then heated in a water bath at 80 ℃ for 3 h until a clear and transparent liquid was obtained. The effects of different DESs and their mass fraction on chiral separation were subsequently studied. The optimal choline chloride-D-fructose mass fraction was ultimately determined to be 1.5%. The resolution of MET increased from 1.30 without DES to 2.61 with 1.5% choline chloride-D-fructose, thereby achieving baseline separation. Finally, the separation effect and mechanism were speculated. The MET chiral separation method established in this study is of great significance for improving the quality of chiral compounds and ensuring the safety and effectiveness of clinical drugs. Furthermore, it may be useful in the research and development of CE-based chiral separation techniques using CD derivatives with DESs.

Recent Progress in Detecting Enantiomers in Food.

The analysis of enantiomers in food has significant implications for food safety and human health. Conventional analytical methods employed for enantiomer analysis, such as gas chromatography and high-performance liquid chromatography, are characterized by their labor-intensive nature and lengthy analysis times. This review focuses on the development of rapid and reliable biosensors for the analysis of enantiomers in food. Electrochemical and optical biosensors are highlighted, along with their fabrication methods and materials. The determination of enantiomers in food can authenticate products and ensure their safety. Amino acids and chiral pesticides are specifically discussed as important chiral substances found in food. The use of sensors replaces expensive reagents, offers real-time analysis capabilities, and provides a low-cost screening method for enantiomers. This review contributes to the advancement of sensor-based methods in the field of food analysis and promotes food authenticity and safety.

Chemoenzymatic Synthesis of Selegiline: An Imine Reductase-Catalyzed Approach.

(R)-Homobenzylic amines are key structural motifs present in (R)-selegiline, a drug indicated for the treatment of early-stage Parkinson's disease. Herein, we report a new short chemoenzymatic approach (in 2 steps) towards the synthesis of (R)-selegiline via stereoselective biocatalytic reductive amination as the key step. The imine reductase IR36-M5 mutant showed high conversion (97%) and stereoselectivity (97%) toward the phenylacetone and propargyl amine substrates, offering valuable biocatalysts for synthesizing alkylated homobenzylic amines.

Comprehensive Review on Chiral Stationary Phases in Single-Column Simultaneous Chiral-Achiral HPLC Separation Methods.

This comprehensive review explores the utilization of chiral stationary phases (CSPs) in the context of single-column simultaneous chiral-achiral high-performance liquid chromatography (HPLC) separation methods. While CSPs have traditionally been pivotal for enantioselective drug analysis, contemporary CSPs often exhibit notable chemoselective properties. Consequently, there is a discernible trend towards the development of methodologies that enable simultaneous enantio- and chemoselective separations utilizing a single CSP-based chromatographic column. This review provides an exhaustive overview of reported HPLC methods in this domain, with a focus on four major CSP types: cyclodextrin-, glycopeptide antibiotic-, protein-, and polysaccharide-based CSPs. This article delves into the diverse applications of CSPs, encompassing various chromatographic modes such as normal phase (NP), reverse phase (RP), and polar organic (PO). This review critically discusses method development, emphasizing the additional chemoselective separation mechanisms of CSPs. It also explores possibilities for method optimization and development, concluding with future perspectives on this evolving field. Despite the inherent challenges in understanding the retention mechanisms involved in chemoselective separations, this review highlights promising trends and anticipates a growing number of simultaneous enantio- and chemoselective methods in pharmaceutical analyses, pharmacokinetic studies, and environmental sample determinations.

Systemic evaluation of novel acaricide hexythiazox for bioactivity improvement and risk reduction at the enantiomer level.

