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Two new tetradentate C2-symmetric pseudopeptidic ligands derived from Val and Phe containing two amino and two amido groups and a central o-substituted aromatic spacer have been prepared. Their complexes with Cu2+, Zn2+, and Ni2+ have been studied by potentiometry, UV−vis spectrophotometry, FT-IR, and ESI-MS. The presence of the aromatic spacer provides Cu2+ complexes with stability constants several orders of magnitude higher than those observed for related ligands containing aliphatic central spacers. Besides, the formation of [MH−2L] complex species is favored. Crystal structures for the corresponding Cu2+ and Ni2+ have been obtained, revealing the metal atom in an essentially square-planar geometry, although, in several instances, the oxygen atom of an amide carbonyl of a second complex species can act as a fifth coordination site. In the case of Zn2+, the only crystal structure obtained displays a square-pyramidal arrangement of the metal center. Finally, preliminary experiments show the catalytic activity of some of these complexes, in particular, Zn2+ complexes, for epoxide ring-opening with using aniline as the nucleophile in a ligand accelerated process. Spanish MINECO CTQ2015-68429-R Generalitat Valenciana PROMETEO/2012/020 GRISOLIA 2012/015 PPI-UJI P1-1B-2013-38

A family of pseudopeptidic macrocycles containing non-natural amino acids have been synthesized. The macrocyclization reaction has been studied experimentally and computationally, demonstrating the key role of both the amino acid side chain and the catalytic bromide anion. The bromide anion acts as an external template assisting the folding of the open-chain precursor in a proper conformation. Computations revealed that in the presence of the anion, the effect of the side chain on the energy barrier for the macrocyclization is very small. However, the effect on the conformational equilibria of the open-chain precursors is very important. Overall, the stabilization of those conformation(s) in which the two reactive ends of the open-chain intermediate are located at short distances from each other with the correct orientation is the critical parameter defining the success of the macrocyclization. The best yield was found for the compound containing cyclohexylalanine, for which the computationally-predicted most stable conformer in the presence of Br- has a proper preorganization for cyclization. The remarkable agreement obtained between experiments and theory reveals that the computational approach here considered can be of great utility for the prediction of the behavior of other related systems and for the design of appropriate synthetic routes to new macrocyclic compounds. © 2013 American Chemical Society., S.V.L. acknowledges GV (PROMETEO/2012/020) and MINECO (CTQ2012-38543-C03-01). C.C. acknowledges Ministerio de Ciencia e Innovación−FEDER (CTQ2010- 17436) and Gobierno de Aragón−FSE (Research Group E40). V.M.-C. thanks MICINN for personal financial support (FPU Fellowship AP2007-02562).