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
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
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)
Ackrill TD
(2015)
Synthesis of Diarylheptanoid Scaffolds Inspired by Calyxins I and J.
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
McCreanor NG
(2016)
Capture-Collapse Heterocyclization: 1,3-Diazepanes by C-N Reductive Elimination from Rhodacyclopentanones.
in Journal of the American Chemical Society
Mora N
(2016)
Targeted anion transporter delivery by coiled-coil driven membrane fusion
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)
Edwards SJ
(2016)
Tilting and Tumbling in Transmembrane Anion Carriers: Activity Tuning through n-Alkyl Substitution.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Jardim GA
(2016)
Rh-Catalyzed Reactions of 1,4-Benzoquinones with Electrophiles: C-H Iodination, Bromination, and Phenylselenation.
in Organic letters
Bailey AM
(2016)
Identification and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased rapid antibiotic production.
in Scientific reports
Millán A
(2016)
Tandem Allylboration-Prins Reaction for the Rapid Construction of Substituted Tetrahydropyrans: Application to the Total Synthesis of (-)-Clavosolide A.
in Angewandte Chemie (International ed. in English)
Ndukwe IE
(2016)
Rapid and safe ASAP acquisition with EXACT NMR.
in Chemical communications (Cambridge, England)
Ndukwe IE
(2016)
EXtended ACquisition Time (EXACT) NMR-A Case for 'Burst' Non-Uniform Sampling.
in Chemphyschem : a European journal of chemical physics and physical chemistry
Mooibroek TJ
(2016)
Synthesis and evaluation of a desymmetrised synthetic lectin: an approach to carbohydrate receptors with improved versatility.
in Organic & biomolecular chemistry
Beattie RJ
(2016)
Stereoselective synthesis of protected l- and d-dideoxysugars and analogues via Prins cyclisations.
in Chemical science
Jones CR
(2016)
Subtle temperature-induced changes in small molecule conformer dynamics - observed and quantified by NOE spectroscopy.
in Chemical communications (Cambridge, England)
Hazelden IR
(2016)
Diverse N-Heterocyclic Ring Systems via Aza-Heck Cyclizations of N-(Pentafluorobenzoyloxy)sulfonamides.
in Angewandte Chemie (International ed. in English)
Shaw MH
(2016)
Synthesis and applications of rhodacyclopentanones derived from C-C bond activation.
in Chemical communications (Cambridge, England)
Byrne MJ
(2016)
The Catalytic Mechanism of a Natural Diels-Alderase Revealed in Molecular Detail.
in Journal of the American Chemical Society
Williams K
(2016)
Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis.
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)
Rios P
(2016)
Synthetic Receptors for the High-Affinity Recognition of O-GlcNAc Derivatives.
in Angewandte Chemie (International ed. in English)
Crisenza GE
(2016)
C2-Alkenylation of N-heteroaromatic compounds via Brønsted acid catalysis.
in Organic & biomolecular chemistry
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)
Singleton W
(2017)
Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model
in International Journal of Nanomedicine
Aichhorn S
(2017)
Enantiospecific Synthesis of ortho-Substituted Benzylic Boronic Esters by a 1,2-Metalate Rearrangement/1,3-Borotropic Shift Sequence.
in Journal of the American Chemical Society
Bootwicha T
(2017)
Iterative assembly line synthesis of polypropionates with full stereocontrol.
in Nature chemistry
Harper MJ
(2017)
Oxidative 1,2-Difunctionalization of Ethylene via Gold-Catalyzed Oxyarylation.
in Journal of the American Chemical Society
Ríos P
(2017)
Enantioselective carbohydrate recognition by synthetic lectins in water.
in Chemical science
Lister F
(2017)
Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor
in Nature Chemistry
Farndon JJ
(2017)
Transition Metal Free C-N Bond Forming Dearomatizations and Aryl C-H Aminations by in Situ Release of a Hydroxylamine-Based Aminating Agent.
in Journal of the American Chemical Society
Williams K
(2017)
Genetic and chemical characterisation of the cornexistin pathway provides further insight into maleidride biosynthesis.
in Chemical communications (Cambridge, England)
Valkenier H
(2017)
A folding decalin tetra-urea for transmembrane anion transport
in Tetrahedron
Wu J
(2017)
Synergy of synthesis, computation and NMR reveals correct baulamycin structures.
in Nature
Costil R
(2017)
Medium-Sized-Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion.
in Angewandte Chemie (International ed. in English)
Varela A
(2017)
Stereocontrolled Total Synthesis of (-)-Stemaphylline.
in Angewandte Chemie (International ed. in English)
Thistlethwaite IRG
(2017)
Elucidation of the relative and absolute stereochemistry of the kalimantacin/batumin antibiotics.
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)
Dickson C
(2017)
Accurate measurement of long range proton-carbon scalar coupling constants
in The Analyst
Ma X
(2017)
A Simple and Broadly Applicable C-N Bond Forming Dearomatization Protocol Enabled by Bifunctional Amino Reagents.
in Angewandte Chemie (International ed. in English)
Pulis AP
(2017)
Asymmetric Synthesis of Tertiary Alcohols and Thiols via Nonstabilized Tertiary a-Oxy- and a-Thio-Substituted Organolithium Species.
in Angewandte Chemie (International ed. in English)
Ndukwe IE
(2017)
Enabling Fast Pseudo-2D NMR Spectral Acquisition for Broadband Homonuclear Decoupling: The EXACT NMR Approach.
in Chemphyschem : a European journal of chemical physics and physical chemistry
Casoni G
(2017)
a-Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters.
in Journal of the American Chemical Society
Gao SS
(2017)
Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics.
in Angewandte Chemie (International ed. in English)
Costil R
(2017)
Heavily Substituted Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of N-Aryl Anthranilamides.
in Angewandte Chemie (International ed. in English)
Tomsett M
(2017)
A tendril perversion in a helical oligomer: trapping and characterizing a mobile screw-sense reversal.
in Chemical science
Race NJ
(2017)
Enantioselective Narasaka-Heck cyclizations: synthesis of tetrasubstituted nitrogen-bearing stereocenters.
in Chemical science
Blair D
(2017)
Selective uni- and bidirectional homologation of diborylmethane
in Chemical Science
Collins BSL
(2017)
Asymmetric Synthesis of Secondary and Tertiary Boronic Esters.
in Angewandte Chemie (International ed. in English)
Corbet B
(2017)
Intramolecular vinylation of carbanions using N -acyl benzomorpholines as masked vinylureas and vinylcarbamates
in Comptes Rendus Chimie
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 |