Supramolecular modeling of mono-copper enzyme active sites with calix[6]arene-based funnel complexes.

Supramolecular bioinorganic chemistry is a natural evolution in biomimetic metallic systems since it constitutes a further degree of complexity in modeling. The traditional approach consisting of mimicking the first coordination sphere of metal sites proved to be very efficient, because valuable data are extracted from these examples to gain insight in natural systems mechanisms. But it does not reproduce several specific aspects of enzymes that can be mimicked by the implementation of a cavity embedding the labile active site and thus controlling the properties of the metal ion by noncovalent interactions. This Account reports on a strategy aimed at reproducing some supramolecular aspects encountered in the natural systems. The cavity complexes described herein display a coordination site constructed on a macrocycle. Thanks to a careful design of the cavity-based ligands, complexes orienting their labile site specifically toward the inside of the macrocycle were obtained. The supramolecular systems are based on the flexible calix[6]arene core that surrounds the metal ion labile site, thereby constraining exogenous molecules to pass through the conic funnel to reach the metal center. Such an architecture confers to the metal ion very unusual properties and behaviors, which in many aspects are biologically relevant. Three generations of calix[6]-based ligands are presented and discussed in the context of modeling the monocopper sites encountered in some enzymes. A wide range of phenomena are highlighted such as the impact that the size and shape of the access channel to the metal center have on the selectivity and rate of the binding process, the possible remote control of the electronics through small modifications operated on the cavity edges, induced-fit behavior associated with host-guest association (shoe-tree effect) that affects the redox properties of the metal ion and the electron exchange pathway, consequences of forbidden associative ligand exchange allowing a redox switch to drive an "antithermodynamic" ligand exchange, drastic effects of the full control of the second coordination sphere, and dioxygen activation in a confined chamber conducted to a selective and unusual four-electron redox process. All these findings bring new clues for better understanding the control exerted by the proteic environment on a metal center, allow the identification of new reaction pathways, and lead to new proposals for enzymatic catalytic cycle (such as the formation of an alkylhydroperoxide intermediate for mononuclear Cu-hydroxylases). The supramolecular systems may also be exploited for designing highly selective and sensitive probes for molecules of particular function and shape or to design new selective catalysts.