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The synthesis and conformational study of N -substituted β-alanines with tert -butyl side chains is described. The oligomers prepared by submonomer synthesis and block coupling methods are up to 15 residues long and are characterised by amide bonds in the cis -conformation. A conformational study comprising experimental solution NMR spectroscopy, X-ray crystallography and molecular modeling shows that despite their intrinsic higher conformational flexibility compared to their α-peptoid counterparts, this family of achiral oligomers adopt preferred secondary structures including a helical conformation close to that described with (1-naphthyl)ethyl side chains but also a novel ribbon-like conformation.

The design of linear peptoid oligomers adopting well-defined secondary structures while mimicking defined peptide primary sequences is a major challenge in the context of drug discovery. To this end, chemists have developed cis-inducing peptoid side chains to build robust polyproline type I helices. However, the number of efficient examples remains scarce and chemical diversity accessible through the use of these side chains is limited. Herein, we introduce an array of NCα-gem-dimethylated peptoid residues mimicking proteinogenic amino acids. Submonomer synthesis and block-coupling approaches were explored to access heterooligomers incorporating these novel types of side chains. NMR studies of monomer and trimer models showed that the NCα-gem-dimethylated groups exert complete cis control on the backbone amide conformation. Lastly, a preliminary molecular modeling study gave an insight into the preferred orientation of the substituents of the NCα-gem-dimethyl side chains relative to the peptoid backbone., (© 2019 Wiley Periodicals, Inc.)

The synthesis and conformational preferences of a set of new synthetic foldamers that combine both the α,β-peptoid backbone and side chains that alternately promote cis- and trans-amide bond geometries have been achieved and addressed jointly by experiment and molecular modeling. Four sequence patterns were thus designed and referred to as cis-β- trans-α, cis-α- trans-β, trans-β- cis-α, and trans-α- cis-β. α- and β NtBu monomers were used to enforce cis-amide bond geometries and α- and β NPh monomers to promote trans-amides. NOESY and molecular modeling reveal that the trans-α- cis-β and cis-β- trans-α tetramers show a similar pattern of intramolecular weak interactions. The same holds for the cis-α- trans-β and trans-β- cis-α tetramers, but the interactions are different in nature than those identified in the trans-α- cis-β-based oligomers. Interestingly, the trans-α- cis-β peptoid architecture allows establishment of a larger amount of structure-stabilizing intramolecular interactions.

The head-to-tail conversion of linear arylopeptoids (oligomeric N-substituted aminomethyl benzamides) into the derived novel macrocycles has enabled the first X-ray structures of arylopeptoid constructs and the identification of well-defined architectures in solution.

The presence of at least one N-Cα branched side chain is crucial for successful cyclization of α,β-tetrapeptoids. The ctct amide sequence revealed in the crystal structure of the 14-membered cyclotetrapeptoid 8 is also the most populated conformation in solution and is reminiscent of the predominant amide arrangement of the 12-membered cyclic tetrapeptides (CTPs).

Access to homogeneous and discrete folded peptoid structures primarily depends on control of the cis/trans isomerism of backbone tertiary amides. This can be achieved by designing specific side chains capable of forming local interactions with the backbone. This is often undertaken at the expense of side-chain diversity, which is a key advantage of peptoids over other families of peptidomimetics. We report for the first time a positively charged triazolium-type side chain that does not compromise diversity and exhibits the best ability reported to date for inducing the cis conformation. The cis-directing effect was studied in N-acetamide dipeptoid model systems and evaluated in terms of K(cis/trans) using NMR spectroscopy in aprotic and protic solvents. Computational geometry optimization and natural bond orbital analysis in combination with NOESY experiments were consistent with a model in which n → π*(Ar) electronic delocalization [from carbonyl (O(i-1)) to the antibonding orbital (π*) of the triazolium motif on residue i] may be operative. In the computational model (gas-phase) and experimentally in CDCl(3), H-bonding between the triazolium C-H proton and the C(i)═O(i) oxygen was also identified and may act cooperatively with the n → π*(Ar) delocalization, resulting in the absence of the trans rotamers in CDCl(3).

The solution-phase synthesis and cyclisation of three α,β-peptoid octamers with differing side chain patterns is reported. One of these, compound C, showed a significantly greater resolution by NMR relative to the other two structurally related octamers. This observation was studied in detail by circular dichroism at a synchrotron light source to facilitate the correlation between the side chain patterns and conformational preference of these three peptoids. The X-ray crystal structure of cyclic octamer C, the first high-resolution structure for the α,β-peptoid backbone, was also obtained from methanol. Combined solid- and solution-phase studies allowed the identification of the N-2-(benzyloxy)ethyl side chain on the β-residue of the heterogeneous backbone as a key structural feature driving the increased conformational stability for octamer C.

The first synthesis of functionalized beta-peptoid macrocycles is reported. X-ray crystallographic structure of tetramer 9 reveals a C2-symmetrical derivative with unexpected all-cis-amide bonds and spatial disposition of the appendages toward the two opposite faces of the ring. Quantum calculations suggest that 9 is locked in this layout. These macrocycles constitute novel promising templates for multimeric ligation of biologically active ligands. The concept was exemplified by chemical decoration of tetramer 9 via "click" reactions.

Abstract: Submonomer synthesis in solution and block‐coupling protocols were combined to prepare amphiphilic peptoid hexamers. The amphipathic character arises from the use of hydrophobic aliphatic tert‐butyl side‐chains imposing the cis‐amide backbone conformation and various cationic side‐chains periodically introduced each three residues. Evaluation of the effect on Gram‐positive and Gram‐negative bacterial strains as well as the capacity to impair biofilm formation and the toxicity of one selected compound allowed to highlight the potential of a short constrained peptoid carrying triazolium‐type cationic pendant groups. [ABSTRACT FROM AUTHOR]