Loughborough University
Thesis-2006-Lumley.pdf (2.48 MB)

A cycloaddition approach to acylpyridone natural products

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posted on 2018-09-25, 13:51 authored by Christopher Lumley
There is a small group of natural products which possess a 3-acyl-4-hydroxypyridin-2- one core. It has been our intention over the course of this Ph.D. to synthesize the acylpyridone core in masked form and then to elaborate from this to a specific natural product. This thesis introduces these natural products and surveys the synthetic work on this class of metabolites. It next describes our strategy, which involved masking the 4-hydroxy and 3-acyl functions jointly as an isoxazole to reduce the polarity of these molecules and hence make handling and purification easier. The isoxazole is made via a 1,3-dipolar cycloaddition of an in situ generated nitrile oxide and a pyrrolidine enamine. Our realization of this approach using 2,3-diaminopropionic acid via its aldehyde as the source of nitrile oxide, and a β-ketoester as the source of the enamine, is described. Manipulation of the initially-formed isoxazole to generate an isoxazolopyridone building block is reported. Elaboration of the isoxazolopyridone at the C-3 substituent by anion generation and aldol-type chemistry, and at the C-7 position by iodination and Pd-mediated Suzuki coupling has been achieved. This methodology has been utilized in making progress towards synthesis of the natural product tenellin. The weak N–O bond of the isoxazole has been easily cleaved in the last step of the synthesis, followed by diazotization to reveal the 3-acyl-4-hydroxy-pyridin-2-one core.



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© C. Lumley

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This work is made available according to the conditions of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence. Full details of this licence are available at: https://creativecommons.org/licenses/by-nc-nd/4.0/

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A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy at Loughborough University.


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