Selective functionalization of complex polyamines through their supramolecular protection by Ox3. In a further series of experiments, we evaluated the potential of the supramolecular protection approach for the selective functionalization of more complex polyamines such as lysine derivatives and a triamine. The substrates were reacted with various reagents in the presence of molecular container Ox3 (Scheme 5). First, the functionalization of tris(3-aminopropyl)amine 6 with 3,5-bis(trifluoromethyl)phenyl isothiocyanate was monitored in the presence of PicH (in CDCl3/CD3CN, 9:1). Difunctionalized product 7 was obtained as the only observable species (91% NMR yield) when using 2 equiv. of the isothiocyanate. This result highlights the efficient protection provided by Ox3 for one of the three amino groups of 6 and opens the door to the iteroselective functionalization of all but one amine groups of polyamines. Even more remarkably, L-lysine ethyl ester.HCl 8 was regio-and iteroselectively monofunctionalized (in CDCl3/CD3OD, 4:1) at the level of its less reactive N-terminal group, leading to products 9a (90% NMR yield) or 9b (95% NMR yield) as the only observable species (Scheme 5). The regioselectivity originates from the selective supramolecular protection of the amine group of the side chain for steric reasons. The fact that molecular containers can provide a size and shape cavity-based selectivity 25 represents another advantage of their use as protection units.