Chiral Receptors Research Articles

An electrochemical sensor for enantiorecognition of tyrosine based on a chiral macrocycle functionalized rGO

A novel chiral sensor was developed to produce the distinguishing response to the enantiomers of tyrosine (Tyr), with high sensitivity and selectivity. The electrochemical sensor was modified by the inorganic-organic nanohybrid material with the functionalization of reduced graphene oxide (rGO) to be the amplifier and a chiral hetero-multifarene[3,2,1] (CHMF[3,2,1]) as the chiral receptor. The as-prepared rGO-CHMF was characterized by transmission electron microscopy (TEM), atomic force microscope (AFM), infrared spectroscopy (IR), thermogravimetric analysis (TGA), Raman spectroscopy and electrochemical methods. It was observed that the composites exhibited different binding ability for Tyr enantiomers. The proposed sensor presented significant difference with peak potential separation value (ΔEp = 70 mV) and the ratio of peak current (IL-Tyr/ID-Tyr = 1.58) for Tyr enantiomers by differential pulse voltammetry. In addition, the peak currents increased linearly with the concentration of Tyr enantiomers in the concentration range 0.1–10 μM with detection limits of 78 nM and 83 nM for l-Tyr and d-Tyr (S/N = 3), respectively. It also exhibited the ability to determine the percentage of one Tyr enantiomer in the racemic mixture. Moreover, the selectivity, reproducibility, and stability of the chiral sensor were investigated to give satisfactory results. The above discoveries offered an alternative technology for chiral recognition with electrochemical response to actualize a real-time and quantitative determination.

Research progress of chiral ligand exchange stationary phases in the enantiomer resolution

The structure of chiral drugs contains at least one asymmetric center. When the enantiomers act on the human body, they are recognized by chiral receptors and enzymes in vivo, which will show different physiological effects and even adverse reactions. Therefore, it is very important for the development of chiral pharmacy to obtain chiral enantiomers with a single configuration by racemic resolution. Some general impurities will be introduced in the production of chiral drugs, thus the detection of impurities is also a crucial step in the quality control of chiral medicines. The chiral ligand exchange stationary phase has a strong recognition effect on enantiomer analytes with multiple chelating sites, and is very suitable for the separation and control of biological samples such as amino acids. In this work, the development of chiral ligand exchange stationary phases in enantiomeric resolution is reviewed, which is expected to provide a basis for the quality control of complex chiral drug components.

A chiral spirobifluorene-based bis(salen) zinc(ii) receptor towards highly enantioselective binding of chiral carboxylates.

We have designed a new chiral receptor based on two salen zinc(ii) complex units connected with a spirobifluorene framework. The chiral receptor is proven to enantioselectively bind chiral carboxylate guests and the differences between the binding constants of enantiomeric guests were up to more than one order of magnitude.

Supramolecular Chirality in Metal-Organic Complexes.

Chirality is a pervasive structural feature of nature and crucial to the organization and function of nearly all biological systems. At the molecular level, the biased availability of enantiomers in nucleic and amino acids forms the basis for asymmetry. However, chirality expression in natural systems remains complex and intriguing across differing length scales. The translation of chirality toward synthetic systems therefore not only is crucial for fundamental understanding but also may address key challenges in biochemistry and pharmacology. From a structural viewpoint, a fascinating class of cavity-containing supramolecular assemblies, homochiral metal-organic complexes (MOCs), provides a good opportunity to study enantioselective processes. Chiral MOCs are constructed by coordination-driven self-assembly, wherein relatively simple molecular precursors are allowed to assemble into structurally well-defined two-dimensional (2D) metallacycles or 3D metallacages spontaneously with complex and varied functions. These aesthetically appealing structures present nanocavities with space-restricted chiral microenvironments capable of interacting distinctly with molecularly asymmetric guests, which is highly beneficial to explore the relay of chiral information from locally chiral molecules to globally chiral supramolecules, which is a significant challenge.In this Account, we specifically discuss our research toward rationally designed, synthetically accessible chiral MOCs over the past 12 years. The globally supramolecular chirality demonstrated by these well-defined MOCs prominently exceeds the constitutive molecular chirality of the components. First, we discuss chirality transfer and amplification in the context of induction and transmission from the constituent organic ligands of self-assembled chiral metallacycles. The creation of subtly chiral microenvironments in the metallacyclic architectures results from a tiny conformational bias of inner hydrophobic groups, subsequently allowing them to interact very specifically with one enantiomer over the other, thus imparting outstanding enantioseparation properties. Second, we have designed a series of chiral metallacycles and helical metallacages that are able to deploy chiral NH groups with available hydrogen bonding capacity, together with hydrophobic/CH-π interactions, bringing about cooperativity for binding of chiral substrates. It turns out that they can be used as artificial chiral receptors capable of exceptionally high enantiorecognition toward a wide range of biologically relevant molecules. Third, we recently developed a group of highly stable chiral metallacages that feature a catalytically confined nanospace with potential as supramolecular asymmetric catalysts. It has been suggested that the use of molecularly nanocaged chiral hosts in solution to substantially increase reactivity and enantioselectivity compared with the unconfined reactions, highlighting the intermetallic synergy, rationalizes the remarkable catalytic performance. Finally, we discuss our personal perspectives on the promises, opportunities, and key issues toward the future development of chiral MOCs. Needless to say that the fundamental understanding of the translation of chirality from molecular to supramolecular to macroscopic scales is crucial to unveil biological mechanisms. We hope the described supramolecular chirality of MOCs could be extendable to develop new and valuable chiral materials in chemistry, medicine, and beyond.

