Hn y n r N Y N A N A x Ao

side view

Fig. 2.7 Foldamers with propensities for 1 ^ 3 H-bonded conformations by introduction of heteroatoms in the backbone of o-peptides. (A) General formulae and comparison with related o-peptide backbones. X-ray structures of N-O turns in a-, b-, g-aminoxy peptides [112, 113, 117, 120]. (B) The Cs H-bonded conformation (1.88-helix) of a-aminoxy peptides [113].

(C) The hydrazino turn and solid state conformation of aza-b3-peptides (dimer and hexamer) [125]. (D) Solid state conformation of an aza-b3-cyclohexapeptide showing the uninterrupted framework of bifidic Cg pseudocycles. For clarity, side chains are omitted on bird's-eye view and side view [128].

bonds. In addition, the lone pair electron repulsion in the N-O segment reduces the flexibility of the backbone, which stabilizes the secondary structure, and promotes H-bonding between adjacent residues by selecting favorable dihedral angles. The crystal structure of a model trimer, in good agreement with the calculated geometry of the N-O turn, comfirm this analysis [116].

Small models of b-aminoxypeptides [117-119] and g-aminoxypeptides [120] (Fig. 2.7A) were subsequently investigated by the group of Yang. FT-IR and NMR spectroscopy as well as X-ray diffraction studies also indicated a net preference for 1 ^ 3 H-bond interaction, leading respectively to the formation of C9 and C10 pseudocycles (Fig. 2.7A). The C9 ring is clearly an inverse bifurcated system where the NHi+2 is H-bonded to both Oi+1 and C=O; (d(Ni+2-Oi+1) = 2.5 A). It is not the case for the C10 pseudocycle (right) where the distance between O;+j to NHi+2 is too long (d(N;+2-Oi+1) = 3.3A).

Hydrazinopeptides Oligomers of hydrazinoacetic acid derivatives are aza3-analogs of b2-peptides (Fig. 2.7A). Secondary structure ensembles for these compounds have been examined at various level of ab initio MO theory by Giinther and Hofmann [121]. The variety of H-bond networks in hydrazinopeptides is increased compared with b-peptides because of the additional N aH centers which act as potential H-bond donors and H-bond acceptors. A C8 based helical conformation (calculated 1.75s-helix), similar to that observed for a-aminoxy peptides, emerged in one mode of calculation. In all other cases the most favorable calculated secondary structure is a new 14-helix that topologically differs from the b-peptide 14-helix because of the participation of the lone pair of the sp3 Na atom in the stabilization of the 14-membered H-bonded ring. Although the synthesis of chiral hydrazinopeptides remains challenging, a series of hydrazinopeptides up to the hexamer have been prepared by Seebach and co-workers [122]. In MeOH, the hexamer displays a CD signature that resembles that of the corresponding 14-helical b2-peptide. However, poor signal dispersion and fast exchange between NHs precluded detailed NMR studies and subsequent molecular modeling. These observations suggest dynamic interconversion between competitive conformations.

Aza-b3-peptides Aza-b3-peptides [123], the aza3-analogs of b3-peptides, are oligomers of Na-substituted hydrazinoacetic acid (Fig. 2.7A, right). The main feature of this unnatural backbone is that nitrogen atoms bearing the side chains are sp3 hybridized. As a result, aza-b3-peptides are chiral molecules of undefined configuration. In CDCl3 solution as well as in the solid state, their backbone is structured by a continuous set of C8 pseudocycles (hydrazinoturn [124] or N-N turn) [125]. Examination of X-ray structures of a dimer and a hexamer (Fig. 2.7C) reveals that the former corresponds to a homochiral sequence (both nitrogen centers have the same absolute configuration) that defines an incipient extended !.758-helix whereas the latter is characterized by an heterochiral arrangement (R,R,S,S,R,R chiral sequence) that drives a more folded conformation. In solution, aza-b3-peptides equilibrate between all possible chiral sequences, all of which share the same C8 based H-bond network. The structural resemblance between a-aminoxypeptide and aza-b3-peptide backbones which both rely on the formation of a C8 H-bonded network is striking. In both cases, the presence of the two adjacent heteroatoms is the driving force of the folding process. In aza-b3-peptide C8 pseudocycles, the aN;+1---H-bN;+2 distance (@2.25A) is typical of a H bond but the corresponding angle (@110° ) is distorted relative to the expected value for a standard H bond. The same holds true for the N-O turn (d(aOj+1---H-bN;+2)). This interaction has been shown to play a crucial role in the stabilization of the secondary structure [126]. The C8 pseudocycle of aza-b3-peptide and probably the N-O turn can thus be described as inverse bifurcated systems combining interactions between nearest and non-nearest neighbors [127]. Conformational analyses of aminoxy- and hydrazino-peptides, and also studies of N,N'-linked oligoureas described in Section illustrate that the amide linkage is not the only polar bond that can sustain a robust intramolecular H-bond network for the design of self-organizing oligomers.

It is noteworthy that the intrinsic features and conformational preferences of linear aza-b3-peptides can be exploited to generate macrocyclized derivatives with remarkable efficiency (for example of self-templated macrocycles, see Chapter 1). This result can be rationalized by invoking a dynamic process, i.e. the ability of linear precursors to populate heterochiral sequences ideally pre-organized for cyc-lization. The resulting macrocycles retain the alternated chiral sequence (the pyramidal inversion of the chiral nitrogen atoms is now considerably slowed down) as well as the basic C8 structure (C3-symetric hexamer, Fig. 2.7D) [128]. The solid state intramolecular organization of the macrocycles perfectly reflects the major conformation present in solution (CDCl3).

To conclude this section, it is interesting to point out that, in contrast to the natural a-peptides, 1 ^ 3 H-bond interaction patterns consistently sustain secondary structures in different classes of designed o-peptides and their related analogs. A survey of the present literature also emphasizes how much folding can be oriented through slight structural modulations, such as stereochemical modifications, side chain tuning, and backbone alteration, which all subtly modulate the set of weak intramolecular interactions and, in the end, the shape of the molecules.

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