An Extraordinary Photochemical Reaction of Pyrrole - A New Tool for Molecular Complexity
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
This proposal aims to explore a powerful photochemical reaction recently discovered in our laboratory. A variety of N-butenyl substituted pyrroles have been found to undergo an extraordinary photocycloaddition/rearrangement sequence to give tricyclic fused aziridines of high molecular complexity. Early studies have shown that as long as the pyrrole bears an electron withdrawing group on the 2-position the reaction sequence is highly tolerant of substitution. We will investigate the scope of the cycloaddition reaction by examining the effects of side chain substitution with a variety of cyclic and acyclic alkenes. The resulting aziridines will themselves be reactive species and should undergo a number of useful bond forming ring opening reactions. Once developed and understood the methodology will be applied as the key step in a very short synthesis of the alkaloid dendrobine. Overall the work in this proposal should serve to highlight the value of photochemistry and photochemical technology in modern chemical synthesis.
Planned Impact
We hope that our work will encourage academics to consider a change of synthetic philosophy by adopting organic photochemistry for the construction of complex molecules. By providing enabling technology and demystifying the practical concerns of synthetic photochemistry we would hope that academics could consider this medium for generating powerful new synthetic methodologies that are the very definition of clean or green. As outlined in the proposal a powerful photochemical sequence can enable the synthesis of complex molecules such as dendrobine in very few steps without recourse to traditional protection-deprotection strategies. If academics adopt this philosophy in their synthetic planning then there would be a very positive impact in the creation of new complexity. Total synthesis would be become the engine for developing new methodologies rather than the slave to existing ones. Our flow-reactor has already had a major impact in the area of anti-malarial drugs: Seeburger has used our reactor in a stunning continuous-flow synthesis of the front-line anti-malaria drug Artemisinin. Seeburger's complete integrated flow system can now synthesize 800 g of this drug per day and an estimated 400 such reactor systems could provide the current world's supply of Artemisinin required to treat a disease which currently kills nearly a million people each year.
We also hope our work will encourage Pharma & Biotech to consider the complex polyheterocyclic structures developed in this proposal as viable templates for exploring new chemical space. The work outlined in this proposal will be attractive to Pharma & Biotech on three counts: (a) this previously unexplored molecular space is now very accessible; (b) flow-photochemistry as developed by us makes photochemical synthesis within the industry realistic for the first time and (c) our flow reactors enable the scale up of photochemistry (ours and others). Previously these molecules would have been considered too difficult and expensive to synthesize as potential drug candidates. If a UK company were able to synthesize complex drug like molecules based on the structures and philosophies outlined in this research, then the economic impact on that company could be enormous. For example they would have the IP rights to drug space that no competitor could match. This would apply equally at the discovery, process and manufacture stages of a drugs evolution to market. Thanks to the omnipresent lighting industry UV radiation has always been cheap and readily available, with powers ranging from a few milliwatts up to kilowatts. It is now time to exploit this by coupling modern technology with new chemistry to make high value molecules.
In a molecular context the UK's economic competitiveness has been seriously challenged in light of the economic downturn and serious levels of outsourcing to China and India. For example most of the large UK based Pharmaceutical companies now outsource significant stages of drug discovery to India and China, yet are doing this under the same, some would say, failed model of drug discovery. This has serious knock on effects for the UK economy, job market and academe. Much of this outsourcing is a direct consequence of the cost of the overall synthetic routes due to local labor, waste, safety, patent issues etc. Therefore, it seems logical to propose that if unique molecular complexity (and its IP) can be created in the UK and fed into drug discovery programs then there would be much less incentive to outsource which would have a very positive impact for UK plc.
