Organic Catalysts Incorporating Catalytic Triads
Lead Research Organisation:
University College London
Department Name: Chemistry
Abstract
New chemical compounds which exhibit potentially useful biological activity / be it toxicity against cancer cells or antibiotic properties, are identified on an almost daily basis in both natural organisms and collections of man-made compounds. Subsequently, closely related structures are often examined to determine which parts of these molecules are responsible for the beneficial effects. In the course of this drug development process, thousands of molecules may be synthesized in pursuit of just one that has the desirable medical effects, is readily absorbed by the body and is non-toxic. Synthetic chemistry is therefore of fundamental importance at every stage. Meanwhile, the many recent advances in the biological sciences (such as the completion of the human genome sequence) have increased the rate at which potential targets for new disease treatments can be identified. As a consequence, the demand for drug molecules directed towards these new targets is increasing rapidly, and efficient, effective methods of chemical synthesis, particularly those which result in the construction of structural features common in drugs, are of paramount importance.The proposed research focuses on the development of new 'catalytic' methods for chemical synthesis, in which only a small quantity of chemical reagent (a 'catalyst') is required in order to convert much larger quantities of starting materials into products. The catalyst design will be inspired by natural enzymes, which are able to carry out countless chemical reactions in a catalytic fashion. We will also take inspiration from existing chemical methods for carrying out the reactions under investigation, adapting them for use in a catalytic manner. The chemical reactions which we will concentrate on have been identified in a number of recent documents (published by representatives of the global pharmaceutical industry, the American Chemical Society and the UK government research councils) as being of fundamental importance in the synthesis of drug molecules. These documents noted that there is currently a lack of efficient and environmentally-friendly chemical methods for carrying out these processes and that academic research directed towards developing such methods is urgently required.For example, amide bonds are found in more than 25% of existing drug molecules, as well as in naturally occurring molecules such as proteins, and their formation is amongst the most common of all transformations in organic chemistry. There are, however, currently no effective catalytic methods for forming these bonds. Indeed, the existing, non-catalytic technologies often require large quantities of chemical reagents that are expensive and/or toxic. We will aim to develop simple organic (carbon-based) molecules as catalysts for this reaction which will act by 'holding onto' and 'organising' the starting materials, and directing them to react together to form the amide bond. The only chemical by-products of this new process will be water and the small quantity of the catalyst itself, which can be recovered and recycled. Such a catalyst would have immediate and far-reaching application in many avenues of scientific research. The concepts outlined in this work will also be applied to the development of catalysts for many other important chemical reactions.These new catalysts will have widespread application in the synthesis of molecules for use as new drugs and agrochemicals and in the study of living cell processes, and as such will be beneficial to scientists working in many areas of chemistry, medicine and biology.
Organisations
Publications
Aliev Abil E.
(2014)
Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics
in PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Arkhipenko S
(2018)
Mechanistic insights into boron-catalysed direct amidation reactions.
in Chemical science
Bachman M
(2012)
Rapid synthesis of highly functionalised a-amino amides and medium ring lactones using multicomponent reactions of amino alcohols and isocyanides.
in Organic & biomolecular chemistry
Chatzidaki A
(2015)
The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of a7 nicotinic acetylcholine receptors.
in Neuropharmacology
D'Oyley Jarryl M.
(2014)
Halohydration of alkynols: Au-catalyzed and non-catalyzed routes to a,a-dihalo-ß-hydroxyketones
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
D'Oyley JM
(2014)
Regioselective dihalohydration reactions of propargylic alcohols: gold-catalyzed and noncatalyzed reactions.
in Angewandte Chemie (International ed. in English)
Foster RW
(2013)
Highly Regioselective Synthesis of Substituted Isoindolinones via Ruthenium-Catalyzed Alkyne Cyclotrimerizations.
in Advanced synthesis & catalysis
Gill JK
(2012)
A series of a7 nicotinic acetylcholine receptor allosteric modulators with close chemical similarity but diverse pharmacological properties.
in Molecular pharmacology
Gill-Thind JK
(2015)
Structurally similar allosteric modulators of a7 nicotinic acetylcholine receptors exhibit five distinct pharmacological effects.
