Alexander McNamara, Linda Mary; (2000) Synthesis of stable α-helical peptides. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The synthesis and conformational properties of a conformationally constrained cyclic peptide are described. The aim was to synthesise a short conformationally constrained peptide that may adopt an α-helical conformation in an aqueous environment. An unnatural amino acid was chosen as the 'constraint' between the i and (i+4) positions within this short cyclic peptide. This constraining residue had two chiral centres joined by an 8-carbon bridge and needed to be synthesised using two enantiospecific methodologies. The route to the synthesis of this amino acid is described, together with the modifications required for large-scale production. This was required for the subsequent solid phase peptide synthesis. The synthesis of the target cyclic peptide (test peptide), using a novel solid phase approach with a triply orthogonal protection strategy is then detailed. The conformational properties of the target test peptide, with the constraining residue, are compared with those of a control linear peptide by CD analysis, in different solutions at various temperatures. In this way, the role of this constraining residue in a synthetic cyclic peptide has been ascertained. In Chapter 1, previous research in the synthesis of stable α-helical peptides is described. Chapter 2 reviews the cyclisation of peptides on solid support. Chapter 3 describes the route to synthesising the unnatural residue. Chapter 4 describes the synthesis of the target cyclic peptide (incorporating the unnatural residue) on-resin. In addition, the conformational properties of the control and test peptide, as determined using CD experiments are discussed, including attempted NMR studies. Chapter 5 contains the experimental procedures.

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