Stereodynamics of nitrogen chiral centers in aza-β3-cyclodipeptides.

The present work is devoted to the synthesis, conformational analysis, and stereodynamic study of aza-β(3)-cyclodipeptides. This pseudopeptidic ring shows E/Z hydrazide bond isomerism, eight-membered ring conformation, and chirotopic nitrogen atoms, all of which are elements that are prone to modulate the ring shape. The (E,E) twist boat conformation observed in the solid state by X-ray diffraction is also the ground conformation in solution, and emerges as the lowest in energy when using quantum chemical calculations.

Z/E isomerism in Nα-Nα-disubstituted hydrazides and the amidoxy bond: application to the conformational analysis of pseudopeptides built of hydrazinoacids and α-aminoxyacids.

We have investigated the Z/E isomerism of the hydrazide link (CO-NH-N) and amidoxy link (CO-NH-O). The study was first focused on small molecular models using NMR and X-ray diffraction. It allowed determination of simple NMR criterions to differentiate easily the Z and E forms, which were then applied to investigate the behavior of these links inside the corresponding oligomers.

Aza-beta3-cyclopeptides: a new way of controlling nitrogen chirality.

Sixteen and 24 membered aza-beta(3)-peptidic macrocycles containing a alpha-hydrazinoacid or a beta(3)-aminoacid were synthesized. The conformation of these pseudopeptides was determined by using NH chemical shift analysis, NH extinction, VT-NMR experiments, and X-ray diffraction. The study shows that a stable conformation is retained between 223 and 413 K.

Aza-beta3-cyclotetrapeptides.

The cyclization of aza-beta(3)-tetrapeptides gives access to new CTP (cyclotetrapeptide) analogues. These stereocontrolled templates are assembled without any asymmetric synthesis. X-ray crystallographic structure and NMR analysis show that the macrocyclic scaffold is characterized by a fully cooperative intramolecular H-bond network, in sharp contrast with the nanotubular assemblies observed for beta(3)-cyclotetrapeptides.

Postsynthetic modification of C3-symmetric aza-beta3-cyclohexapeptides.

We have synthesized a series of C3-symmetric aza-beta3-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 aza-beta3-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.

Aza-beta3-cyclohexapeptides: pseudopeptidic macrocycles with interesting conformational and configurational properties slow pyramidal nitrogen inversion in 24-membered rings!

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.

Conformation of N(alpha)-substituted hydrazino acetamides in CDCl3, the precious help of the analysis of Deltadelta between amidic hydrogens, and correlation to the conformation of aza-beta3-peptides.

[structures: see text] We studied the conformation of a series of primary amides in a solution of chloroform. Classical NMR tools such as dilution experiments, influence of DMSO, and 2D-NOESY, together with X-ray diffraction, were combined with an analysis of the difference of the chemical shift Deltadelta between the geminal amidic protons. This study was addressed in order to understand the conformation adopted by hydrazino acetamides 1a and 1b as model compounds for aza-beta3-peptides.

Crystal structures of aza-beta3-peptides, a new class of foldamers relying on a framework of hydrazinoturns.

Crystals of aza-beta3-peptides have been obtained. This gives the first opportunity for hydrazino peptides, in the sense of oligomers built exclusively with alpha-hydrazinoacetic units, to be observed in the solid state. The structures make it clear that the H-bond network developed by aza-beta3-peptides differs radically from those of the corresponding beta3-peptides but strongly resembles that of the alpha-aminoxy peptides.