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
Race NJ
(2017)
Recent developments in the use of aza-Heck cyclizations for the synthesis of chiral N-heterocycles.
in Chemical science
Baars H
(2017)
Synthesis of Alfaprostol and PGF2a through 1,4-Addition of an Alkyne to an Enal Intermediate as the Key Step.
in Organic letters
Diemer V
(2017)
Dibenzazepinyl ureas as dual NMR and CD probes of helical screw-sense preference in conformationally equilibrating dynamic foldamers.
in Chemical communications (Cambridge, England)
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
Alder RW
(2017)
Perhydrohelicenes and other diamond-lattice based hydrocarbons: the choreography of inversion.
in Chemical science
Alberti F
(2017)
Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives.
in Nature communications
Nofiani R
(2018)
Strobilurin biosynthesis in Basidiomycete fungi
in Nature Communications
Dias CM
(2018)
Anthracene Bisureas as Powerful and Accessible Anion Carriers.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Armstrong RJ
(2018)
Enantiodivergent Synthesis of Allenes by Point-to-Axial Chirality Transfer.
in Angewandte Chemie (International ed. in English)
Iqbal Z
(2018)
Investigations into the biosynthesis of the antifungal strobilurins.
in Organic & biomolecular chemistry
Rubial B
(2018)
Enantiospecific Synthesis of ortho -Substituted 1,1-Diarylalkanes by a 1,2-Metalate Rearrangement/ anti -S N 2' Elimination/Rearomatizing Allylic Suzuki-Miyaura Reaction Sequence
in Angewandte Chemie International Edition
Niwetmarin W
(2018)
(-)-Cytisine: Access to a stereochemically defined and functionally flexible piperidine scaffold.
in Organic & biomolecular chemistry
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
Fawcett A
(2018)
Carbopalladation of C-C s-bonds enabled by strained boronate complexes
in Nature Chemistry
Dias CM
(2018)
Anion transport by ortho-phenylene bis-ureas across cell and vesicle membranes.
in Organic & biomolecular chemistry
Harper MJ
(2018)
Oxidative Addition, Transmetalation, and Reductive Elimination at a 2,2'-Bipyridyl-Ligated Gold Center.
in Journal of the American Chemical Society
Shu C
(2018)
Synthesis of Functionalized Cyclopropanes from Carboxylic Acids by a Radical Addition-Polar Cyclization Cascade.
in Angewandte Chemie (International ed. in English)
Dalling A
(2018)
Carbonylative C-C Bond Activation of Electron-Poor Cyclopropanes: Rhodium-Catalyzed (3+1+2) Cycloadditions of Cyclopropylamides
in Angewandte Chemie International Edition
Noble A
(2018)
Visible-Light-Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to ?-Amino Boronic Esters.
in Angewandte Chemie (International ed. in English)
Wu J
(2018)
Photoinduced Deaminative Borylation of Alkylamines.
in Journal of the American Chemical Society
Stewart P
(2018)
Maltodextrin recognition by a macrocyclic synthetic lectin.
in Chemical communications (Cambridge, England)
Lister F
(2018)
Bis-pyrene probes of foldamer conformation in solution and in phospholipid bilayers
in Chemical Science
Farndon JJ
(2018)
Stereospecific Alkene Aziridination Using a Bifunctional Amino-Reagent: An Aza-Prilezhaev Reaction.
in Journal of the American Chemical Society
Amer MM
(2018)
Substituted Dihydroisoquinolinones by Iodide-Promoted Cyclocarbonylation of Aromatic a-Amino Acids.
in Organic letters
De Mattos-Shipley KMJ
(2018)
The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis.
in Chemical science
Grélaud S
(2018)
Branch-Selective and Enantioselective Iridium-Catalyzed Alkene Hydroarylation via Anilide-Directed C-H Oxidative Addition.
in Journal of the American Chemical Society
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
Leonard DJ
(2018)
Asymmetric a-arylation of amino acids.
in Nature
Abrams R
(2018)
Transition Metal Free Cycloamination of Prenyl Carbamates and Ureas Promoted by Aryldiazonium Salts.
in Angewandte Chemie (International ed. in English)
Silvi M
(2018)
Enantiospecific Three-Component Alkylation of Furan and Indole
in Chemistry - A European Journal
Dalling AG
(2018)
Synthesis of Nitrogen Heterocycles via Directed Carbonylative C-C Bond Activation of Cyclopropanes.
in Chimia
Cooper P
(2018)
Iridium-Catalyzed a-Selective Arylation of Styrenes by Dual C-H Functionalization
in Angewandte Chemie International Edition
Tassoti S
(2018)
High Resolution for Chemical Shifts and Scalar Coupling Constants: The 2D Real-Time J-Upscaled PSYCHE-DIAG
in ChemPhysChem
Wang GW
(2018)
Modular Access to Azepines by Directed Carbonylative C-C Bond Activation of Aminocyclopropanes.
in Journal of the American Chemical Society
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
Costil R
(2018)
a-Methyl phenylglycines by asymmetric a-arylation of alanine and their effect on the conformational preference of helical Aib foldamers.
in Organic & biomolecular chemistry
Mas-Roselló J
(2018)
Enantioselectively functionalised phenytoin derivatives by auxiliary-directed N to C aryl migration in lithiated a-amino nitriles.
in Chemical communications (Cambridge, England)
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)
Adam C
(2018)
The Role of Terminal Functionality in the Membrane and Antibacterial Activity of Peptaibol-Mimetic Aib Foldamers
in Chemistry - A European Journal
Ganesh V
(2018)
Chiral Aniline Synthesis via Stereospecific C(sp 3 )-C(sp 2 ) Coupling of Boronic Esters with Aryl Hydrazines
in Organic Letters
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)
Zhurakovskyi O
(2018)
Enantioselective Synthesis of the Cyclopiazonic Acid Family Using Sulfur Ylides.
in Angewandte Chemie (International ed. in English)
Greco C
(2019)
Structure revision of cryptosporioptides and determination of the genetic basis for dimeric xanthone biosynthesis in fungi.
in Chemical science
Kaiser D
(2019)
1,2-Boron Shifts of ß-Boryl Radicals Generated from Bis-boronic Esters Using Photoredox Catalysis.
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
Shu C
(2019)
Photoredox-Catalyzed Cyclobutane Synthesis by a Deboronative Radical Addition-Polar Cyclization Cascade.
in Angewandte Chemie (International ed. in English)
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
De Zotti M
(2019)
Extended Diethylglycine Homopeptides Formed by Desulfurization of Their Tetrahydrothiopyran Analogues.
in Organic letters
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
Silvi M
(2019)
Radical Addition to Strained s-Bonds Enables the Stereocontrolled Synthesis of Cyclobutyl Boronic Esters
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 |