Enhanced Enantioselective Discrimination Regulated by Achiral Ligands in Chiral Metal-Organic Frameworks.

Enantioselective recognition is a fundamental property of chiral linkers in chiral metal-organic frameworks (CMOFs). However, clarifying the efficient enantioselective discrimination tailored by achiral linkers remains challenging to explain the chiral recognition mechanism and efficiency. Here, two CMOFs ([Zn2(l-Phe)2(bpa)2]n and [Zn2(l-Phe)2(bpe)2]n) with the completely different enantioselective recognition are synthesized from different nonchiral ligands and the same chiral ligands. The enantioselective recognition of CMOF is undoubtedly related to l-Phe, which differs in the hydrogen bonding to the Trp enantiomer. However, the electrochemical signals are weak and undifferentiated. [Zn2(l-Phe)2(bpe)2]n produces a flattened coplanar conformation with the -C═C- tether in the achiral ligand. The flattened achiral bpee ligand and its surrounding chiral phenylalanine molecules interact through multiple π-π stacking and hydrogen bonding, which together create a chiral sensor that facilitates the recognition of l-Trp. However, [Zn2(l-Phe)2(bpa)2]n produces a stepped conformation due to the -C-C- tether in the achiral ligand; despite the recognition effect of bpea, the recognition is unsatisfactory. Therefore, the chiral recognition of the two CMOFs stems from the synergistic effect between chiral and achiral ligands. This work shows that nonchiral ligands are also crucial in determining enantiomeric discrimination and opens up a new avenue for designing chiral materials.

Bionic nanopore recognition receptors for single-molecule enantioselectivity studies of chiral drugs.

BACKGROUND: Enantiodiscrimination of chiral drugs is critical for understanding physiological phenomena and ensuring medical safety. Although enantiomers of these drugs share identical physicochemical properties, they exhibit significant differences in pharmacodynamic, pharmacokinetic, and toxicological properties due to the differences in their three-dimensional shapes. Therefore, the development of effective methods for chiral recognition is of great significance and has been a hot topic in chemo/biological studies. RESULTS: In this study, we designed a recognition receptor comprising a α-hemolysin (α-HL) nanopore and sulfobutyl ether-ß-cyclodextrin (SBEßCD) for identifying the enantiomers of the antidepressant duloxetine at the single-molecule level. Chiral molecules were discriminated based on the different current blockages within the recognition receptor. The results indicated a strong interaction between R-duloxetine and the recognition receptor. By combining the experimental data and molecular docking results, we explored the recognition mechanism of the designed nanopore recognition receptor for chiral drug molecules. It was found that hydrophobic and electrostatic interactions play key roles in chiral recognition. Additionally, by comparing the binding kinetics of enantiomers to cyclodextrins in confined nanospace and bulk solution, we found that enantiomeric identification was better facilitated in the confined nanospace. Finally, the enantiomeric excess (ee) of the enantiomeric duloxetine mixture was measured using this recognized receptor. SIGNIFICANCE: This strategy has the advantages of low cost, high sensitivity, and no need for additional derivative modifications, providing a new perspective on the development of chiral recognition sensors with excellent enantioselectivity in drug design, pharmaceuticals, and biological applications.

A covalent organic framework nanosheet-nanochannel composite with signal amplification strategy for electrochemical enantioselective recognition.

Recognition and separation of chiral isomers are of great importance in both industrial and biological applications. However, owing to identical molecular formulas and chemical properties of enantiomers, signal transduction and amplification are still two major challenges in chiral sensing. In this study, we developed an enantioselective device by integrating chiral covalent organic framework nanosheets (CONs) with nanochannels for sensitive identification and quantification of enantiomers. Using 3,4-dihydroxyphenylalanine (DOPA) as the model analyte, the as-prepared chiral nanofluidic device exhibits a remarkable chiral recognition ability to l-DOPA than d-DOPA. More importantly, due to the chelation of DOPA with Fe3+ ions, it can efficiently block the ion transport through channel and shield the channel surface charge, which will amplify the difference in the electrochemical response of l-DOPA and d-DOPA. Therefore, a sensitive chiral recognition can be achieved using the present nanofluidic device coupled using electrochemical amplification strategy. Notably, using this method, an ultra-low concentration of l-DOPA (as low as 0.21 pM) can be facilely and successfully detected with a linear range of 1 pM-10 µM. This study provides a reliable and sensitive approach for achieving highly selective detection of chiral molecules.

