New methodologies in enantioselective catalysis
Lead Research Organisation:
Manchester Metropolitan University
Department Name: School of Science and the Environment
Abstract
In a world with increasing population and limited resources, the development of new synthetic chemical methods will be judged not only by their overall yield and product selectivity, but also by their ecological and economic footprint. Catalysis provides a means of achieving more efficient and environmentally friendly processes: the reaction is accelerated, the amount of energy required for the process is diminished and fewer wasteful by-products are obtained. Overall, catalysis plays an important role in saving energy, time and costs in chemical processes. Moreover, in the particular case of enantioselective catalysis, the catalyst also provides the source of asymmetry needed to selectively synthetise one of the two possible non-superimposable mirror images of the product - the so-called enantiomers. The selective synthesis of enantiopure compounds is of vital importance in the preparation of a myriad of products in daily life, from pharmaceutical and agricultural products to polymers and smart materials.
This proposal focuses on the development of a robust catalytic methodology for the preparation of enantiopure building blocks from cheap and readily available starting materials. The chemical reaction that is the main subject of this proposal is the addition of an organometallic reagents to a C=O bond. This reaction is one of the most powerful tools in organic chemistry to create a new C-C bond and has been extensively studied with organozinc and organoboron reagents. However, the higher reactivity of organomagnesium and organolithium reagents has hampered their application in this field. The fact that both organomagnesium and organolithium reagents are more accessible and economically viable nucleophiles, drives the development of novel suitable catalytic systems to fulfil the scientific, economic and environmental demands.
Recent discoveries in our laboratories have brought forward a readily available catalyst as part of an outstanding methodology for the addition of organomagnesium and organolithium reagents to C=O bonds. The mechanism of this recently established methodology is still unknown and, by means of the research proposed here, we intend to get a better understanding of the process - which will allow further improvements of the methodology (e.g. by resolving the current limitations regarding substrate scope). In addition, we will also investigate the use of this novel catalytic system in the production of fluorinated molecules, whose unique properties make them especially attractive as pharmaceutical agents and advanced materials.
This proposal focuses on the development of a robust catalytic methodology for the preparation of enantiopure building blocks from cheap and readily available starting materials. The chemical reaction that is the main subject of this proposal is the addition of an organometallic reagents to a C=O bond. This reaction is one of the most powerful tools in organic chemistry to create a new C-C bond and has been extensively studied with organozinc and organoboron reagents. However, the higher reactivity of organomagnesium and organolithium reagents has hampered their application in this field. The fact that both organomagnesium and organolithium reagents are more accessible and economically viable nucleophiles, drives the development of novel suitable catalytic systems to fulfil the scientific, economic and environmental demands.
Recent discoveries in our laboratories have brought forward a readily available catalyst as part of an outstanding methodology for the addition of organomagnesium and organolithium reagents to C=O bonds. The mechanism of this recently established methodology is still unknown and, by means of the research proposed here, we intend to get a better understanding of the process - which will allow further improvements of the methodology (e.g. by resolving the current limitations regarding substrate scope). In addition, we will also investigate the use of this novel catalytic system in the production of fluorinated molecules, whose unique properties make them especially attractive as pharmaceutical agents and advanced materials.
Planned Impact
Enzymes are Nature's catalysts. They are extremely efficient and selective and they make possible essentially all biological reactions. By comparison with today's technology, enzymes show us how much opportunity there is for improvement in the area of catalysis. The development of new catalytic systems with level of control and efficiency comparable to the ones that Nature demonstrates is a timely and relevant topic of research with important economic and social implications.
Catalysis plays an essential role in the solutions to major problems that our society faces: energy production, environmental damage, and more generally, the quality of life. Investigations in catalysis are timely and relevant in a society that needs to develop more efficient reactions that can be applied in both industry and academia to produce relevant materials, from pharmaceuticals to polymers.
This proposal will create impact by exploiting both fundamental and advanced scientific knowledge in order to generate original science in currently unexplored areas. The proposed projectwill provide economic and social benefits by advancing technological development through the improvement of existing techniques and the possible invention of new ones. This will help further the promotion and development of scientific excellence in the UK and will provide long-term potential benefits, including international recognition and making the UK more attractive to first class researchers.
