RS Fellow - EPSRC grant (2014): Application of Tandem Non-Covalent Interactions to the Development of New Enantioselective Reactions
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
A primary goal of organic chemists is the construction of molecules for applications as diverse as medicines, new materials and biomolecules. The field is constantly driven by the need for new, more efficient methods as well as ways to access molecules which may have previously been impossible. The most important tool at an organic chemist's disposal is undoubtedly catalysis, whereby the use of a small amount of a custom-designed catalyst can permit a reaction to occur under much milder conditions than otherwise, or opens up new chemical pathways altogether. For this reason, innovation in catalysis is central to innovation in organic chemistry. Nature's catalysis is performed by enzymes; evolution has made them phenomenally efficient. Often playing a leading role in enzymatic processes are 'hydrogen bonds', special types of electrostatic attraction which are important in facilitating the chemical reaction between two molecules by bringing them into close proximity with one another or by stabilising the pathway leading to product formation. My research seeks to employ these same interactions, but in the context of small molecules which we can readily synthesise and handle in the lab. This approach to catalysis is very exciting as it is still in its infancy yet offers exciting opportunities for both activation and control. This project will seek to take inspiration from a distinct field within chemistry called Supramolecular Chemistry, which explores the behavior of large molecules which are assembled from smaller ones using multiple weak 'temporary' interactions working in tandem. Hydrogen bonds are very important in this regard but there are a number of other key interactions such as ion pairs and pi-cation interactions which have been shown to be powerful in building up molecular structures. It is our aim to apply several of these interactions together in tandem to design new catalysts that will bind with our reactant in a very well defined orientation. The catalyst will also induce the substrate to react with another molecule, allowing the selective synthesis of one mirror image of a molecule over the other (so-called enantiomers). This is a very important pursuit in science, since the inherent 'handedness' of biological systems means that the different mirror image forms of chiral molecules often have very different effects in the body. This is of particular importance in pharmaceutical applications.
Planned Impact
Please refer to attached Royal Society application
Publications
Davis H
(2017)
meta -Selective C-H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand
in Angewandte Chemie
Davis HJ
(2017)
Harnessing non-covalent interactions to exert control over regioselectivity and site-selectivity in catalytic reactions.
in Chemical science
Davis HJ
(2017)
meta-Selective C-H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand.
in Angewandte Chemie (International ed. in English)
Davis HJ
(2016)
Ion Pair-Directed Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C-H Borylation of Aromatic Quaternary Ammonium Salts.
in Journal of the American Chemical Society
Douthwaite J
(2022)
Extended sulfonated bipyridine ligands targeting the para-selective borylation of arenes
in Tetrahedron
Fanourakis A
(2021)
Enantioselective Intermolecular C-H Amination Directed by a Chiral Cation.
in Journal of the American Chemical Society
Description | We first developed an ion-pair directed borylation of several classes of ammonium salt that are highly selective for the meta position of the aromatic portion. This is a difficult position to functionalise using traditional methods and could expedite the synthesis of compounds useful to society, such as pharmaceuticals and agrochemicals. Furthermore, we demonstrated that it is viable to use ion pairing interactions to achieve this, between ligand and substrate which is rather novel and has hardly been explored. Subsequently, we showed that our successful ligand was able to act as a hydrogen bond acceptor and to direct borylation to the meta position on a range of different substrates containing amide functional groups (published late 2017), significantly expanding the scope of our process, all using the same ligand. Since that time we have developed a related strategy which is complementary and targets the para position of arenes for borylation, which was published in mid 2018. Furthermore, we have developed the first example of an enantioselective Minisci reaction. This reaction type is very often used in medicinal chemistry and pharma as it rapidly attaches new groups to heteroarenes such as pyridines and quinolines. However, control of enantioselectivity and regioselectivity has always been a challenge. In our work, published in Science in 2018, we were able to control both using a non-covalent catalyst. In subsequent developments we have expanded the scope of this considerably through a collaboration with the group of Prof. Matthew Sigman at the University of Utah, USA. We have also collaborated with researcher who use computational tools to investigate reaction mechanism. |
