Convergent Acyliminium Methodology: Diversity in Heterocyclic Scaffolds
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
Heterocyclic compounds are the cornerstone of the pharmaceutical and agrochemical industries. As part of our on-going research programme geared towards the synthesis of heterocyclic systems of biological interest, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to valuable heterocycles. We now propose to develop Convergent Acyliminium Methodology (CAM) to establish an efficient "one-pot" route to convert readily available imines and carboxylic acids into a diverse range of highly functionalised heterocyclic systems. We believe that such a simple and reliable procedure leading to novel heterocyclic scaffolds will be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry.
Preliminary studies have been carried out which establish the viability of this novel approach; the main aims of the proposal are therefore:
(i) to optimise the novel Convergent Acyliminium Methodology (CAM) to develop an efficient "one-pot" route to convert readily available imines and carboxylic acids into a diverse range of heterocyclic systems,
(ii) to expand the range of acylating agents to include benzannelated examples and functionalized sulfonic acids, phosphonic acids, chloroformates and isocyanates,
(iii) to explore asymmetric catalysis to prepare heterocycles in enantio-enriched forms,
(iv) to extend the range of imine substrates to encompass acyclic imines, imidates, oxazolines, imidazolines and thiazolines,
(v) to exploit the CAM sequence in an iterative sense utilising repeated ring-expansions to produce medium-sized and macrocyclic lactams and cyclic peptides,
(vi) to extend the methodology to prepare the complex natural product, 'upenamide, in order to showcase this new synthetic approach,
(vii) to apply, and therefore validate, the new CAM sequence in simple target synthesis with jamtinine and loracarbef as possible targets (although targets from collaborators will also be considered).
It is our aim to develop this new procedure into a powerful synthetic procedure with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes (letters of support from AstraZeneca and Novartis (pharma) and Bayer (Agro) are attached and plans for collaborations with these companies are well advanced).
This ambitious programme will be carried out by a PDRA over a 3 year period.
Preliminary studies have been carried out which establish the viability of this novel approach; the main aims of the proposal are therefore:
(i) to optimise the novel Convergent Acyliminium Methodology (CAM) to develop an efficient "one-pot" route to convert readily available imines and carboxylic acids into a diverse range of heterocyclic systems,
(ii) to expand the range of acylating agents to include benzannelated examples and functionalized sulfonic acids, phosphonic acids, chloroformates and isocyanates,
(iii) to explore asymmetric catalysis to prepare heterocycles in enantio-enriched forms,
(iv) to extend the range of imine substrates to encompass acyclic imines, imidates, oxazolines, imidazolines and thiazolines,
(v) to exploit the CAM sequence in an iterative sense utilising repeated ring-expansions to produce medium-sized and macrocyclic lactams and cyclic peptides,
(vi) to extend the methodology to prepare the complex natural product, 'upenamide, in order to showcase this new synthetic approach,
(vii) to apply, and therefore validate, the new CAM sequence in simple target synthesis with jamtinine and loracarbef as possible targets (although targets from collaborators will also be considered).
It is our aim to develop this new procedure into a powerful synthetic procedure with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes (letters of support from AstraZeneca and Novartis (pharma) and Bayer (Agro) are attached and plans for collaborations with these companies are well advanced).
This ambitious programme will be carried out by a PDRA over a 3 year period.
Planned Impact
Heterocyclic compounds are the cornerstone of the pharmaceutical and agrochemical industries. As part of our on-going research programme geared towards the synthesis of heterocyclic systems of biological interest, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to valuable heterocycles. We now propose to develop Convergent Acyliminium Methodology (CAM) to establish an efficient "one-pot" route to convert readily available imines and carboxylic acids into a diverse range of highly functionalised heterocyclic systems. We believe that such a simple and reliable procedure leading to novel heterocyclic scaffolds will be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry.
We believe that the potential of this new CAM methodology is enormous, and in this proposal we will optimise the procedure, explore its scope, and extend it to prepare the products as single enantiomers, as required by the regulatory authorities. Finally, we will apply this new cyclisation procedure to prepare complex pharmaceuticals and bioactive natural products in order to validate and showcase the novel chemistry and highlight its utility. Letters of support from AstraZeneca and Novartis (pharma) and Bayer (Agro) are attached and plans for collaborations with these companies are well advanced.
It is our aim to develop the CAM procedure into a really 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, and those involved in the development of improved "green" routes to high value synthetic intermediates.
In addition, these new CAM 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 and agrochemical 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 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 CAM methodology is enormous, and in this proposal we will optimise the procedure, explore its scope, and extend it to prepare the products as single enantiomers, as required by the regulatory authorities. Finally, we will apply this new cyclisation procedure to prepare complex pharmaceuticals and bioactive natural products in order to validate and showcase the novel chemistry and highlight its utility. Letters of support from AstraZeneca and Novartis (pharma) and Bayer (Agro) are attached and plans for collaborations with these companies are well advanced.
It is our aim to develop the CAM procedure into a really 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, and those involved in the development of improved "green" routes to high value synthetic intermediates.
In addition, these new CAM 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 and agrochemical 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 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
Chambers SJ
(2016)
From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Coulthard G
(2015)
Propylphosphonic anhydride (T3P) mediated synthesis of ß-lactams from imines and aryl-substituted acetic acids
in Tetrahedron Letters
James MJ
(2016)
Synthesis of Spirocyclic Indolenines.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Kitsiou C
(2014)
Substrate scope in the direct imine acylation of ortho-substituted benzoic acid derivatives: the total synthesis (±)-cavidine
in Tetrahedron
Ronson T
(2016)
Synthetic approaches to pallimamine and analogues using direct imine acylation
in Tetrahedron
Rossi-Ashton JA
(2017)
Selective synthesis of three product classes from imine and carboxylic acid precursors via direct imine acylation.
in Organic & biomolecular chemistry
Unsworth WP
(2013)
Direct imine acylation: synthesis of the proposed structures of 'upenamide.
in Organic letters
Unsworth WP
(2014)
Direct imine acylation for molecular diversity in heterocyclic synthesis.
in The Journal of organic chemistry
Unsworth WP
(2013)
Direct imine acylation: rapid access to diverse heterocyclic scaffolds.
in Organic letters
Description | New methods for the efficient construction of useful heterocyclic building blocks. This work will be of great value to synthetic chemists in industry and universities. |
Sectors | Agriculture Food and Drink Chemicals Pharmaceuticals and Medical Biotechnology |
Description | EPSRC |
Amount | £400,000 (GBP) |
Funding ID | EP/M018601/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2015 |
End | 06/2018 |
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 |