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Details of Grant 

EPSRC Reference: EP/S03269X/1
Title: Enantioselective C-H C-H Coupling of Alcohols with Heteroarenes
Principal Investigator: Phipps, Professor RJ
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department: Chemistry
Organisation: University of Cambridge
Scheme: Standard Research
Starts: 25 November 2019 Ends: 24 February 2023 Value (£): 355,413
EPSRC Research Topic Classifications:
Asymmetric Chemistry Catalysis & Applied Catalysis
EPSRC Industrial Sector Classifications:
No relevance to Underpinning Sectors
Related Grants:
Panel History:
Panel DatePanel NameOutcome
09 Apr 2019 EPSRC Physical Sciences - April 2019 Announced
Summary on Grant Application Form
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.

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