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Synthesis of conformationally restrained peptides

Andrews, Martin James Inglis; (1997) Synthesis of conformationally restrained peptides. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The synthesis of an artificial amino acid residue, bearing two a-amino acid centres, is detailed. The residue has been designed to act as a conformational restraint when incorporated into peptides. The intended target structural motif is the a-helix, and the restraint takes the form of a macrocycle in a central position in the peptide chain, which is intended to nucleate helix formation. The synthesis has been achieved by the use of two different asymmetric methodologies. Details of the final synthetic route to the residue are included, as well as details of several other synthetic routes which proved unsuccessful. The final route involves the use of an octanoic acid derivative. This is initially reacted with a chiral lithiated pyrazine cyanocuprate complex to generate the R-chiral centre, followed by the introduction of the S-chiral centre using an asymmetric azidation methodology. These reactions have been employed in sequence to give optimum yield and efficiency. The sequence of reaction followed also simplifies the differentiation of the two chiral centres, giving the molecule in a form suitable for solid phase peptide synthesis. The attempted syntheses of peptides bearing this residue is also detailed. This process has been performed by standard Fmoc methodology, using the triply orthogonal allyl based protecting group, cleaved by palladium catalysis, to allow selective reaction to form the macrocycle. This loop is arranged in an i-(i+4) substitution pattern, suggested in the literature to be the most effective spacing for performing this task. Other sections of this thesis describe the general background to helical structure stabilisation, the asymmetric synthesis of amino acids and the solid phase synthesis of peptides.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Synthesis of conformationally restrained peptides
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Artificial amino acid residue; Conformationally restrained peptides
URI: https://discovery.ucl.ac.uk/id/eprint/10098578
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