Chiral Macrocycles Research Articles

An ultrasensitive photoelectrochemical sensor with layer-by-layer assembly of chiral multifarene[3,2,1] and g-C3N4 quantum dots for enantiorecognition towards thyroxine

A photoelectrochemical sensor was developed with stepwise decoration of g-C 3 N 4 quantum dots and chiral multifarene[3,2,1] to achieve the ultrasensitive enantiorecognition for L -thyroxine. • A facile method for preparation of g-C 3 N 4 quantum dots was discovered. • A photoelectrochemical sensor built with g-C 3 N 4 QDs and chiral macrocycle was developed. • The ultrasensitive enantiorecognition for thyroxine was reached with the proposed photoelectrochemical sensor. With a facile preparation for graphitic carbon nitride quantum dots (g-C 3 N 4 QDs), an ultrasensitive photoelectrochemical (PEC) sensor was developed with the supramolecular affinity of chiral multifarene[3,2,1] (CMF) to a hormone drug, thyroxine (T 4 ), for efficient identification of thyroxine enantiomers. In the principle that g-C 3 N 4 QDs was employed to achieve the photocurrent response and the macrocyclic compound served as the supramolecular enantiorecognition for thyroxine, the photoelectrochemical electrode was constructed by layer-by-layer assembly of g-C 3 N 4 QDs and CMF on the surface of ITO (ITO-g-C 3 N 4 -CMF QDs). The proposed PEC sensor produced the limits of detection low to 67 pM towards L -T 4 and 85 pM towards D -T 4 in a concentration range from 0.1 nM to 10 nM, which was superior to the values in pioneering reports with colorimetric or electrochemical methods. With good stability, reproducibility, repeatability anti-interference ability, and acceptable recoveries, the proposed PEC sensor was employed for quantitative determination of L/D -T 4 in water, human serum and commercial tablet.

Alkene Epoxidations Mediated by Mn-Salen Macrocyclic Catalysts

Three new chiral Mn macrocycle catalysts containing 20 or 40 atoms in the macrocycle were synthetized and tested in the enantioselective epoxidation of cis-β-ethyl-styrene and 1,2-dihydronathalene. The effect of the presence of a binaphtol (BINOL) compound in the catalyst backbone has been evaluated, including by Density Functional Theory (DFT) calculations.

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.

Racemic Dimers as Models of Chiral Macrocycles Self-Assembled on Pyrolytic Graphite

Fully aromatic helicenes are fascinating building blocks for the construction of inherently chiral macrocyclic nanocarbons. Such helicene-based non-planar macrocycles interact with each other and underlying substrate and form various 2D crystals. However, the role of their chirality remains unknown. In Atomic Force Microscopy (AFM) the macrocycles show stripes with six-fold symmetry but only faintly visible internal structure that is not sufficient to see individual adsorbed molecules and identify their chirality. Here, AFM data of self-assembled helicene-based 2D molecular crystals are analyzed by a new computational method that combines various information from AFM image and expected molecular shape taken from molecular dynamic simulations. Possible molecule arrangements are thereby computed and four basic structural elements (dimers) with the smallest deviation from AFM topography image are found. Validation procedure using larger AFM image with many 2D crystal domains improves the resolution in AFM data above the expected value for ultrasharp cantilevers and allows reliable and reproducible reconstruction of molecular shape, precise molecules position within the 2D crystal as well their chirality. The presented results and developed mathematical method are generally applicable to study ensembles of molecules with known atom coordinates and to any image with periodic pattern.

Chiral macrocycle-induced circularly polarized luminescence of a twisted intramolecular charge transfer dye.

The host-guest binding between a chiral macrocycle and an achiral dye could suppress the twisted intramolecular charge transfer (TICT) process, leading to enhanced emission and bright circularly polarized luminescence (CPL) from the originally achiral TICT-dye.

Xenon binding by a tight yet adaptive chiral soft capsule

Xenon binding has attracted interest due to the potential for xenon separation and emerging applications in magnetic resonance imaging. Compared to their covalent counterparts, assembled hosts that are able to effectively bind xenon are rare. Here, we report a tight yet soft chiral macrocycle dimeric capsule for efficient and adaptive xenon binding in both crystal form and solution. The chiral bisurea-bisthiourea macrocycle can be easily synthesized in multi-gram scale. Through assembly, the flexible macrocycles are locked in a bowl-shaped conformation and buckled to each other, wrapping up a tight, completely sealed yet adjustable cavity suitable for xenon, with a very high affinity for an assembled host. A slow-exchange process and drastic spectral changes are observed in both 1H and 129Xe NMR. With the easy synthesis, modification and reversible characteristics, we believe the robust yet adaptive assembly system may find applications in xenon sequestration and magnetic resonance imaging-based biosensing.

