The synthesis and biological activities of certain polyoxygenated natural products and various analogues

Abstract

This dissertation is concerned with the synthesis of two distinct classes of polyoxygenated systems, namely analogues of the phomentrioloxin and the pterocarpan classes of natural product. The first part of this thesis deals with the synthesis of analogues of the phytotoxic geranylcyclohexenetriol (neg)-phomentrioloxin, the main metabolite of liquid cultures of the Phomopsis sp., a known fungal pathogen of the invasive weed Carthamus lanatus (Saffron thistle). Accordingly, the opening Chapter details the origins of this natural product, its biological activities and its synthesis as well as those of closely related compounds. The second Chapter discusses the chemoenzymatic origins, reactivity and general synthetic utility of the enantiopure cis-1,2-dihydrocatechols and their application to the production of the four C3,C4-modified phomentrioloxin analogues. The herbicidal activity of (neg)-phomentrioloxin, these new analogues and a tranche of other derivatives is also presented as is a rationale for the variation in their activities. The second part of this thesis focuses on the pterocarpan class of natural products, plant phytoalexins produced within the Fabaceae family, primarily in response to infection. They display a significant range of interesting and potentially useful biological activities. Chapter Three introduces the pterocarpans, their diversity of structure, their origins, biological activities and their synthesis, both biogenetically and chemically. Particular attention is paid to the 2,3,9-trimethoxypterocarpans. Chapter Four details the synthesis of racemic 2,3,9-trimethoxypterocarpan through the use of the Mizoroki-Heck oxyarylation reaction, the separation of the constituent enantiomers using chiral HPLC techniques and the elaboration of the racemate into two C8-functionalised analogues. Although widely applied, The Mizoroki-Heck oxyarylation reaction does not allow for an enantioselective synthesis and, as such, studies towards establishings an enantioselective route were undertaken. Chapter Five details the synthesis of a model pterocarpene through the manipulation of tolans. Two different methods were explored. The first was a tandem 5-endo-dig 6-endo-trig cyclisation protocol and the second a stepwise approach using the Pt(II)-catalysed carboalkoxylation reaction. In the event, the latter process proved to be more reliable. It was envisaged that this synthesis would provide valuable insights into the protocols that best pursued for the synthesis of 2,3,9-trimethoxypterocapene, the C6a,C11a dehydro-analogue of 2,3,9-trimethoxypterocarpan. Accordingly, Chapter Six outlines efforts directed towards this goal. Specifically, it details the intention of preparing then subjecting the pterocarpene to enantioselective hydrogenation, using analogues of Crabtree's catalyst, to deliver (pos)-2,3,9-trimethoxypterocarpan. Various difficulties with protecting groups meant that only a protected 2,3-disubstituted benzofuran, a potential precursor to the target pterocarpene, could be obtained. Work directed towards the synthesis of two nitrogen-containing analogues of 2,3,9-trimethoxypterocarpan is also presented. The penultimate Chapter (Seven) details the outcomes of the biological testing of the 2,3,9-trimethoxypterocarpans. Mode of action studies have shown that the (pos)-form elicits its impressive antiproliferative activity via arrest of cell mitosis. Mode of action studies established that the compound binds to the motor domain of the mitotic kinesin Eg5 and thereby inhibits the spindle pole separation. Finally, Chapter Eight presents all of the associated experimental protocols and characterisations for the compounds produced as part of this work.