Conformational Studies of Phe-Rich Foldamers by VCD Spectroscopy and ab Initio Calculations

Employing VCD spectroscopy, we demonstrate that the structural behavior of the oligomers Boc-(l-Phe-l-Oxd)_<i>n</i>-OBn is similar from <i>n</i> = 2 to <i>n</i> = 6; ab initio calculations for the <i>n</i> = 1 case provide physical insight into the conformational properties. Further information is gained by IR, ¹H NMR, and ECD spectroscopies. ECD spectra suggest the presence of different conformations between n = 1 on one side and longer chain foldamers on the other side. VCD and absorption IR spectra in methanol solutions can be interpreted as indicative of a PPII structure. In the case of Boc-l-Phe-l-Oxd-OBn, VCD spectra in CCl₄ and detailed DFT computational analysis allow one to demonstrate that the most populated conformers exhibit backbone dihedral angles similar to those of a PPII geometry. This is a remarkable outcome, as we had previously demonstrated that the Boc-(l-Ala-d-Oxd)<i>_n</i>-OBn series folds in a β-band ribbon spiral that is a subtype of the 3₁₀ helix

Synthesis of 1,8-Diazaanthracenes as Building Blocks for Internally Functionalized Aromatic Oligoamide Foldamers

The synthesis of a variety of 9-functionalized 1,8-diazaanthracene diesters and amino acids is described. Derivatization at the 9-position relies on facile reactions performed on the 9-chloro and 9-bromomethyl precursors. This has allowed the incorporation of nucleophilic or sensitive functional groups that otherwise cannot be incorporated under standard methods for synthesizing these compounds. Additionally, the synthesis of the protected amino acids via a high-yielding monosaponification and subsequent Curtius rearrangement has been accomplished on a multigram scale. These units, together with the functionalized derivatives, should prove to be useful monomers in the synthesis of aromatic oligoamide foldamers

α,ε-Hybrid Foldamers with 1,2,3-Triazole Rings: Order versus Disorder

Two epimeric series of foldamers characterized by the presence of a repeating α,ε-dipeptide unit have been prepared and characterized by ¹H NMR and ECD spectroscopies together with X-ray diffraction. The first series contains l-Ala and d-4-carboxy-5-methyl-oxazolidin-2-one (d-Oxd). The other series contains l-Ala and l-Oxd. The l,d series of oligomers forms ordered β-turn foldamers, characterized by a 3₁₁ pattern. The l,l series is not ordered. Simulations show that an ordered l,l trimer lies more than 2 kcal/mol higher than the more stable nonfolded extended conformations. Cu²⁺ forms complexes with both series but is not able to order the l,l series. Analysis of the EPR spectra shows that the l,d foldamers bear two types of complexation sites that are assigned as a nitrogen donor of the triazole ring and a carboxylate ligand. The l-Ala-d-Oxd-Tri-CO motif may be introduced in any peptide sequence requiring the presence of a stable β-turn conformations, like in the study of protein–protein interactions