We also hope our work will encourage Pharma & Biotech to consider the complex polyheterocyclic structures developed in this proposal as viable templates for exploring new chemical space. The work outlined in this proposal will be attractive to Pharma & Biotech on three counts: (a) this previously unexplored molecular space is now very accessible; (b) flow-photochemistry as developed by us makes photochemical synthesis within the industry realistic for the first time and (c) our flow reactors enable the scale up of photochemistry (ours and others). Previously these molecules would have been considered too difficult and expensive to synthesize as potential drug candidates. If a UK company were able to synthesize complex drug like molecules based on the structures and philosophies outlined in this research, then the economic impact on that company could be enormous. For example they would have the IP rights to drug space that no competitor could match. This would apply equally at the discovery, process and manufacture stages of a drugs evolution to market. Thanks to the omnipresent lighting industry UV radiation has always been cheap and readily available, with powers ranging from a few milliwatts up to kilowatts. It is now time to exploit this by coupling modern technology with new chemistry to make high value molecules.
In a molecular context the UK's economic competitiveness has been seriously challenged in light of the economic downturn and serious levels of outsourcing to China and India. For example most of the large UK based Pharmaceutical companies now outsource significant stages of drug discovery to India and China, yet are doing this under the same, some would say, failed model of drug discovery. This has serious knock on effects for the UK economy, job market and academe. Much of this outsourcing is a direct consequence of the cost of the overall synthetic routes due to local labor, waste, safety, patent issues etc. Therefore, it seems logical to propose that if unique molecular complexity (and its IP) can be created in the UK and fed into drug discovery programs then there would be much less incentive to outsource which would have a very positive impact for UK plc.
Organisations
People |
ORCID iD |
Kevin Booker-Milburn (Principal Investigator) |
Publications
Blackham EE
(2016)
Combining photochemistry and catalysis: rapid access to sp3 - rich polyheterocycles from simple pyrroles.
in Chemical science
Elliott LD
(2014)
Batch versus flow photochemistry: a revealing comparison of yield and productivity.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Knowles JP
(2016)
Unusually Facile Thermal Homodienyl-[1,5]-Hydrogen Shift Reactions in Photochemically Generated Vinyl Aziridines.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Gerry CJ
(2016)
Real-Time Biological Annotation of Synthetic Compounds.
in Journal of the American Chemical Society
Yu W
(2018)
Short, Gram-Scale Syntheses of ß- and ?-Lycorane Using Two Distinct Photochemical Approaches
in Organic Letters
Koovits PJ
(2016)
Conformationally Driven Two- and Three-Photon Cascade Processes in the Stereoselective Photorearrangement of Pyrroles.
in Organic letters
Elliott L
(2018)
Using batch reactor results to calculate optimal flow rates for the scale-up of UV photochemical reactions
in Reaction Chemistry & Engineering
Description | This grant enabled the further development of of a unique photochemical process for converting simple pyrrole building blocks into complex heterocyclic products just by the application of light. These products are likely to have application in natural product synthesis and drug development. Right at the end of the grant period we discovered a novel 3-photon process resulting in a massive increase of molecular complexity which was published recently. Findings from this grant have benefited a PhD student who has just completed the total synthesis of a tetracyclic alkaloid. |
Exploitation Route | Statement Last year: "Both the transformations and the arising products may find use in natural product synthesis (alkaloids) by the academic community. It is likely the complex 3D products formed will be of interest to Medicinal chemistry working in Drug Discovery" Original statement borne out by the Harvard/Broad Institutes use of this chemistry in a real time biological assay - JACS paper. Also by our own successful application of this chemistry to a PhD students alkaloid synthesis. |
Sectors | Agriculture Food and Drink Chemicals Pharmaceuticals and Medical Biotechnology |
Description | The photochemical processes and products produced are of interest to clients through our recently launched Photodiversity spin-out company. |
First Year Of Impact | 2015 |
Sector | Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | Photo-Electro: Transforming Chemical Synthesis, Discovery and Manufacture |
Amount | £6,486,390 (GBP) |
