Enantioselective C-H C-H Coupling of Alcohols with Heteroarenes

A primary goal of organic chemists is the construction of molecules for applications as diverse as medicines, new materials and biomolecules. One particular molecular structure which crops up over and over again in medicines is the heteroaromatic ring. This is a planar structure over the surface of which is a ring of delocalised electrons. What differentiates this from a normal aromatic ring is that it is not just comprised of carbons but has a 'heteroatom', often a nitrogen. This nitrogen can be particularly useful in biological systems as, when basic, it allows for interaction with biomolecules which can be crucial to the efficacy of new medicines. The challenge for chemists who want to synthesise these useful molecules is that often the basic nitrogen may interfere with chemical methodology due to this basicity. This challenge is particularly acute when stereocentres are to be formed next to the heteroatom with control of absolute stereochemistry - ie the 'handedness' of the product. Control of this factor is essential in potential medicines since nature itself is inherently chiral or 'handed' due to the point chirality of individual amino acid residues, or the helical chirality of DNA.
We have recently developed an enantioselective reaction which allows the addition of prochiral radicals to the most commonly used basic heteroarenes, pyridine and quinoline (Science, 2018, 360, 419). This reaction has been known in a non-enantioselective sense for many years and is typically described as a Minisci-type addition and to the best of our knowledge our recent contribution constitutes the first enantioselective version of this very important chemical reaction. However, our original protocol only allowed access to chiral amines and the method we used to obtain the prochiral radical also possessed a number of practical disadvantages that would likely limit its broader use within the synthetic community.
In this research we will develop a method to start from simple alcohols to generate the radicals that will add to the heteroarenes in Minisci-type additions. This is challenging for a number of reasons, laid out in detail in the proposal, but when made successful the payoff will be substantial as it will formally allow two C-H bonds to be transformed into a C-C bond with full control of stereochemistry. Additionally we will also investigate the interruption of a Minisci type addition in which an intermediate radical is trapped by a pendent functional group in the substrate to generate unique partially saturated heterocycles that will be of great interest in library for pharmaceutical research.
The time and cost required to develop new medicines directly impacts our society. Chemistry such as that proposed herein lies at the heart of drug development; expediting this is crucial for faster access to new, affordable medicines. The world-leading scientific research performed in UK universities is crucial to growth and jobs; this research will operate at the cutting edge of catalysis and our findings will strengthen this crucial sector.

The work detailed in this proposal will realise a method that directly enables the preparation of classes of compounds that are central to the pharmaceutical industry ie basic heteroarenes bearing adjacent defined stereocentres. As soon as this work is published in open access form we envisaged that medicinal chemists in the UK in the UK Pharma sector will begin to use this straight away as the knowledge will be there for all to read. It is widely accepted within the pharma industry that drug candidates containing more saturation and stereocentres is highly beneficial as candidate molecules progress from discovery, through clinical trials, to drugs. Hence the method we will develop will be a perfect match for urgent needs in drug discovery. As the development of new medicines to treat disease is central to quality of life and stable society, the outputs of this research program will have direct impact more broadly. It will make it much easier and quicker to synthesise drug-like scaffolds and thus enable more candidates to me made in a given timeframe and with complete control of selectivity. Thus, it has the genuine potential to expedite the drug discovery process. This impact will be promoted by the PI visiting pharmaceutical and agrochemical companies in the UK and abroad. The PI already has collaborations with AstraZeneca, GlaxoSmithKline, Pfizer and Syngenta and visits these companies regularly as a consequence, giving a perfect forum to discuss research outcomes directly with industrial scientists who will be able to implement the methods in the development of new pharmaceuticals and agrochemicals.
The outputs from this program will greatly advance knowledge in a very challenging area of synthetic chemistry - controlling absolute stereochemistry in reactions that proceed via radical mechanisms. This work will have immediate impact in the academic community - the synthetic chemistry community internationally is placing a huge amount of effort in the development of new photoredox catalysis processes. This new approach to designing radical processes has led to massive advances in the last 5-10 years which show no sign of slowing down. It is widely accepted that one of the major challenges in the area lies in developing ways to make these processes enantioselective. As such, the realisation of this project will have major academic impact in one of the most fast moving areas of contemporary synthetic chemistry and feed knowledge into existing programs in research groups both in the UK and abroad.
The outputs from the research will be published in the highest impact general science and chemistry journals meaning that they will reach the largest audience possible both academically and industrially.
The PRDA researcher employed on this grant will be impacted on by the training delivered in the Phipps group and at Cambridge university. This in turn will greatly impact on the industrial or academic teams they join in the future and the people they train and mentor in those environments.
In economic terms, the UK pharma sector contributes a very significant amount to the UK economy and research that will directly benefit this sector has undeniable economic impact on the UK.