Crystalline Naphthylene Macrocycles Capturing Gaseous Small Molecules in Chiral Nanopores.

A series of chiral naphthylene macrocycles, [n]cyclo-epi-naphthylenes ([n]CeNAPs), possessing epi-linkages were synthesized by one-pot macrocyclization. With chiral (R)- or (S)-1,1'-linkages embedded in binaphthyl precursors, the macrocycles were assembled in polygonal structures possessing chiral hinges as corners. Among four chiral [n]CeNAP variants, [8]CeNAP with eight naphthylene panels formed robust columnar assemblies in crystals. The nanoporous crystals maintained a columnar assembly structure even after the removal of encapsulated solvent molecules, and their gas adsorption behavior was thoroughly investigated. Gas adsorption, including state-of-the-art in situ crystallographic analyses, revealed accurate atomic-level structures of the nanopores trapping gaseous N2 molecules in chiral C2 arrangements. With macrocycles as basic frameworks, functional nanopores may be exploited for chiral small-molecule alignments.

Catalytic Enantioselective Synthesis and Switchable Chiroptical Property of Inherently Chiral Macrocycles.

We report herein a strategy to construct enantiopure inherently chiral macrocycles, ABCD-type heteracalix[4]aromatics, through a catalytic enantioselective intramolecular C-N bond forming reaction. A chiral ligand-palladium complex was found to efficiently induce the inherent chirality of molecules during the macrocyclization process with ee values up to >99%. The resulting ABCD-type heteracalix[4]aromatics displayed excellent and pH-triggered switchable electronic circular dichroism and circularly polarized luminescence properties.

An Overview on Glyco-Macrocycles: Potential New Lead and their Future in Medicinal Chemistry.

Macrocycles cover a small segment of molecules with a vast range of biological activity in the chemotherapeutic world. Primarily, the natural sources derived from macrocyclic drug candidates with a wide range of biological activities are known. Further evolutions of the medicinal chemistry towards macrocycle-based chemotherapeutics involve the functionalization of the natural product by hemisynthesis. More recently, macrocycles based on carbohydrates have evolved a considerable interest among the medicinal chemists worldwide. Carbohydrates provide an ideal scaffold to generate chiral macrocycles with well-defined pharmacophores in a decorated fashion to achieve the desired biological activity. We have given an overview on carbohydrate-derived macrocycle involving their synthesis in drug design and discovery and potential role in medicinal chemistry.

Functionalized Chiral Bambusurils: Synthesis and Host-Guest Interactions with Chiral Carboxylates.

Bambusurils are a class of macrocyclic anion receptors that exhibit notable anion recognition properties, able to bind various inorganic anions as well the carboxylates or sulfonates. Recently, we reported enantioselective recognition of chiral carboxylates using non-functionalized chiral bambusuril derivatives. Herein, we report the synthesis and host-guest properties of two new representatives of chiral bambusuril macrocycles bearing ester functional groups, differing by the substituents attached to their portals. Their supramolecular properties in terms of carboxylate binding were studied by means of NMR in DMSO-d6 . The reported bambusurils bind selected chiral carboxylates with enantioselectivity factors up to 3.1. The results indicated that the selectivity towards different carboxylates is governed by the steric constraint of the substituents surrounding bambusuril portals. No clear trend in the binding affinities and their enantioselectivities was found.

Versatile Binding Modes of Chiral Macrocyclic Amine towards Rare Earth Ions

Depending on the reaction conditions, the enantiopure macrocycle H3L containing three phenolic units is able to form mono‐ and trinuclear coordination compounds with rare earth metal ions. In these complexes this macrocycle can act as protonated H4L+, neutral H3L, monodeprotonated H2L–, bis‐deprotonated HL2– or tris‐deprotonated L3– ligand. X‐ray crystal structure of the Y(III) derivative of the protonated macrocycle shows highly folded conformation of the ligand with N2O3 set of donor atoms, while the structure of the Y(III) complex of the monodeprotonated macrocycle shows more regular helically twisted conformation of the ligand. Under basic conditions trinuclear complexes of the type [M3L(OH)2] are formed with most of rare earth ions, where the macrocycle acts as N6O3 ligand. This type of complex is not formed for the La(III) and Ce(III) ions of the largest radii within the lanthanide(III) series, instead trinuclear complexes of the type [M3L2] are formed. The X‐ray crystal structures of La(III) complex with fully deprotonated or bis‐deprotonated macrocycles indicate that each macrocyclic unit binds only two metal ions, while one of them is shared by two macrocycles.

