Bioactive Natural Product Assembly Using Precious Metal Catalysis: Total Synthesis of Phyllostictine A

This project is focused on realizing the first total synthesis of phyllostictine A, the most potent member of a structurally unique class of natural product isolated from the fungus Phyllosticta cirsii. Phyllostictine A constitutes a formidable synthetic challenge, and its assembly will require us to develop a variety of new chemical reactions and processes. Emphasis will be placed on sustainable, catalytic transformations and on adhering to the principles of the 'ideal' synthesis (e.g. atom, step and redox economy). For example, the 4-, 5- and 11-membered rings will be made using palladium, gold, and ruthenium catalysis respectively. This natural product displays potent herbicidal activity against a variety of weeds, and most recently, anti-cancer activity. In parallel with the total synthesis, a selection of analogues and intermediates will be tested for bioactivity. This will help advance our understanding of the mode of action of phyllostictine A, and will pave the way for the development of simplified analogues of the natural product for use in medicine and agriculture.

There is significant potential for economic impact. In the UK, weeds result in higher yield losses and greater input costs than either pests or diseases. Herbicides have provided excellent weed control, though now, legislation to reduce the environmental and human health risks associated with them is reducing the range of options available. Escalating levels of evolved resistance to herbicides are further reducing options for weed control. There has been no new herbicide mode of action discovered since the early 1990s and there is a desperate need for novel herbicides with high potency and minimal impact on the wider environment. The structurally unique phyllostictines are an exciting new lead in herbicide discovery, but supply issues mean that their true potential is not yet known. By solving the supply problem though chemical synthesis, it will be possible to gain more knowledge regarding their suitability as crop protection agents. The team has the appropriate mix of expertise to tackle all elements of this multi-disciplinary problem from the chemistry laboratory to glasshouse trials. The project will also give us the tools and expertise to make molecular probes (through tagging of the natural product and/or derivatives) with which to undertake comprehensive mode of action studies. We will also learn what parts of the molecular architecture of phyllostictine are responsible for the biological activity. Based on our early findings, we believe there is a good chance that we will discover fragments or derivatives with useful herbicidal activity that ultimately could be commercialised. Simpler derivatives would likely be much cheaper to produce and hence more viable as commercial products. Our plans for translating such discoveries into economic value for the UK are detailed in the Pathways to Impact section. Thus, in the long-term, we hope that this project could make important contributions to the field of sustainable agriculture. These natural products (and analogues) may also be of interest in the context of the treatment of human diseases (e.g. cancer) and work to further explore these avenues with a view to potential development will be undertaken.

The project places much emphasis on developing sustainable, catalytic reactions and the realisation of a total synthesis that is atom, step, and redox efficient. As such, the project is well aligned with the EPSRC Dial-a-Molecule (DaM) Grand Challenge and will assist in the fulfilment of the Roadmap for Synthesis in the 21st Century. As such, it will help ensure that the UK chemical, pharmaceutical and agrochemical industries sustain their leading global positions through the delivery of innovative chemistry, new products and skilled people. Active engagement with such stakeholders will be a key component of the Impact Plan.

This project provides a great opportunity to illustrate the importance of sustainability in modern life to the general public, especially school children. We will develop an accessible lecture that illustrates several of the following points: (i) the concept of waste in chemical production and how chemical catalysis can reduce it; (ii) the importance of agrochemicals for current food production and the need for more sustainable agricultural practises in the future; (iii) the role of natural products in modern agriculture and medicine; (iv) how nature can inspire scientists to produce innovative solutions to societal Grand Challenges.