Control and Transfer of Chirality Within Well-Defined Tripodal Supramolecular Cages.

The development of new strategies to turn achiral artificial hosts into highly desirable chiral receptors is a crucial challenge in order to advance the fields of asymmetric transformations and enantioselective sensing. Over the past few years, C3 symmetrical cages have emerged as interesting class of supramolecular hosts that have been reported as efficient scaffolds for chirality dynamics (such as generation, control, and transfer). On this basis, this mini review, which summarizes the existing examples of chirality control and propagation in tripodal supramolecular cages, aims at discussing the benefits and perspectives of this approach.

Dihomooxacalix[4]arene-Based Fluorescent Receptors for Anion and Organic Ion Pair Recognition.

Fluorescent dihomooxacalix[4]arene-based receptors 5a–5c, bearing two naphthyl(thio)ureido groups at the lower rim via a butyl spacer, were synthesised and obtained in the cone conformation in solution. The X-ray crystal structures of 1,3- (5a) and 3,4-dinaphthylurea (5b) derivatives are reported. Their binding properties towards several anions of different geometries were assessed by 1H-NMR, UV-Vis absorption and fluorescence titrations. Structural and energetic insights of the naphthylurea 5a and 5b complexes were also obtained using quantum mechanical calculations. The data showed that all receptors follow the same trend, the association constants increase with the anion basicity, and the strongest complexes were obtained with F−, followed by the oxoanions AcO− and BzO−. Proximal urea 5b is a better anion receptor compared to distal urea 5a, and both are more efficient than thiourea 5c. Compounds 5a and 5b were also investigated as heteroditopic receptors for biologically relevant alkylammonium salts, such as the neurotransmitter γ-aminobutyric acid (GABA·HCl) and the betaine deoxycarnitine·HCl. Chiral recognition towards the guest sec-butylamine·HCl was also tested, and a 5:2 selectivity for (R)-sec-BuNH3+·Cl− towards (P) or (M) enantiomers of the inherently chiral receptor 5a was shown. Based on DFT calculations, the complex [(S)-sec-BuNH3+·Cl−/(M)-5a] was indicated as the more stable.

Reversible Chromatic Change of Supramolecular Gels for Visual and Selective Chiral Recognition of Histidine.

In the present work, a chemical reaction has been performed for supramolecular gels to achieve multiple-stimuli-responsive smart soft materials. Simple chiral binaphthalene-based receptors can condense with histidine (His) to yield a Schiff base, which would help to achieve visual chiral recognition of unprotected l/d-His through gel formation along with specific selectivity toward 20 amino acids. Through intermolecular hydrogen bonds, the resultant Schiff base molecules assemble with excess His molecules to form three-dimensional (3D) networks of metastable cross-linked nanospheres and stable nanofibers in EtOH/water and MeOH/water, respectively. Significantly, this condensation reaction exhibits unique reversible and chromatic phenomena between sol-gel phase transitions in EtOH/water, which provide a way to design chemical reaction-based multivisual-change supramolecular gels for sensing and switching applications.

