Author: Mowat, Jeffrey Stuart
The primary focus of the research described in this document relates to the development and application of new synthetic methodologies relevant for the concise construction of four natural products. In Chapter 2, a discussion of our investigation of the total synthesis of eleutherobin (1) is disclosed. Eleutherobin (1), first isolated in 1997 from the rare soft coral Eleutherobia sp., is a member of a class of microtubule stabilising natural products. Although it displays potent cytotoxicity, its development as an anticancer drug has been hampered by the scarcity of material available from the natural source. In an effort to produce quantities of eleutherobin required for further biological testing, four conceptually unique approaches to eleutherobin were investigated which culminated in the development of an unprecedented palladium-catalysed α-arylation reaction/Friedel-Crafts cyclisation methodology for tetralone synthesis. This strategy permitted the production of multi-gram quantities of an advanced tetralone intermediate, and enabled the synthesis of a functionalised epoxyenone intermediate along our intended synthetic route. These investigations have provided a solid foundation for an eventual synthesis of eleutherobin that may also facilitate the evaluation of this natural product as an anticancer drug. In Chapter 3, the total synthesis of two potent anthelmintic oxylipid natural products, isolated from Notheia anomala, is discussed. Specifically, a silver-mediated cyclisation of two chlorodiols afforded two diastereomeric styryl-tetrahydrofurans, which were rapidly elaborated into the desired natural products. In addition, these syntheses featured a remarkable example of inverse-temperature dependence in the diastereoselective addition of Grignard reagents to tetrahydrofurfurals. Ultimately, these natural products were prepared in six synthetic transformations in excellent overall yield and efficiency. The last two topics presented in this thesis are contained in two separate appendices and highlight our interest in the synthesis of ecologically relevant natural products. In Appendix A, we report the synthesis and structure determination of the unknown banana volatile, (3R,2’S)-(2’-pentyl)-3-hydroxyhexanoate, and its olfactory recognition by the common fruit fly. The work presented in Appendix B focuses on the development of a scalable synthesis of mathuralure, the sex pheromone of the pink gypsy moth, Lymantria mathura, a potentially devastating invasive species.
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Thesis advisor: Britton, Robert
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