A Unified Route to Bicyclic Heterocycles: Synthesis and Applications

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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.