in The Journal of biological chemistry
Ishikawa S
(2013)
A rapid route to aminocyclopropanes via carbamatoorganozinc carbenoids.
in Angewandte Chemie (International ed. in English)
Description | The research project was focused on developing new reactions for achieving dehydration reactions (chemical reactions involving the formation of a new bond with the loss of a molecule of water) and hydration reactions (reactions involving the addition of a molecule of water to another compound to generate new chemical bonds). Many of these reactions are very important in the synthesis of useful everyday molecules such as pharmaceuticals, but current methods for achieving these processes are far from ideal. We developed a new chemical reagent for making amide bonds (a common dehydration reaction) which has a broad scope and is extremely easy to use for small scale reactions. The products of these reactions can easily be isolated and purified via a simple filtration process. We developed a new chemical reaction for the addition of water to carbon-carbon triple bonds (alkynes) which enables these simple molecules to undergo complex reactions to generate several new chemical bonds in a single step. This process is potentially useful for the assembly of complex molecules from very simple precursors. We are currently extending this chemistry to carbon-carbon double bonds (alkenes), as well as exploring several other reactions of alkynes discovered during the course of this work. We also identified novel catalysts for the direct substitution reactions of a particular class of alcohols (another important dehydration reaction) which we are currently studying in further detail. |
Exploitation Route | Our follow up work in both of these areas has attracted industrial funding as well as further support from the EPSRC. The newly discovered reactions can potentially be used to synthesise a wide variety of useful molecules with potential industrial applications. Further work is underway to explore the scope of the processes and identify potential applications. |
Sectors | Agriculture, Food and Drink,Chemicals,Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
URL | http://www.tomsheppard.eu/ |
Description | The new reagent we developed for amide formation has been used by researchers in both charitable and industrial research laboratories. The reagent is now marketed by Sigma-Aldrich as 'The Sheppard Amidation Reagent'. In a subsequent industry-funded project, we have now developed conditions where the reagent can be used as a catalyst for amide bond formation. |
First Year Of Impact | 2013 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | AstraZeneca Research Funding |
Amount | £10,500 (GBP) |
Funding ID | Research Support |
Organisation | AstraZeneca |
Sector | Private |
Country | United Kingdom |
Start | 12/2009 |
End | 12/2012 |
Description | EPSRC Organic Synthesis Studentships |
Amount | £106,805 (GBP) |
Funding ID | EP/G040680/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2009 |
End | 09/2013 |
Description | EPSRC Responsive Mode |
Amount | £342,356 (GBP) |
Funding ID | EP/K001183/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2012 |
End | 09/2015 |
Description | EPSRC Sustainable Chemical Feedstocks |
Amount | £2,426,238 (GBP) |
Funding ID | EP/K014897/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2013 |
End | 09/2016 |
Description | GlaxoSmithKline Research Funding |
Amount | £101,121 (GBP) |
Funding ID | GSK CASE Award |
Organisation | GlaxoSmithKline (GSK) |
Sector | Private |
Country | Global |
Start | 09/2011 |
End | 09/2015 |
Description | GlaxoSmithKline Research Funding |
Amount | £32,000 (GBP) |
Organisation | GlaxoSmithKline (GSK) |
Sector | Private |
Country | Global |
Start | 09/2014 |
End | 09/2018 |
Description | Leverhulme Trust Research Grant |
Amount | £71,358 (GBP) |
Funding ID | F/00 134/CL |
Organisation | The Leverhulme Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2009 |
End | 03/2012 |
Description | Pfizer CASE Awards |
Amount | £92,443 (GBP) |
Funding ID | CASE award |
Organisation | Pfizer Ltd |
Sector | Private |
Country | United Kingdom |
Start | 09/2013 |
End | 03/2017 |
Description | Royal Society Research Grants |
Amount | £7,000 (GBP) |
Funding ID | RG081170 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2008 |
End | 04/2009 |
Title | B(OCH2CF3)3 Amidation Reagent |
Description | Reagent for preparing amides from carboxylic acids/amines |
Type Of Material | Technology assay or reagent |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | Reagent is now sold commercially by a major commercial supplier (Sigma-Aldrich) as a direct result of our work. |
URL | https://www.sigmaaldrich.com/technical-documents/articles/chemistry/professor-and-product-portal/tom... |