Abstract
Peptidomimetic foldamers, oligomers that can fold into a well defined conformation in solution, can control functions that would not be possible in nature. Their specific conformation can mimic peptides and therefore control a variety of biological function via protein-protein interactions in absence of proteolysis, which is a typical feature of peptidomimetics.This thesis describes the synthesis of γ-amino acid precursors as building blocks for the synthesis of foldamers. First, an investigation on an envisaged unprecedented mechanistic rearrangement observed during a 6-endo-trig cyclisation assisted by organocatalysis was performed. Then, a novel enantio- and diastereoselective synthesis of 5-membered ring cis-γ-amino acid precursor was developed. The targeted product was obtained in 72% yield, 9:1 cis/trans ratio and 92% ee. A mechanistic discussion of the studied 5-exo-trig cyclisation is presented. NMR and computational studies suggested that two joint catalytic cycles characterise the synthesis of cis- and trans-diastereomers. It was found that control of the observed diastereoselectivity degradation may be due to the epimerisation of the cis-product to the trans-product leading to a change of enantioselectivity with time. Control of this process is crucial to isolate efficiently the cis-product.
The synthesised 5-membered ring cis-γ-precursor was then incorporated in a γ/α-oligomer. The synthesised peptide proved to populate a 10/12-helical structure in spite of the smallest ζ angle yet observed for a helix of this type, therefore introducing a possible new class of foldamers.
| Date of Award | 1 Feb 2020 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Andre Cobb (Supervisor) |