Mixed Oligoureas Based on Constrained Bicyclic and Acyclic β‐Amino Acids Derivatives: On the Significance of the Subunit Configuration for Folding

Abstract

The combination of a non-functionalized constrained bicyclo[2.2.2]octane motif along with urea linkages allowed the formation of a highly rigid 2.5(12/14) helical system both in solution and the solid state. In this work, we aimed at developing stable and functionalized systems as promising materials for biological applications in investigating the impact of this constrained motif and its configuration on homo and heterochiral mixed-oligourea helix formation. Di-, tetra-, hexa-, and octa-oligoureas alternating the highly constrained bicyclic motif of (R) or (S) configuration with acyclic (S)-β(3)-amino acid derivatives were constructed. Circular dichroism (CD), NMR experiments, and the X-ray crystal structure of the octamer unequivocally proved that the alternating heterochiral R/S sequences form a stable left-handed 2.5-helix in contrast to the mixed (S/S)-oligoureas, which did not adopt any defined secondary structure. We observed that the (-)-synclinal conformation around the C(α)-C(β) bond of the acyclic residues, although sterically less favorable than the (+)-synclinal conformation, was imposed by the (R)-bicyclic amino carbamoyl (BAC) residue. This highlighted the strong ability of the BAC residue to drive helical folding in heterochiral compounds. The role of the stereochemistry of the BAC unit was assessed and a model was proposed to explain the misfolding of the S/S sequences.

12/14/14‐Helix Formation in 2:1 α/β‐Hybrid Peptides Containing Bicyclo[2.2.2]octane Ring Constraints

“…NMR structures of 3 superimposed well with the predicted structure of b/a/a-hydrid peptides (Supporting Information, FigureS5). Furthermore, it could be noticedt hat the ABOC backbonet orsional angles were nearly similar to those previously observedw ithin the 12/14 helix of the ABOC-based oligoureas [25,26] and also within the 11/9-and 18/16-helices of the 1:1 a-AA/ABOCo ligoamides, [16] emphasizing its high conformationalr estriction. The 1:1a nd 2:1 a-AA/ABOC-peptide helices exhibited different helical parameters that affect their stabilitya nd the relative distribution of the ABOC and a residues along the axis of the helices ( Figure 4).…”

“…Incorporation of proteogenic or unnatural α‐amino acids constitutes a convenient way to generate well‐structured hybrid peptides with a large diversity of functional groups. In this context, we recently investigated the structural properties of short oligomers containing both the constrained β 2,3,3 ‐trisubstituted bicyclic amino acid ABOC residue that has showed to promote helical conformations in homo‐ and mixed oligoureas, and proteogenic α‐amino acid in a 1:1 alternating pattern . We demonstrated that these α/β‐hybrid peptides adopt an 11/9‐helix in the solid state, while a conformational polymorphism as a chain‐dependent phenomenon was observed in solution.…”

C1‐Symmetric 1,2‐Diaminobicyclo[2.2.2]octane Ligands in Copper‐Catalyzed Asymmetric Henry Reaction: Catalyst Development and DFT Studies

“…We recently reported on the synthesis of a bicyclic C 1 ‐symmetric chiral 1,2‐diamine [( R )‐DABO] containing a bicyclo[2.2.2]octane motif with one amine function at the bridgehead position . This bridged bicyclic skeleton was recently proven to highly restrict the conformation of ( R )‐ and ( S )‐1‐aminobicyclo[2.2.2]octane‐2‐carboxylic acid (ABOC), which are useful as potent helix inducers in homo‐ and mixed oligoureas,[10a] and in 1:1 or 2:1 α,β‐hybrid peptides,[10b], [10c] or as part of α,β‐peptide organocatalysts used in asymmetric aldol reactions . Considering the significance of steric factors in chiral catalyst systems based on C 1 ‐symmetric ligands and the high constraint capacity of DABO, we investigated a series of its copper–diamine ligand derivatives for the asymmetric Henry reaction.…”

12/10‐Helix in Mixed β‐Peptides Alternating Bicyclic and Acyclic β‐Amino Acids: Probing the Relationship between Bicyclic Side Chain and Helix Stability

“…Over the last few years, we investigated the ability of peptide sequences incorporating the ( S )‐1‐aminobicyclo[2.2.2]octane‐2‐carboxylic acid [( S )‐ABOC] residue, a constrained β 2, 3, 3 ‐trisubstituted bicyclic amino acid, to adopt well‐defined structures. We previously showed the high propensity of the ABOC residue to drive helical architectures in both oligoureas and hybrid‐oligoamides in alternation with α‐amino acids –. Importantly, the ABOC torsion angle values (typical average values φ =75°, θ =58°, ψ =−91°) were almost identical in these various edifices, highlighting the high rigidity of this moiety, which is of great interest to develop predictable and stable scaffolds.…”