Trapping an Achiral Anion Inside a Chiral Macrocycle for Enantioselective Catalysis

Trapping an Achiral Anion Inside a Chiral Macrocycle for Enantioselective Catalysis

Synthetic complexity created by lipases

The chemoenzymatic potential for the construction of complex chiral molecules has not been fully explored. Now, Candida antarctica lipase B has been used to synthesize complex functionalized planar chiral macrocycles, providing a platform for the efficient and sustainable preparation of molecules that are of particular interest in drug discovery.

Enzyme smooths path to planar chiral macrocycles

Planar chiral molecules are relatively common in natural products, kind of funny looking, and largely ignored. Though they can be useful as pharmaceuticals or agrochemicals, they are difficult to make. Now, Shawn Collins and coworkers at the University of Montreal have developed an enzyme-catalyzed synthesis to form planar chiral molecules with high enantioselectivity (example shown) from readily available starting materials, which can be easily functionalized (Science 2020, DOI: 10.1126/science.aaz7381). The team made target compounds with up to 99% yield and 66–99% enantioselectivity. Instead of a more traditional metal catalyst, which can create toxic waste, Collins decided to look for one with a biological origin. The serine hydrolase Candida antarctica lipase B “is the organic chemist’s dream because it’s an enzyme that is superstable to high temperatures and actually more active in organic solvents than in water,” he says. The natural enzymatic pocket evolved to accommodate a secondary alcohol, so Collins

Biocatalytic synthesis of planar chiral macrocycles.

Macrocycles can restrict the rotation of substituents through steric repulsions, locking in conformations that provide or enhance the activities of pharmaceuticals, agrochemicals, aroma chemicals, and materials. In many cases, the arrangement of substituents in the macrocycle imparts an element of planar chirality. The difficulty in predicting when planar chirality will arise, as well as the limited number of synthetic methods to impart selectivity, have led to planar chirality being regarded as an irritant. We report a strategy for enantio- and atroposelective biocatalytic synthesis of planar chiral macrocycles. The macrocycles can be formed with high enantioselectivity from simple building blocks and are decorated with functionality that allows one to further modify the macrocycles with diverse structural features.

Enzymes lock in planar chirality

Biocatalysis Molecules with very large rings—macrocycles—are often conformationally constrained, and some exhibit planar chirality when substituents of the ring cannot rotate freely. Restricted rotation is generally valued in macrocycles because it can hold the molecule in functional conformations. Using a well-established lipase enzyme, Gagnon et al. developed a synthesis of planar chiral macrocycles with handles that can be easily functionalized. Computational docking suggests how using an enzyme as the catalyst for sequential acylation reactions can impart the observed stereochemistry. Science , this issue p. [917][1] [1]: /lookup/doi/10.1126/science.aaz7381

Monomeric and dimeric nitrate lanthanide(III) and yttrium(III) coordination compounds of (2 + 2) imine macrocycle derived from 2,6-diformylpyridine and trans-1,2-diaminocyclopentane