Modulating Helix-Preference of an Axially-Twisted Molecular Scaffold Through Diastereomeric Salt Formation with Tartaric Acid Stereoisomers.

Herein, we designed a chiral, axially-twisted molecular scaffold (ATMS) using pyridine-2,6-dicarboxamide (PDC) unit as pivot, chiral trans-cyclohexanediamine (CHDA) residues as linkers, and pyrene residues as fluorescent reporters. R,R-ATMS exclusively adopted M-helicity and produced differential response in UV-vis, fluorescence, and NMR upon addition of tartaric acid (TA) stereoisomers allowing naked-eye detection and enantiomeric content determination. Circular dichroism (CD) profile of R,R-ATMS underwent unique changes during titration with TA stereoisomers - while loss of CD signal at 345 nm was observed with equimolar D-TA and meso-TA, inversion was seen with equimolar L-TA. Temperature increase weakened these interactions to partially recover the original CD signature of R,R-ATMS. 2D NMR studies also indicated the significant structural changes in R,R-ATMS in the solution state upon addition of L-TA. Single crystal X-ray diffraction (SCXRD) studies on the crystals of the R,R-ATMS⊃D-TA salt revealed the interacting partners stacked in arrays and ATMS molecules stabilized by π-π stacking between its PDC and pyrene residues. Contrastingly, tightly-packed supramolecular cages comprised of four molecules each of R,R-ATMS and L-TA were seen in R,R-ATMS⊃L-TA salt, and the ATMS molecules contorted to achieve CH-π interactions between its pyrene residues. These results may have implications in modulating the helicity of topologically-similar larger biomolecules.

Enhancing Electrochemical Signal for Efficient Chiral Recognition by Encapsulating C60 Fullerene into Chiral Lanthanum-Based MOFs.

Chiral metal-organic frameworks (MOFs) have attracted much attention due to their highly tunable regular microporous structures. However, chiral electrochemical recognition based on chiral MOFs is often limited by poor charge separation and slow charge transfer kinetics. In this case, C60 can be encapsulated into the cavity of [La(BTB)]n by virtue of host-guest interactions through π-π stacking to synthesize the chiral composite C60@[La(BTB)]n and amplify electrochemically controlled enantioselective interactions with the target enantiomers. A large electrostatic potential difference is generated in chiral C60@[La(BTB)]n due to the host-guest interaction and the inhomogeneity of the charge distribution, leading to the generation of a strong built-in electric field and thus an overall enhancement of the conductivity of the chiral material. Their enantioselective detection of tryptophan enantiomers was demonstrated by electrochemical measurement. The results showed that chiral MOF materials can be used for enantiomeric recognition. It is worth noting that this new material derived from the concept of host-guest interaction to enhance charge separation opens up unprecedented possibilities for future enantioselective recognition and separation.

pH-Tuned Enantioselectivity Reversal in a Defective Chiral Metal Organic Framework.

The introduction of chirality into easy-scalable metal-organic frameworks (MOFs) gives rise to the development of advanced electrochemical sensors. However, integrating chirality by directly connecting metal ions and chiral ligands is unpredictable. Postmodification synthesis is a common method for synthesizing chiral MOFs, but it reduces the size of chiral channels and poses obstacles to the approach of chiral guest molecules. In this work, missing connection defects were introduced into the chiral MOFs through defect engineering strategies, which enhance the recognition of the target enantiomers. pH can tune enantioselectivity reversal in defective chiral MOFs. The chiral MOFs show enantioselectivity for d-Trp at pH = 5 and l-Trp at pH = 8. From the results of zeta potential, regardless of pH 5 or 8, the chiral MOF has a positive potential. The chiral MOFs are positively charged, while tryptophan is negatively charged when pH = 8. The difference in the positive and negative charge interactions between the two amino acids and chiral MOFs leads to chiral recognition. However, the difference in π-π interaction between chiral MOF and Trp enantiomers mainly drives chiral recognition under pH = 5. This study paves a pathway for the synthesis of defective chiral MOFs and highlights the pH-tuned enantioselectivity reversal.

