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.
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).
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).
Organisations
Publications
Bailey AM
(2016)
Identification and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased rapid antibiotic production.
in Scientific reports
Gerrard W
(2020)
IMPRESSION - prediction of NMR parameters for 3-dimensional chemical structures using machine learning with near quantum chemical accuracy.
in Chemical science
Bame J
(2018)
Improved NOE fitting for flexible molecules based on molecular mechanics data - a case study with S -adenosylmethionine
in Physical Chemistry Chemical Physics
Dewis L
(2019)
Improving the accuracy of 1 H-19 F internuclear distance measurement using 2D 1 H-19 F HOESY.
in Magnetic resonance in chemistry : MRC
Corbet B
(2017)
Intramolecular vinylation of carbanions using N -acyl benzomorpholines as masked vinylureas and vinylcarbamates
in Comptes Rendus Chimie
Mykura R
(2018)
Investigation of the Deprotonative Generation and Borylation of Diamine-Ligated a-Lithiated Carbamates and Benzoates by in Situ IR spectroscopy
in Journal of the American Chemical Society
Iqbal Z
(2018)
Investigations into the biosynthesis of the antifungal strobilurins.
in Organic & biomolecular chemistry
Cooper P
(2018)
Iridium-Catalyzed a-Selective Arylation of Styrenes by Dual C-H Functionalization
in Angewandte Chemie International Edition
Bootwicha T
(2017)
Iterative assembly line synthesis of polypropionates with full stereocontrol.
in Nature chemistry
Lister F
(2017)
Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor
in Nature Chemistry
Stewart P
(2018)
Maltodextrin recognition by a macrocyclic synthetic lectin.
in Chemical communications (Cambridge, England)
Costil R
(2017)
Medium-Sized-Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion.
in Angewandte Chemie (International ed. in English)
Yu S
(2019)
Methylenespiro[2.3]hexanes via Nickel-Catalyzed Cyclopropanations with [1.1.1]Propellane.
in Journal of the American Chemical Society
Wang GW
(2018)
Modular Access to Azepines by Directed Carbonylative C-C Bond Activation of Aminocyclopropanes.
in Journal of the American Chemical Society
Abas H
(2019)
N-Chloroformylimidazolidinone Enolates as 1,3-Dipolar Reagents for the Stereoselective Synthesis of 3,4-Dihydroisoquinolones.
in Organic letters
Wang GW
(2016)
New Initiation Modes for Directed Carbonylative C-C Bond Activation: Rhodium-Catalyzed (3 + 1 + 2) Cycloadditions of Aminomethylcyclopropanes.
in Journal of the American Chemical Society
Szwalbe AJ
(2015)
Novel nonadride, heptadride and maleic acid metabolites from the byssochlamic acid producer Byssochlamys fulva IMI 40021 - an insight into the biosynthesis of maleidrides.
in Chemical communications (Cambridge, England)
Pradeilles JA
(2020)
Odd-even alternations in helical propensity of a homologous series of hydrocarbons.
in Nature chemistry
Harper MJ
(2017)
Oxidative 1,2-Difunctionalization of Ethylene via Gold-Catalyzed Oxyarylation.
in Journal of the American Chemical Society
Harper MJ
(2018)
Oxidative Addition, Transmetalation, and Reductive Elimination at a 2,2'-Bipyridyl-Ligated Gold Center.
in Journal of the American Chemical Society
Alder RW
(2017)
Perhydrohelicenes and other diamond-lattice based hydrocarbons: the choreography of inversion.
in Chemical science
Wu J
(2018)
Photoinduced Deaminative Borylation of Alkylamines.
in Journal of the American Chemical Society
Wu J
(2019)
Photoinduced Deoxygenative Borylations of Aliphatic Alcohols.
in Angewandte Chemie (International ed. in English)
Shu C
(2020)
Photoinduced Fragmentation Borylation of Cyclic Alcohols and Hemiacetals
in Organic Letters
Shu C
(2019)
Photoredox-Catalyzed Cyclobutane Synthesis by a Deboronative Radical Addition-Polar Cyclization Cascade.
in Angewandte Chemie (International ed. in English)
Carter TS
(2016)
Platform Synthetic Lectins for Divalent Carbohydrate Recognition in Water.
in Angewandte Chemie (International ed. in English)
Bennett SH
(2020)
Prostaglandin Total Synthesis Enabled by the Organocatalytic Dimerization of Succinaldehyde.
in Chemical record (New York, N.Y.)