Monomeric nitrate coordination compounds [Ln(L1)](NO3)3·nH2O (Ln = Y(III), Tm(III), Yb(III) and Lu(III)); n = 0, 0.75 or 3)11For simplicity of description we included the Y(III) in the abbreviation of Ln(III), commonly reserved for lanthanide(III) ions. It is well known that although yttrium does not belong to the lanthanides, the ionic radius of the Y(III) cation is similar to ionic radii of lanthanide(III) cations. Y(III) coordination compounds resemble very much in their chemical properties those of the respective lanthanide(III) coordination compounds. of the chiral macrocyclic (2 + 2) imine L1 (L1RRRR, L1SSSS and/or L1rac), derived from enantiomerically pure or racemic trans-1,2-diaminocyclopentane (DACP) and 2,6-diformylpyridine (DFP), have been synthesized in the templated condensation of precursors in the presence of appropriate metal salts. From these monomers their homochiral μ-hydroxodimers [Ln2(L1)2(μ-OH)2](NO3)4·nH2O (Ln = Y(III), Tm(III), Yb(III) and Lu(III)); n = 4, 5 or 7) have been obtained and isolated by addition of NaOH to the respective monomeric form of coordination compound solution. All synthesized coordination compounds have been characterized by NMR spectroscopy, mass spectrometry, elemental analyses and/or circular dichroism (CD). 1H NMR signals of CDCl3/CD3OD solutions of the diamagnetic Y(III) and Lu(III) monomers have been assigned on the basis of their COSY and HMQC spectra, and for the remaining paramagnetic lanthanide coordination compounds (Tm(III) and Yb(III)) the signals were tentatively assigned on the basis of linewidths analyses. 1H NMR signals of D2O solutions of diamagnetic Y(III) and Lu(III) representatives of dimeric species have been established taking into account their COSY, HMQC, HMBC and NOESY spectra. The NOESY spectra confirm that the structure of the dimmers observed in solids is also maintained in a solution.The axial ligand exchange in all monomeric coordination compounds was investigated by 1H NMR titration experiments with acetate and chloride anions in organic solvents as well as with hydroxide anion in D2O. The formation of homochiral heterobimetallic μ-hydroxodimers [Ln’Ln”(L1)2(μ-OH)2](NO3)4 was investigated in a solution by mixing the solutions of two different [Ln’2(L1)2(μ-OH)2](NO3)4·nH2O and [Ln”2(L1)2(μ-OH)2](NO3)4·nH2O homochiral homobimetallic precursors. This experiment proves the chiral recognition between two macrocyclic units of the same chirality in a solution. The μ-hydroxodimers may convert with time to the corresponding peroxo-dimers of the general formula [Ln2(L1)2(μ-η2: η2-O2)](NO3)4.The X-ray crystal structures of the representative monomeric and dimeric coordination compounds [Yb(L1RRRR)(NO3)2]NO3, [Yb2(L1SSSS)2(OH)2(H2O)2](NO3)4·2MeOH·2H2O, [Yb2(L1RRRR)2(OH)2(H2O)2][Yb2(L1SSSS)2(OH)2(H2O)2](NO3)8·1.5MeOH·5H2O and [Y2(L1SSSS)2(O2)(NO3)2](NO3)2·2MeOH with enantiomerically pure or racemic ligand L1 have been determined. The structure of [Yb2(L1RRRR)2(OH)2(H2O)2][Yb2(L1SSSS)2(OH)2(H2O)2] (NO3)8·1.5MeOH·5H2O crystal confirms chiral recognition of macrocyclic units of the same chirality in solids.

Substrate‐Induced Dimerization Assembly of Chiral Macrocycle Catalysts toward Cooperative Asymmetric Catalysis

AbstractAn artificial system of substrate‐induced dimerization assembly of chiral macrocycle catalysts enables a highly cooperative hydrogen‐bonding activation network for efficient enantioselective transformation. These macrocycles contain two thiourea and two chiral diamine moieties and dimerize with sulfate to form a sandwich‐like assembly. The macrocycles then adopt an extended conformation and reciprocally complement the hydrogen‐bonding interaction sites. Inspired by the guest‐induced dynamic assembly, these macrocycles catalyze the decarboxylative Mannich reaction of cyclic aldimines containing a sulfamate heading group. The imine substrate can be activated toward nucleophilic attack of β‐ketoacid by a cooperative hydrogen‐bonding network enabled by sulfamate‐induced dimerization assembly of the macrocycle catalysts. Highly efficient (>95 % yield in most cases) and enantioselective (up to 97.5:2.5 er) transformation of a variety of substrates using only 5 mol % macrocycle was achieved.

Substrate-Induced Dimerization Assembly of Chiral Macrocycle Catalysts toward Cooperative Asymmetric Catalysis.

An artificial system of substrate-induced dimerization assembly of chiral macrocycle catalysts enables a highly cooperative hydrogen-bonding activation network for efficient enantioselective transformation. These macrocycles contain two thiourea and two chiral diamine moieties and dimerize with sulfate to form a sandwich-like assembly. The macrocycles then adopt an extended conformation and reciprocally complement the hydrogen-bonding interaction sites. Inspired by the guest-induced dynamic assembly, these macrocycles catalyze the decarboxylative Mannich reaction of cyclic aldimines containing a sulfamate heading group. The imine substrate can be activated toward nucleophilic attack of β-ketoacid by a cooperative hydrogen-bonding network enabled by sulfamate-induced dimerization assembly of the macrocycle catalysts. Highly efficient (>95 % yield in most cases) and enantioselective (up to 97.5:2.5 er) transformation of a variety of substrates using only 5 mol % macrocycle was achieved.

Highly Enantioselective Extraction of Phenylglycine by a Chiral Macrocyclic Receptor Based on Supramolecular Interactions.

Using supramolecular interactions, a novel macrocyclic receptor is able to selectively extract zwitterionic phenylglycine from neutral aqueous solutions into chloroform with up to 91.8% ee. Modeling studies, nuclear magnetic resonance experiments, and X-ray diffraction analysis were carried out to explain the high enantioselectivity observed.