Cu(II)-Catalysed C-H Activation Routes to Heterocycles; Applications in Target Synthesis
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
Heterocyclic compounds are the mainstay of the pharmaceutical and agrochemical industries. As part of our on-going research programme geared towards the synthesis of heterocyclic systems of medicinal interest, we have placed a great deal of emphasis on designing streamlined and environmentally friendly synthetic procedures. Thus, we have successfully developed a number of improved routes to heterocyclic building blocks utilising cascade and telescoped processes.
As part of this programme, we recently developed a high yielding moisture- and air-insensitive procedure for the preparation of 3,3'-disubstituted oxindoles from simple aniline-derived starting materials via a formal double C-H activation approach using an extremely cheap and readily available reagent, cupric acetate monohydrate (ACS grade, < £1/10 g), in DMF as solvent. Such a straightforward method of generating quaternary stereogenic centres is noteworthy. In 2010, we discovered a much improved procedure which uses catalytic amounts of cupric acetate monohydrate in toluene or mesitylene as solvent and gives equally high yields of oxindole products without the need to exclude air and moisture.
We are now fully focused on demonstrating the broad utility of the improved cupric acetate monohydrate procedure and we believe that the potential of this methodology is enormous, particularly, given that many of today's drugs are based on oxindoles (e.g. the blockbuster anti-cancer drug, Sutent).
The main aims of this proposal are therefore: (i) to further exploit the novel copper-based C-H activation chemistry to develop a route to spirocyclic oxindoles, (ii) to explore the development of asymmetric variants for all substrate classes, (iii) to extend the methodology to the synthesis of related heterocyclic systems, and, very importantly, (iv) to apply, and therefore validate, the new copper-catalysed cyclisation procedure in complex pharmaceutical and natural product target synthesis. It is our aim to develop this new procedure into a truly powerful synthetic tool with far-reaching applications in both academic research and industrial medicinal chemistry and scale-up processes. This ambitious programme will be carried out by a PDRA over a 3 year period.
As part of this programme, we recently developed a high yielding moisture- and air-insensitive procedure for the preparation of 3,3'-disubstituted oxindoles from simple aniline-derived starting materials via a formal double C-H activation approach using an extremely cheap and readily available reagent, cupric acetate monohydrate (ACS grade, < £1/10 g), in DMF as solvent. Such a straightforward method of generating quaternary stereogenic centres is noteworthy. In 2010, we discovered a much improved procedure which uses catalytic amounts of cupric acetate monohydrate in toluene or mesitylene as solvent and gives equally high yields of oxindole products without the need to exclude air and moisture.
We are now fully focused on demonstrating the broad utility of the improved cupric acetate monohydrate procedure and we believe that the potential of this methodology is enormous, particularly, given that many of today's drugs are based on oxindoles (e.g. the blockbuster anti-cancer drug, Sutent).
The main aims of this proposal are therefore: (i) to further exploit the novel copper-based C-H activation chemistry to develop a route to spirocyclic oxindoles, (ii) to explore the development of asymmetric variants for all substrate classes, (iii) to extend the methodology to the synthesis of related heterocyclic systems, and, very importantly, (iv) to apply, and therefore validate, the new copper-catalysed cyclisation procedure in complex pharmaceutical and natural product target synthesis. It is our aim to develop this new procedure into a truly powerful synthetic tool with far-reaching applications in both academic research and industrial medicinal chemistry and scale-up processes. This ambitious programme will be carried out by a PDRA over a 3 year period.
Planned Impact
Heterocyclic compounds are the mainstay of the pharmaceutical and agrochemical industries. Oxindoles are of particular importance, as indicated by the recent success of Sutent, Pfizer's blockbuster anti-cancer drug. In 2010, we discovered a high yielding and practically straightforward procedure for the preparation of 3,3'-disubstituted-oxindoles from simple aniline-derived starting materials via a formal double C-H activation approach. This "green" procedure uses cupric acetate monohydrate (< £1/10 g), in catalytic amounts, with toluene as solvent and gives high yields without the need to exclude air and moisture.
