Cascade Catalysis: From Alkynes to Polycycles

The efficient and rapid preparation of cyclic (ring-containing) organic molecules is one of the most important challenges for organic chemists. The construction of these molecules as single enantiomers - that is, one of two mirror image forms which are related as are left and right hands - is an equally vital consideration for modern applications of organic chemistry. In this proposal, we aim to develop chemistry which prepares multiple ring systems by short synthetic routes, and as single enantiomers (i.e asymmetrically).

We will achieve this aim through the use of palladium catalysts to control the formation of ring systems which are connected to alkynes (carbon-carbon triple bonds). In this arena, our group has established itself as an internationally leading team through a recent high profile publication, and in this project we intend to expand our understanding and use of this reaction principle to prepare complex but fundamentally useful ring systems containing oxygen and nitrogen atoms - heterocycles - which form the core of many pharmaceuticals and agrochemicals.

In our planned chemistry, the alkyne serves not only to mediate ring formation through its interaction with the palladium catalyst, but is also a valuable functional group in its own right which can undergo a wide range of useful chemistry after the ring-forming step. We intend to use the unique properties of the alkyne to explore the formation of additional ring systems.

While we expect these processes to be successful, of greater ambition and adventure is the preparation of multiple rings in a single step using "cascade" reactions, processes which intrinsically lead to higher reaction efficiency and yields than the previously described separate reaction sequences - a principle which fundamentally links to the EPSRC Dial-A-Molecule Grand Challenge. The reactions we propose to study in this context also form their respective products as single stereoisomers (i.e. single three-dimensional structures where several possibilities exist). This is important, as applications in the design of new pharmaceuticals will rely on this selectivity.

The project also aims to push boundaries in sequenced and dual catalysis - where multiple catalytic reactions take place in direct succession, either in separate reactions (sequenced) or more ambitiously and appealingly in the same reaction flask (dual catalysis). This leads to even greater molecular complexity but with no extra cost to the number of steps needed to prepare starting materials, and is an area at the forefront of catalysis research.

In summary, we aim to employ new and contemporary catalytic processes to build molecules in a flexible and novel fashion. The variety of functional groups we intend to explore in these processes will lead to a broad expanse of product types, which will enhance possibilities for applications in medicinal chemistry, agrochemicals, chemical biology, and materials chemistry.

The fundamental aim of this project is the development of a catalytic reactivity principle to enable the rapid construction of carbocyclic and heterocyclic ring systems in a stereocontrolled and enantioselective manner. These systems are ubiquitous throughout medicinal chemistry research and marketed drugs. The main impacts of our work (beyond the increases in knowledge outlined in the academic beneficiaries section) therefore lie with human health.

The most obvious impact of this work in the commercial private sector will be with pharmaceutical and agrochemical companies, who will be able to access a wider range of functional (hetero)cycles using our technology. The technology is tuneable and flexible, positioning substituents at precise positions in rings, and enabling subsequent diversification through a variety of chemistry. We also expect public sector organisations such as disease-related charities to benefit from this work, as the nature of our products is of direct relevance to numerous diseases. These benefits will be realised within the course of the grant and beyond, as delivered through our publication and communication strategies.

This will lead to a longer term benefit to society (>10 years), as these methods could facilitate the development (and streamline the production) of new drugs, thus improving the standard of public healthcare - an overriding aim for chemical research in the UK and worldwide. Our work has direct relevance to the cost of drugs, and therefore availability of therapies to the community, and influences drug design by providing new tools for lead discovery. Although this impact follows a longer timescale, the technology will be immediately available to these beneficiaries through our dissemination plans - journal articles, conferences and invited seminars. Overall, the development and application of bioactive compounds through the UK pharmaceutical and agrochemical industry, and charity-funded research, will have a positive impact on society and the UK economy.

The PDRA employed on the grant will receive training in a diverse range of organic chemistry, and significant opportunities for innovation in the project. They will build leadership and mentorship experience, as they will play a vital role in training students in the PI's research group. They will have opportunities to present their results at national and international level, enhancing their own standing. In these respects, they offer an immediate and long term impact on the supply of skilled workers to the UK economy, via their own development and the students they will influence. These effects directly benefit the quality of chemical-related industry in the UK, with resultant economic benefits.

These impacts match the aims of: The EPSRC mission and vision (advancing knowledge and technology, providing trained scientists to meet the needs of user groups); the Dial-a-Molecule Grand Challenge (100% efficient synthesis - the vital nature of catalytic processes and cascade assemblage of complex molecules); and the EPSRC 2009 International Review of Chemistry (recognition of the impact of organic chemistry research on other fields such as analytical, materials, biological and medical sciences).

Finally, an additional societal impact will be public engagement. The PI was recently awarded a Pathways to Impact grant, linked to the University Botanic Garden. Through this award, the PI will engage with the wider community and present many aspects and applications of organic chemistry (including our research) to the public through a connection of organic chemistry to plants. This is achieved through poster displays and guided walks. As we can readily relate the catalytic processes and heterocyclic products of this project to plants, the PI will be able to increase public awareness of the role of chemistry in society, and in particular the uses of organic methodology in the preparation of biologically active molecules.