Exploitation Route | This strategy could be applied to a diverse range of reactions catalysed by transition metals, for control of regioselectivity or site selectivity. Also a range of different common functional groups could potentially be used with a small collection of ligands to direct site-selective borylation. The enantioselective Minisci reaction is likely to be used extensively in the Pharmaceutical industry due to the prevalence of basic heterocycles in medicinal compounds and also the preference for compounds with stereocentres and three dimensional scaffolds. |
Sectors | Agriculture, Food and Drink,Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
URL | https://phippsgroup.wixsite.com/home |
Description | I have visited a number of pharmaceutical companies over the past years and the interest in our chemistry that has been developed is high and I am sure that our methods will be evaluated by such companies if opportunities arise to solve problems that they are experiencing. By publishing in high impact journals that are widely read, visiting pharma companies and also by making efforts to cultivate ties with industry in the UK I am maximizing the visibility of our methods that we are developing in the hope for future use. For example since 2018 I have given talks to disseminate the results of the grant at GlaxoSmithKline, Syngenta, Eli Lilly, UCB, AstraZeneca (USA and UK), Merck (USA) and Pharmaron. The pharma and biotech industry is crucial to UK future growth and our development of highly relevant chemistry is a draw of companies to set up and look for staff recruitment in the UK. |
First Year Of Impact | 2018 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | AstraZeneca CASE Studentship |
Amount | £29,400 (GBP) |
Organisation | AstraZeneca |
Sector | Private |
Country | United Kingdom |
Start | 10/2016 |
End | 03/2020 |
Description | ERC Starting Grant |
Amount | € 1,499,756 (EUR) |
Funding ID | 757381 |
Organisation | European Research Council (ERC) |
Sector | Public |
Country | Belgium |
Start | 01/2018 |
End | 12/2022 |
Description | Enantioselective C-H C-H Coupling of Alcohols with Heteroarenes |
Amount | £355,412 (GBP) |
Funding ID | EP/S03269X/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2019 |
End | 06/2023 |
Description | GSK CASE Studentship Topup |
Amount | £28,000 (GBP) |
Organisation | GlaxoSmithKline (GSK) |
Sector | Private |
Country | Global |
Start | 10/2016 |
End | 03/2020 |
Description | GSK/EPSRC iCASE PhD Studentship |
Amount | £84,000 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2018 |
End | 09/2021 |
Description | Research Fellows Enhancement Award 2017 |
Amount | £108,742 (GBP) |
Funding ID | RGF\EA\180005 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2017 |
End | 09/2021 |
Description | Syngenta/EPSRC iCASE PhD Studentship |
Amount | £83,296 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2017 |
End | 10/2021 |
Description | Collaboration with Prof Jonathan Goodman and Dr Kristaps Ermanis, Cambridge |
Organisation | University of Cambridge |
Department | Department of Chemistry |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Experimental expertise |
Collaborator Contribution | expertise in performing DFT calculations |
Impact | A manuscript resulting from the collaboration was published last year in the the Journal of the American Chemical Society: Ermanis, K.;* Colgan, A. C.; Proctor, R. S. J. ; Hadrys, B. W.; Phipps, R. J.;* Goodman, J. M.* A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction. J. Am. Chem. Soc. 2020,142, 21091 https://pubs.acs.org/doi/10.1021/jacs.0c09668 |
Start Year | 2018 |
Description | Collaboration with Prof Matthew Sigman |
Organisation | University of Utah |
Country | United States |
Sector | Academic/University |
PI Contribution | We provided experimental expertise to the collaboration |
Collaborator Contribution | The partner in the Sigman group provided expertise in statistical analysis |
Impact | A paper has been published: Predictive Multivariate Linear Regression Analysis Guides Successful Catalytic Enantioselective Minisci Reactions of Diazines J. Am. Chem. Soc. 2019, 141, 48, 19178-19185 https://pubs.acs.org/doi/10.1021/jacs.9b11658 |
Start Year | 2018 |