Peptidomimetic foldamers of β-secondary structural elements

Thesis

Foldamers have the potential to be the synthetic equivalent of Nature's macromolecules; man-made oligomers that use a range of non-covalent interactions to fold into well defined structures.

Chapter 1 introduces the challenges laid down by Gellman to chemists in creating foldamers; i) to design new polymers that reliably display interesting folding properties; ii) to be able to include novel and unnatural functional groups; and iii) make them easy to synthesise. Each of the foldamers made in this thesis will be evaluated against these challenges.

Chapter 2 develops a mimic of the linear β-strand, based on alternating pyridyl/urea units, with the conformation enforced by dipolar repulsion. Conformational bias is demonstrated in the solution phase by computational and NMR studies, and in the solid phase by X-ray crystallography. The concept is extended to the inclusion of hydrophilic residues and conformation is maintained in a polar protic solvent.

Chapter 3 describes the design and synthesis of a three- and four-stranded β-sheet mimic templated by the diphenylacetylene motif. The folding is enforced by a hydrogen bonding network demonstrated via extensive solution phase studies and X-ray crystallography.

Chapter 4 explores the scope of this new architecture. The meander is successfully elongated to seven strands, and the structure shown to be amenable to the inclusion of D-amino acids and hydrophilic residues. The foldamer is therefore shown to meet all of Gellman's criteria.

Chapter 5 uses the diphenylacetylene motif to study the factors involved in the formation of β-sheets, specifically the effect of side-chain identity on hydrogen bond strength. The difference in strengths is shown to be minimal, suggesting that β-sheet propensity is due to the energy changes in forming the extended conformation rather than forces between strands.

Authors: Ross, J

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Peptidomimetics; Organic Chemistry; Peptides