Enantioselective sensing of (S)-Thalidomide in blood plasma with a chiral naphthalene diimide derivative

Fast, simple in use and highly effective voltammetric enantiosensor dedicated for determination of thalidomide (TD) enantiomers (especially towards the toxic (S)-enantiomer) in blood plasma is still desirable. Here we have proven that newly synthesized chiral naphthalene diimide (NDI) derivatives are excellent electroactive materials for TD enantiosensors. The recognition process relies on the specific interaction between the chiral NDI receptor and the thalidomide enantiomer of the opposite configuration. This unique specific interaction between (S)-thalidomide and (R)-NDI derivative counterparts, evident in the DPV voltammograms, was confirmed by molecular modeling. The demonstrated voltammetric enantiosensors are characterized by the low detection limit at the level of μg·L−1, wide analytical range from 5·10−4 – 10 mg·L−1, high selectivity and long lifetime. The results of the recovery rates showed a very good degree of accuracy towards the determination of (S)-thalidomide in the blood samples, so it can be successfully used in the analysis of clinical samples.

Bio-catalytic asymmetric synthesis of β-adrenergic receptor blocker precursor: (R)-2-bromo-1-(naphthalen-2-yl)ethanol

Aromatic α-halohydrins, particularly 2-haloethanols as significant precursor of drugs, can easily be converted to chiral β-adrenergic receptor blockers. Eight strains of Lactobacillus curvatus were tested as biocatalysts for asymmetric reduction of 2-bromo-1-(naphthalen-2-yl)ethanone 1 to 2-bromo-1- (naphthalen-2-yl) ethanol 2. The parameters of the bioreduction were optimized using L. curvatus N4, the best biocatalyst found. As a result, (R)-2-bromo-1-(naphthalen-2-yl)ethanol 2, which can be β-adrenergic receptor blocker precursor, was produced for the first time in high yield and enantiomerically pure form using biocatalysts. Moreover, the gram scale synthesis was performed and 7.54 g of (R)-2 was synthesized as enantiopure form (enantiomeric excess >99%) in 48 h. The important advantages of this process are that it produces of (R)-2 for the first time in enantiopure form, in excellent yield and under environmentally friendly and moderate reaction conditions. This system is of the potential to be applied at a commercial scale.

Enantioselective Recognition of Neutral Molecules in Water by a Pair of Chiral Biomimetic Macrocyclic Receptors

Enantioselective recognition in water remains an ongoing challenge in supramolecular chemistry but is routine in nature. Herein, we report the first enantiopure pair of biomimetic macrocyclic recep...

Chiral recognition and enantiomer excess determination based on emission wavelength change of AIEgen rotor

Chiral recognition, such as enantioselective interactions of enzyme with chiral agents, is one of the most important issues in the natural world. But artificial chiral receptors are much less efficient than natural ones. For tackling the chiral recognition and enantiomer excess (ee) analysis, up until now all the fluorescent receptors have been developed based on fluorescence intensity changes. Here we report that the chiral recognition of a large number of chiral carboxylic acids, including chiral agrochemicals 2,4-D, is carried out based on fluorescent colour changes rather than intensity changes of AIEgen rotors. Moreover, the fluorescence wavelength of the AIEgen rotor linearly changes with ee of the carboxylic acid, enabling the ee to be accurately measured with average absolute errors (AAE) of less than 2.8%. Theoretical calculation demonstrates that the wavelength change is ascribed to the rotation of the AIEgen rotor upon interaction with different enantiomers.

Desymmetrization of 2‐Cyano‐N‐tosylbenzylidenimine with Thiols and Organocatalytic Heterocyclization by Dynamic Resolution: Mechanism Investigation

Integrated experimental and computational approach provides a rationale for the mode of action of cinchona‐based alkaloids as chiral receptors in the observed dynamic chiral resolution of the titled tandem reaction. In particular, a mechanism based on a dynamic kinetic asymmetric transformation has been unravelled in detail. Furthermore, the crucial role of “distal” H‐bonding donor functionality in directing the enantioselectivity reversal of homochiral cinchona‐based catalysts has been convincingly explained. The access to enantiopure tertiary isoindolinone N,S‐acetals has been achieved for the first time.

Chiral discrimination of 2-heptlyaminium salt by planar-chiral monohydroxy-functionalized pillar[5]arenes

A chiral receptor was synthesized based on monohydroxy-functionalized pillar[5]arenes and its ability to discriminate alkyl aminium salts is demonstrated.

