The Huisgen thermal reaction between an organic azide and an acetylene was employed for the selective monofunctionalization of a X6-azacryptand ligand bearing a tren coordinating unit [X6 stands for calixarene and tren for tris(2-aminoethyl)amine]. Supramolecular assistance, originating from the formation of a host–guest inclusion complex between the reactants, greatly accelerates the reaction while self-inhibition affords a remarkable selectivity. The new ligand possesses a single amino-leg appended at the large rim of the calixarene core and the corresponding Zn2+ complex was characterized both in solution and in the solid state. The coordination of Zn2+ not only involves the tren cap but also the introverted amino-leg, which locks the metal ion in the cavity. Compared with the parent ligand deprived of the amino-leg, the affinity of the new monofunctionalized X6tren ligand 6 for Zn2+ is found to have a 10-fold increase in DMSO, which is a very competitive solvent, and with an enhancement of at least three orders of magnitude in CDCl3/CD3OD (1:1, v/v). In strong contrast with the fast binding kinetics, decoordination of Zn2+ as well as transmetallation appeared to be very slow processes. The monofunctionalized X6tren ligand 6 fully protects the metal ion from the external medium thanks to the combination of a cavity and a closed coordination sphere, leading to greater thermodynamic and kinetic stabilities.