Asymmetric Synthesis of Cyclic Boronic Esters using Lithiation-Borylation
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Cyclobutanes have a structural rigidity which provides a well-defined spatial arrangement of their substituents and gives rise to diverse bioactivities.
The aim of the project is to develop an efficient asymmetric synthesis of cyclobutanes with a highly versatile boronic ester substituent. The synthesis will proceed via the ring contraction of a 5-membered ring boronate complex formed by lithiation-borylation of a homoallylic alcohol derived boronic ester.
The easy accessibility of enantiopure homoallylic alcohols and the potential of homologation to be used for increasing ring size and installing additional chirality before ring formation makes this method particularly attractive.
The use of this method for the medicinally relevant materials will also be investigated in collaboration with Bayer.
The aim of the project is to develop an efficient asymmetric synthesis of cyclobutanes with a highly versatile boronic ester substituent. The synthesis will proceed via the ring contraction of a 5-membered ring boronate complex formed by lithiation-borylation of a homoallylic alcohol derived boronic ester.
The easy accessibility of enantiopure homoallylic alcohols and the potential of homologation to be used for increasing ring size and installing additional chirality before ring formation makes this method particularly attractive.
The use of this method for the medicinally relevant materials will also be investigated in collaboration with Bayer.
Planned Impact
1. PEOPLE: We will train students with skills that are in demand across a spectrum of industries from pharma/biotech to materials, as well as in academia, law and publishing. The enhanced experience they receive - through interactive brainstorming, problem and dragons' den type business sessions - will equip them with confidence in their own abilities and fast-track their leadership skills. 100% Employment of students from the previous CDT in Chemical Synthesis is indicative of the high demand for the skills we provide, but as start-ups and SMEs become increasingly important in the healthcare, medicine and energy sectors, training in IP, entrepreneurship and commercialisation will stimulate our students to explore their own ventures. Automation and machine learning are set to transform the workplace in the next 20 years, and our students will be in the vanguard of those primed to make best use of these shifts in work patterns. Our graduates will have an open and entrepreneurial mindset, willing to seek solution to problems that cross disciplines and require non-traditional approaches to scientific challenges.
2. ECONOMY: Built on the country's long history of scientific ingenuity and creativity, the >£50bn turnover and annual trade surplus of £5 bn makes the British chemical sector one of the most important creators of wealth for the national economy. Our proposal to integrate training in chemical synthesis with emerging fields such as automation/AI/ML will ensure that the UK maintains this position of economic strength in the face of rapidly developing competition. With the field of drug development desperately looking for innovative new directions, we will disseminate, through our proposed extensive industrial stakeholders, smarter and more efficient ways of designing and implementing molecular synthesis using automation, machine learning and virtual reality interfaces. This will give the UK the chance to take a world-leading position in establishing how molecules may be made more rapidly and economically, how compound libraries may be made broader in scope and accessed more efficiently, and how processes may be optimized more quickly and to a higher standard of resilience. Chemical science underpins an estimated 21% of the economy (>£25bn sales; 6 million people), so these innovations have the potential for far-reaching transformative impact.
3. SCIENCE: The science emerging from our CDT will continue to be at the highest academic level by international standards, as judged by an outstanding publication record. Incorporating automation, machine learning, and virtual reality into the standard toolkit of chemical synthesis would initiate a fundamental change in the way molecules are made. Automated methods for making limited classes of molecules (eg peptides) have transformed related biological fields, and extending those techniques to allow a wide range of small molecules to be synthesized will stimulate not only chemistry but also related pivotal fields in the bio- and materials sciences. Synthesis of the molecular starting points is often the rate-limiting step in innovation. Removing this hurdle will allow selection of molecules according to optimal function, not ease of synthesis, and will accelerate scientific progress in many sectors.
