Upper rim-bridged calixarenes.

Calix[]arenes represent a very attractive family of macrocyclic compounds with many potential supramolecular applications. Due to their well-established chemistry and many different synthetic strategies, enabling practically any derivatization of the basic skeleton, calixarenes are among the very popular building blocks used for the design and construction of various receptors, sensors and other sophisticated supramolecular systems. Regio- and/or stereo-selective derivatization of calixarenes currently represents a very extensive set of reactions, the overview of which would fill many thick books.

Reactivity of phenoxathiin-based thiacalixarenes towards -nucleophiles.

A starting thiacalix[4]arene can be easily transformed into oxidized phenoxathiin-based macrocycles 9 and 9', representing an unusual structural motif in calixarene chemistry. The presence of electron-withdrawing groups (SO, SO) and the considerable internal strain caused by the condensed heterocyclic moiety render these molecules susceptible to nucleophilic attack. The reaction with various organolithium reagents provides a number of different products resulting from the cleavage of either the calixarene skeleton or the phenoxathiin group or both ways simultaneously.

Upper Rim-Bridged Calix[4]arenes via Cyclization of Alkynyl Intermediates with Diphenyl Diselenide.

A Sonogashira coupling of -iodocalix[4]arene with various terminal acetylenes confirmed that the position of calixarene is well addressable, and that both thermal and microwave protocols led to good yields of alkynylcalixarenes. Alkynes thus obtained were subjected to the ferric chloride and diphenyl diselenide-promoted electrophilic closure. It turns out that the calix[4]arenes give completely different bridging products than those described for the non-macrocyclic starting compounds.

Chemoselective Electrochemical Cleavage of Sulfonimides as a Direct Way to Sulfonamides.

A new method for selective cleavage of sulfonimides into sulfonamides in high yields using a simple electrochemical approach is shown. As revealed by the electrochemical study, the aromatic sulfonimides can be selectively cleaved by electrolysis of the starting compound at a given potential (only -0.9 V vs SCE for the nosyl group).

Synthesis of Thiapillar[6]arenes Bearing Redox-Active (Hydro)quinone Groups. Electrochemical and XRD Study.

Pillar[]arenes are among the newest members of the macrocyclic family. Nevertheless, their conformational behavior and binding properties as well as redox properties of dealkylated pillar[]arenes are well-studied. At the same time, introducing a heteroatom into a cyclophane macrocycle is already known to alter all the above properties drastically.

Galectin-targeting glycocalix[4]arenes can enter the cells.

Elevated levels of galectin-3 are associated with tumorigenesis. Its inhibition with high-affinity carbohydrate ligands opens new therapeutic routes. Targeting of intracellular galectin-3 is challenging for polar inhibitors like carbohydrates.

The Unexpected Chemistry of Thiacalix[4]arene Monosulfoxide.

Thiacalix[4]arene monosulfoxide possesses a very unusual chemistry, as demonstrated by several unprecedented derivatives in calixarene chemistry. Interestingly, compound cannot be prepared by the dealkylation of its corresponding tetramethoxy derivative using BBr. Instead, the borate complex is formed with a boron bound by the two neighboring phenolic oxygens and a sulfoxide group.

Enantiodiscrimination of Inherently Chiral Thiacalixarenes by Residual Dipolar Couplings.

Inherently chiral compounds, such as calixarenes, are chiral due to a nonplanar three-dimensional (3D) structure. Determining their conformation is essential to understand their properties, with nuclear magnetic resonance (NMR) spectroscopy being one applicable method. Using alignment media to measure residual dipolar couplings (RDCs) to obtain structural information is advantageous when classical NMR parameters like the nuclear Overhauser effect (NOE) or -couplings fail.

Glycocalix[4]arenes and their affinity to a library of galectins: the linker matters.

Galectins are lectins that bind β-galactosides. They are involved in important extra- and intracellular biological processes such as apoptosis, and regulation of the immune system or the cell cycle. High-affinity ligands of galectins may introduce new therapeutic approaches or become new tools for biomedical research.

The Formation of Inherently Chiral Calix[4]quinolines by Doebner-Miller Reaction of Aldehydes and Aminocalixarenes.

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.

Direct substitution of calix[4]arenes.

