The Stereoselective Synthesis of Heterocycles Through Cation-Triggered Annulation
Lead Research Organisation:
University of Oxford
Abstract
This project falls within the EPSRC Synthetic Organic Chemistry research area.
Methods for the stereoselective synthesis of highly functionalized saturated heterocycles from simple and readily available starting materials are highly desirable due to their value in medicinal and agro- chemical industries along with their widespread presence in natural products. For example, piperidines, the 6-membered saturated nitrogen heterocycles are the third most prevalent ring system in small molecule drugs listed by the FDA, with pyrrolidines, (tetrahydro) -furans and -pyrans also featuring in the top twelve. Not only do the starting materials have to be easily accessible but the process needs to be cheap, efficient and atom economical. One such method has been established in the Donohoe group, using the unique properties of hexafluoroisopropanol (HFIP) as a polar and hydrogen bonding solvent to enable the stereoselective functionalization of alkenes. Recently, this has been applied to the synthesis of oxygen heterocycles through reaction of a homoallylic alcohol with an activated alcohol to generate a new C-C and C-O bond with high stereoselectivity. The use of sub-stoichiometric amounts of Ti(OiPr)4 and HFIP as the solvent generates a carbocation from the alcohol electrophile which is trapped by an electron rich olefin in a formal endo-trig cyclisation, generating water as the only stoichiometric by-product. There is potential to extend this methodology to the synthesis of other heterocycles with work currently underway on the synthesis of nitrogen containing heterocycles. We aim to improve on the current hydroamination methods, which although well precedented, often rely on the use of expensive metal catalysts and suffer from a lack of diastereoselectivity and functionalization of the product. Once this has been achieved, further diversification of the products will be undertaken in order to increase their utility as building blocks in the medicinal and agro- chemical industries. In addition, we hope to make the process enantioselective, through the use of asymmetric metal catalysis, this would in turn make the methodology more applicable to the synthesis of natural products. Finally, we hope to probe the limits of this process through the synthesis of other complex heterocycles which have a wide array of uses in coordination and medicinal chemistry. Other heterocycles containing two heteroatoms in the ring will be evaluated giving an additional class of highly functionalized molecules. Overall, the development of this methodology aims to offer a more efficient and selective alternative to the current methods for accessing saturated heterocycles without compromising cost or operational simplicity. In addition, we hope that the complex molecules accessed will prove to be useful building blocks for medicinal and agro- chemistry giving 3D Templates for "Lead-Like" compounds.
Methods for the stereoselective synthesis of highly functionalized saturated heterocycles from simple and readily available starting materials are highly desirable due to their value in medicinal and agro- chemical industries along with their widespread presence in natural products. For example, piperidines, the 6-membered saturated nitrogen heterocycles are the third most prevalent ring system in small molecule drugs listed by the FDA, with pyrrolidines, (tetrahydro) -furans and -pyrans also featuring in the top twelve. Not only do the starting materials have to be easily accessible but the process needs to be cheap, efficient and atom economical. One such method has been established in the Donohoe group, using the unique properties of hexafluoroisopropanol (HFIP) as a polar and hydrogen bonding solvent to enable the stereoselective functionalization of alkenes. Recently, this has been applied to the synthesis of oxygen heterocycles through reaction of a homoallylic alcohol with an activated alcohol to generate a new C-C and C-O bond with high stereoselectivity. The use of sub-stoichiometric amounts of Ti(OiPr)4 and HFIP as the solvent generates a carbocation from the alcohol electrophile which is trapped by an electron rich olefin in a formal endo-trig cyclisation, generating water as the only stoichiometric by-product. There is potential to extend this methodology to the synthesis of other heterocycles with work currently underway on the synthesis of nitrogen containing heterocycles. We aim to improve on the current hydroamination methods, which although well precedented, often rely on the use of expensive metal catalysts and suffer from a lack of diastereoselectivity and functionalization of the product. Once this has been achieved, further diversification of the products will be undertaken in order to increase their utility as building blocks in the medicinal and agro- chemical industries. In addition, we hope to make the process enantioselective, through the use of asymmetric metal catalysis, this would in turn make the methodology more applicable to the synthesis of natural products. Finally, we hope to probe the limits of this process through the synthesis of other complex heterocycles which have a wide array of uses in coordination and medicinal chemistry. Other heterocycles containing two heteroatoms in the ring will be evaluated giving an additional class of highly functionalized molecules. Overall, the development of this methodology aims to offer a more efficient and selective alternative to the current methods for accessing saturated heterocycles without compromising cost or operational simplicity. In addition, we hope that the complex molecules accessed will prove to be useful building blocks for medicinal and agro- chemistry giving 3D Templates for "Lead-Like" compounds.
Planned Impact
This programme is focused on a new cohort-driven approach to the training of next-generation doctoral scientists in the practice of novel and efficient chemical synthesis coupled with an in-depth appreciation of its application to biology and medicine.
This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.
We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.
The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.
We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.
We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).
Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.
The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.
This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.
We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.
The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.
We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.
We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).
Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.
The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.
Organisations
People |
ORCID iD |
| Timothy Donohoe (Primary Supervisor) | |
| Lydia Cox (Student) |