Synthesis of chiral tripodal receptors under solvent-free conditions using microwave irradiation for investigation of anion and cation recognition properties

Synthesis of chiral tripodal receptors under solvent-free conditions using microwave irradiation for investigation of anion and cation recognition properties

Pyrene-based bisboronic sensors for multichannel enantioselective recognition of tartaric acid

New chiral bisboronic receptors based on pyrene-excimer were synthesized and applied for the determination of absolute configuration and enantiomeric composition of tartaric acid. The distinction was visualized by portable UV lamp in certain concentration range. There were three ways for the sensors to enantioselectively recognize tartaric acid, including the fluorescence spectrum, UV–vis spectrum, and CD spectrum. The enantiomeric excess of tartaric acid was measured quantitatively by using fluorescence analytical technique. Compared with the previous chiral boronic acid sensors, sensor 1 showed weaker background fluorescence and excellent chiral recognition ability of D/l-tartaric acid throughout the whole pH range.

Chiral Receptors for Lysine Based on Covalently Linked Bis- and Tris-binaphthylphosphoric Acids.

The synthesis and application of three chiral receptors based on the covalent linkage of 1,1'-binaphthylphosphoric acids is reported. The binding of the lysine enantiomers to the chiral receptors was investigated by DOSY-NMR and NMR titrations, revealing that the bisphosphoric acid 1d acts as a highly stereoselective receptor for binding of d-lysine.

Cross-Coupling Approach to an Array of Macrocyclic Receptors Functioning as Chiral Solvating Agents.

Chiral macrocyclic receptors 1 with multiple hydrogen-bonding sites in the cavity were synthesized and used as NMR chiral solvating agents (CSAs). The Suzuki-Miyaura cross-coupling reaction gave rapid access to a series of variants 1b-p of unsubstituted parent compound 1a. Among them, 1d with the 4-cyanophenyl group at the 3,3'-positions of the binaphthyl moiety was the most excellent CSA for a benchmark analyte compound, 2-chloropropionic acid (CPA); both of the quartet and doublet signals of CPA were split most completely in CDCl3. Binding constants ( Ka) determined in CDCl3 by NMR titrations indicated that ( R)-1d was the most enantioselective ( Ka( S)/ Ka( R) = 5.4). Interestingly, the Ka value of ( R)-1d for ( S)-CPA (5900) was greater than that of ( R)-1a for ( S)-CPA (3080), which strongly suggests an attractive interaction between the 4-cyanophenyl group of ( R)-1d and ( S)-CPA. The X-ray crystal structure of 1d indicates that one of the two H atoms meta to the cyano group is directed toward the cavity. DFT calculations suggested that this H atom of the 4-cyanophenyl group of ( R)-1d forms a weak hydrogen bond with the Cl atom of ( S)-CPA (C-H···Cl-C hydrogen bond).

Direct Synthesis of Chiral Porphyrin Macrocyclic Receptors via Regioselective Nitration.

Nitration of tetraphenylporphyrin cage compound 1, at −40 °C, leads to the regioselective formation of the chiral mononitro compound 2 (75% isolated yield) and, at −30 °C, to the achiral syn-dinitro-derivative 3 and the chiral anti-dinitro derivative 4 in a diastereomeric ratio of 5:2, which were separated by chromatography (46 and 20% yields, respectively). The structures of the compounds were confirmed by X-ray crystallography.

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression.

A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F-S-CH3 (2), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reversed PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral (S)-CH3 ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the liable ester functionality in 2 to improve the metabolic stability, cytotoxicity, and activity as compared to 2. Based on the data to date, the most promising ligands are the N-cyclopropyl amide GL-I-55 (8c) and the methyl bioisostere GL-I-65 (9a). The in vitro metabolic stability, cytotoxicity and in vivo locomotor effects are described in this report. Based on these results, 8c and 9a are the most promising for further in vivo pharmacology.

Chiral Heterocycle-Based Receptors for Enantioselective Recognition

The majority of biomolecules found in living beings are chiral, therefore chiral molecular recognition in living systems is crucial to life. Following Cram’s seminal work on the crown-based chiral recognition, prominent research groups have reported innumerable chiral receptors with distinctly different geometrical features and asymmetry elements. Main applications of such chiral receptors are found in chiral chromatography, as for analytical purposes and for bulk separation of racemates.Incorporation of heterocyclic rings in these recognition systems added a new dimension to the existing group of receptors. Heterocycles have additional features such as availability of unshared electron pairs, pronounced conformational features, introduction of hydrogen bonding and presence of permanent dipoles as well as specific spectral properties in certain cases. These features are found to enhance binding properties of the receptors and the selectivity factors between opposite enantiomers, allowing them to be effectively separated. The review presents the synthetic approaches towards these heterocyclic receptors and their distinctly different behavior vis-à-vis carbocyclic receptors.