Funding ID | EP/P013341/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2017 |
End | 02/2022 |
Title | New compounds for drug discovery |
Description | Unusual compounds from this study were used by a Harvard/Broad Institute team to develop a real time biological assay for drug discovery. Due to our pioneering photochemistry and assistance with analysis, we were co-authors on the paper (Booker-Milburn & Knowles). |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | One JACS paper published and as far as we are aware the Harvard group are still active with this work. |
Company Name | Photodiversity |
Description | Photodiversity develops and produces a range of photochemically-derived molecules to be used in biological screening. |
Year Established | 2015 |
Impact | Since trading started in November 2015, £125k in sales have been generated and £2.5m in contracts are in place. |
Description | FiaF Presentation to Process Development at Astra Zeneca Macclesfield 18/1/17 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Industry/Business |
Results and Impact | Lecture to update on AZ staff (not involved in FiaF) of the outputs of the grant |
Year(s) Of Engagement Activity | 2017 |
Description | FiaF Presentation to Process Development at GSK Stevenage 22/4/16 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Presentation of outputs and know-how from grant to ~80 Process Chemists |
Year(s) Of Engagement Activity | 2016 |
Description | Final FiaF Presentation to Process Development at GSK Stevenage 3/2/17 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Industry/Business |
Results and Impact | Dissemination of final outputs of FiaF grant to a wider GSK audience (with 2 other speakers in a mini-symposium) |
Year(s) Of Engagement Activity | 2017 |
Description | Flow Chemistry Conference Southampton |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | A one day international Flow Chemistry conference organised by Southampton University Chemistry Department as part of their INTEREG CDT-type training program. |
Year(s) Of Engagement Activity | 2019 |
Description | Hans Schutszy Symposium Salford 29/4/16 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker at Synthetic Chemistry Symposium held in Honour of late Professor Hans Schutszy |
Year(s) Of Engagement Activity | 2016 |
Description | Invited lecture to Beilstein Conference -Advancing Chemical Synthesis through Automation, Processes and Thinking Conference - Potsdam |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited lecture entitled: "Flow Photochemistry in Organic Synthesis - Generating Molecular Complexity on the Gram and Kilogram Scales" |
Year(s) Of Engagement Activity | 2017 |
Description | Invited lecture to Charles River - Saffron Walden |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Lecture entitled:"Generating Molecular Complexity by Synthetic Photochemistry: From Grams to Kilograms" |
Year(s) Of Engagement Activity | 2017 |
Description | Invited lecture to Evotec - Abbingdon |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Lecture entitled: "Generating Molecular Complexity by Synthetic Photochemistry: From Grams to Kilograms" |
Year(s) Of Engagement Activity | 2017 |
Description | Invited lecture to Flow Chemistry Society Europe |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Lecture entitled:"Complexity Generation by Photochemistry In Flow : From Grams to Kilograms' |
Year(s) Of Engagement Activity | 2017 |
Description | Invited lecture to: Bayer - Photochemistry for the Life Sciences Conferences: The Future is Bright- Dusseldorf |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Lecture entitled: "Generating Molecular Complexity by Synthetic Photochemistry: From Grams to Kilograms" |
Year(s) Of Engagement Activity | 2017 |
Description | Presentation and Research Collaboration Discussion at Syngenta Stein (Switzerland) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | A research lecture on Photochemical Synthesis followed by a round table discussion on future collaboration in this area |
Year(s) Of Engagement Activity | 2016 |
Description | Presentation to Flow Chemistry Europe Cambridge 7/2/17 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited Presentation to two day Flow Chemistry Europe conference in Cambridge 7/2/17 |
Year(s) Of Engagement Activity | 2017 |
Description | Presentations to Eli Lilly Chemists on Photochemical Technology and Synthesis 27/4/16 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Delivered 2 lectures to Lilly Chemists (UK) on Photochemical Synthesis and then Photochemical Technology and Methods. Video link to another site in Spain. |
Year(s) Of Engagement Activity | 2016 |
Description | UKASF Invited Lecture 7/11/16 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited lecture on Photochemical technology to UK Automated Synthesis Forum |
Year(s) Of Engagement Activity | 2016 |