A 500MHz 13C-cryoprobe and NMR Spectrometer @ Bristol

Lead Research Organisation: University of Bristol
Department Name: Chemistry

Abstract

Nuclear Magnetic Resonance (NMR) Spectroscopy is the most information-rich tool for molecular structure analysis, allowing scientists to probe the environment of individual atoms in molecules. The NMR analysis of carbon atoms (specifically their nuclei) is, in turn, the most desirable technique as carbon is ubiquitous in the vast majority of cutting-edge chemical compounds being studied in UK research centres - from plastics and polymers, through detergents, petrochemicals to modern pharmaceuticals and organic electronics. Unfortunately, NMR of carbon suffers from a serious challenge - it is incredibly insensitive, primarily due to the very low-abundance of the NMR-active carbon-13 (13C) nucleus.

This project will install a cutting-edge 13C-sensitive NMR cryogenic probe into the existing large-scale University of Bristol NMR Facility, which serves hundreds of researchers studying a wide range of scientific problems, from manipulation of biosynthetic processes in organisms, ultra-efficient chemical catalysis to the development of controlled nano-architectures with applications in nanoscience. The superconducting coils in this cryogenic NMR probe increase the sensitivity for detection of weak 13C NMR signals by around 10-fold over the most modern room temperature probes used in the vast majority of NMR facilities (including Bristol's). The sensitivity of this 13C-cryoprobe will fill a substantial void in current capabilities of the Bristol NMR Facility, enabling a suite of otherwise impractical NMR techniques to be applied to this broad spectrum of scientific problems - in particular making experiments up to 100-times faster (so minutes or hours for data collection, rather than days or even weeks).

The incorporation of a 13C-cryoprobe into the University of Bristol NMR Facility will create a UK-leading NMR centre that will compete with the best laboratories for these studies anywhere in the world. This instrument will be integrated into the current UoB NMR Facility, alongside the existing suite of 9 other liquids NMR instruments (11 by late summer) and will be supported by an expert team of support staff who between them have over 5 decades of experience in supporting major multi-project, multi-user NMR instrumentation. It is this combination of cutting-edge technology, a highly efficient UoB NMR Facility and the associated research environment that will ensure a highly effective use of this equipment investment, and ensure optimal results for the scientists relying on the capabilities of this critical hardware.

Planned Impact

The Impact from this equipment arises through the science enabled for our collaborators. This can be seen in two ways - enabling new Impact and accelerating current Impact.

New Impacts will be enabled for collaborating researchers through access to 13C-based experimental methods which are simply not possible with current UoB equipment and, in some cases, anywhere else in the UK. For example, Crump will have access, for the first time, to the highest sensitivity 13C-13C NOESY and 13C-HETCOR techniques - enabling these tools to offer new insights into multi-protein complexes and ligand/fragment binding respectively in industrial collaborations with UCB. Neither of these approaches would be even remotely possible with room temperature probes and are only realised by the unique capabilities of 13C-cryoprobe technology. In this way, the proposed spectrometer opens new windows of opportunity to collaborating researchers, offering access to entirely new experimental insights and outcomes that could not be envisaged when they originally designed their research programs.

Acceleration of current Impact is delivered by the cutting-edge sensitivity of the instrument - reducing weeks/days of experiment time to hours/minutes. For example, Davis will be able to routinely employ 13C-titration as a powerful technique for studying supramolecular binding. His development of new anion and carbohydrate binders, with substantial diagnostic and therapeutic potential relies on such time-consuming titration methods. This will enable more rapid progress in their endeavours to, e.g., develop cutting-edge 'anionophore' therapies for the treatment of the incurable genetic disorder Cystic Fibrosis - enabling the body to re-establish channels for clearing lung blockages rather than relying on harsh agents such as steroid-treatments.

At a national/international level, the probe will enable a suite of projects supported by major industrial partners in Healthcare Technology and Manufacturing the Future (UCB, AstraZeneca, GSK, Syngenta, Daiichi Sankyo, Pfizer, Bayer, Novartis, Topokine) and will be especially attractive for industrial programs where speed of development is a key competitive advantage e.g. structure-activity screening program with 13C-based 2-dimensional NMR (UCB/Crump) or catalyst design programs based on mechanistic insights from 13C-based labelling and kinetics studies (Lloyd-Jones/ AstraZeneca). A case of current Impact from these groups is the accelerated prostaglandin synthesis of Aggarwal FRS, which is already being taken up by biotechnology firm Topokine Therapeutics to examine concise plant-scale production of prostaglandins in high yields and purity, for incorporation into a topical treatment for reducing adipose tissue (i.e. a cream for reducing fat).

Publications

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Abrams R (2018) Transition Metal Free Cycloamination of Prenyl Carbamates and Ureas Promoted by Aryldiazonium Salts. in Angewandte Chemie (International ed. in English)

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Armstrong RJ (2018) Enantiodivergent Synthesis of Allenes by Point-to-Axial Chirality Transfer. in Angewandte Chemie (International ed. in English)

 
Description This grant funded the purchase and installation of a 500MHz 13C-cryoprobe enhanced NMR spectrometer which has been used across a wide variety of Research Council funded projects. Over 250 scientific researchers have been trained to use it, assisting a further ~250 researchers and have published dozens of papers derived from results on this instrument.
Exploitation Route Not applicable.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description This award funded equipment used by >500 researchers, hence specific non-academic Impacts are impossible to capture in depth. However the most compelling example is the use of this instrument in the development of the science leading to the spin-out company Ziylo (Professor Tony Davis) which develloped pharmaceutical technologies leading to it's purchase in 2018 by NovoNordisk in a deal worth up to £800M (subject to targets).
First Year Of Impact 2018
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic