Search

Inherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt‐catalyzed C−H activation/annulation strategy in high yield with excellent enantio‐ and diastereoselectivity (up to >99 % ee and >20 : 1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio‐ and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials. [ABSTRACT FROM AUTHOR]

Inherently chiral eight‐membered rings embedded in tetraphenylene derivatives and hetero‐analogues exhibit unique properties and allow diverse applications. A conceptually viable and straightforward approach to these frameworks is [4+4] cycloaddition, which still remains elusive. Herein, we describe the stereoselective cross‐[4+4] cycloaddition of quinone methides (QMs), leading to the formation of oxa‐analogues of tetraphenylene with exceptional chemo‐, diastereo‐, and enantioselectivity. The structures of these novel rigid eight‐membered O‐heterocycles were explored by single‐crystal X‐ray diffraction, and their stereochemical stability was elaborated through both density functional theory (DFT) calculations and thermal racemization experiments. The developed methodology exhibited broad substrate scope and the resulting cross‐[4+4] cycloadducts could be readily transformed into valuable chiral building blocks. Our findings expand the library of inherently chiral medium‐sized rings and also contribute to the advancement of asymmetric cross‐[4+4] cycloadditions of quinone methides. [ABSTRACT FROM AUTHOR]

Inherently chiral calix[4]arenes are an excellent structural scaffold for enantioselective synthesis, chiral recognition, sensing, and circularly polarized luminescence. However, their catalytic enantioselective synthesis remains challenging. Herein, we report an efficient synthesis of inherently chiral calix[4]arene derivatives via cascade enantioselective cyclization and oxidation reactions. The three‐component reaction features a broad substrate scope (33 examples), high efficiency (up to 90 % yield), and excellent enantioselectivity (>95 % ee on average). The potential applications of calix[4]arene derivatives are highlighted by their synthetic transformation and a detailed investigation of their photophysical and chiroptical properties. [ABSTRACT FROM AUTHOR]

Inherent chirality is used to describe chiral cyclic molecules devoid of central, axial, planar, or helical chirality and has tremendous applications in chiral recognition and enantioselective synthesis. Catalytic and divergent syntheses of inherently chiral molecules have attracted increasing interest from chemists. Herein, we report the enantioselective synthesis of inherently chiral tribenzocycloheptene derivatives via chiral phosphoric acid (CPA)‐catalyzed condensation of cyclic ketones and hydroxylamines. This chemistry paves the way to accessing the less stable derivatives of 7‐membered rings with inherent chirality. A series of chiral tribenzocycloheptene oxime ethers was synthesized in good yields (up to 97 %) with excellent enantioselectivities (up to 99 % ee). [ABSTRACT FROM AUTHOR]

Inherent chirality represents a distinct category of molecular chirality that does not fall within the traditional classification of four chiral elements: central, axial, planar, and helical chirality. While extensive research has been conducted on the catalytic enantioselective construction of these conventional chiralities, the corresponding synthesis of inherently chiral molecules has remained largely unexplored. This minireview provides a comprehensive summary of recent advancements in this field, focusing on the catalytic asymmetric synthesis of inherently chiral calixarenes, saddle‐shaped tetraphenylenes and their heterocycle derivatives, mechanically planar chiral rotaxanes and chiral multilayer 3D frameworks, as well as our perspective in this field. [ABSTRACT FROM AUTHOR]

The formation of inherently chiral calix[4]arenes by the intramolecular cyclization approach suffers from a limited number of suitable substrates for these reactions. Here, we report an easy way to prepare one class of such compounds: calixquinolines, which can be obtained by the reaction of aldehydes with easily accessible aminocalix[4]arenes in acidic conditions (Doebner–Miller reaction). The synthetic procedure represents a very straightforward approach to the inherently chiral macrocyclic systems. The complexation studies revealed the ability of these compounds to complex quaternary ammonium salts with different stoichiometries depending on the guest molecules. At the same time, the ability of enantioselective complexation of chiral N-methylammonium salts was demonstrated. [ABSTRACT FROM AUTHOR]

Potassium phosphate-promoted cross-cyclotetramerization of 2,6-dichloro-3-nitropyridine 1 with resorcinol derivatives 2 gave rise to thermodynamically favored 1,3-alternate tetraoxacalix[2]arene[2]pyridines and kinetically controlled 1,2-alternate isomers. The kinetic product could convert into its 1,3-alternate conformational isomer by a macrocycle to macrocycle conversion pathway. Enantiomerically enriched C 2 -symmetric inherently chiral tetraoxacalix[2]arene[2]pyridines were synthesized via a Cinchonine-derived chiral phase-transfer catalyst (PTC). This synthesis involved the cross-cyclotetramerization of 1 with 2, featuring a key enantioselective intramolecular aromatic nucleophilic substitution (S N Ar) step., (© 2025 Wiley-VCH GmbH.)

Since the introduction of the concept of inherent chirality by Böhmer, an important part of research focused on the asymmetric synthesis of calixarene macrocycles. However, long synthetic procedures and tedious separation strategies hampered the application of this technology in many topics of organic chemistry, including enantioselective molecular recognition and catalysis. Very recently, a new generation of enantioselective catalytic methodologies has been reported, able to provide highly functionalized, inherently chiral calixarenes in a straightforward manner. In this review, we will discuss these new catalytic methods and the versatile properties of such macrocycles that call for potential applications in many areas of science., (© 2025 The Chemical Society of Japan and Wiley-VCH GmbH.)

A preparative method for the synthesis of optically pure N‐(1‐phenylethyl)amides of inherently chiral (cR)‐ and (cS)‐dibenzoyloxy‐calix[4]arene acetic acids has been developed. Their absolute stereochemical configuration was determined by X‐ray diffraction analysis. [ABSTRACT FROM AUTHOR]

Proximally single-atom-bridged calix[4]arenes possess a rigidified cavity and, thus, unusual complexation properties. Here, we report on the synthesis of the first such heteroatom-bridged compound: amine-bridged calix[4]arene. This compound, prepared by thermal decomposition of 4-azidocalix[4]arene, was obtained alongside very interesting rearranged, inherently chiral 10 H -azepino[1,2- a ]indole derivatives. NMR titration confirmed the suitability of the amine cavity for the complexation of methylammonium cations; moreover, the –NH– bridge function enables its further derivatization. [ABSTRACT FROM AUTHOR]

Distorting linear polyaromatic hydrocarbons (PAHs) out of planarity affects their physical properties and breaks their symmetry to induce inherent chirality. However, the chirality cannot be achieved in large distorted PAHs‐based macrocycles due to a low racemization barrier for isomerization. Herein, we report the precise synthesis and tuning size‐dependent (chir)optical properties of a new class of chiral PAHs‐containing conjugated macrocycles (cyclo[n]paraphenylene‐2,6‐anthrylene, [n]CPPAn2,6; n=6–8). Their inherent chiralities were squeezed out in small anthrylene‐based macrocycles. Efficient resolutions for chiral enantiomers with (P)/(M)‐helicity of small [6‐7]CPPAns were achieved by HPLC. Interestingly, these macrocycles showed enriched size‐dependent physical, chiral, and (chir)optical properties. Theoretical calculations indicate that these macrocycles have high strain energy (Estrain=60.8 to 73.4 kcal/mol) and very small Egap (∼3.0 eV). Notably, these enantiomers showed strong chiroptical properties and dissymmetry factors (|gabs| and |glum|∼0.01 for an enantiomer of [6]CPPAn2,6), which can give them potential applications in optically active materials. [ABSTRACT FROM AUTHOR]

An evidence for the formation of a rare meta-metalated inherently chiral calix[4]arene is described. Our strategy involved using a mesoionic carbene to direct C–H activation, but proved to form an unexpectedly unstable intermediate that was identified through high-resolution mass spectrometry. On route to our target, a new optimized method to mononitrocalix[4]arenes was developed, including optimized and high yielding transformations to azide and 1,2,3-triazole derivatives which may have application in other areas of research.

2,2′‐Bis[2‐(5,2′‐bithienyl)]‐3,3′‐bithianaphthene (1) is the progenitor of a class of C2 symmetric thiophene‐based electroactive monomers that, when electrooxidized in the enantiomerically pure form, produce inherently chiral films endowed with outstanding electrochemical enantiorecognition properties. The enantioselective high‐performance liquid chromatography (HPLC) is the only approach used so far to resolve the racemic form of 1 into enantiomers. In this work, an improved HPLC method for multimilligram enantiomer production is presented. Key factors controlling the enantioseparation, such as mobile phase composition and column temperature, were identified using a 100 × 4.6 mm i.d. Chiralpak IB‐3 column and subsequently scaled up to a 250 × 10.0 mm i.d. Chiralpak IB column. In the optimized semipreparative conditions, about 34 mg of pure (P) and (M) enantiomers per hour could be produced. [ABSTRACT FROM AUTHOR]

• A miniaturized, enantioselective electrochemical microsensor was crafted by integrating high-purity SWCNTs with a carbon fiber microelectrode. • The practicability of the microsensor was validated by discriminating DOPA enantiomers. • This paves the way for a new breed of chiral sensors that are simpler, more efficient, and cost-effective. A range of electrochemical sensors capable of enantiomer discrimination have been developed, but the creation of their electrochemical interfaces remains complex. This often entails combining externally introduced chiral centers with conductive materials. This study marks a significant departure from this approach by exploiting the inherent chirality of single-walled carbon nanotubes (SWCNTs) for enantiomer discrimination. We have crafted a miniaturized, enantioselective electrochemical microsensor by seamlessly integrating high-purity SWCNTs, possessing inherent chirality, with an ultra-sensitive carbon fiber microelectrode. Using differential pulse voltammetry, we observed a notable difference in peak current, highlighting the sensor's precise ability to distinguish between enantiomers of 3,4-dihydroxyphenylalanine (DOPA). Furthermore, we investigated the intricacies of the interplay between enantioselective interfaces and the molecules under discrimination, offering deeper insights into the mechanisms governing this phenomenon. This study provides substantial momentum into the realm of enantioselective electrochemical sensing and sheds light on the unique attributes of inherently chiral carbon nanotubes in such applications. This paves the way for a new breed of chiral sensors that are simpler, more efficient, and cost-effective. We crafted a miniaturized, enantioselective electrochemical microsensor by integrating high-purity SWCNTs with a carbon fiber microelectrode. [Display omitted] [ABSTRACT FROM AUTHOR]

Electronic circular dichroism (ECD) can be used to study various aspects of self-assembly (definition of stoichiometric ratios, chirality amplification during self-assembly, host-guest complexation). In this work, we show that ECD is a valuable tool for monitoring the self-assembly of chiral peptide-based capsules. By analyzing the signs, intensities, and temperature dependences of ECD bands, the effects of the non-specific processes can be separated from the restriction of intramolecular motion (RIM) caused by discrete self-assembly. Analysis of experimental and theoretical ECD spectra show that the differences between assembled and non-assembled species originate from induction of inherently chiral conformation and restriction of conformational freedom that leads to amplification of ECD signals during self-assembly of discrete species.

