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.

Molecular recognition and self-assembly special feature: Multipoint molecular recognition within a calix[6]arene funnel complex.

A multipoint recognition system based on a calix[6]arene is described. The calixarene core is decorated on alternating aromatic subunits by 3 imidazole arms at the small rim and 3 aniline groups at the large rim. This substitution pattern projects the aniline nitrogens toward each other when Zn(II) binds at the Tris-imidazole site or when a proton binds at an aniline. The XRD structure of the monoprotonated complex having an acetonitrile molecule bound to Zn(II) in the cavity revealed a constrained geometry at the metal center reminiscent of an entatic state. Computer modeling suggests that the aniline groups behave as a tritopic monobasic site in which only 1 aniline unit is protonated and interacts with the other 2 through strong hydrogen bonding. The metal complex selectively binds a monoprotonated diamine vs. a monoamine through multipoint recognition: coordination to the metal ion at the small rim, hydrogen bonding to the calix-oxygen core, CH/pi interaction within the cavity's aromatic walls, and H-bonding to the anilines at the large rim.

Directional control and supramolecular protection allowing the chemo- and regioselective transformation of a triamine.

A Zn(II)-funnel complex based on a calix[6]arene ligand decorated with three tris(imidazolyl) arms at one end of the cone and three NH(2) substituents at the other end, acts as a multipoint recognition host for polyfunctionalized guests. The selectivity is ensured by coordination to Zn(II), CH-pi interaction within the calix cone, and H-bonding at both rims of the cavity. As a result of these multiple interactions, the host can wrap and orient an unsymmetrical triamine guest with a high selectivity. Furthermore, a proton-monitored switch between the regio-isomeric adducts allows reversible inversion of the directionality of the system. Thanks to this directional control, the regioselective mono-carbamoylation of the unsymmetrical triamine guest was successfully achieved on a preparative scale. This case study shows that a funnel-like receptor can be used as a supramolecular protecting tool allowing a transformation which would be impracticable with conventional covalent chemistry.

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.

Enantioselective artificial metalloenzymes based on a bovine pancreatic polypeptide scaffold.

Site creation: Enantioselective artificial metalloenzymes have been created by grafting a new active site onto bovine pancreatic polypeptide through the introduction of an amino acid capable of coordinating a copper(II) ion. This hybrid catalyst gave good enantioselectivities in the Diels-Alder and Michael addition reactions in water (see scheme) and displayed a very high substrate selectivity.

Spectacular induced-fit process for guest binding by a calix[6]arene Zn(II) funnel complex.

The host properties of a calix[6]arene cone capped by a Zn(II) tris-imidazole core at the small rim and decorated by three NH(2) substituents at the large rim are described and compared to the hexa-tBu parent complex. It is shown that the replacement of three bulky tBu substituents by three hydrophilic and small NH(2) groups has three major impacts: the receptor is now soluble in aqueous media, it accepts large guests such as dimethyldopamine and, most interestingly, undergoes a spectacular induced-fit behavior for guest binding.

Innovative methodologies for the N-protection of N-alkylimidazole groups: application to the first synthesis of a water-soluble calix[6]arene presenting three ammonium substituents at the large rim and three neutral N-donors at the small rim.

The first synthesis of a cationic amphiphile calixarene ligand, which bears three neutral imidazole donors on one side of the hydrophobic cone and three quaternary ammonium substituents on the other side, is reported. The synthetic strategy relies on two key steps: (i) the "small rim-directed" selective ipso-nitration at the large rim and (ii) a protection-deprotection sequence of the N-alkylimidazole groups, for which two equally efficient novel methods (coordination to Zn(II) or to a cyanoborane) are presented.

Encapsulation of a (H3O2)- unit in the aromatic core of a calix[6]arene closed by two Zn(II) ions at the small and large rims.

The coordination of a first Zn(II) ion to a calix[6]arene presenting three imidazolyl arms at the small rim and three aniline moieties at the large rim allows the binding of a second Zn(II) ion while hosting a (H3O2)- unit in the aromatic cavity.

Catalytic enantioselective syn hydration of enones in water using a DNA-based catalyst.

The enantioselective addition of water to olefins in an aqueous environment is a common transformation in biological systems, but was beyond the ability of synthetic chemists. Here, we present the first examples of a non-enzymatic catalytic enantioselective hydration of enones, for which we used a catalyst that comprises a copper complex, based on an achiral ligand, non-covalently bound to (deoxy)ribonucleic acid, which is the only source of chirality present under the reaction conditions. The chiral ß-hydroxy ketone product was obtained in up to 82% enantiomeric excess. Deuterium-labelling studies demonstrated that the reaction is diastereospecific, with only the syn hydration product formed. So far, this diastereospecific and enantioselective reaction had no equivalent in conventional homogeneous catalysis.

Ipso-chlorosulfonylation of calixarenes: a powerful tool for the selective functionalization of the large rim.

In our quest for the elaboration of supramolecular models of metallo-enzyme active sites, we became interested in developing new methodologies for the selective functionalization of the large rim of calix[6]arenes. Here, we describe a novel reaction, i.e. the ipso-chlorosulfonylation of calixarene derivatives. The process has been found to be highly efficient, selective and versatile. The regioselectivity is controlled by the nature of the O-substituents at the small rim. Indeed, when O-alkylated by a protonable imidazole group, the aromatic rings are deactivated toward an electrophilic attack and the anisol units can be selectively ipso-chlorosulfonylated under mild conditions (rt). Performing the reaction at a higher temperature allowed the per-chlorosulfonylation to take place. Hence, the synthesis of various sulfonate and sulfonamide derivatives is reported. Finally, a combination of ipso-nitration and chlorosulfonylation allows the per-functionalization of the aromatic units at the large rim in selective alternate positions. Overall, this novel methodology opens new routes to a variety of calixarenes, allowing the tuning of their physical properties without drastically altering their hydrophobic conic cavities.

Efficient synthesis of calix[6]tmpa: a new calix[6]azacryptand with unique conformational and host-guest properties.

A new C(3v)-symmetrical calix[6]azacryptand, that is, calix[6]tmpa (11), was synthesized by efficient [1+1] macrocyclization reactions. Remarkably, both linear and convergent synthetic strategies that were applied lead to equally good overall yields. Calix[6]tmpa behaves as a single proton sponge and appeared reluctant to undergo polyprotonation, unlike classical tris(2-pyridylmethyl)amine (tmpa) derivatives. It also acts as a good host for ammonium ions. Interestingly, it strongly binds a sodium ion and a neutral guest molecule, such as a urea, an amide, or an alcohol, in a cooperative way. A (1)H NMR study indicated that the ligand, as well as its complexes, adopt a major flattened cone conformation that is the opposite of that observed with the previously reported calix[6]cryptands. Characterization of the monoprotonated derivative 11H(+) by X-ray diffraction also revealed the presence of a 1,3-alternate conformation, which is the first example of its kind in the calix[6]arene family. This conformer is probably also present in solution as a minor species. The important covalent constraint induced by the polyaromatic tmpa cap on the calixarene skeleton, and conversely from the calix core onto the tmpa moiety, is the likely basis for the unique conformational and chemical properties of this host.