Ulrich Darbost

Biomimetic and self-assembled calix[6]arene-based receptors for neutral molecules

The selective recognition of substrates or cofactors is a key feature of biological processes. It involves coordination bonds, hydrogen bonding, charge/charge and charge/dipole interactions. In this Perspective, we describe how the calix[6]arene core can be functionalized and shaped to act as a biomimetic molecular receptor. The strategy relies on the selective introduction of three amino arms on alternate phenolic positions. Upon metal ion binding or self-assembly via multiple ion-pairing and H-bonding, these amino arms are projected towards each other, thus closing the calixarene small rim. The resulting cone-shaped receptors act as molecular funnels displaying high affinities for a variety of neutral guests. Their hosting properties can be finely tuned by changing the small or the large rim or by allosteric effects. Induced-fit processes are also often observed as the cavity can expand for large guests or shrink for small ones. Hence, the different families of calix[6]arene-based receptors presented here highlight the importance of having a flexible and polarized hydrophobic structure to accommodate the guest.

A Calix[6]arene Receptor Rigidified by a Self-assembled Triammonium Cap: X-ray and NMR Characterization of the Binding of Polar Neutral Guests

A calix[6]arene has been rigidified by three primary ammonium arms self-assembled with the counter anions. This supramolecular edifice provides a well-defined conic hydrophobic cavity closed at the narrow rim by a tricationic site. X-ray and NMR analyses show that the resulting polarized host behaves as a remarkable endo-receptor for small molecules such as amides, alcohols and even nitriles. This study highlights the efficiency of a system that associates a cationic site with a hydrophobic cavity to host dipolar neutral molecules.

Ipso-Nitration of calix[6]azacryptands: intriguing effect of the small rim capping pattern on the large rim substitution selectivity.

The ipso-nitration of calix[6]arene-based molecular receptors is a important synthetic pathway for the elaboration of more sophisticated systems. This reaction has been studied for a variety of capped calixarenes, and a general trend for the regioselective nitration of three aromatic units out of six in moderate to high yield has been observed. This selectivity is, in part, attributed to the electronic connection between the protonated cap at the small rim and the reactive sites at the large rim. In addition, this work highlights the fact that subtle conformational properties can drastically influence the outcome of this reaction.

Easy and selective method for the synthesis of various mono-O-functionalized calix[4]arenes: de-O-functionalization using TiCl4.

An efficient and selective method for the monofunctionalization of p-tert-butylcalix[4]arene is described. A mono-de-O-functionalization of disubstituted p-tert-butylcalix[4]arenes using titanium tetrachloride was developed to synthesize a series of monosubstituted p-tert-butylcalix[4]arenes with the pendant functions being ethoxycarbonylmethyloxy, 3-ethoxycarbonylpropyloxy, cyanomethyloxy, 3-cyanopropyloxy, 4-bromobutyloxy, 3-hydroxypropyloxy, propyloxy, 2-methylpropyloxy, 3-butynyloxy, and 3-cyanopropyloxy groups. The reaction mechanism of the formation of 5,11,17,23-tetra-tert-butyl-26,27,28-trihydroxy-25-(3-ethoxycarbonylpropyloxy) calix[4]arene was studied by (1)H NMR and GC/mass spectroscopy monitoring. Reaction of TiCl4 with the disubstituted p-tert-butylcalix[4]arene produced the corresponding dioxocalix[4]arene titanium dichloride complex, which undergoes elimination of ethyl 4-chlorobutyrate, leading to a trioxocalix[4]arene titanium dichloride complex and to monosubstituted calix[4]arene after hydrolysis. These two complexes were also synthesized, isolated, and fully characterized.

Copper complexes bearing an NHC–calixarene unit: synthesis and application in click chemistry

The synthesis of N-heterocyclic carbene (NHC) copper complexes supported by calix[4]arene is reported. Mono-substituted calix[4]arene was prepared through conventional procedures, followed by the attachment of an imidazolyl group to create the precursor of NHC ligands. Alkylation with two alkyl bromides followed by metalation resulted in fully characterized original complexes. The X-ray structure showed an “out” conformation for copper. The catalytic activity of the complexes was studied in click chemistry, and revealed good performances. In particular, three new triazoles were synthesized in high yields, under solvent-free conditions and a fast reaction time. The newly synthesized chiral complex was tested in the kinetic resolution of racemic azide.

Eaton’s Reagent‐Mediated Domino π‐Cationic Arylations of Aromatic Carboxylic Acids to Iasi‐Red Polymethoxylated Polycyclic Aromatic Hydrocarbons: Products with Unprecedented Biological Activities as Tubulin Polymerization Inhibitors

A rapid domino π-cationic arylation of aromatic carboxylic acids, mediated by Eatons reagent, has been developed for the synthesis of Iasi-red polymethoxylated polycyclic aromatic hydrocarbons (PAHs). This route is currently the easiest method to obtain such popular PAH compounds, which bear in addition numerous methoxy groups. The domino process was generalized, the structure of the obtained red products and the mechanism of their formations were elucidated, and some of their photophysical properties were determined. Newly synthesized polymethoxylated-PAHs were tested for their interaction with tubulin polymerization as well as for their cytotoxicity on a panel of NCI-60 human cancer cell lines. Interestingly, one of these rubicene derivatives exhibited remarkable cytotoxicity in vitro, including inhibition of leukemia, colon, melanoma, CNS, and ovarian cancer cell lines with GI50 values in the low nanomolar range (GI50 < 10 nM).

Synthesis and crystal structures of palladium(II) complexes of bis-(N-heterocyclic carbenes) on a calix[4]arene platform

A series of calix[4]arene supported N-heterocyclic carbene palladium complexes were successfully prepared and characterised. Their X-ray crystal structures were obtained and are discussed. Notably, the dimeric compound b[5-(3-N-4,5-diphenylimidazol-2-yliden-1-yl)-25,26,27,28-tetrapropyloxy calix[4]arene] palladium(II) dibromide (cone) showed pseudo-polymorphism.