Self-assembled chiral dimeric capsules from difunctionalized N,C-linked peptidocalix[4]arenes: scope and limitations

In this paper we report the synthesis of the first examples of upper (wide) rim calix[4]arene amino acids 5 and 27, together with the conformational, self-assembly and molecular inclusion properties of the N,C-linked peptidocalix[4]arenes obtained from them. Whereas the dipropyl derivative 5 readily undergoes peptide synthesis allowing a small library of calix[4]arene pseudopeptides 12–21 to be obtained, the tetrapropoxy compound 27 preferentially gives upper-rimbridged derivatives (e.g., 28) which are formed through an intramolecular condensation reaction. The tetrapropoxycalix[ 4]arene pseudopeptide 33 shows conformational and self-assembly properties quite different to those of the dipropoxy derivatives 12–21. The observed differences are explained on the basis of the different conformational flexibilities of the two calix[4]arene scaffolds. Calixarene 5 is more rigid than 27 thanks to the presence of two OH groups at the lower (narrow) rim that are involved in strong intramolecular hydrogen bonds. Only peptidocalix[4]arenes 12–21 but not 33 form hydrogen-bonded dimeric capsules in which the two macrocycles approach each other face-to-face and rotated by 180° with respect to the other in order to allow hydrogenbonding complementarity between the interacting peptide chains, which, in some cases (17–19), form an antiparallel β sheet enhancing the stability of the capsule. The structures of the chiral dimeric capsules were established by molecular modelling calculations and NOESY NMR experiments, which give consistent results, whereas their stability in CDCl3 (69Kdim950 M–1) was determined by dilution NMR experiments. Compound 12 forms both 1:1 and 2:1 [K11 = (7.81.2)102 M–1, K21 = (1.80.2)105 M–2] host:guest complexes with the methylpyridinium (MePy+) cation in CD2Cl2/ CDCl3 (10:1, v/v). There is no evidence for a guest template effect in stabilizing the supramolecular capsule.