The research proposed here will be disseminated in several different ways to ensure the widest possible impact:
(1) Publication of articles in international scientific journals will ensure that the work reaches relevant scientific audiences and will prove the quality of the research.
(2) Participation in conferences, seminars and symposiums will bring our work closer to the scientific community and help in the development of possible collaborations.
(3) The implementation of this project will provide international scientific benefits in terms of developing a possible long lasting collaboration with researchers in Spain, which could be funded by European programmes in the future.
(4) The establishment of collaborations with pharmaceutical and chemical companies (e.g. with Syntor Fine Chemicals, Cheshire) will promote dissemination and potential economic impact. It will also allow discussions about opportunities to investigate further routes towards more efficient and sustainable processes and/or commercially exploit the project findings with businesses.
(5) This research will also have impact on teaching activities. In particular, the results of this project would be incorporated and disseminated through Unit 6ACH4117: Research Frontiers in Materials Chemistry, taught in the fourth year of Chemistry Studies at MMU.
(6) A project website will be maintained and regularly updated with the latest information about the project and the research results, allowing a very wide potential audience to see how the research is progressing.
(7) Several outreach activities have also been planned to raise the profile of this research area in society at large: (i) presentations at the Manchester Science festival; (ii) poster presentations during 'Open Days' at MMU; (iii) visits to primary and secondary schools; (iii) Publication of short videos in YouTube; (iv) publication of articles on Wikipedia.
In summary, catalysis is a solution to the sustainability problems that we face nowadays and the promotion of the research proposed here will offer real profit and impact, not only for academia or industry, but also for society in general.
Catalysis plays an essential role in the solutions to major problems that our society faces: energy production, environmental damage, and more generally, the quality of life. Investigations in catalysis are timely and relevant in a society that needs to develop more efficient reactions that can be applied in both industry and academia to produce relevant materials, from pharmaceuticals to polymers.
This proposal will create impact by exploiting both fundamental and advanced scientific knowledge in order to generate original science in currently unexplored areas. The proposed projectwill provide economic and social benefits by advancing technological development through the improvement of existing techniques and the possible invention of new ones. This will help further the promotion and development of scientific excellence in the UK and will provide long-term potential benefits, including international recognition and making the UK more attractive to first class researchers.
The research proposed here will be disseminated in several different ways to ensure the widest possible impact:
(1) Publication of articles in international scientific journals will ensure that the work reaches relevant scientific audiences and will prove the quality of the research.
(2) Participation in conferences, seminars and symposiums will bring our work closer to the scientific community and help in the development of possible collaborations.
(3) The implementation of this project will provide international scientific benefits in terms of developing a possible long lasting collaboration with researchers in Spain, which could be funded by European programmes in the future.
(4) The establishment of collaborations with pharmaceutical and chemical companies (e.g. with Syntor Fine Chemicals, Cheshire) will promote dissemination and potential economic impact. It will also allow discussions about opportunities to investigate further routes towards more efficient and sustainable processes and/or commercially exploit the project findings with businesses.
(5) This research will also have impact on teaching activities. In particular, the results of this project would be incorporated and disseminated through Unit 6ACH4117: Research Frontiers in Materials Chemistry, taught in the fourth year of Chemistry Studies at MMU.
(6) A project website will be maintained and regularly updated with the latest information about the project and the research results, allowing a very wide potential audience to see how the research is progressing.
(7) Several outreach activities have also been planned to raise the profile of this research area in society at large: (i) presentations at the Manchester Science festival; (ii) poster presentations during 'Open Days' at MMU; (iii) visits to primary and secondary schools; (iii) Publication of short videos in YouTube; (iv) publication of articles on Wikipedia.
In summary, catalysis is a solution to the sustainability problems that we face nowadays and the promotion of the research proposed here will offer real profit and impact, not only for academia or industry, but also for society in general.