Construction and Application of a Pepsin-Functionalized Covalent Organic Framework with Prominent Chiral Recognition Ability.

The stable Pepsin@covalent organic framework (Pepsin@COF) were constructed base on matching COF pore diameter to pepsin dimension. It exhibits excellent chiral recognition capabilities (e. e. % up to 62.63 %) and potential for enantioseparation. Furthermore, a positive correlation between the immobilized enzyme activity and chiral recognition was revealed, offering insights for the design of biocatalytic nanosystems in chiral separation.

Molecular Dynamics Simulations of Amylose- and Cellulose-Based Selectors and Related Enantioseparations in Liquid Phase Chromatography.

In the last few decades, theoretical and technical advancements in computer facilities and computational techniques have made molecular modeling a useful tool in liquid-phase enantioseparation science for exploring enantioselective recognition mechanisms underlying enantioseparations and for identifying selector-analyte noncovalent interactions that contribute to binding and recognition. Because of the dynamic nature of the chromatographic process, molecular dynamics (MD) simulations are particularly versatile in the visualization of the three-dimensional structure of analytes and selectors and in the unravelling of mechanisms at molecular levels. In this context, MD was also used to explore enantioseparation processes promoted by amylose and cellulose-based selectors, the most popular chiral selectors for liquid-phase enantioselective chromatography. This review presents a systematic analysis of the literature published in this field, with the aim of providing the reader with a comprehensive picture about the state of the art and what is still missing for modeling cellulose benzoates and the phenylcarbamates of amylose and cellulose and related enantioseparations with MD. Furthermore, advancements and outlooks, as well as drawbacks and pitfalls still affecting the applicability of MD in this field, are also discussed. The importance of integrating theoretical and experimental approaches is highlighted as an essential strategy for profiling mechanisms and noncovalent interaction patterns.

Interfacial Self-assembly of Chiral Selenide Nanomembrane for Enantiospecific Recognition.

Here, we report the synthesis of chiral selenium nanoparticles (NPs) using cysteine and the interfacial assembly strategy to generate a self-assembled nanomembrane on a large-scale with controllable morphology and handedness. The selenide (Se) NPs exhibited circular dichroism (CD) bands in the ultraviolet and visible region with a maximum intensity of 39.96 mdeg at 388 nm and optical anisotropy factors (g-factors) of up to 0.0013 while a self-assembled monolayer nanomembrane exhibited symmetrical CD approaching 72.8 mdeg at 391 nm and g-factors up to 0.0034. Analysis showed that a photocurrent of 20.97±1.55 nA was generated by the D-nanomembrane when irradiated under light while the L-nanomembrane generated a photocurrent of 20.58±1.36 nA. Owing to the asymmetric intensity of the photocurrent with respect to the handedness of the nanomembrane, an ultrasensitive recognition of enantioselective kynurenine (Kyn) was achieved by the ten-layer (10L) D-nanomembrane exhibiting a photocurrent for L-kynurenine (L-Kyn) that was 8.64-fold lower than that of D-Kyn, with a limit of detection (LOD) of 0.0074 nM for the L-Kyn, which was attributed to stronger affinity between L-Kyn and D-Se NPs. Noticeably, the chiral Se nanomembrane precisely distinguished L-Kyn in serum and cerebrospinal fluid samples from Alzheimer's disease patients and healthy subjects.

Revelation of the Electrochemical Chiral Recognition of l-Proline-Tuned Zr-MOFs.

Chirality plays an extremely important role in nature. In this work, a highly ordered and non-clustered crystalline material UiO-88-LP was synthesized by using l-proline (l-Pro)-tuning Zr-MOF and the solvothermal method, which was then modified on the glassy carbon electrode (GCE) to construct an electrochemical chiral interface for the recognition of tryptophan (Trp) configuration. UiO-88-LP composites were characterized by scanning electron microscopy, X-ray transmission diffraction, X-ray photoelectron spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy. After optimization of the experimental conditions, redox peaks for l-Trp and d-Trp were clearly observed at the UiO-88-LP/GCE electrochemical sensing interface with a peak-to-current ratio (IL/ID) of 2.47. The peak current was positively correlated with the concentration of Trp. The electrochemical recognition behavior of l-Trp and d-Trp was investigated by differential pulse voltammetry. The electrochemical characterization showed that UiO-88-LP/GCE had an enantiomeric resolution of amino acids. The recognition mechanism showed that l-Pro entering the UiO-66 molecular cage provided a site for the system to be recognized, so the purpose of recognition was achieved. The relevant data provide theoretical support for the practical application of UiO-88-LP in electrochemical sensors.

