Catalytic Asymmetric Dearomative Spirocyclisations
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
The design of new methods to synthesize and manipulate complex heterocyclic molecules is extremely important , especially given that such compounds form the basis of a vast array of biologically useful natural products, pharmaceuticals and crop protection products. In particular, procedures which allow complex 3D molecular architectures to be constructed quickly from simple precursors are of great importance, as they facilitate the biological testing of previously unexplored regions of 'chemical space' for potential applications (e.g. in drug discovery). As part of our on-going research programme geared towards the synthesis of diverse heterocyclic scaffolds, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to biologically active heterocycles. This proposal centres on the formation and subsequent elaboration of spirocyclic 3D scaffolds from far simpler, readily available 2D aromatic precursors. A series of two-step protocols based of 'dearomatisation' (to form the key 3D building block) and 'functionalisation' (to exploit its high reactivity and further increase molecular complexity) are proposed. Highly promising preliminary studies have been carried out which establish the viability of this novel approach; the key dearomatsation step is performed using a very small quantity of a simple copper or silver catalyst and is easy to perform, employing mild conditions and non-toxic reagents. The discovery of a number of extremely versatile one-pot protocols is anticipated. The methods developed will also be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry. The main aims of the proposal are therefore:
(i) to establish electrophilic alkyne activation as versatile method for the dearomatisation of heteroaromatics leading to novel spirocycles;
(ii) to investigate the use of solid supported catalysts and 'flow' variants of the key dearomatisation / spirocyclisation reaction;
(iii) to develop asymmetric variants (building on the 77% ee, 99% yield obtained in preliminary studies);
(iv) to exploit the synthetic potential of the 3D 'building blocks' generated by examining additional functionalisation modes, including reactions with a range of nucleophiles, cross-coupling reactions and redox processes;
(v) to investigate alternative electrophilic activation modes;
(vi) to develop cascade reaction sequences and to apply these methods in target synthesis: Satavaptan, spirobacillene B, plicamine, coerulescine, spirobenzofuran, coixspiroeneones A-E, rychnophylline, mollenine A and cephalotaxine have all been identified as potential natural product/pharmaceutical targets. In addition, medicinal targets suggested by collaborators will also be considered.
It is our aim that the dearomatisation/functionalisation protocols will become indispensable tools for the construction of biologically important 3D scaffolds, with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes.
This ambitious programme will be carried out by a PDRA over a 3 year period.
(i) to establish electrophilic alkyne activation as versatile method for the dearomatisation of heteroaromatics leading to novel spirocycles;
(ii) to investigate the use of solid supported catalysts and 'flow' variants of the key dearomatisation / spirocyclisation reaction;
(iii) to develop asymmetric variants (building on the 77% ee, 99% yield obtained in preliminary studies);
(iv) to exploit the synthetic potential of the 3D 'building blocks' generated by examining additional functionalisation modes, including reactions with a range of nucleophiles, cross-coupling reactions and redox processes;
(v) to investigate alternative electrophilic activation modes;
(vi) to develop cascade reaction sequences and to apply these methods in target synthesis: Satavaptan, spirobacillene B, plicamine, coerulescine, spirobenzofuran, coixspiroeneones A-E, rychnophylline, mollenine A and cephalotaxine have all been identified as potential natural product/pharmaceutical targets. In addition, medicinal targets suggested by collaborators will also be considered.
It is our aim that the dearomatisation/functionalisation protocols will become indispensable tools for the construction of biologically important 3D scaffolds, with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes.
This ambitious programme will be carried out by a PDRA over a 3 year period.
Planned Impact
As part of our on-going research programme geared towards the synthesis of diverse heterocyclic scaffolds, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to biologically important heterocycles. This proposal centres on the formation and subsequent elaboration of versatile spirocyclic building blocks from simple aromatic precursors. The methods proposed are expected to expedite the synthesis of a vast array of diverse, highly functionalised 3D scaffolds with high therapeutic potential from simple, readily available aromatic precursors. A straightforward two-step system of 'dearomatisation' and 'functionalisation' is proposed; these methods use mild reagents and conditions and are expected to lead to the development of a range of extremely versatile one-pot protocols. Thus they 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.
In view of the operational simplicity and versatility of the proposed methods we believe that its potential is enormous. We plan to optimise the procedure, explore its scope, develop solid supported/flow variants and prepare the products as single enantiomers, as required by the regulatory authorities. We will also seek to further increase molecular complexity by adapting the methods developed for use in cascade reaction sequences. 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. Given the novelty and efficiency of the chemistry carried out in preliminary studies, and the highly encouraging asymmetric possibilities, high profile publications are likely.
It is our aim that the key dearomatisation process and the resulting spirocyclic building blocks will have 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 procedures, which dramatically increase the ease with which bioactive heterocycles can be prepared, could well lead to the discovery of new drugs or agrochemicals which would 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 pharma/agro-chemical 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 80 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.
In view of the operational simplicity and versatility of the proposed methods we believe that its potential is enormous. We plan to optimise the procedure, explore its scope, develop solid supported/flow variants and prepare the products as single enantiomers, as required by the regulatory authorities. We will also seek to further increase molecular complexity by adapting the methods developed for use in cascade reaction sequences. 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. Given the novelty and efficiency of the chemistry carried out in preliminary studies, and the highly encouraging asymmetric possibilities, high profile publications are likely.
It is our aim that the key dearomatisation process and the resulting spirocyclic building blocks will have 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 procedures, which dramatically increase the ease with which bioactive heterocycles can be prepared, could well lead to the discovery of new drugs or agrochemicals which would 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 pharma/agro-chemical 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 80 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
Clarke AK
(2016)
Dearomatisation approaches to spirocyclic dienones via the electrophilic activation of alkynes.
in Organic & biomolecular chemistry
James M
(2016)
Catalytic Dearomatization Approach to Quinolizidine Alkaloids: Five Step Total Synthesis of (±)-Lasubine II
in Organic Letters
Liddon J
(2016)
Preparation and Reactions of Indoleninyl Halides: Scaffolds for the Synthesis of Spirocyclic Indole Derivatives
in Organic Letters
Liddon JT
(2016)
Catalyst-Driven Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles and Quinolines from Indolyl Ynones.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Liddon JTR
(2018)
Dearomatizing Spiroannulation Reagents: Direct Access to Spirocycles from Indoles and Dihalides.
in Organic letters
Description | Research is ongoing. However, already novel variations of the indole dearomative spirocyclisation have been developed which lead to tetracyclic products - and most intriguingly, a completely novel rrearrangement has been discovered which generates complex products. Also palladium catalysed coupling process have been developed. Two papers have been published and another, on a novel radical variant, are in preparation. |
Exploitation Route | In the chemical, pharma and agro industries. |
Sectors | Agriculture Food and Drink Chemicals Pharmaceuticals and Medical Biotechnology |
Description | The findings have played a role in a general change of direction in medicinal chemistry oriented research to explore more complex, 3D scaffolds - often called 'escape from flatland'. This is can help accelerate the discovery of new biologically active lead compound in medicinal chemistry, with more novelty and fewer IP constraints on the novel 'hits' obtained. This in turn can help new drugs to be discovered more effectively. |
First Year Of Impact | 2020 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal 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 |