Traditional risk assessments of chiral pesticides mainly depend on racemic form, which is often incomprehensive. This study conducted systemic investigations on the bioactivity, toxicity, and ecotoxicological effects of hexythiazox (HTZ) at the enantiomer level. The elution order and absolute configuration of HTZ enantiomers were determined. (4R, 5R)-(+)-HTZ exhibited 708 and 1719 times higher bioactivity against Tetranychus cinnabarinus and Tetranychus urticae eggs than (4S, 5S)-(-)-HTZ, respectively. Molecular docking indicated greater interactions between (4R, 5R)-(+)-HTZ and chitin synthase leading to higher bioactivity of (4R, 5R)-(+)-HTZ. However, (4S, 5S)-(-)-HTZ induced greater changes in protein and malondialdehyde content, and antioxidant and detoxification enzyme activities than (4R, 5R)-(+)-HTZ in earthworms. Furthermore, integrated biomarker response results indicated (4S, 5S)-(-)-HTZ exhibited higher toxic effects on earthworms than (4R, 5R)-(+)-HTZ. Finally, significant differentially expressed genes (DEGs) were observed in earthworms after exposure to (4R, 5R)-(+)-HTZ and (4S, 5S)-(-)-HTZ, respectively. These DEGs were mainly enriched in glycolysis/gluconeogenesis and purine metabolism pathways in earthworms. Additionally, six metabolism pathways were also enriched, including pyruvate metabolism, fatty acid biosynthesis, oxidative phosphorylation, citric acid cycle, fatty acid degradation, and ATP-binding cassette transporters. These findings suggest that earthworms exhibited enantiomer-specific responses to (4R, 5R)-(+)-HTZ and (4S, 5S)-(-)-HTZ. This study provides systemic insight into the toxicity mechanism of HTZ at the enantiomer level and the potential to develop (4R, 5R)-(+)-HTZ as a high-efficiency and low-risk pesticide.

Enantiomeric analysis of γ(δ)-lactones by reversed phase high performance liquid chromatography using amylose tris(5-chloro-2-methylphenylcarbamate) as stationary phase.

A Chiralpak AY-3R column was investigated for analytical enantiomeric separation of twelve racemic γ(δ)-lactones using reversed phase high performance liquid chromatography. Main influence factors, including organic modifier, flow rate and column temperature, were optimized. Five kinds of γ(δ)-lactones were successfully enantioseparated using the established method: γ-nonanolactone, δ-decalactone, δ-undecalactone, δ-dodecalactone and δ-tetradecalactone. Under optimized conditions, enantiomeric peak resolution (Rs) for the five γ(δ)-lactones reached more than 1.09, 1.08, 1.54, 1.43, and 1.11, respectively. Their chromatographic elution behavior was investigated using Van't Hoff equation and Van Deemter equation. It was found that an exothermic process occurred during enantiomeric separation of γ(δ)-lactones using this chromatographic column, and it showed a typical Van Deemter curve. Finally, this method was applied in enantiomeric ratio analysis of γ(δ)-lactones contents for purchased butter samples, and results confirmed the predominant content of the (R)-configuration of δ-dodecalactone in natural animal butter, while in margarine, an equal proportion of (R/S)-configuration of δ-dodecalactone was detected.

Preparation and evaluation of two chiral stationary phases based on imidazolyl-functionalized bromoethoxy pillar[5]arene-bonded silica.

Chiral pillar[5]arene-based mesoporous silica, an emerging class of chiral structure, possesses excellent characteristics such as abundant chiral active sites, encapsulated cavity and excellent chiral modification, which make them a promising candidate as new chiral stationary phases (CSPs) in enantioseparation. In this study, two imidazole-containing (S)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine and (S)-Histidinol were respectively modified to bromoethoxy pillar[5]arene-bonded silica to construct new chiral stationary phases (sPIE-BP5-Sil and sHol-BP5-Sil) for the separation and analysis of enantiomers. The separation conditions such as mobile phase composition, flow rate and temperature were optimized. Under optimal conditions, both sPIE-BP5-Sil and sHol-BP5-Sil showed good separation performance for different types of enantiomers. Interestingly, sPIE-BP5-Sil and sHol-BP5-Sil showed better enantioselectivity for chiral aromatic compounds and chiral aliphatic compounds, respectively. This enantioseparation result was closely related to the presence of additional aromatic rings and abundant hydroxyl groups in the side chains of the two chiral groups. In addition, the enantioseparation process was further studied by molecular docking simulation. Therefore, this work provided a new strategy for the preparation and application of imidazolyl-derived pillar[5]arene-based chiral stationary phases, which can be efficiently used for screening and separating enantiomers.

Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation.

Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization of unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products are formed in excellent yield and enantioselectivity with no observed bis-acylation. A data-science-driven approach to substrate scope evaluation was coupled to high throughput experimentation (HTE) to facilitate statistical modeling in order to inform mechanistic studies. Reaction kinetics, catalyst structural studies, and density functional theory (DFT) transition state analysis elucidated the turnover-limiting step to be the collapse of the tetrahedral intermediate and provided key insights into the catalyst-substrate structure-activity relationships responsible for the origin of the enantioselectivity. This study offers a reliable method for accessing enantioenriched sulfonimidamides to propel their application as pharmacophores and serves as an example of the mechanistic insight that can be gleaned from integrating data science and traditional physical organic techniques.

Enantioselective Divergent Syntheses of Diterpenoid Pyrones.

Capitalizing a synergy between late-stage C(sp3)-H alkynylation and a series of transition metal-catalyzed alkyne functionalization reactions, we reported herein enantioselective divergent synthesis of 10 diterpenoid pyrones within 14-16 steps starting from chiral pool enoxolone, including the first enantioselective synthesis of higginsianins A, B, D, E, and metarhizin C. Our synthesis also highlights an unprecedented biomimetic oxidative rearrangement of α-pyrone into 3(2H)-furanone, as well as applications of Echavarren C(sp3)-H alkynylation reaction and Toste chiral counterion-mediated Au-catalyzed intramolecular allene hydroalkoxylation in natural product synthesis.

Scalable Synthesis of All Stereoisomers of 2-Aminocyclopentanecarboxylic Acid─A Toolbox for Peptide Foldamer Chemistry.

Although the construction of peptides with well-defined three-dimensional structures and predictable functions, including biological activity, using conformationally constrained ß-amino acids has been shown to be a very successful strategy, their broad application is limited by access to the appropriate building blocks. In particular, trans- and cis-stereoisomers of 2-aminocyclopentanecarboxylic acid (ACPC) are of high interest. The scalable synthesis of all four stereoisomers of Fmoc derivatives of ACPC is presented with NMR-based analysis methods for their enantiomeric purity.

Simultaneous Determination of Enantiomeric Purity and Organic Impurities of Dexketoprofen Using Reversed-Phase Liquid Chromatography-Enhancing Enantioselectivity through Hysteretic Behavior and Temperature-Dependent Enantiomer Elution Order Reversal on Polysaccharide Chiral Stationary Phases.

A reversed-phase high-performance liquid chromatographic (HPLC) method was developed for the simultaneous determination of the potential impurities of dexketoprofen, including the distomer R-ketoprofen. After screening the separation capability of four polysaccharide columns (Lux Amylose-1, Lux Amylose-2, Lux Cellulose-1 and Lux Cellulose-2) in polar organic and in reversed-phase modes, appropriate enantioseparation was observed only on the Lux Amylose-2 column in an acidified acetonitrile/water mixture. A detailed investigation of the mobile phase composition and temperature for enantio- and chemoselectivity showed many unexpected observations. It was observed that both the resolution and the enantiomer elution order can be fine-tuned by varying the temperature and mobile phase composition. Moreover, hysteresis of the retention times and enantioselectivity was also observed in reversed-phase mode using methanol/water mixtures on amylose-type columns. This could indicate that the three-dimensional structure of the amylose column can change by transitioning from a polar organic to a reversed-phase mode, which affects the enantioseparation process. Temperature-dependent enantiomer elution order and rare enthalpic/entropic controlled enantioseparation in the operative temperature range were also observed in reversed-phase mode. To find the best methodological conditions for the determination of dexketoprofen impurities, a full factorial optimization design was performed. Using the optimized parameters (Lux Amylose-2 column with water/acetonitrile/acetic acid 50/50/0.1 (v/v/v) at a 1 mL/min flow rate at 20 °C), baseline separations were achieved between all compounds within 15 min. Our newly developed HPLC method was validated according to the current guidelines, and its application was tested on commercially available pharmaceutical formulations. According to the authors' knowledge, this is the first study to report hysteretic behavior on polysaccharide columns in reversed-phase mode.