Calixarenes represent very popular building blocks in supramolecular chemistry. Compared to other macrocyclic families, they exhibit an almost infinite possibility of derivatization of the basic skeleton, which makes them ideal candidates for the design of new receptors or other functional systems. Although the chemistry of calixarenes is well established, there are still some substitution patterns that are unavailable or require a very lengthy synthetic approach.

Regioselective Lithiation of Tetrabromocalix[4]arenes: A Simple Way for the Desymmetrization of the Macrocyclic Skeleton.

Desymmetrization of persubstituted calix[4]arenes represents an interesting way to yield distally disubstituted derivatives. The reaction of tetrabrominated calixarenes in three different conformations (, , and ) with an excess of -BuLi surprisingly leads with high selectivity to distally dilithiated derivatives that, by reaction with electrophiles, give substitution patterns which are difficult to obtain by other ways. Using a combination of synthetic and theoretical approaches (DFT), we tried to demonstrate the usefulness of this method and provide a possible explanation for this unexpected selectivity.

Breaking thiacalix[4]arene into pieces - a novel synthetic approach to higher calixarenes bearing mixed (-S-, -CH-) bridges.

A novel approach to calix[5-7]arenes possessing mixed (S and CH) bridges within the skeleton is based on the reaction of thiacalix[4]arene monosulfoxide with BuLi leading to a linear phenolic tetramer in essentially quantitative yield. This key intermediate is then cyclized with suitable building blocks to give macrocyclic calixarene analogues. Compared to the traditional stepwise construction of similar systems, this procedure based on thiacalixarene cleavage represents a scalable, robust, and straightforward synthesis and enables the preparation of larger calixarenes on a gram scale.

Nucleophile-induced transformation of phenoxathiin-based thiacalixarenes.

Oxidized phenoxathiin-based macrocycles, easily accessible thiacalix[4]arene derivatives, consist of a unique set of structural elements representing a key prerequisite for the unexpected reactivity described in this paper. As proposed, the internal strain, imposed by the presence of a heterocyclic moiety, together with a number of electron-withdrawing groups (SO) opens the way to the cleavage of the macrocyclic skeleton through a cascade of three SAr reactions triggered by the nucleophilic attack of an SH anion. The whole transformation, which is unparalleled in classical calixarene chemistry, leads to unique linear sulfinic acid derivatives with a rearranged phenoxathiin moiety that can serve as building blocks for macrocyclic systems of a new type.

Chemistry of 2,14-Dithiacalix[4]arene: Searching for the Missing Fifth Conformer.

Contrary to theoretical predictions, direct alkylation of 2,14-dithiacalix[4]arene provides only four out of five basic conformers (atropisomers). To prepare the missing conformer, the indirect alkylation strategy was applied using 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane as a protective agent. As proved by the combination of NMR and X-ray crystallography, the position of the disiloxane bridge on the macrocycle is not fixed and can be changed under basic conditions, representing thus so far unknown rearrangement of the siloxane moiety.

Chiral anion recognition using calix[4]arene-based ureido receptors in a conformation.

The introduction of chiral alkyl substituents into the lower rim of calix[4]arene immobilised in the conformation led to a system possessing a preorganised ureido cavity hemmed with chiral alkyl units in the near proximity. As shown by the H NMR titration experiments, these compounds can be used as receptors for chiral anions in DMSO- . The chiral recognition ability can be further strengthened by the introduction of another chiral moiety directly onto the urea N atoms.

Ketone transformation as a pathway to inherently chiral rigidified calix[4]arenes.

The preparation of inherently chiral rigidified calix[4]arenes with an intact cavity is a synthetic challenge due to the complicated synthesis of the starting compounds. Here, we report on a novel strategy for bridging the upper rim of calix[4]arenes consisting in carbonyl group formation and subsequent "extension" into a two-atom bridge using corresponding rearrangement reactions (Baeyer-Villiger, Beckmann). The resulting inherently chiral compounds are potentially applicable in the design of novel receptors.

Regioselective SAr reaction of the phenoxathiin-based thiacalixarene as a route to a novel macrocyclic skeleton.

