The design of biomimetic complexes for the modeling of metallo-enzyme active sites is a fruitful strategy for obtaining fundamental information and a better understanding of the molecular mechanisms at work in Nature's chemistry. The classical strategy for modeling metallo-sites relies on the synthesis of metal complexes with polydentate ligands that mimic the coordination environment encountered in the natural systems. However, it is well recognized that metal ion embedment in the proteic cavity has key roles not only in the recognition events but also in generating transient species and directing their reactivity. Hence, this review focuses on an important aspect common to enzymes, which is the presence of a pocket surrounding the metal ion reactive sites. Through selected examples, the following points are stressed: (i) the design of biomimetic cavity-based complexes, (ii) their corresponding host-guest chemistry, with a special focus on problems related to orientation and exchange mechanisms of the ligand within the host, (iii) cavity effects on the metal ion binding properties, including 1st, 2nd, and 3rd coordination spheres and hydrophobic effects and finally (iv) the impact these factors have on the reactivity of embedded metal ions. Important perspectives lie in the use of this knowledge for the development of selective and sensitive probes, new reactions, and green and efficient catalysts with bio-inspired systems.

A series of capped metallo-cyclodextrins were synthesized, affording a variety of artificial chiral metallo-pockets through modulation of the space around the metal. Carbene ligands were used as caps for placing a silver, gold, or copper center at a well-defined location inside the cyclodextrin cavity. Multiple weak interactions involving the d 10 metal center and intra-cavity hydrogen atoms, including anagostic interactions, were observed in solution. Thus, the metal was used as a probe for assessing intra-cavity metal-H distances for building 3D models, revealing the very different shapes of capped a-, band nd g-cyclodextrins and the helical shape of the chiral pocket of some modified cyclodextrins. This series of N-heterocyclic-carbene-based cyclodextrins were compared in gold-catalyzed cycloisomerization reactions, for which the 3D models were used to rationalize the observed regio-and stereoselectivities.

Low‐price coupling: A versatile, practical, and cost‐efficient iron‐catalyzed O‐arylation protocol is applied to the synthesis of a variety of diaryl ethers, which are formed in high yields. Best results were obtained by using FeCl3 and a β‐diketo ligand.

A water-soluble calix[6]arene-based tris(imidazole) ligand behaves as a highly selective receptor for primary amines in the presence of Zn(II) in water near physiological pH. It represents the first compound of this family of ligands that binds a Zn dication and an organic guest in water, thus giving rise to a stable host-guest adduct in spite of the highly competitive medium. The herein described selfassembly process displays a remarkable set of biomimetic properties. The ternary system (calix/Zn/ amine) is formed in a very synergistic and allosteric manner and stabilizes the neutral form of the amino guest with a spectacular pseudo-pK a shift of ca. 7 units. This system constitutes an interesting structural model of metalloenzymes in aqueous solution.

Supramolecular chemistry in water is a very challenging research area. In biology, water is the universal solvent where transition metal ions play major roles in molecular recognition and catalysis. In enzymes, it participates in substrate binding and/or activation in the heart of a pocket defined by the folded protein. The association of a hydrophobic cavity with a transition metal ion is thus a very appealing strategy for controlling the metal ion properties in the very competitive water solvent. Various systems based on intrinsically water-soluble macrocyclic structures such as cyclodextrins, cucurbituryls, and metallo-cages have been reported. Others use calixarenes and resorcinarenes functionalized with hydrophilic substituents. One approach for connecting a metal complex to these cavities is to graft a ligand for metal ion binding at their edge. Early work with cyclodextrins has shown Michaelis-Menten like catalysis displaying enhanced kinetics and substrate-selectivity. Remarkable examples of regio- and stereo-selective transformation of substrates have been reported as well. Dynamic two-phase systems for transition metal catalysis have also been developed. They rely on either water-transfer of the metal complex through ligand embedment or synergistic coordination of a metal ion and substrate hosting. Another strategy consists in using metallo-cages, which provide a well-defined hydrophobic space, to stabilize metal complexes in water. When the cages can host simultaneously a substrate and a reactive metal complex, size- and regio-selective catalysis was obtained. Finally, construction of a polydentate coordination site closely interlocked with a calixarene or resorcinarene macrocycle has been shown to be a very fruitful strategy for obtaining metal complexes with remarkable hosting properties. For each of these systems, the synergism resulting from the biomimetic association of a hydrophobic cavity and a metal ion is discussed within the objective of developing new tools for either selective molecular recognition (with analytical perspectives) or performant catalysis, in water.

The synthesis of N-cyanosulfilimines can readily be achieved by reaction of the corresponding sulfides with cyanogen amine in the presence of a base and NBS or I2 as halogenating agents. Oxidation followed by C-N bond cleavage affords synthetically useful NH-free sulfoximines.

The selective and efficient functionalisation of large concave molecules is a chemical challenge opening the door to various applications, such as artificial enzymes. We propose here a method, based on deprotection of benzylated cyclodextrins, to selectively access a variety of complex structures with two or three new different functionalities on the primary platform. Our strategy is based on a mechanistic hypothesis involving the approach of an aluminium reagent between the primary oxygen atom and the endocyclic one of the same sugar unit. Due to its cyclic directionality, a change in steric hindrance on a given position of the cyclodextrin has a different effect on the clockwise or the counterclockwise directions. This concept is illustrated and exploited in two complementary ways: deoxygenation of the primary position of two diametrically opposed sugars induces a debenzylation reaction on the neighbouring clockwise sugars of alpha- and beta-cyclodextrins. Reversible capping, or bascule-bridging, of the same pair of sugars has the same effect on the debenzylation of alpha-cyclodextrin, but induces an important change of the geometry of beta-cyclodextrin, hence allowing the selective access to yet another functionalisation pattern. A combined use of deoxygenation and bascule-bridging allows the access to an alpha-cyclodextrin with its three pairs of primary functions differentiated and ready for further modifications. Bascule-bridge or deoxy-sugars are two complementary means to operate steric decompression and induce selective reactions to efficiently access a number of new patterns of functionalities on concave molecules.

New beta-cyclodextrin (beta-CD) dimeric species have been synthesised in which the two CD moieties are connected by one or two hydrophilic oligo(ethylene oxide) spacers. Their complexation with sodium adamantylacetate (free adamantane) and adamantane-grafted chitosan (AD-chitosan) was then studied by different complementary techniques and compared with their hydrophobic counterparts that contain an octamethylene spacer. Isothermal titration calorimetry experiments have demonstrated that the use of hydrophilic spacers between the two CDs instead of aliphatic chains makes almost all of the CD cavities available for the inclusion of free adamantane. Investigation of the interaction of the CDs with AD-chitosan by viscosity measurements strongly suggests that the molecular conformation of the CD dimeric species plays a crucial role in their cross-linking with the biopolymer. The derivative doubly linked with hydrophilic arms, also called a duplex, has been shown to be a more efficient cross-linking agent than its singly bridged counterpart, referred to as a dimer. Hence, only 0.5 molar equivalents of the hydrophilic duplex with respect to adamantane was required to obtain the maximum viscosity, whereas in the case of the duplex with aliphatic spacers, the maximum viscosity was achieved with a [duplex]/[AD] ratio of about 1.7 (corresponding to a [CD]/[AD] ratio of 2.5), but with a higher value. To clarify the relationships between the molecular architecture and complexation properties, computational studies were also performed that clearly confirmed the importance of double bridging.