C-H activation offers an intriguing access into inherently chiral calix[4]arenes, but has been little explored in the literature. In this article, we report our investigation into a published C-H activation method that uses carbamates to direct a palladium catalyzed C-H activation and subsequent reaction with N-bromosuccinimide. However, we show that this report is unfortunately flawed on a number of points. An earlier reported study revealed the more likely SEAr mechanism of the bromination reaction, which did not involve palladium catalysis. We nevertheless employed the SEAr bromination in an attempt to form inherently chiral calix[4]arenes, using a chiral (+)-menthyl carbamate as a directing group. Unfortunately, although the reaction was high yielding, the diastereomers formed were inseparable and we were unable to quantify their ratio. Subsequent removal of the chiral (+)-menthyl carbamate, returned a small positive optical rotation, suggesting that at least a level of asymmetric induction was achieved in the bromination to afford a non-racemic product. [ABSTRACT FROM AUTHOR]

Self‐standing chiral electroactive synthetic membranes are presented, prepared by oxidative electro‐oligomerization of a thiophene‐based "inherently chiral" electroactive monomer on indium tin oxide (ITO) or fluorine‐doped tin oxide (FTO) electrodes, followed by detachment of the electrodeposited thin films in aqueous solution. The membranes, possibly mesoporous, consist of a mixture of open and cyclic "inherently chiral" oligomers, that is, in which both chirality and electroactivity originate from the same source, and this is the main conjugated backbone featuring a tailored torsion. Such a combination can afford outstanding chirality manifestations. The electrosynthesis conditions significantly modulate the oligomer distribution. Racemate films are compared to enantiopure ones. Circular dichroism confirms that (R)‐ or (S)‐ enantiopure films are obtained, starting from the corresponding (R)‐ or (S)‐ enantiopure monomers. Reliable transmembrane potential readings are obtained in preliminary tests in ion‐selective electrode (ISE)‐like setups, consistent with those predicted considering the membrane features, offering a first step towards extension of the protocol to chiral experiments. [ABSTRACT FROM AUTHOR]

Configurationally stable 5-aza[6]helicene (1) was envisaged as a promising scaffold for non-conventional ionic liquids (IL)s. It was prepared, purified, and separated into enantiomers by preparative HPLC on a chiral stationary phase. Enantiomerically pure quaternary salts of 1 with appropriate counterions were prepared and fully characterized. N-octyl-5-aza[6]helicenium bis triflimidate (2) was tested in very small quantities as a selector in achiral IL media to perform preliminary electrochemical enantiodifferentiation experiments on the antipodes of two different chiral probes. The new organic salt exhibited outstanding enantioselection performance with respect to these probes, thus opening the way to applications in the enantioselective electroanalysis of relevant bioactive molecules.

Calixarene-analogous metacyclophanes (CAMs) are a special class of cyclophanes that are cyclic polyaromatic hydrocarbons containing three or more aromatic rings linked by one or more methylene bridging groups. They can be considered to be analogues of calixarenes, since, in both types of molecules, the component aromatic rings are linked by methylene groups, which are meta to each other. Since the prototype or classical calix[4]arene consists of four benzene rings each linked by methylene bridges, which are also meta to each other, it can be considered to be an example of a functionalized [1.1.1.1]metacyclophane. A metacyclophane (MCP) that consists of three individual hydroxyl-group functionalized aromatic rings linked by methylene groups, e.g., a trihydroxy[1.1.1]MCP may therefore, by analogy, be termed in the broadest sense as a “calix[3]arene” or a “calix[3]arene-analogous metacyclophane”. Most of the CAMs reported have been synthesized by fragment coupling approaches. The design, synthesis and development of functionalized CAMs, MCPs, calixarenes and calixarene analogues has been an area of great activity in the past few decades, due their potential applications as molecular receptors, sensors and ligands for metal binding, and for theoretical studies, etc. In this review article, we focus mainly on the synthesis, structure and conformational properties of [1.1.1]CAMs, i.e., “calix[3]arenes” and their analogues, which contain three functionalized aromatic rings and which provide new scaffolds for further explorations in supramolecular and sensor chemistry.