Chiral MOFs encapsulated by polymers with poly-metallic coordination as chiral biosensors.

Chiral materials have drawn the widespread attention for their its chiral recognition ability. The design and synthesis of chiral material are of importance owing to the unpredictability in controlling chirality during the synthesis process. To circumvent problems, a chiral MOF (D-His-ZIF-8) was synthesized by ligand exchange of 2-methylimidazole (Hmim) on ZIF-8 by D-histidine (D-His), which can be treated as chiral host to distinguish amino acid enantiomers. The obtained D-His-ZIF-8 can provide chiral nanochannels for amino acid guests. Meanwhile, polynary transition-metal ion (Co2+ and Fe3+) coordinating with polydopamine (PDA) wrapped on the surface of D-His-ZIF-8 can increase the active sites. The electrochemical chiral recognition behavior showed that D-His-ZIF-8@CoFe-PDA exhibited good recognition of the tryptophan enantiomer (L/D-Trp) (working potential of -0.2 V vs. Hg/HgCl2). The LOD and LOQ of L-Trp were 0.066 mM and 0.22 mM, respectively, while the LOD and LOQ of D-Trp were 0.15 mM and 0.50 mM, respectively. Finally, the usefulness of D-His-ZIF-8@CoFe-PDA/GCE was evaluated with a recovery of 94.4-103%. The analysis of real  samples shows that D-His-ZIF-8@CoFe-PDA/GCE is a feasible sensing platform for the detection of L-Trp and D-Trp.

Chiral zinc oxide functionalized quartz crystal microbalance sensor for enantioselective recognition of amino acids.

Chiral transition metal oxides with tunable structures and multiple physicochemical features have been increasingly applied for chiral sensing and detection. In this work, chiral zinc oxide (ZnO) was first applied as selector to construct quartz crystal microbalance (QCM) sensor for enantioselective recognition of amino acids. The chiral ZnO was prepared by a methionine-induced self-assembly strategy and its high topological chirality was confirmed by several techniques such as circular dichroism spectrum. The chiral discrimination factors were calculated by frequency shifts in response to aspartic acid, phenylalanine, lysine and arginine on L-ZnO surface, achieving 1.89 ± 0.04, 1.76 ± 0.11, 1.66 ± 0.07 and 1.54 ± 0.09, respectively. Notably, L-enantiomers preferred stronger absorptions on L-ZnO surface as compared to D-forms. It was further found that this sensor was appropriate for quantitative analysis and enantiomer excess analysis and adsorption kinetics study. Furthermore, molecular docking revealed the recognition mechanism, where chiral distinction was caused by the different steric interactions between enantiomers and chiral ZnO. This method enjoyed merits of high enantioselectivity, simple preparation and low cost, offering newly chiral sensing method for other molecules.

Enantioselective Recognition of L-Lysine by ICT Effect with a Novel Binaphthyl-Based Complex.

A novel triazole fluorescent sensor was efficiently synthesized using binaphthol as the starting substrate with 85% total end product yield. This chiral fluorescence sensor was proved to have high specific enantioselectivity for lysine. The fluorescence intensity of R-1 was found to increase linearly when the equivalent amount of L-lysine (0-100 eq.) was gradually increased in the system. The fluorescence intensity of L-lysine to R-1 was significantly enhanced, accompanied by the red-shift of emission wavelength (389 nm to 411 nm), which was attributed to the enhanced electron transfer within the molecular structure, resulting in an ICT effect, while the fluorescence response of D-lysine showed a decreasing trend. The enantioselective fluorescence enhancement ratio for the maximum fluorescence intensity was 31.27 [ef = |(IL - I0)/(ID - I0)|, 20 eq. Lys], thus it can be seen that this fluorescent probe can be used to identify and distinguish between different configurations of lysine.

Detection of Glucose Based on Noble Metal Nanozymes: Mechanism, Activity Regulation, and Enantioselective Recognition.

