Reactivity of phenoxathiin-based thiacalixarenes towards C-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 (SO2, 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. This enables the preparation of thiacalixarene analogues with unusual structural features, including systems containing a biphenyl fragment as a part of the macrocyclic skeleton. The above-described transformations, unparalleled in classical calixarene chemistry, clearly demonstrate the synthetic potential of this thiacalixarene subgroup.

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

A Sonogashira coupling of meta-iodocalix[4]arene with various terminal acetylenes confirmed that the meta 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. This can be demonstrated not only by the isolation of products with a six-membered ring (6-exo-dig), but mainly by the smooth formation of the 5-endo-dig cyclization, which has never been observed in the aliphatic series. An attempt at electrocyclization led to a high yield of the 1,2-diketone (oxidation of the starting alkyne), again in contrast to the reaction described for the acyclic derivatives. The structures of the unexpected products were unequivocally established by X-ray analysis and clearly demonstrate how the preorganized macrocyclic skeleton favors a completely different regioselectivity of cyclization reactions compared to common aliphatic 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). The high chemoselectivity was confirmed by preparative electrolysis, and the results were supported with DFT calculations of a set of substances bearing different sulfonimide functions. Moreover, various experimental setups together with other attempts to simplify the procedure were tested. Finally, the removal of the p-nosyl group from the corresponding sulfonimides proceeds smoothly regardless of the number of nosyl groups and the overall shape of the complex molecule. Thus, the method is interesting for use in the field of multifunctional molecules such as calix[n]arenes.

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. We demonstrate the potential of novel biomedical research tools, glycocalix[4]arenes, to enter epithelial cells, which may allow their interaction with galectin-3.

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

Pillar[n]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[n]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. This study presents a simple synthetic approach based on thia-Michael addition cyclization that readily resulted into hexathiapillar[6]arene with four phenylene units alternated by two redox-active hydroquinone moieties. The straightforward synthesis of the macrocycle enabled a systematic study of its conformation and redox behavior. The modification of hexathiapillar[6]arene afforded five functionalized derivatives, which were studied structurally in detail. The findings revealed interesting redox and structural properties of the macrocycle and its derivatives including the formation of crystal lattices with continuous channels and empty voids.

The Unexpected Chemistry of Thiacalix[4]arene Monosulfoxide.

Thiacalix[4]arene monosulfoxide 4 possesses a very unusual chemistry, as demonstrated by several unprecedented derivatives in calixarene chemistry. Interestingly, compound 4 cannot be prepared by the dealkylation of its corresponding tetramethoxy derivative using BBr3. Instead, the borate complex is formed with a boron bound by the two neighboring phenolic oxygens and a sulfoxide group. A similar type of borate complex with a spirodienone fragment was then isolated as a by-product. The oxidation of monosulfoxide with Chloramine-T did not provide the expected spirodienone moiety, but rather a complex oxathiane-based spiroheterocyclic part containing a chlorine atom. X-ray analyses confirmed the structures of the unusual products and feasible formation mechanisms were proposed. These results provide further evidence of the distinction between thiacalixarene chemistry and the chemistry of classical CH2 analogues.

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 J-couplings fail. Besides providing more accurate structural information, the alignment media can induce different orientations of enantiomers. In this study, we examined the ability of polyglutamates with different side-chain moieties─poly-γ-benzyl-l-glutamate (PBLG) and poly-γ-p-biphenylmethyl-l-glutamate (PBPMLG) ─to enantiodifferentiate the inherently chiral phenoxathiin-based thiacalix[4]arenes. Both media, in combination with two solvents, allowed for enantiodiscrimination, which was, to the best of our knowledge, proved for the first time on inherently chiral compounds. Moreover, using the experimental RDCs, we investigated the calix[4]arenes conformational preferences in solution, quantitatively analyzed the differences in the alignment of the enantiomers, and discussed the pitfalls of the use of the RDC analysis.

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

Galectins are lectins that bind ß-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. One way of increasing the low affinity of ß-galactoside ligands to galectins is their multivalent presentation, e.g., using calixarenes. We report on the synthesis of glycocalix[4]arenes in cone, partial cone, 1,2-alternate, and 1,3-alternate conformations carrying a lactosyl ligand on three different linkers. The affinity of the prepared compounds to a library of human galectins was determined using competitive ELISA assay and biolayer interferometry. Structure-affinity relationships regarding the influence of the linker and the core structure were formulated. Substantial differences were found between various linker lengths and the position of the triazole unit. The formation of supramolecular clusters was detected by atomic force microscopy. The present work gives a systematic insight into prospective galectin ligands based on the calix[4]arene core.

