Determining Conformational Preferences of Shape-Persistent Aromatic Oligoamides and Folding of Aromatic Oligoureas with Ion-Pair Associations
MetadataShow full item record
The synthesis and characterization of folding aromatic oligoamides with reducedconstraint, ion-pair associations and solvent-mediated folding of aromatic oligoureas, andoligoamides with unique conformational variations involving simple structural inversion arepresented in this thesis.Chapter 1 is a review of the foldamer field defining structural features of peptides that aredesired for replication by artificial building blocks. Foldamers are characterized as eitherpeptidomimetic or abiotic based on intrinsic properties of the building blocks utilized. Eachsection of peptidomimetic and abiotic foldamers demonstrates the systematic design andcharacterization utilized for each system, including highlights of progressive developmentswithin the field. This leads into the early development of helical aromatic oligoamides,developed by Gong and coworkers, incorporating rotation restricting three-center hydrogenbonds imbedded in the backbone. Overall, providing the relationship between our helicalaromatic oligoamides and their place in the foldamer field.Chapter 2 presents modifications in the design of robust aromatic oligoamides toincorporate reduced hydrogen bonding constraint within the backbone. This increased flexibilitywas to improve protein-like folding behavior for these previously robust oligoamides. Flexibilitywas designed by removing aromatic side chains adjacent to the benzene residues allowing only5-membered ring (two-center) hydrogen bonding to remain. Two variations of oligoamides weresynthesized involving alternating constraint consisting of interchanging three- and two-centerhydrogen bonding along the aromatic backbone, and reduced constraint with only 2-centerhydrogen bonding. Folding potentials are presented utilizing a combination of circulardichroism, 1D/ 2D NMR experiments, thermal denaturation and titration experiments in varyingsolvent conditions.Chapter 3 begins with an overview of past aromatic oligourea design and cationicrecognition of uncyclized and cyclized aromatic tetraureas. Anionic recognition of halides withureas observed in literature was confirmed by concentration-dependent 1H-NMR experiments foraromatic urea dimers, similar in structure to elongated oligourea sequences. Anions were alsoobserved to associate with oligourea trimers with similar affinities compared to theirivtetraethylammonium salt counterions, not previously observed for the dimers. Cation bindingwithin the cavity of these trimers was confirmed by 2D NMR experiments. Correlations between2D NMR spectra and results from concentration-dependent 1H-NMR experiments led to theconclusion of positive cooperative association between anion and cation pairs with oligoureatrimer hosts. The conformational preference of longer aromatic oligoureas, incorporating fivemembered hydrogen bonding constraining the urea-linkage, was determined to favor a transtrans conformation based on urea-linkage bond rotations that were computationally derived incollaboration with Professor Eva Zurek and Daniel Miller. Longer oligoureas were confirmed toalso to bind tetraethyl- and tetrabutylammonium cations by 2D NMR experiments. Folding andchain-length dependence of these longer oligoureas were characterized by circular dichroism and1H-NMR, confirming solvent-dependent folding and aggregation. Finally an aromatic oligourea9mer was confirmed to favor a helical structure stabilized by dimethylformamide.Chapter 4 presents two aromatic oligoamides with a simple inversion between their αβand βα-amino acid spacers which caused the individual conformational identity to differdramatically, preventing these complementary strands to associate. A qualitative examinationcompared differences in structural properties by 1H-NMR concentration-dependent, titrationdependent and temperature-dependent experiments. It was concluded that the oligoamideinvolving the αβ spacer preferred to fold upon itself, generating a stable β-turn which wasconfirmed by 2D NMR. The oligoamide incorporating a βα spacer self-dimerized withsignificant conformational interconversion, requiring the oligoamide to be examined at cryogenictemperatures to derive a specific conformation. In collaboration with Professor Eva Zurek andDaniel Miller, conformations derived from NOEs observed by 2D NMR experiments wereexamined computationally. A favored model paired with atomic distances calculated fromoptimized NOEs concluded the refinement of a specific conformation regarding this oligoamide.