Ndukwe I
(2015)
Pure-shift IMPRESS EXSIDE - Easy measurement of 1 H- 13 C scalar coupling constants with increased sensitivity and resolution
in RSC Advances
Hazelden IR
(2018)
Pyrrolidines and Piperidines by Ligand-Enabled Aza-Heck Cyclizations and Cascades of N-(Pentafluorobenzoyloxy)carbamates.
in Angewandte Chemie (International ed. in English)
Silvi M
(2019)
Radical Addition to Strained s-Bonds Enables the Stereocontrolled Synthesis of Cyclobutyl Boronic Esters
in Journal of the American Chemical Society
Ndukwe IE
(2016)
Rapid and safe ASAP acquisition with EXACT NMR.
in Chemical communications (Cambridge, England)
Race NJ
(2017)
Recent developments in the use of aza-Heck cyclizations for the synthesis of chiral N-heterocycles.
in Chemical science
Buxton CS
(2017)
Reductive Coupling of Acrylates with Ketones and Ketimines by a Nickel-Catalyzed Transfer-Hydrogenative Strategy.
in Angewandte Chemie (International ed. in English)
Fawcett A
(2016)
Regio- and Stereoselective Homologation of 1,2-Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3-Diols and Sch 725674.
in Angewandte Chemie (International ed. in English)
Eccles N
(2019)
Remote conformational responses to enantiomeric excess in carboxylate-binding dynamic foldamers.
in Chemical communications (Cambridge, England)
Pelšs A
(2018)
Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of ? 12 -Prostaglandin J 3
in Chemistry - A European Journal
Kornilov A
(2019)
Revising the structure of a new eicosanoid from human platelets to 8,9-11,12-diepoxy-13-hydroxyeicosadienoic acid.
in The Journal of biological chemistry
Jardim GA
(2016)
Rh-Catalyzed Reactions of 1,4-Benzoquinones with Electrophiles: C-H Iodination, Bromination, and Phenylselenation.
in Organic letters
Hari DP
(2020)
Ring-Expansion Induced 1,2-Metalate Rearrangements: Highly Diastereoselective Synthesis of Cyclobutyl Boronic Esters.
in Journal of the American Chemical Society
Nandakumar M
(2020)
Ring-Opening Lithiation-Borylation of 2-Trifluoromethyl Oxirane: A Route to Versatile Tertiary Trifluoromethyl Boronic Esters.
in Angewandte Chemie (International ed. in English)
Gao SS
(2017)
Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics.
in Angewandte Chemie (International ed. in English)
Blair D
(2017)
Selective uni- and bidirectional homologation of diborylmethane
in Chemical Science
Noble A
(2016)
Short Enantioselective Total Synthesis of Tatanan A and 3-epi-Tatanan A Using Assembly-Line Synthesis.
in Angewandte Chemie (International ed. in English)
Gratzer K
(2017)
Signal transduction in oligoamide foldamers by selective non-covalent binding of chiral phosphates at a urea binding site.
in Organic & biomolecular chemistry
Millán A
(2018)
Stereocontrolled Synthesis of Polypropionate Fragments based on a Building Block Assembly Strategy using Lithiation-Borylation Methodologies.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Varela A
(2017)
Stereocontrolled Total Synthesis of (-)-Stemaphylline.
in Angewandte Chemie (International ed. in English)
Beattie RJ
(2016)
Stereoselective synthesis of protected l- and d-dideoxysugars and analogues via Prins cyclisations.
in Chemical science
Wang H
(2020)
Stereospecific 1,2-Migrations of Boronate Complexes Induced by Electrophiles.
in Angewandte Chemie (International ed. in English)
Farndon JJ
(2018)
Stereospecific Alkene Aziridination Using a Bifunctional Amino-Reagent: An Aza-Prilezhaev Reaction.
in Journal of the American Chemical Society
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 >600 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 |