This thesis describes work focused on the use of oxetane rings as isosteres and incorporation of this functional group into pharmaceutically relevant scaffolds. Chapter 1 describes work directed towards the synthesis of 1,5-dioxaspiro[2.3]hexanes via three different strategies, namely ring-closure to form the oxetane ring, Corey epoxidation of the corresponding 3-oxetanones, and epoxidation of the corresponding 3-methylene oxetane. Nucleophilic ring-opening of substituted 1,5-dioxaspiro[2.3]hexanes to give amino acid type isosteres is also investigated. Chapter 2 details the synthesis of novel oxetane-containing peptidomimetics. A ‘one-pot’ conjugate addition process from commercially available 3-oxetanone to give nitro dipeptide precursors in good yields was developed. Various methods for the reduction of the nitro group were explored to optimise the synthesis of the corresponding amine. Amide coupling, followed by deprotection, gave peptidomimetics containing the oxetane at the C-terminus and mid-chain in good yields over the 3 steps, whilst an N-terminus oxetane peptidomimetic was obtained in 45% yield through hydrogenation of the conjugate addition product. X-ray diffraction studies, alongside molecular dynamics simulations, provided structural insights into these new oxetane-containing peptidomimetics. Detailed experimental procedures for the synthesis of all novel compounds are described in Chapter 3.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:640974 |
| Date | January 2014 |
| Creators | Powell, Nicola Helen |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/66720/ |
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