People |
ORCID iD |
Beatriz Macia Ruiz (Principal Investigator) |
Publications
Collados J
(2016)
Catalytic Synthesis of Enantiopure Chiral Alcohols via Addition of Grignard Reagents to Carbonyl Compounds
in ACS Catalysis
Fernández-Ibáñez M
(2016)
Synthesis of a-Substituted Diphenylphosphinocarboxylic Acids and Their Palladium Complexes
in Synlett
Fernández-Mateos E
(2014)
Catalytic Enantioselective Addition of Aryl Grignard Reagents to Ketones
in European Journal of Organic Chemistry
Flores-Ferrándiz J
(2018)
Stereoselective synthesis of 1,3-disubstituted dihydroisoquinolines vial-phenylalanine-derived dihydroisoquinoline N-oxides.
in Organic & biomolecular chemistry
Hudson AD
(2019)
Synthesis of Optimized Molecularly Imprinted Polymers for the Isolation and Detection of Antidepressants via HPLC.
in Biomimetics (Basel, Switzerland)
Ryan J
(2016)
Transaminase Triggered Aza-Michael Approach for the Enantioselective Synthesis of Piperidine Scaffolds
in Journal of the American Chemical Society
Solà R
(2017)
Ball mill and microwave assisted synthetic routes to Fluoxetine
in Sustainable Chemistry and Pharmacy
Solà R
(2018)
Catalytic Enantioselective Addition of Organozirconium Reagents to Aldehydes.
in Molecules (Basel, Switzerland)
Vaccari J
(2021)
Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes.
in Molecules (Basel, Switzerland)
Veguillas M
(2016)
Catalytic enantioselective addition of methyltriisopropoxititanium to aldehydes
in Tetrahedron: Asymmetry
Veguillas M
(2016)
Catalytic Asymmetric Addition of Organolithium Reagents to Aldehydes
in European Journal of Organic Chemistry
Description | We have developed a novel catalytic system for the challenging use of organometallic reagents (organomagnesium and organolithium reagents, in particular) in the asymmetric addition to carbonyl compounds. This methodology allows the synthesis of very versatile chiral alcohols with very good enantioselectivities (only one of the two nonsuperimposable mirror-image alcohols is generated). These chiral alcohols are of special interest for both pharmaceutical and agricultural sectors. |
Exploitation Route | The methodologies developed under this research are one of the very few methods available in the literature for the enantioselective addition of organometallic reagents to carbonyl compounds using catalytic amounts of a chiral ligand. |
Sectors | Chemicals Pharmaceuticals and Medical Biotechnology |
Description | Faculty PhD Studentship |
Amount | £45,000 (GBP) |
Organisation | Manchester Metropolitan University |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2017 |
End | 02/2021 |
Description | Faculty studentships |
Amount | £35,000 (GBP) |
Organisation | Manchester Metropolitan University |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2017 |
End | 06/2021 |
Description | International Exchanges Scheme |
Amount | £12,000 (GBP) |
Funding ID | IE150375 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2015 |
End | 11/2017 |
Title | Catalytic system for the addition of organolithium reagents to aldehydes |
Description | We have developed an efficient catalytic system for the titanium-promoted enantioselective addition of organolithium reagents to aldehydes, based on chiral Ar-BINMOL ligands. Unprecedented yields and enantioselectivities are achieved in the alkylation reactions of aliphatic aldehydes. Remarkably, methyllithium can be added to a wide variety of aromatic and aliphatic aldehydes, providing versatile chiral methyl carbinol units in a simple one-pot procedure under mild conditions and in very short reaction times. |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | This methodology is the only method available in the literature to perform an effective enantioselective addition of organolithium reagents to aliphatic aldehydes, using catalytic amounts of a chiral ligand under mild conditions. We expect interest from scientific community. |
Title | Catalytic system for the enantioselective addition of aryl Grignard reagents to ketones |
Description | We have developed a catalytic system for the challenging enantioselective addition of aryl Grignard reagents to ketones. Using a simple, one-pot procedure under mild conditions, a wide range of aromatic ketones are converted into diaryl alcohols in good yields and with good enantioselectivities. The system is based in catalytic amounts of a readily available chiral ligand and excess of titanium tetraisopropoxide. |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | This is the first catalytic enantioselective addition of aryl Grignard reagents to ketones reported in the literature. We expect interest from scientific community. |
Title | Catalytic system for the enantioselective synthesis of piperidines |
Description | We have developed an extremely efficient and "green" strategy for using enzymes to synthetise enantiopure piperidine systems. |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | This research has the potential to help the pharmaceutical chemical industry develop much-needed medicines, agrochemicals and novel materials. We have been in contact with a company in Germany and a possible collaboration might be established. |