Glucose monitoring is essential to evaluate the degree of glucose metabolism disorders. The enzymatic determination has been the most widely used method in glucose detection because of its high efficiency, accuracy, and sensitivity. Noble metal nanomaterials (NMs, i.e., Au, Ag, Pt, and Pd), inheriting their excellent electronic, optical, and enzyme-like properties, are classified as noble metal nanozymes (NMNZs). As the NMNZs are often involved in two series of reactions, the oxidation of glucose and the chromogenic reaction of peroxide, here the chemical mechanism by employing NMNZs with glucose oxidase (GOx) and peroxidase (POD) mimicking activities is briefly summarized first. Subsequently, the regulation strategies of the GOx-like, POD-like and tandem enzyme-like activities of NMNZs are presented in detail, including the materials, size, morphology, composition, and the reaction condition of the representative NMs. In addition, in order to further mimic the enantioselectivity of enzyme, the design of NMNZs with enantioselective recognition of d-glucose and l-glucose by using different chiral compounds (DNA, amino acids, and cyclodextrins) and molecular imprinting is further described in this review. Finally, the feasible solutions to the existing challenges and a vision for future development possibilities are discussed.

Enantioselective Recognition of Lysine and Phenylalanine Using an Imidazole Salt-Type Fluorescent Probe Based on H8-BINOL.

An imidazole bromide fluorescent probe (R)-1 based on chiral H8-BINOL was synthesized with a high yield; it was found to have good enantioselective recognition of lysine and phenylalanine using fluorescence analysis. When L-lysine was recognized, the enantioselective fluorescence enhancement ratio was 2.7 (ef = IL - I0/ID - I0, ef = 2.7, 20 eq Lys); as the amount of L-Lys increased, a distinct red shift was observed (the wavelength varied by 55.6 nm, 0-100 eq L-Lys), whereas D-Lys had a minimal red shift. The generation of this red shift phenomenon was probably due to the ICT effect; the probe's intramolecular charge transfer was affected after (R)-1 bound to L-Lys, and this charge transfer was enhanced, leading to a red shift in fluorescence. In addition to the enantioselective recognition of lysine, phenylalanine was also recognized; the enantioselective fluorescence enhancement ratio was 5.1 (ef = IL - I0/ID - I0, ef = 5.1, 20 eq Phe).

BINOL-Containing Chiral Porous Polymers as Platforms for Enantiorecognition.

The enantioselective discrimination of racemic compounds can be achieved through the design and preparation of a new family of chiral conjugated BINOL-porous polymers (CBPPs) from enantiopure (R)- or (S)-BINOL derivatives and 1,3,5-tris(4-phenylboronic acid)benzene or 1,3,5-tris(4-ethynylphenyl)benzene, 1,3,5-triethynyl-2,4,6-trifluorobenzene, and tetra(4-ethynylphenyl)methane as comonomers following Suzuki-Miyaura and Sonogashira-Hagihara carbon-carbon coupling approaches. The obtained CBPPs show high thermal stability, a good specific surface area, and a robust framework and can be applied successfully in the fluorescence recognition of enantiomers of terpenes (limonene and α-pinene) and 1-phenylethylamine. Fluorescence titration of CBPPs-OH in acetonitrile shows that all Sonogashira hosts exhibit a preference for the (R)-enantiomer over the (S)-enantiomer of 1-phenylethylamine, the selectivity being much higher than that of the corresponding BINOL-based soluble system used as a reference. However, the Suzuki host reveals a preference toward (S)-phenylethylamine. Regarding the sensing of terpenes, only Sonogashira hosts show enantiodifferentiation with an almost total preference for the (S)-enantiomer of limonene and α-pinene. Based on the computational simulations and the experimental data, with 1-phenylethylamine as the analyte, chiral recognition is due to the distinctive binding affinities resulting from N···H-O hydrogen bonds and the π-π interaction between the host and the guest. However, for limonene, the geometry of the adsorption complex is mostly governed by the interaction between the hydroxyl group of the BINOL unit and the C═C bond of the iso-propenyl fragment. The synthetic strategy used to prepare CBPPs opens many possibilities to place chiral centers such as BINOL in porous polymers for different chiral applications such as enantiomer recognition.

Common materials, extraordinary behavior: An ultrasensitive and enantioselective strategy for D-Tryptophan recognition based on electrochemical Au@p-L-cysteine chiral interface.

