Towards the Syntheses of Biologically Relevant Secondary Metabolites

Abstract

The realm of natural product synthesis constitutes a major part of the interactions between chemistry and the living world. By designing and developing new synthetic routes to natural products, a better insight is gained in terms of new methodology, biological activity and structural novelty. As the field of natural products chemistry advances, ideal syntheses must be strived towards with the investigation of new methodology with high efficiency. Outlined herein are efforts towards the synthesis of four natural products of varying synthetic interests. Although many factors drive interest in their synthesis, they are united by a common goal of pursuing good synthesis. (+-)-Angelmarin (43) has potential a therapeutic agent in the treatment of pancreatic cancer and was synthesised in only 7 linear steps without the use of protecting groups. This was enabled by the recently developed gold(I) catalysed intramolecular hydroarylation chemistry which allowed synthesis of the key coumarin heterocycle in (+-)-columbianetin (44) under mild conditions from the propiolate ester. Investigations were made into the synthesis of the ochrosamines A (117) and B (118), isolated from the endangered rainforest tree Ochrosia moorei, exploring the scope and limitations of novel chemistry such as the vinyl aziridine rearrangement and interrupted Fischer indole synthesis. A number of interesting results were obtained from which much was learnt about the polycyclic system. The hasubanan framework (204) was of synthetic interest as the unnatural enantiomer has potential as a new opiate analogue. The research hoped to expand on recently developed methodology for an intramolecular Alder-ene reaction and its application in a high value context. Lastly, significant progress was made towards the synthesis of bicuculline (228) with the successful synthesis of the advanced intermediate (326) utilising an innovative osmium catalysed intramolecular amidohydroxylation reaction. This carries the possibility of developing an enantioselective synthesis. It is hoped that the natural product can ultimately be synthesised from this late stage material.