Description | Alicante University |
Organisation | University of Alicante |
Department | Department of Organic Chemistry |
Country | Spain |
Sector | Academic/University |
PI Contribution | Progress on the asymmetric synthesis of valuable heterocyclic compounds using nitrones |
Collaborator Contribution | The university of Alicante has funded one PhD student to do an exchange in our labs. The project (see title above) has been successful and results will be published soon. |
Impact | manuscript under preparation |
Start Year | 2012 |
Description | Amsterdam University |
Organisation | University of Amsterdam |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | A travel grant was recently awarded to start this collaboration. Mechanistic investigations on the titanium promoted enantioselective addition of Grignard reagents to carbonyl compounds will be carried out by our team with the expert support of our collaborators in Amsterdam University. |
Collaborator Contribution | A travel grant was recently awarded to start this collaboration. Mechanistic investigations on the titanium promoted enantioselective addition of Grignard reagents to carbonyl compounds will be carried out. The facilities at the University of Amsterdam will facilitate this task. Also, our partner, Dr M. A. Fernandez has extensive experience in mechanistic investigations, which will be very beneficial for the development of the project. |
Impact | Not applicable. Collaboration has just started. |
Start Year | 2015 |
Description | Groningen University |
Organisation | University of Groningen |
Department | Stratingh Institute for Chemistry |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | Collaboration to write a book on copper chemistry and a review on the enantioselective adddition of organometallic reagents to carbonyl compounds |
Collaborator Contribution | Editor of the book |
Impact | Production of a Book: Topics in Organometallic Chemistry. Springer International Publishing. Switzerland 2015. DOI: 10.1007/3418_2015_158 Review has been written and it is currently under review. |
Start Year | 2015 |
Description | Nottingham University |
Organisation | University of Nottingham |
Department | School of Chemistry Nottingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | In collaboration with Elaine O'Reilly (Nottingham University) and Vittorio Caprio (Manchester Metropolitan University, MMU) we are studying novel biocatalytic approaches for the synthesis of heterocyclic compounds. A PhD student is working at MMU in this topic. |
Collaborator Contribution | Elaine O'Reilly (Nottingham University) provides expertise in biocatalysed transamination reactions. |
Impact | Multi-disciplinary collaboration involving organic synthesis and biocatalysed transformations. Outputs include participation (poster presentation) in 3 conferences (2 national, 1 international) |
Start Year | 2015 |
Description | Article in MMU Research Bulletin |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Article about our research was published in our Research Bulletin. Readers showed interest in our research. Several students contacted the group. |
Year(s) Of Engagement Activity | 2013 |
Description | Laboratory based workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | Laboratory workshop based on the used of advance laboratory techniques was organized. The practicals were associated to our research and asymmetric catalysis on general. Undergraduate students from chemistry but also Biology and Medical Sciences joined the workshop. |
Year(s) Of Engagement Activity | 2014,2015 |
Description | Laboratory workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | A laboratory workshop to highlight the importance of asymmetric catalysis in the synthesis of relevant compounds was organized. Ten chemistry undergraduate students attended, mainly from year 2. They all gave very positive feedback on the course. |
Year(s) Of Engagement Activity | 2016 |
Description | Oral presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation given during MMU Research day. Several academics approached us afterwards and we discussed about possible collaborations, including multidisciplinary ones |
Year(s) Of Engagement Activity | 2016 |
Description | Poster presentation |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Poster presentation during university open day. Prospective students were interested in our research |
Year(s) Of Engagement Activity | 2016 |
Description | Presentation Chemistry Simposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | A presentation was given in a regional chemistry meeting/symposium. It made our regional community aware of our research. Questions/debates/expressions of interest took place after the presentation. |
Year(s) Of Engagement Activity | 2014 |
Description | Research Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | Research talk was given to our undergraduate students. A discussion and debate was established afterwards. Undergraduates seemed very interested in joining our group and carry out their Master projects with us. |
Year(s) Of Engagement Activity | 2014 |