We believe that the potential of this new copper-based methodology is enormous, not only for the preparation of oxindoles, but also to prepare other important heterocyclic compounds. In this proposal we will first extend this novel copper-based route to prepare spirocyclic oxindoles, and will then go on to develop procedures which enable the substituted oxindoles to be prepared as single enantiomers, as required by the regulatory authorities. In addition, we will extend the copper-based methodology to prepare related heterocyclic systems. Finally, we will apply this new cyclisation procedure to prepare complex pharmaceuticals and bioactive natural products in order to validate this novel chemistry and highlight its utility.
It is our aim to develop this copper-based procedure into a truly powerful synthetic tool with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes. In particular, we believe that this research will impact greatly on academic groups involved with the preparation of biological lead compounds and in natural product synthesis. In addition, these novel copper-catalysed Ar-H / C-H double activation processes will be of direct relevance to the rapidly growing number of research groups involved in C-H activation projects and in the development of improved "green" routes to high value synthetic intermediates. Researchers interested in mechanistic organic chemistry, particularly involving copper-catalysis and radical processes, will also be intrigued by the results of this research, which should inspire new synthetic and mechanistic advances. Collaborations will be established in these areas.
In addition, these new copper-based procedures, which dramatically increase the ease with which bioactive heterocycles can be prepared, could well lead to the discovery of new drugs which would enhance the quality of life and thus make a direct societal impact. In terms of compounds prepared in York on this project, we will make novel synthetic analogues and natural products available for bioassay in the laboratories of our collaborators in order to identify potentially useful drug candidates. We will also seek to establish collaborations with the discovery arms of UK/EU pharmaceutical and agrochemical companies, and later with scale-up and production chemists in industry.
All potentially valuable IP arising from this research programme will then be discussed with the University of York Industrial Liaison Office, and with any industrial collaborator, and patent protection will be investigated. Once IPR is secure, the results will be published in the scientific literature and described in lectures/poster displays and using the www.
This research programme will also have a direct impact in terms of the production of highly trained manpower. Around 75 research personnel from the Taylor group have entered the chemical industry and many have also gone into academic and teaching appointments. The postdoctoral researcher on this grant, together with any associated students (final year project, Erasmus etc.), will be experienced in the development and optimisation of organic methodology, and in heterocyclic and natural product chemistry, at the frontiers of the area, and so will be in great demand for industrial, teaching or academic vacancies.
We believe that the potential of this new copper-based methodology is enormous, not only for the preparation of oxindoles, but also to prepare other important heterocyclic compounds. In this proposal we will first extend this novel copper-based route to prepare spirocyclic oxindoles, and will then go on to develop procedures which enable the substituted oxindoles to be prepared as single enantiomers, as required by the regulatory authorities. In addition, we will extend the copper-based methodology to prepare related heterocyclic systems. Finally, we will apply this new cyclisation procedure to prepare complex pharmaceuticals and bioactive natural products in order to validate this novel chemistry and highlight its utility.
It is our aim to develop this copper-based procedure into a truly powerful synthetic tool with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes. In particular, we believe that this research will impact greatly on academic groups involved with the preparation of biological lead compounds and in natural product synthesis. In addition, these novel copper-catalysed Ar-H / C-H double activation processes will be of direct relevance to the rapidly growing number of research groups involved in C-H activation projects and in the development of improved "green" routes to high value synthetic intermediates. Researchers interested in mechanistic organic chemistry, particularly involving copper-catalysis and radical processes, will also be intrigued by the results of this research, which should inspire new synthetic and mechanistic advances. Collaborations will be established in these areas.
In addition, these new copper-based procedures, which dramatically increase the ease with which bioactive heterocycles can be prepared, could well lead to the discovery of new drugs which would enhance the quality of life and thus make a direct societal impact. In terms of compounds prepared in York on this project, we will make novel synthetic analogues and natural products available for bioassay in the laboratories of our collaborators in order to identify potentially useful drug candidates. We will also seek to establish collaborations with the discovery arms of UK/EU pharmaceutical and agrochemical companies, and later with scale-up and production chemists in industry.