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. 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.

Direct meta 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. Among such synthetic challenges is the meta substitution of the aromatic skeleton (relative to phenolic oxygen), which, in conjunction with the 3D structure of calixarenes, leads to the inherent chirality and enables the synthesis of derivatives with a hitherto undescribed topology. This review deals with the current achievements in the meta substitution of calixarenes.

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 (cone, partial cone, and 1,3-alternate) with an excess of n-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.

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 (SO2) opens the way to the cleavage of the macrocyclic skeleton through a cascade of three SNAr 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 1,2 (C)-alternate 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. The subsequent dialkylation/deprotection and dialkylation enabled the synthesis of the last missing conformer. As demonstrated by several examples, the mixed-bridge macrocycle (with both CH2 and S bridging units) enables preparation of unusual conformers or substitution patterns, which are difficult to obtain, if at all, in classical calixarene chemistry. This feature makes 2,14-dithiacalix[4]arene a very promising candidate for the role of molecular scaffold or platform in various supramolecular applications.

Breaking thiacalix[4]arene into pieces - a novel synthetic approach to higher calixarenes bearing mixed (-S-, -CH2-) bridges.

A novel approach to calix[5-7]arenes possessing mixed (S and CH2) 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. As shown by 1H NMR and UV-vis titration experiments, the mixed-bridge calix[7]arene is able to recognize fullerenes C60 and C70, thus showing possible applications of such systems. The structures of the mixed bridge systems were confirmed by single crystal X-ray analysis, and the behavior of novel macrocyclic skeletons in solution was studied using dynamic NMR techniques.

Chiral anion recognition using calix[4]arene-based ureido receptors in a 1,3-alternate conformation.

The introduction of chiral alkyl substituents into the lower rim of calix[4]arene immobilised in the 1,3-alternate conformation led to a system possessing a preorganised ureido cavity hemmed with chiral alkyl units in the near proximity. As shown by the 1H NMR titration experiments, these compounds can be used as receptors for chiral anions in DMSO-d 6. The chiral recognition ability can be further strengthened by the introduction of another chiral moiety directly onto the urea N atoms. The systems with double chiral units being located around the binding ureido cavity showed better stereodiscrimination, with the highest selectivity factor being 3.33 (K L/K D) achieved for N-acetyl-ʟ-phenylalaninate. The structures of some receptors were confirmed by single crystal X-ray analysis.

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. The complexation properties towards selected quaternary ammonium salts were studied by 1H NMR titration. Unusual complexation stoichiometries can be observed depending on the enantiomeric purity (racemic mixture versus pure enantiomers) of an amidic receptor 7 used.

Regioselective SNAr 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 (-CH2- 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.g., 1,2-alternates) are easily prepared in very good yields in the case of 2,14-dithiacalix[4]arene, which makes this mixed-bridge system attractive as molecular scaffold for supramolecular applications.

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 P2O5 or Nafion-H, leading (apart from polymers) to a macrocyclic product with a rearranged basic skeleton. The methylene bridge next to the fluorene moiety is intramolecularly shifted from position 2 to position 4 of the phenolic subunit to minimize the tension. As revealed by single-crystal X-ray analysis and by application of the residual dipolar coupling method, the rearrangement occurs without altering the original conformation.

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. As AFL and RSL originate from important human (Aspergillus fumigatus) and plant (Ralstonia solanacearum) pathogens, the inhibition potency of both leading structures was assessed by surface plasmon resonance. With AFL, both structures exhibited an approximately three orders of magnitude increase in affinity compared to the reference l-fucose. The role of tertBu groups as "aglycon-assisted" events was illustrated by NMR. Furthermore, both compounds showed significantly increased ability to inhibit BC2L-C (from human pathogen Burkholderia cenocepacia) cell agglutination and were able to cross-link whole B. cenocepacia cells. Although the ligands failed to significantly inhibit the agglutination activity of LecA and LecB from Pseudomonas aeruginosa, tetra-C-galactosylated calix[4]arene with tertBu groups at the upper rim of the 1,3-alternate conformation inhibited P. aeruginosa biofilm formation efficiently. This systematic and comprehensive study highlights the fact that hydrolytically stable polyvalent C-glycomimetics should be regarded as potent and selective ligands capable of acting as antiadhesive agents.