4. SOCIETY: Health benefits will emerge from the ability of both academia and the pharmaceutical industry to generate drug targets more rapidly and innovatively. Optimisation of processes opens the way for advances in energy efficiency and resource utilization by avoiding non-renewable, environmentally damaging, or economically volatile feedstocks. The societal impact of automation will extend more widely to the freeing of time to allow more creative working and also recreational pastimes. We thus aim to be among the pioneers in a new automation-led working model, and our students will be trained to think through the broader consequences of automation for society as a whole
2. ECONOMY: Built on the country's long history of scientific ingenuity and creativity, the >£50bn turnover and annual trade surplus of £5 bn makes the British chemical sector one of the most important creators of wealth for the national economy. Our proposal to integrate training in chemical synthesis with emerging fields such as automation/AI/ML will ensure that the UK maintains this position of economic strength in the face of rapidly developing competition. With the field of drug development desperately looking for innovative new directions, we will disseminate, through our proposed extensive industrial stakeholders, smarter and more efficient ways of designing and implementing molecular synthesis using automation, machine learning and virtual reality interfaces. This will give the UK the chance to take a world-leading position in establishing how molecules may be made more rapidly and economically, how compound libraries may be made broader in scope and accessed more efficiently, and how processes may be optimized more quickly and to a higher standard of resilience. Chemical science underpins an estimated 21% of the economy (>£25bn sales; 6 million people), so these innovations have the potential for far-reaching transformative impact.
3. SCIENCE: The science emerging from our CDT will continue to be at the highest academic level by international standards, as judged by an outstanding publication record. Incorporating automation, machine learning, and virtual reality into the standard toolkit of chemical synthesis would initiate a fundamental change in the way molecules are made. Automated methods for making limited classes of molecules (eg peptides) have transformed related biological fields, and extending those techniques to allow a wide range of small molecules to be synthesized will stimulate not only chemistry but also related pivotal fields in the bio- and materials sciences. Synthesis of the molecular starting points is often the rate-limiting step in innovation. Removing this hurdle will allow selection of molecules according to optimal function, not ease of synthesis, and will accelerate scientific progress in many sectors.
4. SOCIETY: Health benefits will emerge from the ability of both academia and the pharmaceutical industry to generate drug targets more rapidly and innovatively. Optimisation of processes opens the way for advances in energy efficiency and resource utilization by avoiding non-renewable, environmentally damaging, or economically volatile feedstocks. The societal impact of automation will extend more widely to the freeing of time to allow more creative working and also recreational pastimes. We thus aim to be among the pioneers in a new automation-led working model, and our students will be trained to think through the broader consequences of automation for society as a whole
People |
ORCID iD |
Varinder Aggarwal (Primary Supervisor) | |
Christopher Cope (Student) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
EP/S024107/1 | 30/09/2019 | 30/03/2028 | |||
2273438 | Studentship | EP/S024107/1 | 30/09/2019 | 29/02/2024 | Christopher Cope |
Description | A method for the preparation of useful synthetic building blocks, namely cyclobutanes with versatile boronic ester handles, has been developed. The reaction demonstrates excellent regioselectivity in the cases where two possible boronic esters can react, and in some cases give excellent diastereoselectivity. |
Exploitation Route | The hope is that this method can be shown to work for a range of compounds, in the synthesis of a natural product or drug candidate, and potentially be carried out in flow or an automated system. |
Sectors | Agriculture Food and Drink Chemicals Pharmaceuticals and Medical Biotechnology |
Description | Collaboration with Daniel Otero Callerias from Universidade de Vigo |
Organisation | University of Vigo |
Country | Spain |
Sector | Academic/University |
PI Contribution | I have carried out most of the lab work and analysis day to day as well as contributed to the optimization and overall direction of the the project with guidance from Varinder and Julien. |
Collaborator Contribution | Daniel has partially contributed to substrate scope and direction of the project. |
Impact | Daniel has partially contributed to substrate scope and direction of this project. |
Start Year | 2022 |
Description | Collaboration with Jana Sendra Viscarro from Universitat Rovira i Virgili |
Organisation | Rovira i Virgili University |
Country | Spain |
Sector | Academic/University |
PI Contribution | I have carried out most of the lab work and analysis day to day as well as contributed to the optimization and overall direction of the the project with guidance from Varinder and Julien. |
Collaborator Contribution | Jana contributed to reaction optimisation and early substrate scope. |
Impact | Jana contributed to reaction optimisation and early substrate scope of the current project. |
Start Year | 2021 |
Description | Collaboration with Julien Lefranc at Merck, Darmstadt. |
Organisation | Merck |
Country | Germany |
Sector | Private |
PI Contribution | I have carried out most of the lab work and analysis day to day as well as contributed to the optimization and overall direction of the the project with guidance from Varinder and Julien. |
Collaborator Contribution | Through Zoom calls and in person meetings Julien has been updated on the project every 1-3 months, where he gives synthetic advice/suggestions as well as desirable substrates from a medicinal chemistry perspective. |
Impact | The entire project has been in collaboration with Julien, first at Bayer/Nuvisan and currently at Merck. |
Start Year | 2020 |