Postsynthetic modification of C3-symmetric aza- β3-cyclohexapeptides

Article abstract of DOI:10.1021/jo7021394

(Chemical Equation Presented) We have synthesized a series of C ₃-symmetric aza-β³-cyclohexapeptides with functionally diverse side chains carrying a good functional diversity. The very simple chemical sequence that we used (debenzylation/acylation) makes it certain that the series synthesized could be easily expanded, leading to a wide family of C₃-symmetric cyclohexapeptides analogues. The macrocyclic backbone of the azaβ³-cyclohexapeptides shows a highly ordered conformation that is sustained by a dense intramolecular H-bond network where all endocyclic NHs are hydrogen bonded, the side chains being projected in equatorial position around the macrocycle. The resulting internal secondary structure relies on the cooperative alternation of two slightly different C ₈-bifidic pseudocycles, which differ mainly by the hybridization of the N^α nitrogen atom (N-N_sp²-turn and N-N_sp²-turn). In both cases, the nitrogen lone pair participates to stabilize the pseudocycle. This has been established by NMR experiments and X-ray diffraction analysis. As in the precursors, the nitrogen stereocenters are characterized by a strikingly slow rate of pyramidal inversion, considering the size of the macrocycle.