School of Chemistry - Theses
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ItemStudies toward a divergent synthesis of the ustiloxins( 2015)The total synthesis of natural products is an endeavour with roots dating back at least 200 years. Over the course of this field’s development, its protagonists have sought to justify their work through reference to other domains. With the passing of time, natural products chemistry has evolved to service the requirements of an ever- changing scientific landscape. In the early part of the twenty-first century it has been suggested that the field of natural product chemistry is a ‘mature science’. In order to assess this claim, an analysis of the introduction of Nicolaou’s Classics in Total Synthesis was carried out. Nicolaou’s assertions in support of continuing investment in natural products synthesis were subjected to a close reading. It was found that while some of his claims do not stand up to scrutiny, there remain compelling reasons for the continued practice of total synthesis. A family of cyclic tetrapeptides, the ustiloxins, were identified as a viable target for total synthesis. The ustiloxins have demonstrated low micromolar activity against various cancer cell lines. A divergent synthesis of all members of the ustiloxins was proposed. It was envisaged that this synthesis would serve a number of purposes: Firstly, it would enable further work to be carried out toward the elucidation of the mechanism of action of the ustiloxins. Secondly, it would enable confirmation of the structural assignment of the members of the family that had not yet succumbed to total synthesis. We were able to complete the synthesis of ustiloxin D in a convergent manner. Our strategy incorporated an asymmetric allylic alkylation to construct a tertiary- alkyl–aryl ether linkage between the dopa and isoleucine residues. The elaborated hydroxydopa derivative was then rapidly converted to a linear tripeptide through an ammonia-Ugi reaction. Subsequent cyclisation and global deprotection afforded ustiloxin D in six steps from a known hydroxydopa derivative. We had planned to synthesise ustiloxins A and B using a late stage intermediate from the synthesis of ustiloxin D. This required an iodination at the 6- position of the dopa aromatic-ring. Unfortunately, this transformation proved to be problematic. As a consequence, our synthetic strategy was revised to incorporate an early stage aromatic iodination. Using this strategy we were able to synthesise an iodinated cyclic tetrapeptide. Unfortunately, the planned transition-metal catalysed cross coupling to install the desired sulfinylnorvaline sidechain was unsuccessful.