Biological Evaluations, NMR Analyses, Molecular Modeling Studies, and Overview of the Synthesis of the Marine Natural Product (-)-Mucosin.

Natural products obtained from marine organisms continue to be a rich source of novel structural architecture and of importance in drug discovery, medicine, and health. However, the success of such endeavors depends on the exact structural elucidation and access to sufficient material, often by stereoselective total synthesis, of the isolated natural product of interest. (-)-Mucosin (1), a fatty acid derivative, previously presumed to contain a rare cis-bicyclo[4.3.0]non-3-ene moiety, has since been shown to be the trans-congener. Analytically, the fused bicyclic ring system in (-)-1 constitutes a particular challenge in order to establish its relative and absolute stereochemistry. Herein, data from biological evaluations, NMR and molecular modeling studies of (-)-1 are presented. An overview of the synthetic strategies enabling the exact structural elucidation of (-)-mucosin (1) is also presented.

Biocatalytic enantioselective synthesis of cenobamate, an antiepileptic drug.

A green and efficient process for the synthesis of cenobamate has been accomplished in 70% yield and >99% ee through the bio-reduction of ß-ketotetrazole using Daucus carota whole plant cells. The corresponding ß-hydroxytetrazole was isolated in 60% yield and >98% ee. This is the first report on the biocatalytic reduction of ß-ketotetrazole using plant enzymes derived from D. carota root cells with excellent enantioselectivity.

Unified Strategy Enables the Collective Syntheses of Structurally Diverse Indole Alkaloids.

Natural products and their analogues are significant sources of therapeutic lead compounds. However, synthetic strategies for generating large collections of these molecules remain a significant challenge. The most difficult step in their synthesis is the design of a common intermediate that can be easily transformed into natural products belonging to different families. This study demonstrates the evolution of synthetic tactics designed to assemble the functionalized piperidines present in indole alkaloids from a common intermediate. More importantly, we also report a previously unknown Ir- and Er-catalyzed dehydrogenative spirocyclization reaction that enables direct access to spirocyclic oxindole alkaloids. As a practical application, the asymmetric total syntheses of 29 natural alkaloids belonging to different families were accomplished by following a uniform synthetic route. The proposed methodology extends the capability of the iridium-catalyzed dehydrogenative coupling reaction to the realm of indole-alkaloid synthesis and provides new opportunities for the efficient preparation of natural product-like molecules.

High anti Diastereoselectivity in a Tandem Oxyhomologation-Coupling Protocol for the Preparation of Amides and Peptides Incorporating α-Hydroxy ß-Amino Acids.

The one-pot MAC (Masked Acyl Cyanide) reaction is used to perform the tandem oxyhomologation reaction of N,N-dibenzyl-l-phenylalaninal and coupling with nitrogen nucleophiles to provide a wide selection of amide and peptide derivatives of (2S,3S)-allophenylnorstatin in generally good yields and with high anti selectivity, often with dr >98:2. The procedure works equally well with other selected N,N-dibenzyl α-amino aldehydes, and is used to achieve a very short synthesis of (2S,3S,S)-epibestatin.

Enantioselective Total Synthesis of the Marine Macrolides Salarins A and C.

Here we report the first total synthesis of the marine macrolide salarin C, a potent anticancer agent, and demonstrate the biomimetic oxidation-Wasserman rearrangement to access salarin A. This synthesis relies on L-proline catalysis to install a chlorohydrin function that masks the sensitive C16-C17 epoxide and potentially mimics the biosynthesis of these compounds where a related chlorohydrin may yield both THF- and epoxide-containing salarins. Additional and key features of the synthesis include (i) macrocycle formation via ring-closing metathesis, (ii) macrocyclic substrate-controlled epoxidation of the C12-C13 allylic alcohol, and (iii) a late-stage Julia-Kocienski olefination to install the side chain. Importantly, this work provides a platform for the synthesis of other salarins and analogues of these potentially important anticancer natural products.