A Unified Route to Bicyclic Heterocycles: Synthesis and Applications

Bicyclic heterocycles - molecules containing two rings with at least one nitrogen, oxygen or sulfur atom - form the mainstay of medicinal chemistry and are absolutely fundamental to the development of new drugs, as evidenced by the 21 of the top 50 selling pharmaceuticals which contain this type of molecular core. Unsurprisingly, a multitude of methods have been devised to synthesise these important molecules, however most methods are specific to a single type of bicycle, such as an indole or quinolone synthesis. In this proposal, we describe an exciting cascade reaction (in which several steps are achieved in one synthetic operation) that can be applied to the synthesis of a number of different bicyclic skeletons, and thus indeed represents the first truly unified approach to bicyclic heterocycles. This is a challenging extension of methodology we have previously developed in all-carbon (no N/O/S) systems, which will lead to new opportunities for pharmaceutical development.Both rings of the heterocycle are formed in a single step, using a type of reaction that is almost entirely unexplored in such systems, and the highly tuneable nature of the substrate means we can potentially access many different bicycles - not just a single example. Furthermore, we have the option to introduce a wide range of groups on the all-carbon ring of the heterobicycle, which is usually the hardest ring to functionalise at a late stage in traditional syntheses. We propose to demonstrate this work through the synthesis of some important pharmaceutical and natural product targets.The proposed research is not limited to aromatic bicycles. We also intend to exploit the reactivity of the cascade reaction products in other types of complexity-inducing reactions, including applications in asymmetric synthesis. This will include processes which lead to a number of novel fused-ring (two rings joined through a common bond) and spirocyclic (two rings joined through a single atom) cores, containing up to five adjacent stereocentres, all in just two or three steps from simple starting materials. One of the main challenges for modern synthesis is this introduction of molecular complexity in a short number of steps, as this is often accompanied by high reaction efficiency (yield) and low cost.In summary, we aim to develop the first truly general approach to bicyclic heterocycles, which are of key importance in human health. Our solution to this problem uses new and interesting methodology which will find much application by other chemists. We propose to use our initially prepared bicyclic products in a wide range of adventurous complexity-inducing transformations, leading to a plethora of unusual, challenging, and potentially highly useful heteroatom-containing molecules.

General impact: The fundamental aim of this proposal is the development of a common route to numerous bicyclic heterocycle scaffolds, which are ubiquitous throughout medicinal chemistry research and marketed drugs. The main benefits of our work therefore lie with human health, and we expect that both the types and substitution patterns of the products we target will promote advances in this area. The most obvious beneficiaries of this work within the commercial private sector are pharmaceutical companies, who will be able to access a wide range of bicyclic heterocycles using a single synthetic approach - so far, despite the plethora of different routes to these cores, this remains an unattained objective. However, we also expect public sector organisations such as disease-related charities to benefit from this work, as again the nature of our methodology targets is of direct relevance to numerous disease therapies. These benefits will be realised within the course of the grant, as our publications will enable other organisations to use our methodology. As a result of the above two considerations, we also expect that the public as a whole will benefit in the longer term, as our methods could facilitate the development of new drugs, and streamline their production, thus improving the standard of public healthcare. For example, our work would have direct relevance to the cost of drugs and therefore on the availability of therapies to the community. This outcome naturally follows a longer timescale, although as described above our work will be immediately useful to those organisations who can impact this longer term benefit. We will ensure that our results are accessible to these beneficiaries through our dissemination plans - journal articles, conferences and invited seminars. Overall, the development of therapeutic compounds in collaboration with the UK pharmaceutical industry will have a positive impact on the UK economy. Communications and engagement: The main method of dissemination our results will be publication in high quality journals, which will be accessible to scientists in all major research institutions. A summary of our research results and links to publications will be available on the PI's group webpage. To actively engage with potential beneficiaries of our research we will participate in conferences at which there are both academic and industrial delegates. The PI gives multiple lectures at universities and companies worldwide, which will enable additional interaction with potential beneficiaries of our research. We also intend to communicate this work to the public through articles in more accessible journals (e.g. Chemistry World), and through departmental Open Day presentations. In the coming academic year, we will commence CASE studentship awards with Syngenta and Pfizer, strengthening our growing relationship with industry, and we expect further opportunities with industry to arise in the course of this grant. Collaboration: As described in the case for support, no direct collaborations have been established at this point due to the entirely new nature of the project. However, given the importance of the molecules we target, it is highly likely that collaborations will arise from this work, which we expect to be of great value to both the academic and pharmaceutical community. Exploitation and application: Oxford University has a strong ethos of protecting and exploiting the intellectual property discovered by its scientists. This activity is handled in Oxford by Isis innovation, who have more than 20 years experience and a proven track record in this area. The knowledge and reactions developed during this grant will also be exploited by academic, medical and pharmaceutical researchers.