White, C.; (2008) Stabilisation of peptide secondary structure by incorporation of side-chain linked amino acids. Doctoral thesis , University of London.

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Abstract

The aim of the project was to synthesise a novel small peptide containing an ether linkage between two side chains. Computer modelling had shown the structure was likely to form a stable p turn in solution and would therefore be a good candidate to study this class of protein secondary structure. To do this a differentially protected bis-amino acid containing the ether linkage was retrosynthesised to chiral pool synthons L-aspartic acid and L-methionine. Many attempts were then made to differentially protect and manipulate the respective acid and sulfide side chains into synthons that would participate in Williamson ether synthesis. Techniques explored included N-chlorosuccinimide hemithioacetal formation, sulfonium salt displacement, bismuth trichloride and silver salt induced etherifications. Using molecules made during this research we then worked towards making a similarly constrained peptide containing a homolanthionine bridge, a thioether analogue of the anti-tryptic reactive site loop of Bowman Birk Inhibitor, a proteinase inhibitor protein. Chapter 1 contains a review of peptides constrained through bridging of side chains and the effects that this has upon them. Chapters 2 and 3 outline the synthetic steps that were used in the process of synthesising an ether linked bis-amino acid. Subchapter 2.2 shows the synthesis of protected homoserine, a nucleophile for ether reactions. Subchapter 2.3 highlights the difficulty in making differentially protected electrophilic amino acids and coupling reactions between the two synthons. In chapter 3 the protected electrophilic homoserine is coupled with cysteine to make a homolanthionine bridge which is then integrated into a short peptide. Chapter 6 contains the experimental procedures for the reactions carried out and the spectral data for isolated compounds.

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