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We have synthesized a series of
C3-symmetric aza-
3-cyclohexapeptides with functionally diverse sidechains 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, leadingto a wide family of
C3-symmetric cyclohexapeptides analogues. The macrocyclic backbone of the aza-
3-cyclohexapeptides shows a highly ordered conformation that is sustained by a dense intramolecularH-bond network where all endocyclic NHs are hydrogen bonded, the side chains being projected inequatorial position around the macrocycle. The resulting internal secondary structure relies on thecooperative alternation of two slightly different C
8-bifidic pseudocycles, which differ mainly by thehybridization of the N
nitrogen atom (N-N
sp3-turn and N-N
sp2-turn). In both cases, the nitrogen lonepair participates to stabilize the pseudocycle. This has been established by NMR experiments and X-raydiffraction analysis. As in the precursors, the nitrogen stereocenters are characterized by a strikinglyslow rate of pyramidal inversion, considering the size of the macrocycle.