Abstract
The study of peptides constructed with β, γ-amino acids has rapidly developed in recent years. In contrast, research on δ-amino acids is still in its infancy due to the difficulty in synthesizing enantiopure δ-amino acids. Regarding the mimicry of natural peptides, δ-amino acids are unique among artificial amino acids because the length of the δ-amino acid backbone is nearly equal to that of the α-dipeptide. Consequently, peptides constructed with δ-amino acids are more likely to adopt an H-bond pattern resembling the 13-helix that α-helices adopt.In this thesis, we successfully synthesized an enantiopure δ-amino acid precursor and solved the lactam formation issue during the peptide synthesis. The XRD and refined solution state characterization of the 13/11 helix is presented in Chapter 2. Based on the structure we got, several features were discovered in this 13/11 helix: (i) the adjacent α-residues are relatively proximal, which is possible for the bifunctional catalyst design. (ii) The α-residue in the helix was embedded in the center of the helix circle, and the δ-residue is located at the outer circle of the helix, which builds up the environment for enantioselectivity. (iii) The ethyl of the δ-residue is pointing to the cyclohexane of the following δ-residue, which, on the one hand, might help stabilize the secondary structure, on the other hand, could be a candidate for the bifunctional catalyst design.
Chapter 3 explores the functionality of the bis-ornithine foldamer through retro-aldol cleavage. In chloroform, where the secondary structure was maintained, the bis-ornithine heptamer demonstrated the anticipated bifunctionality. Additionally, the crystal structure of the Boc-protected bis-ornithine foldamer confirmed the proximity of two side chains on adjacent α-residues. In aqueous solution, where the secondary structure might experience some degree of unfolding, the phase-transfer ability of the bis-ornithine foldamer was discovered.
Chapter 4 delves into the study of retro-aldol reactions catalyzed by foldamers with shorter amine side chains. Enantioselectivity was achieved, and it was found that reversible enantioselectivity of the foldamer is achievable by altering the position of the amine side chain.
This investigation extended to photocatalysis in Chapter 5 by conjugating a flavin residue to the foldamer via reductive amination, revealing the foldamer's effectiveness in the decarboxylative cyanation of tyrosine.The thesis primarily focuses on constructing the 13/11 helix structure and the catalytic functionalities derived from this secondary structure. Each chapter meticulously describes organic synthesis, kinetic studies, enantioselectivity, and photocatalysis. Major methods employed for characterizations and analyses included NMR, MS, XRD, Plate reader, MS, CD, and HPLC.
| Date of Award | 1 Nov 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Andre Cobb (Supervisor) & Manuel Muller (Supervisor) |