The poly-L-cysteine modified Au nanoparticles (Au@p-L-Cys) were constructed on electrode surface as a highly efficient chiral interface for tryptophan (Trp) enantiomers recognition via one step electropolymerization. With the aid of Cu2+, L-Cys residues and D-Trp target formed a sandwich complex D-Trp-Cu2+-L-Cys, while L-Trp was unable to form such complex due to the steric hindrance provided by the chiral interface, which was confirmed by the electrochemical and SEM results. With the introduction of ferricyanide probe, D-Trp produced significant current decrease while L-Trp produced a slight current increase, which implied the successful enantioselective recognition of Trp enantiomers (specifically D-Trp) in the true sense. This novel sensor showed a surprisingly wide linear range toward D-Trp of 6 × 10-7 M to 1 × 10-2 M, with a detection limit as low as 75 nM (S/N = 3). Moreover, the exclusive enantioselectivity toward D-Trp was discovered since other amino acids showed negligible interference to detection of D-Trp. The recovery of D-Trp in human serum was between 91.30 and 109.3%, which further verified the satisfying specificity and practicality of the proposed strategy. The coordination thermodynamics by UV-Vis spectroscopy and DFT simulation were also used to investigate the enantioselective mechanism. These results highlight the great potential of using Au@p-L-Cys to construct chiral interface for enantiomers recognition and hold the promise of practical application of electrochemical chiral sensors in fields like pharmaceutics and bioanalysis.

A Racemic Naphthyl-Coumarin-Based Probe for Quantitative Enantiomeric Excess Analysis of Amino Acids and Enantioselective Sensing of Amines and Amino Alcohols.

A new racemic naphthyl-coumarin-based probe was found to bind covalently with amino acids in MeOH-KOH system and thereby generates distinct CD responses. The induced strong CD signals allowed quantitative enantiomeric excess analysis of amino acids and enantioselective sensing of amines and amino alcohols. The mechanism for the reaction of the coumarin-aldehyde probe with an amino acid was investigated by CD, UV-Vis, NMR, ESI-MS analyses and ECD calculation.

Visualization of Enantiorecognition and Resolution by Chiral AIEgens.

Enantioselective recognition and separation have attracted much attention in pharmaceutical analysis, food chemistry, and life science. Herein, we propose an efficient strategy to achieve such purposes using optically active luminogens with aggregation-induced emission (AIE) characteristics. These AIE luminogens (AIEgens) show strong enantiomeric discrimination for 12 kinds of chiral acids and unprotected amino acids. In particular, an exceptionally high enantioselectivity for d/l-Boc-glutamic acid was observed, as demonstrated by the large difference between the formed AIEgen/acid complexes. Due to the AIE effect, enantioselective separation was achieved by aggregation of the AIEgens with one enantiomer in the mixed acid solution. Through analysis of the fluorescence standard curve, the aggregates of AIEgen/chiral acid possessed 90% d-analyte, from which the enantiomeric excess (ee) value was assessed to be 80% ee. Such a result is in good agreement with that (91% d-analyte and 82% ee) by chiral HPLC analysis. Thus, this simple one-step aggregation method can serve as a preliminary screening tool for high-throughput analysis or separation of chiral chemicals.

Enantiomeric Water-Soluble Octopus[3]arenes for Highly Enantioselective Recognition of Chiral Ammonium Salts in Water.

Study of enantioselective recognition in water by synthetic chiral macrocyclic receptors is undoubtedly of theoretical and practical significance, but it is a big challenge to achieve the enantioselective recognition with both high enantioselectivity and high affinity in water probably due to the deficiency of such water-soluble macrocyclic receptors with stable chiral cavities. Herein, we report a new class of chiral macrocyclic arenes named octopus[3]arenes. The enantiomeric macrocycles are composed of three homochiral ethenoanthracene subunits, and they can be synthesized by two pathways and then easily converted into water-soluble octopus[3]arenes P-1 and M-1. Notably, P-1 and M-1 with the rigid hexagonal structures and stable chiral hydrophobic cavities exhibit highly enantioselective recognition towards three pairs of chiral ammonium salts in water with the association constant up to 106  M-1 and the S/R selectivity up to 12.89.