The work described in this thesis details the design, synthesis and evaluation of molecules intended as mechanistic probes to the enediyne anticancer antibiotics. In particular it examines the role of radical and ionic accepting groups in analogue systems related to the DNA cleaving agent Neocarzinostatin chromophore (NCS). The application of novel methodologies towards the synthesis of a number of key precursors and model systems is discussed. Initial studies concentrated on the versatile synthesis of a model system bearing dienediyne and styryl motifs, from 2-cyclopentenone. The role of cyclic amine bases in a critical Stille type cross-coupling was investigated, leading to an efficient and robust synthetic route. Attempts to selectively cyclopropanate, or epoxidise, the styryl olefin under a range of conditions however, failed to give the desired phenylcyclopropyl or phenyloxiranyl analogues. A novel application of the Kulinkovich reaction, to form an alkynylcyclopropanol is discussed. Attempts to synthesise a phenylcyclopropanol analogue via an advanced tris-silyl pre-cursor are also detailed. The successfulu se of Salaun's cyclopropanone-hemiacetatl o complete the synthesis of a novel analogue system bearing a cyclopropanol motif is detailed and discussed, with some mention of related synthetic endeavours. The analogue's reactivity to a range of nucleophiles, radicals and reaction conditions is evaluated, though no conclusive evidence for cycloaromatised products was found. Finally, approaches to the synthesis of a fully functionalised analogue system incorporating dienediyne, cyclopropanol and selectively protected trans-diol moieties (for possible coupling to DNA binding agents) are detailed. Although this synthesis incorporates some methodology previously reported, significant improvementsnotably the synthesis of a key pyrano-3-one directly from furfuryl alcohol using Nbromosuccinimide and aqueous sodium bicarbonate- make it noteworthy of inclusion
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:401478 |
| Date | January 1999 |
| Creators | Barr, Douglas MacPherson |
| Publisher | University of Sussex |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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