Enantioselective electroanalysis, which aims to discriminate the enantiomers of electroactive chiral probes in terms of potential difference, is a very attractive goal. To achieve this, its implementation is being studied for various "inherently chiral" selectors, either at the electrode surface or in the medium, yielding outstanding performance. In this context, the new inherently chiral monomer Naph2T4 is introduced, based on a biaromatic atropisomeric core, which is advantageously obtainable in enantiopure form without HPLC separation steps by a synthetic route hinging on enantiopure 2,2’-dibromo-1,1’-binaphthalenes. The antipodes of the new inherently chiral monomer can be easily electrooligomerized, yielding inherently chiral electrode surfaces that perform well in both cyclic voltammetry (CV) enantiodiscrimination tests with pharmaceutically interesting molecules and in magnetoelectrochemistry experiments.

Graphical abstract Highlights • meta -Substituted aminocalix[4]arene was acylated by amino acids derivatives (Phe, Ala). • The combination of inherent chirality with chiral AAs led to diastereomers separable by preparative TLC. • Cyclization with Tf 2 O/2-ClPyr yielded the corresponding enantiomerically pure oxazoles. • Straightforward and scalable approach towards enantiomerically pure inherently chiral calix[4]arenes. Abstract A meta -substituted aminocalix[4]arene 4 immobilized in the cone conformation was prepared via mercuration of the starting tetra -propoxy derivative, followed by nitrosation and reduction reactions. Acylation of the amino group by chiral amino acid residues ((S)- N -trifluoroacetyl-Ala or (S)- N -trifluoroacetyl-Phe) allowed for the preparation of diastereomeric amides that were separated by preparative TLC on silica gel. Subsequent cyclization under Bischler-Napieralski reaction conditions yielded calixarenes 7b and 7c bearing an oxazole moiety in the meta position instead of the expected upper rim-bridged compounds. The reaction sequence represents a straightforward approach towards enantiomerically pure inherently chiral calix[4]arene derivatives (without HPLC separation steps). The absolute configuration of the enantiomers were confirmed by single crystal structure determination (X-ray). [ABSTRACT FROM AUTHOR]

Abstract: Two new inherently chiral oligothiophenes characterized by the atropisomeric 3,3′‐bithianaphtene scaffold functionalized with fused ring bithiophene derivatives, namely 4H‐cyclopenta[2,1‐b3:4b′]dithiophene (CPDT) and dithieno[3,3‐b:2′,3′‐d]pyrrole (DTP), were synthesized. The racemates were fully characterized and resolved into antipodes by enantioselective HPLC. The enantiomers were analyzed through different chiroptical techniques: electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) were employed to attribute the absolute configuration (AC). Comparison of experimental and calculated VCD spectra confirmed the DFT calculated conformational characteristics. The compound functionalized with two CPDT units was oxidized with FeCl3, and ECD and CPL of the resulting material were measured. Circularly polarized luminescence (CPL) was measured to verify if inherently chiral oligothiophenes could be promising systems for chiral photonics applications. [ABSTRACT FROM AUTHOR]

A dialkyl-1,1′-bibenzimidazolium salt, consisting of an atropisomeric dication ( i.e. featuring a stereogenic axis and thus “inherently chiral”) and an achiral counteranion, is employed as a chiral additive in three commercial ionic liquids, providing successful enantiodiscrimination in voltammetry experiments on screen-printed electrodes (SPEs) with the enantiomers of N,N′ -dimethyl-1-ferrocenyl-ethylamine as model chiral probes. Significant differences in redox potentials are observed for the probe enantiomers despite the low concentration (0.01 M) of the chiral additive. The nature of the achiral ionic liquid in which the additive is employed significantly affects the peak potentials and potential differences, but does not alter the enantiomer sequence. [ABSTRACT FROM AUTHOR]

