A new, catalytic strategy for piperidine syntheses and a unified approach to the synthesis of sparteine alkaloids
Lead Research Organisation:
University of Nottingham
Department Name: Sch of Chemistry
Abstract
A wide range of natural products also contain chiral piperidine moieties - especially alkaloids. Since natural products frequently display biological activity, they are important leads for or precursors to pharmaceutical compounds. As a result of this, methodologies that facilitate access to chiral piperidines are of great value to the pharmaceutical industry; these methodologies enable the development of new drugs and the treatment of disease. In this project, we aim to develop a new strategy for the synthesis of chiral piperidines.
Sparteine is an alkaloid of considerable value to chemists, as a ligand in a variety of asymmetric metal-mediated processes. In addition to its synthetic applications, sparteine also possesses medicinal properties: it has long been known as an antiarrhythmic agent, and recent research shows that it also acts as an anticonvulsive.
Extraction of sparteine from plants enabled access to this compound for many years. In around 2010, however, this changed: sparteine became completely unavailable on the market. Since then, access has been restored, but the price of sparteine has hugely increased, and the compound remains scarce. It is clear that we cannot rely on traditional extraction procedures in the production of this compound. Extraction techniques are also highly wasteful, producing tens of litres of solvent waste per gram of alkaloid.
While total syntheses of sparteine have been achieved, they are - at best - very wasteful, and can only produce reasonable quantities of one enantiomer of sparteine. No method currently exists for the synthesis of both enantiomers and all other diastereoisomers of sparteine - compounds that are much less well-known. Given the known value of sparteine as a ligand and in medical research, we believe that it is important that a new route towards all sparteine alkaloids be developed. In achieving this, we aim to increase access to sparteine, and enable research into the less well-known diastereoisomers of sparteine as ligand platforms and compounds of possible medicinal relevance.
Proposed solution and methodology
By making use of a catalytic azide reduction developed by the Denton group, we intend to trigger asymmetric ring closure to access a wide variety of enantiomerically enriched piperidines. Once the efficacy of this methodology has been established, we aim to apply this chemistry in the synthesis of a number of alkaloid targets. In addition to target syntheses, we also hope to expand the ring-closing methodology to include other ring sizes.
Our proposed synthesis of sparteine will make use of the above methodology, as well as a number of other catalytic methodologies. We anticipate that this will allow us to develop a new, efficient synthesis of all sparteine alkaloids, in which we can match the appropriate piperidine coupling partners to build any single diastereoisomer of sparteine.
Sparteine is an alkaloid of considerable value to chemists, as a ligand in a variety of asymmetric metal-mediated processes. In addition to its synthetic applications, sparteine also possesses medicinal properties: it has long been known as an antiarrhythmic agent, and recent research shows that it also acts as an anticonvulsive.
Extraction of sparteine from plants enabled access to this compound for many years. In around 2010, however, this changed: sparteine became completely unavailable on the market. Since then, access has been restored, but the price of sparteine has hugely increased, and the compound remains scarce. It is clear that we cannot rely on traditional extraction procedures in the production of this compound. Extraction techniques are also highly wasteful, producing tens of litres of solvent waste per gram of alkaloid.
While total syntheses of sparteine have been achieved, they are - at best - very wasteful, and can only produce reasonable quantities of one enantiomer of sparteine. No method currently exists for the synthesis of both enantiomers and all other diastereoisomers of sparteine - compounds that are much less well-known. Given the known value of sparteine as a ligand and in medical research, we believe that it is important that a new route towards all sparteine alkaloids be developed. In achieving this, we aim to increase access to sparteine, and enable research into the less well-known diastereoisomers of sparteine as ligand platforms and compounds of possible medicinal relevance.
Proposed solution and methodology
By making use of a catalytic azide reduction developed by the Denton group, we intend to trigger asymmetric ring closure to access a wide variety of enantiomerically enriched piperidines. Once the efficacy of this methodology has been established, we aim to apply this chemistry in the synthesis of a number of alkaloid targets. In addition to target syntheses, we also hope to expand the ring-closing methodology to include other ring sizes.
Our proposed synthesis of sparteine will make use of the above methodology, as well as a number of other catalytic methodologies. We anticipate that this will allow us to develop a new, efficient synthesis of all sparteine alkaloids, in which we can match the appropriate piperidine coupling partners to build any single diastereoisomer of sparteine.
Planned Impact
This CDT will have a positive impact in the following areas:
PEOPLE. The primary focus is people and training. Industry needs new approaches to reach their sustainability targets and this is driving an increasing demand for highly qualified PhD graduates to lead innovation and manage change in the area of chemicals production. CDT based cohort training will provide industry ready scientists with the required technical competencies and drive to ensure that the sector retains its lead position in both innovation and productivity. In partnership with leading chemical producers and users, we will provide world class training to satisfy the changing needs of tomorrow's chemistry-using sector. Through integrated links to our Business School we will maximise impact by delivering dynamic PhD graduates who are business aware.
