Studies Towards the Total Synthesis of Madeirolide A
Yip, Adam Christopher Loy
Paterson , Ian A
University of Cambridge
Department of Chemistry
Doctor of Philosophy (PhD)
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Yip, A. C. L. (2018). Studies Towards the Total Synthesis of Madeirolide A (Doctoral thesis). https://doi.org/10.17863/CAM.32287
Madeirolide A (1) is a structurally novel polyketide natural product first isolated from the deep-sea sponge Leiodermatium sp. by Wright in 2009. Initial biological investigations of madeirolide A revealed potent inhibition of the fungal pathogen Candida albicans but failed to determine any appreciable cytotoxicity when tested against a limited range of cancer cell lines. The unusual bioactivity of madeirolide A coupled with uncertainty over the true stereostructure of the natural product makes it a compelling target for synthesis. This thesis discloses synthetic efforts towards the total synthesis of madeirolide A with an emphasis on the construction of the all-cis C21 – C27 eastern tetrahydropyran. Chapters 1 and 2 provide an introduction to the importance of natural products in drug discovery and outline the context of this project with details of the isolation and biological activity of madeirolide A. Previous synthetic efforts are also reviewed including those from within the group which formed the basis of the present studies. Chapter 3 describes the synthesis of a fully elaborated C1 - C11 fragment, building upon previously published work in the group. Specifically, it details the successful completion of a modified approach designed to avoid some of the major challenges previously encountered such as undesired migration of protecting groups and challenges in selectively installing an (E)-vinyl iodide. Chapter 4 discusses ongoing efforts towards the challenging C12 - C27 fragment of madeirolide A. The stereocontrolled synthesis of several linear C19 – C27 precursors is outlined, followed by details of screening reactions conducted to affect the desired oxy- Michael cyclisation. Additionally, extensive computational studies have been undertaken in an attempt to rationalise the frustrating lack of reactivity observed with the goal of developing a substrate suitably elaborated to cyclise. Finally, the asymmetric synthesis of the C13 – C17 subfragment is outlined, which will provide eventual access to the eastern tetrahydrofuran. Chapter 5 summarises the synthetic work carried out thus far and explores potential strategies for the future completion of the natural product with a focus on alternative disconnections of the eastern tetrahydropyran.
organic chemistry, natural products, total synthesis, marine natural product, polyketide, macrocycle, anti-fungal, madeirolide
This project was funded by the EPSRC.
This record's DOI: https://doi.org/10.17863/CAM.32287
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