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

Lead Research Organisation: University of York
Department Name: Chemistry

Abstract

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.

Planned Impact

This project will explore the development of new synthetic tools for use in drug discovery programmes in the pharmaceutical industry. To ensure that our methods are of direct relevance to drug discovery, we will collaborate with AstraZeneca as a Project Partner. By collaborating and interacting with medicinal chemists at AstraZeneca throughout the lifetime of this project, we will ensure that the novel scientific methods we develop are suitable for drug discovery. Compounds from our project will be available for use in current AstraZeneca drug development programmes and could therefore impact on medicines of the future. Society has already benefitted greatly from discoveries at AstraZeneca from treating diseases such as cancer to depression. This has led to improved quality of life for numerous people.

The researchers on this project will also interact with the pharmaceutical industry and drug discovery programmes in other ways. For example, the compounds generated in this project will be available for the following programmes: (i) an academia-industry consortium (Astex, AstraZeneca, Lilly, Pfizer, Vernalis) that is building a library of novel 3-D fragments (set up by the PI); (ii) an EU training network on fragment-based drug discovery (FRAGNET) - with industrial partners (Novartis, GlaxoSmithKline, Vernalis, ZoBio, Beatica); (iii) 3-D scaffolds will be submitted to the European Lead Factory for evaluation; (iv) 3-D lead-like compounds will be submitted to the AstraZeneca Open Innovation New Molecule Profiling Programme programme. This will deliver potential societal impacts in a range of disease areas.

This project is of direct relevance to the UK pharmaceutical industry, the UK's most successful research-based industry. In 2013, the UK pharmaceutical industry had a trade surplus of £2.8 billion, employed ~73,000 people (23,000 people in R & D) and its exports were valued at £21.3 billion. In addition, the Global Chiral Technology market is predicted to grow to $5.83 billion by 2017, with chiral synthesis accounting for ~80% of the total market share. Since results from this project will feed into the pharmaceutical industry, then this will impact on wealth creation. The inclusion of SME YProTech as a Project Partner provide potential economic impact in two ways. First, compounds from this project that will be suitable for AstraZeneca's Strategic Reagent Initiative will be developed and synthesised on scale by YProTech and sold to AstraZeneca. Second, the PDRA will work in tandem with YProTech in identifying series of new 3-D fragments/scaffolds that could then be synthesised and made commercially available by YProTech. This will provide a product range for sale as well as a set of specialist building blocks whose novelty gives YProTech a competitive edge when applied to customer medicinal chemistry projects.

This grant will deliver a PDRA who will be a highly skilled individual, with expertise in mechanistic chemistry, synthetic chemistry and medicinal chemistry. The interactions with industry (including placements at AstraZeneca and YProTech) will give them significant exposure to different aspects of the industrial sector, providing a complementary skill-set to the academic skills that will be developed in the project. The PDRA will also deliver skills in organisation and time management, presentations, IT, critical thinking and problem solving. Given such expertise, he/she will be highly competitive in jobs in industry or academia. This will ensure that the people pipeline is maintained. Indeed, the UK has produced world-leading organolithium researchers and maintaining this expertise is key as organolithium reagents are widely used in the agrochemical, materials and pharmaceutical industries.

Publications

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K. Kasten (2020) Organic Reaction Volme 100

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Seling N (2023) a-Functionalisation of Cyclic Sulfides Enabled by Lithiation Trapping. in Angewandte Chemie (International ed. in English)

 
Description We have found some new ways of synthesising molecules that are of potential relevance to the pharmaceutical industry. In particular, we have identified new routes to cyclic oxygen containing compounds which are common motifs in pharmaceutical drug molecules.
Exploitation Route Medicinal chemistry researchers in the pharmaceutical industry may find use for our methods.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Routes to Disubstituted Nitrogen and Oxygen Heterocycles: Stereoselective Functionalisation of 3- and 4-Substituted Piperidines and Tetrahydropyrans
Amount £85,000 (GBP)
Funding ID 2107318 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 09/2022
 
Description Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates
Amount £120,885 (GBP)
Funding ID 2602928 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 08/2021 
End 09/2025
 
Description Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: A Transformative Disconnection for Drug Discovery
Amount £202,414 (GBP)
Funding ID EP/V048139/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 04/2021 
End 01/2023
 
Description Stereospecific Suzuki-Miyaura Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: Programmable Exploration of 3-D Space
Amount £118,513 (GBP)
Funding ID 2602986 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 09/2025
 
Description The Royal Society Industry Fellowship
Amount £164,313 (GBP)
Funding ID INF\R1\191028 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2019 
End 05/2022