C-H Functionalisation of Cyclic Ethers: New Routes to 3-D Fragments, Scaffolds and Pharmaceuticals

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Cyclic ethers (ring compounds that contain a series of carbon atoms and at least one oxygen atom) are very common structural units in a wide range of commercial pharmaceuticals. One example, that contains a morpholine cyclic ether, is Roboxetine which was developed by Pfizer for the treatment of depression. Two other common cyclic ethers are tetrahydrofuran (5-ring) and tetrahydropyran (6-ring). Indeed, a survey (published in 2014) of the most frequently used ring systems from a survey of 1157 FDA-approved drugs reported that tetrahydropyran was 6th, tetrahydrofuran was 11th and morpholine was 29th. One of the reasons that these very useful ring systems are not used even more widely in pharmaceuticals is that, starting from the parent ring structures, there are very few methods for the direct, easy introduction of other groups on the carbon atoms already present in those rings. In particular, methods which take a carbon-hydrogen bond and convert it directly into a new carbon-carbon bond are highly desirable. Another aspect that is important is the generation of so-called chiral cyclic ethers - these are compounds which exist in mirror image forms (just like our hands) - drugs need to be prepared with one handedness (known as single enantiomers) as each enantiomer can have different biological properties. Thus, to address these challenges, in this project, we will develop novel methodology for the conversion of tetrahydrofurans, tetrahydropyrans and morpholines (inputs) into chiral drug fragments, drug scaffolds and pharmaceuticals (outputs). We will do this by using commercially available organolithium reagents to convert a carbon-hydrogen bond into a wide range of new carbon-carbon bonds. In order to optimise the processes, we will make use of an in-depth exploration of the mechanisms involved and a variety of techniques will be employed, including computational modelling. We will then explore the possibility of using our methods to synthesise chiral compounds and prepare a range of drug-like compounds of just one handedness. Catalytic versions of our reactions will also be investigated. The full scope of the technology will be investigated with a range of different substrates containing tetrahydrofuran, tetrahydropyran and morpholine rings. We also plan to develop short syntheses of drug molecules such as the anti-depressant, Robexetine. Finally, we have identified two industrial project partners from the pharmaceutical industry - AstraZeneca and YProTech. These collaborations are key to developing methods that will be useful for the pharmaceutical industry - medicinal chemists will guide our choice of substrates and we anticipate that YProTech will scale up some of the procedures and make selected compounds commercially available to be more widely used. Overall, through this project, we will deliver new synthetic tools for medicinal chemistry as well as mechanistic understanding that will be of much academic interest. This project fits squarely within the EPSRC "Dial-a-Molecule" Grand Challenge - we will be able to dial-an-oxygen ring system at will via simple C-H functionalisations with high efficiency. It also relates to the EPSRC Challenge Themes of Healthcare Technologies and Manufacturing the Future, together with the EPSRC priority area catalysis.