Abstract: This article looks at the chemistry surrounding the concept of inherently chiral calixarenes (ICCs), whose synthesis and application have only recently being realised. One challenge in the area of ICC chemistry is the sheer breadth and scope for installing different aspects of inherent chirality. The aim of this article is not to cover every known method, but rather to give the reader an overview of the main themes that have emerged in this area, including more recent additions to the literature. This overview will also touch on the very limited reports on the applications of ICCs which give a glimpse into the potential these compounds may have in future studies. [ABSTRACT FROM AUTHOR]

A linearly linked triscalix[4]arene, in which each calix[4]arene unit possesses both axial chirality and inherent chirality, was synthesized by repeated use of two stereoselective Williamson etherification on calix[4]arene. In the crystal lattice of the biscalix[4]arene intermediate, there are interesting alternate layers of biscalixarene molecules and solvent molecules in the ab plane. [ABSTRACT FROM AUTHOR]

To achieve enantioselective electroanalysis either chiral electrodes or chiral media are needed. High enantiodiscrimination properties can be granted by the 'inherent chirality' strategy of developing molecular materials in which the stereogenic element responsible for chirality coincides with the molecular portion responsible for their specific properties, an approach recently yielding outstanding performances as electrode surfaces. Inherently chiral ionic liquids (ICILs) have now been prepared starting from atropisomeric 3,3′-bicollidine, synthesized from inexpensive reagents, resolved into antipodes without need of chiral HPLC and converted into long-chain dialkyl salts with melting points below room temperature. Both the new ICILs and shorter family terms, solid at room temperature, employed as low-concentration additives in achiral ILs, afford impressive enantioselection for the enantiomers of different probes on achiral electrodes, regularly increasing with additive concentration. [ABSTRACT FROM AUTHOR]

The facile method of generating internal chirality into the calixarene with two hydroxy groups at the lower rim via an attached chiral substituent has been proposed. The reaction with acylisocyanates, catalyzed by a small amount of triethylamine, proceeds forming predominantly one of the two possible calixarene carbamates. The best diastereomeric excess (60 %) has been achieved in the reaction of trichloroacyl isocyanates with 1,3-hydroxycalixarene substituted with the chiral phenylethyl amide moiety. The individual diastereomers of trichloroacetyl-carbamoylcalix[4]arenas were isolated by crystallization, and their absolute configuration was determined by X-ray diffraction study. The most favored conformations predicted for 1,3-dihydroxy calixarene structures by quantum chemical calculations possess very similar stability. However, the triethylamine molecule preferably connects to the one hydroxyl group of the two available ones, providing the most favorable adduct, which predominantly participates in the reaction with acylisocyanates. This gives rise to the observed diastereomeric excess. The subsequent treatment of the formed carbamoyl with n-propyl bromide in presence of NaH and hydrolysis of the product of alkylation easily provide a persistent internally chiral calixarene. [ABSTRACT FROM AUTHOR]

Inherently chiral acetophenones and benzaldehydes bearing the large, bowl-shaped framework of tribenzotriquinacene (TBTQ) were synthesized in enantiomerically pure form employing enzyme catalysis. Five-step sequences involving lipase CAL-B lead to the (M)-enantiomers, (+)-2-acetyl-TBTQ (M)- 5 and (+)-2-formyl-TBTQ (M)- 6, whereas use of lipase PS leads to the (P)-enantiomers, (−)-2-acetyl-TBTQ (P)- 5 and (−)-2-formyl-TBTQ (P)- 6, with at least 99 % ee in each case. The absolute configuration of these rigid 3D building blocks was determined by X-ray diffraction analysis of the ketones 5 and by comparison of their chiroptical properties with those of the aldehydes 6. [ABSTRACT FROM AUTHOR]

All six possible stereoisomers of calix[4]arenes with four different substituents on the lower rim of the macrocycle have been synthesized by stepwise alkylation of the hydroxyl groups of tert -butylcalix[4]arene using ( R )- or ( S )-1-phenylethylamide groups as chiral auxiliaries. They form three enantiomeric pairs, as confirmed by the values of their specific rotation. [ABSTRACT FROM AUTHOR]