ECONOMY. Sustainability is the major issue facing the global chemical industry. Not only is there concern for our environment, there is also is a strong economic driver. Shareholders place emphasis on the Dow Jones Sustainability Index that tracks the performances of the sector and engenders competition. As a result, major companies have set ambitious targets to lower their carbon footprints, or even become carbon neutral. GSK CEO Sir Andrew Witty states that "we have a goal to reduce our emissions and energy use by 45% compared with 2006 levels on a per unit sales basis... " Our CDT will help companies meet these challenges by producing the new chemistries, processes and people that are the key to making the step changes needed.
SOCIETY. The diverse range of products manufactured by the chemical-using industries is vital to maintain a high quality of life in the UK. Our CDT will have a direct impact by ensuring a supply of people and new knowledge to secure sustainability for the benefit of all. The role of chemistry is often hidden from the public view and our CDT will provide a platform to show chemical sciences in a positive light, and to demonstrate the importance of engineering and applications across biosciences and food science.
The "green and sustainable" agenda is now firmly fixed in the public consciousness, our CDT will be an exemplar of how scientists and engineers are providing solutions to very challenging scientific and technical problems, in an environmentally benign manner, for the benefit of society. We will seek sustainable solutions to a wide range of problems, whilst working in sustainable and energy efficient facilities. This environment will engender a sustainability ethos unique to the UK. The CNL will not only serve as a base for the CDT but also as a hub for science communication.
Public engagement is a crucial component of CDT activities; we will invite input and discussion from the public via lectures, showcases and exhibition days. The CNL will form a hub for University open days and will serve as a soft interface to give school children and young adults the opportunity to view science from the inside. Through Dr Sam Tang, public awareness scientist, we have significant expertise in delivering outreach across the social spectrum, and she will lead our activities and ensure that the CDT cohorts engage to realise the impact of science on society. Martyn Poliakoff, in his role as Royal Society Foreign Secretary, will ensure that our CDT dovetails with UK science policy.
KNOWLEDGE. In addition to increasing the supply of highly trained people, the results of the PhD research performed in our CDT will have a major impact on knowledge. Our student cohorts will tackle "the big problems" in sustainable chemistry, and via our industrial partners we will ensure this knowledge is applied in industry, and publicised through high level academic outputs. Our knowledge-based activities will drive innovation and economic activity, realising impact through creation of new jobs and securing the future.
PEOPLE. The primary focus is people and training. Industry needs new approaches to reach their sustainability targets and this is driving an increasing demand for highly qualified PhD graduates to lead innovation and manage change in the area of chemicals production. CDT based cohort training will provide industry ready scientists with the required technical competencies and drive to ensure that the sector retains its lead position in both innovation and productivity. In partnership with leading chemical producers and users, we will provide world class training to satisfy the changing needs of tomorrow's chemistry-using sector. Through integrated links to our Business School we will maximise impact by delivering dynamic PhD graduates who are business aware.
ECONOMY. Sustainability is the major issue facing the global chemical industry. Not only is there concern for our environment, there is also is a strong economic driver. Shareholders place emphasis on the Dow Jones Sustainability Index that tracks the performances of the sector and engenders competition. As a result, major companies have set ambitious targets to lower their carbon footprints, or even become carbon neutral. GSK CEO Sir Andrew Witty states that "we have a goal to reduce our emissions and energy use by 45% compared with 2006 levels on a per unit sales basis... " Our CDT will help companies meet these challenges by producing the new chemistries, processes and people that are the key to making the step changes needed.
SOCIETY. The diverse range of products manufactured by the chemical-using industries is vital to maintain a high quality of life in the UK. Our CDT will have a direct impact by ensuring a supply of people and new knowledge to secure sustainability for the benefit of all. The role of chemistry is often hidden from the public view and our CDT will provide a platform to show chemical sciences in a positive light, and to demonstrate the importance of engineering and applications across biosciences and food science.
The "green and sustainable" agenda is now firmly fixed in the public consciousness, our CDT will be an exemplar of how scientists and engineers are providing solutions to very challenging scientific and technical problems, in an environmentally benign manner, for the benefit of society. We will seek sustainable solutions to a wide range of problems, whilst working in sustainable and energy efficient facilities. This environment will engender a sustainability ethos unique to the UK. The CNL will not only serve as a base for the CDT but also as a hub for science communication.
Public engagement is a crucial component of CDT activities; we will invite input and discussion from the public via lectures, showcases and exhibition days. The CNL will form a hub for University open days and will serve as a soft interface to give school children and young adults the opportunity to view science from the inside. Through Dr Sam Tang, public awareness scientist, we have significant expertise in delivering outreach across the social spectrum, and she will lead our activities and ensure that the CDT cohorts engage to realise the impact of science on society. Martyn Poliakoff, in his role as Royal Society Foreign Secretary, will ensure that our CDT dovetails with UK science policy.
KNOWLEDGE. In addition to increasing the supply of highly trained people, the results of the PhD research performed in our CDT will have a major impact on knowledge. Our student cohorts will tackle "the big problems" in sustainable chemistry, and via our industrial partners we will ensure this knowledge is applied in industry, and publicised through high level academic outputs. Our knowledge-based activities will drive innovation and economic activity, realising impact through creation of new jobs and securing the future.
