Methodology for, and Synthesis of Biologically Active Pyrrolidinone Natural Products.

Five-membered ring compounds with contain one nitrogen atom, are ubiquitous structural units present on thousands of natural products, in numerous brand-name drugs and agrochemicals, and are widely used to modify catalysts for a particular purpose. These nitrogen "heterocycles" are present in a family of highly complex natural products which exhibit antitumour and antibiotic activity. The search for new antibiotics is particularly important now we are in the "post-penicillin" era and our entering the era when even resistance to antibiotics such as vancomycin is regularly encountered. The search for new antibiotics with different modes of action is an important challenge facing academia and the pharmaceutical industry. The aim of our work is to develop new and efficient methods for the synthesis of nitrogen heterocycles which will have particular application to the synthesis of these antitumour antibiotics. A major part of the project will involve using the developed methodologies to synthesise one of the natural products and, importantly, to prepare simplified analogues. The simplified analogues will be tested for both antibiotic and antitumour activity. In the long term, this research may have an impact on the discovery of new antibiotics and antitumour agents. Moreover, the developed methodologies will have application in the synthesis of a whole range of other biologically important natural products and small molecules.

(i) Who will benefit from the research?
(ii) How will they benefit from the research?

Outside of my direct academic environment the likely beneficiaries of the research will likely include the pharmaceutical and agrochemical industries as well as the fine chemical industry. Functionalised pyrrolidines and pyrrolidinones, and 5-membered nitrogen heterocycles in general, are key moieties in numerous pharmaceuticals and agrochemicals. Additionally they are widely used as ligands in asymmetric catalysis and as catalysts themselves in the burgeoning field of organocatalysis and as such will be of interest to the fine chemicals industry. The developed methodology could have immediate impact allowing these three "end-users" to prepare commercially valuable targets in increasingly efficient ways. Each of these beneficiaries contributes enormously to the UK economy and they may well gain from the proposed research. In order for the Chemical Industry to benefit immediately from the research it is imperative that the results be rapidly disseminated. The quickest way for this dissemination is through lectures in industry. In 2010, I gave 3 lectures at UK pharmaceutical companies. Moreover, I have a number of CASE collaborations and regularly meet with representatives of the UK pharmaceutical companies at the University of Oxford and informal dissemination of results may occur at these meetings.

The project will result in a highly skilled individual in the area of synthetic organic chemistry methodology development and total synthesis. Organic synthesis in general and natural product synthesis in particular, require day-to-day innovation and problem solving. The individual who works on this grant will obtain problem solving skills and the ability to think inventively. These skills will not only make them employable in the Chemical Industry but in numerous professions which will have a positive impact on the UK economy.

This project aims to prepare an antitumour antibiotic natural product as well as simplified analogues thereof. These simplified analogues will be tested "in-house" for biological activity. In the long term (5-10 years), the results from this project may influence the development of new antibiotics and antitumour agents and as such could have a positive societal benefit.