The 3-acyl-4-hydroxy-pyridin-2-one core is a common feature observed in a number of natural products. This thesis describes the design and the development of an isoxazolopyridone as a masked form of this core and elaboration at the sites C-3 (Me), C-7 and N-5 of the related isoxazolopyridone. The polar nature of the heterocyclic trione makes these compounds difficult to work with, particularly with regards to purification and handling. A strategy is applied to disguise this polar nature, by masking the 4-hydroxy and 3-acyl functions as an isoxazole.
The isoxazolopyridone building block is available from diaminopropionic acid or β-alanine. A 1,3-dipolar cycloaddition of a nitrile oxide with a pyrrolidine enamine resulted in an isoxazole. In the case of the β-alanine series, a photolytic dehydrochlorination reaction was employed to introduce the C6-C7 unsaturation. The isoxazolopyridone building block was then elaborated at the sites, C-3 (Me), N-5 and C-7 to work towards the development of natural products and non-natural analogues. The use of anion-type aldol reaction was applied to construct a number of side chains at C-3 (Me). The use of Suzuki cross-coupling reactions, with a palladium-based catalyst for C-C coupling with a 7-iodoisoxazolopyridone was developed. The construction of the hydroxamic acid functionality at N-5 was investigated with little success. The unmasking of the isoxazolopyridone revealed the heterocyclic trione in the final step of the synthesis, by cleavage of the N-O bond followed by diazotization to prove its validity as a synthetic strategy.
A Doctoral Thesis. Submitted in partial fulfillment of the requirements for the award of Doctor of Philosophy of Loughborough University.