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

Abstract

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.

Impact of Cα‐Chirality on Supramolecular Self‐Assembly in Cyclo‐2:1‐[α/aza]‐Hexamers (d/l‐Phe‐azaPhe‐Ala)2

“…Indeed the N α atom of the azaPhe (i + 2) residue showed a slight pyramidal character with a distance of 0.202 Å from the plane and it has d ‐configuration, whereas the N α atom of the azaPhe (i + 5) residue also shows a pyramidal character but with l ‐configuration and is located out of the plane by 0.232 Å. This inversion of configuration may be a result of interconversion from intramolecular to intermolecular hydrogen bonding with increases in concentration, which has been already observed in literature, and we will discuss this later in this paper . Moreover, X‐ray diffraction experiments revealed that the interatomic distance between the polar sites (NH i+3 ··· O i ) is 2.83 Å, which is an adequate value for intramolecular hydrogen bond interaction by leading to the formation of pseudocycle of 10 atoms between the (CO i ) Ala and (NH i+3 ) Ala from the type (i + 3→i) as shown in Figure (see Supporting Information, Table S2).…”

“…This inversion of configuration may be a result of interconversion from intramolecular to intermolecular hydrogen bonding with increases in concentration, which has been already observed in literature, and we will discuss this later in this paper. [16] More-over, X-ray diffraction experiments revealed that the interatomic distance between the polar sites (NH i+3 ···O i ) is 2.83 Å, which is an adequate value for intramolecular hydrogen bond interaction [17] by leading to the formation of pseudocycle of 10 atoms between the (CO i ) Ala and (NH i+3 ) Ala from the type (i + 3→i) as shown in Figure 1 (see Supporting Information, Table S2). In addition, the distance between C α of residues (i) and (i + 3) of the pseudocycle is less than 7 Å, which supports the existence of -turn conformation.…”

Synthesis and Chemistry of α‐Hydrazino Acids

“…Quantum chemical calculations carried out on b-3-aza-peptides reveal the presence of a wide variety of secondary structures [85]. Experimental studies with linear or macrocyclic oligomers of N 1 -substituted hydrazinoacetic acid (b 3 -3-aza peptides) showed remarkable conformations, the presence of hydrazino turns, and foldamer behavior [86][87][88][89]. …”

“…Activation of acids using carbodiimides allows the acylation of hydrazino acetic derivatives 94 (R 1 ¼ H) in fair to very good yields, in solution-phase synthesis (entries 1-3) [43,49,84,87] and in solid-phase synthesis (entry 4) [70]. Activation of acids using carbodiimides allows the acylation of hydrazino acetic derivatives 94 (R 1 ¼ H) in fair to very good yields, in solution-phase synthesis (entries 1-3) [43,49,84,87] and in solid-phase synthesis (entry 4) [70].…”

“…In the case of N 1 ,N 2 -diprotected a-hydrazino acids, activation and coupling proceed without any problems using liquid-phase [43,59,68,84,87] or solid-phase synthesis techniques [70,202]. Activation of the carboxyl group and subsequent peptidic coupling have been realized using several reagents.…”