Aza-β3-Cyclohexapeptides:  Pseudopeptidic Macrocycles with Interesting Conformational and Configurational Properties Slow Pyramidal Nitrogen Inversion in 24-Membered Rings

• Published in: Journal of organic chemistry 2006-07, Vol.71 (15), p.5638-5645
• Main Authors: Le Grel, Philippe, Salaün, Arnaud, Potel, Michel, Le Grel, Barbara, Lassagne, Fredéric
• Format: Article
• Language: English
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Chemistry; Exact sciences and technology; Organic chemistry; Preparations and properties
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0608467

Among pseudopeptidic foldamers, aza-β3-peptides have the unique property to possess nitrogen stereocenters instead of carbon stereocenters. As the result of pyramidal inversion at Nα-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-β3-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-β3-cyclohexapeptides is reminiscent of the interchange between the two chair forms of cyclohexane.