A Claisen-Sakurai Strategy to Highly Substituted Cyclopentenols: Applications to the Syntheses of Echinopine A and B

The development of new synthetic method is key to the evolution of organic chemistry. In particular new methods that can produce molecules with dense functionality in just a few steps is a shared goal. We are proposing combining two well know reactions (the Claisen rearrangement and Sakurai allylation) to create a new domino reaction that can produce molecules with complex functionalilty embedded within it in a single transformation. These densly functionalised small molecules could be of use in both the total synthesis of natural products and in the discovery of new pharmaceutical products. With this grant a new way of making complex molecules rapidly will be developed. We hope to apply this to the rapid synthesis of compounds that exhibit potent biological properties, both natural and unnatural. We will embark on a synthesis of echinopinine A and B two complex natural products with novel architectures. Although their biological properties have not been fully elucidated they were isolated from plants known to exhibit many medicinal properties including anti-cancer activity.

Through the development of these new approaches to cyclopentenols, it is anticipated that this research will result in several publications in high quality and high impact journals. We will strive to make these methods as general and applicible as possible, thus making these methods attractive for others to use. If these goals are met, significant exposure in the wider chemistry community will be generated and citations produced. The graduate student (funded by Queen's) working on this project will be will be mentored in the art of contemporary organic synthesis. This will include developing their synthetic laboratory skills, strategic thinking ability and teaching the fundamental theoretical basis that governs both reactivity and selectivity in organic chemistry. Through this training and by enhancing these aptitudes the student will be well placed to pursue a career within chemistry, be it industry or academia. The densly functionalised small moelcules we will produce could have significant applications in medicinal chemistry and could potentially lead to the discovery of new pharmaceutical agents. We will work with our academic and industrial partners to explore these possibilities.We will test any compounds we synthesise against several disease areas to probe if these molecules exhibit any biological activity. This will either be performed in collaboration with the Centre for Cancer Research and Cell Biology (CCRCB) here at Queen's or with a pharmaceutical company partner. The result of this could be leads towards potential new therapeutic compounds and the intellecual property associated with this. We will register intellectual property associated with discoveries of potential commercial interest. This will be carried out by the Knowledge Exploitation Unit located at Queen's University Belfast. The results and achievements we accomplish during the course of the project will be made available to the wider community through publishing in the peer reviewed literature. We anticipated that this research will result in several publications in high quality and high impact journals. It is also envisaged that the student attend at least one national and one international conference during the term of their PhD to present their results. We anticipate that this should occur during the summer of their second year which would fit within the timeframe of this funding and would be at an ACS or Gordon Research Conference. I would also present our work at several major conferences and at Universities/Companies should I be invited to present a seminar. The EPSRC funding contribution to our work would be acknowledged in any of our papers, posters, talks and seminars.