The sulfonyl analogue of phenoxathiin-based thiacalix[4]arene, easily accessible from the parent thiacalix[4]arene, reacts with sodium alkoxides to yield a cleaved product representing a novel type of macrocyclic skeleton with a quasi-calixarene structure. As shown by comparison with other derivatives, the internal strain imposed by the heterocyclic moiety is a driving force of this SNAr reaction.

Chemistry of 2,14-Dithiacalix[4]arene: Alkylation and Conformational Behavior of Peralkylated Products.

2,14-Dithiacalix[4]arene, prepared on a multigram scale, was alkylated using the reaction conditions well known from the chemistry of classical calixarenes or thiacalixarenes to study the specific conformational preferences and dynamic behavior of the corresponding tetraalkylated derivatives. As proved by the combination of the X-ray crystallography and dynamic NMR techniques, the presence of mixed bridges (-CH- and -S- groups) within the basic skeleton brings about considerable changes in the mutual ratios of the individual conformers compared to the parent macrocycles. Interestingly, certain conformers, hardly accessible for common calixarenes/thiacalixarenes (e.

Rearrangement of meta-Bridged Calix[4]arenes Promoted by Internal Strain.

The meta-bridged calixarenes possess a rigidified and highly distorted cavity, where the additional single-bond bridge imposes an extreme internal strain on the whole system. As a consequence, these compounds exhibit a reasonably amended reactivity, compared with common calix[4]arene derivatives, which is governed by the release of internal strain. This can be documented by the reaction of the bridged calix[4]arene with PO or Nafion-H, leading (apart from polymers) to a macrocyclic product with a rearranged basic skeleton.

Selectivity of original C-hexopyranosyl calix[4]arene conjugates towards lectins of different origin.

As a part of ongoing activities towards the design of ligands against pathogenic lectins, a synthesis of original α-C-galacto/α-C-manno/α-C-fucopyranosyl glycomimetics based on a calix[4]arene scaffold and their binding evaluation is described. The interactions of the glycomimetics with seven lectins of various origins were carried out using agglutination inhibition assays. The 1,3-alternate tetra-C-fucosylated ligand and its derivative having a tertBu group at the upper rim of the calix[4]arene scaffold were the most potent towards the AAL lectin family (RSL, AFL, AAL, AOL) and BC2L-C.

Inherently Chiral Upper-Rim-Bridged Calix[4]arenes Possessing a Seven Membered Ring.

The mercuration of calix[4]arene immobilized in the cone conformation allowed the introduction of an amino group at the meta position of the basic skeleton. Acylation and subsequent intramolecular Bischler-Napieralski-type cyclization led to a novel type of bridged calixarene containing a seven-membered ring. These compounds with an enlarged and rigidified cavity represent a unique and inherently chiral system that may potentially be applicable for the design of chiral receptors.

Synthesis of inherently chiral calixarenes via direct mercuration of the partial cone conformation.

Direct mercuration of calix[4]arene immobilized in the partial cone conformation led to the meta-substituted isomer which was subsequently subjected to Pd-catalysed coupling (C-H activation) with the neighbouring aromatic subunit. Regioselective mercuration thus enabled access to a novel type of inherently chiral calixarenes with a highly distorted cavity potentially applicable to the design of new chiral receptors.

Intramolecularly Bridged Calix[4]arenes with Pronounced Complexation Ability toward Neutral Compounds.

Regioselective derivatization via an organomercury intermediate allowed for the introduction of carboxylic acid functionality into the meta position of the calix[4]arene skeleton. Intramolecular Friedel-Crafts cyclization led to a novel type of calixarene containing a ketone bridging moiety. Subsequent attack of the ketone by organometallic compounds occurred selectively from outside providing tertiary alcohols with the OH group oriented inside the cavity.

2,14-Dithiacalix[4]arene and its homooxa analogues: synthesis and dynamic NMR study of conformational behaviour.

A simple and scalable synthesis of 2,14-dithiacalix[4]arene with alternating bridges (-CH2- and -S-) is reported. Proper selection of the bisphenol-based starting building blocks can provide not only the title compound (58%) but also yet unreported homooxa analogues possessing three different bridging units (-CH2-, -S- and -CH2-O-CH2-) in the molecule. These systems exhibit interesting conformational behaviour allowing for the study of flip-flop motion of the circular hydrogen bond arrays using dynamic NMR techniques.