All potentially valuable IP arising from this research programme will then be discussed with the University of York Industrial Liaison Office, and with any industrial collaborator, and patent protection will be investigated. Once IPR is secure, the results will be published in the scientific literature and described in lectures/poster displays and using the www.
This research programme will also have a direct impact in terms of the production of highly trained manpower. Around 75 research personnel from the Taylor group have entered the chemical industry and many have also gone into academic and teaching appointments. The postdoctoral researcher on this grant, together with any associated students (final year project, Erasmus etc.), will be experienced in the development and optimisation of organic methodology, and in heterocyclic and natural product chemistry, at the frontiers of the area, and so will be in great demand for industrial, teaching or academic vacancies.
Organisations
People |
ORCID iD |
Richard Taylor (Principal Investigator) |
Publications
Drouhin P
(2015)
Substrate scope in the copper-mediated construction of bis-oxindoles via a double C-H/Ar-H coupling process
in Tetrahedron
Drouhin P
(2014)
Copper-mediated construction of spirocyclic bis-oxindoles via a double C-H, Ar-H coupling process.
in Organic letters
Drouhin P
(2015)
A Copper-Mediated Oxidative Coupling Route to 3 H - and 1 H -Indoles from N -Aryl-enamines
in European Journal of Organic Chemistry
Gorman R
(2019)
A copper(II)-mediated radical cross-dehydrogenative coupling/sulfinic acid elimination approach to 2-quinolones
in Tetrahedron
Hurst TE
(2014)
A direct C-H/Ar-H coupling approach to oxindoles, thio-oxindoles, 3,4-dihydro-1 H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Hurst TE
(2017)
A Cu-Catalysed Radical Cross-Dehydrogenative Coupling Approach to Acridanes and Related Heterocycles.
in European journal of organic chemistry
Description | Efficient new and cheap routes to prepare heterocycles, key building blocks in industrial and academic labs. These procedures use copper catalysts which are cheap and readily available. |
Sectors | Agriculture Food and Drink Chemicals Pharmaceuticals and Medical Biotechnology |
Description | New methods for the preparation of heterocycles are of wide interest. This work is highly cited and presumably being used in academic and industrial labs. |
First Year Of Impact | 2014 |
Sector | Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | 15th RSC-SCI Joint Meeting on Heterocyclic Chemistry |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Research talk at a national conference |
Year(s) Of Engagement Activity | 2016 |
Description | Conference and colloquia presentations |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Research presentation with many questions |
Year(s) Of Engagement Activity | 2015 |
Description | Dearomatisation and Spirocycle Synthesis |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Lecture to industry on York research |
Year(s) Of Engagement Activity | 2016 |
Description | From Natural Products to Organic Diversity, University of Bath |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Lecture on York research at Bath Uni |
Year(s) Of Engagement Activity | 2016 |
Description | Industrial seminars |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited lectures at Syngenta (UK) and Janssen (Belgium) to industrialists andf visitjn g PhD students. Lots of discussion and questions. Transfer of new methods. |
Year(s) Of Engagement Activity | 2015 |
Description | International Meeting in Shanghai, China |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | (Keynote/plenary speaker), 25 Nov 2016, International Meeting in Shanghai, China |
Year(s) Of Engagement Activity | 2016 |
Description | International conference plenary lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | International meeting on Synthesis at University of Cambridge, UK. Plenary lecture with many questions and follow-up contact. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.rsc.org/ConferencesAndEvents/RSCConferences/Organic_Synthesis_24/ |
Description | International lecturer at one day meeting in Peking University, Beijing |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Research lecture to advertise reserach in York |
Year(s) Of Engagement Activity | 2016 |
Description | International lecturer at one day meeting in Sichuan University, Chengdu |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lecture on research at York. |
Year(s) Of Engagement Activity | 2016 |
Description | SFST6 Rennes France |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lecture of York research at an international conference |
Year(s) Of Engagement Activity | 2016 |