Among pseudopeptidic foldamers, aza-beta3-peptides have the unique property to possess nitrogen stereocenters instead of carbon stereocenters. As the result of pyramidal inversion at N(alpha)-atoms along the backbone, they behave as a set of C8-based secondary structures in equilibrium. This structural modulation is exploited here to prepare 24-membered macrocycles with great efficiency. Both crystal structures and spectroscopic data establish that aza-beta3-cyclohexapeptides adopt a highly organized conformation where the relative configuration of chiral nitrogen atoms is alternated. This makes them an interesting scaffold as the stereocontrol occurs spontaneously through the cyclization. These compounds reveal an unprecedented slow pyramidal nitrogen inversion in macrocycles. Pyramidal ground state stabilization, hindered rotation, steric crowding, and H-bond cooperativity are proposed to participate in this striking phenomenon. The equilibrium between invertomers of aza-beta3-cyclohexapeptides is reminiscent of the interchange between the two chair forms of cyclohexane.
International audienceThe metallation of aryl ketones was achieved by using LiTMP in the presence of ZnCl2 center dot TMEDA, as evidenced by subsequent interception with iodine or by a palladium-catalysed cross-coupling reaction. One of the synthesized iodo ketones has been further elaborated to reach derivatives of biological interest
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