Imperial College London

ProfessorAlanArmstrong

Faculty of Natural SciencesDepartment of Chemistry

Professor of Organic Synthesis
 
 
 
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Contact

 

+44 (0)20 7594 5876a.armstrong

 
 
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Location

 

501EMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

122 results found

Evans LE, Krishna A, Ma Y, Webb TE, Marshall DC, Tooke CL, Spencer J, Clarke TB, Armstrong A, Edwards Aet al., 2019, Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug., Journal of Medicinal Chemistry, ISSN: 0022-2623

Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic pro-drug that combines ciprofloxacin with a β-lactamase-cleavable motif. The pro-drug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically-relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our pro-drug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.

Journal article

Craven G, Affron D, Raymond P, Mann D, Armstrong Aet al., 2019, Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy, MedChemComm, Vol: 10, Pages: 158-163, ISSN: 2040-2503

Vinyl sulfonamides are valuable electrophiles for targeted protein modification and inhibition. We describe a novel approach to the synthesis of terminal vinyl sulfonamides which uses mild oxidative conditions to induce elimination of an α-selenoether masking group. The method complements traditional synthetic approaches and typically yields vinyl sulfonamides in high purity after aqueous work-up without requiring column chromatography of the final electrophilic product. The methodology is applied to the synthesis of covalent fragments for use in irreversible protein tethering and crucially enables the attachment of diverse fragments to the vinyl sulfonamide warhead via a chemical linker. Using thymidylate synthase as a model system, ethylene glycol is identified as an effective linker for irreversible protein tethering.

Journal article

Craven G, Affron D, Allen C, Matthies S, Greener J, Morgan R, Tate E, Armstrong A, Mann Det al., 2018, High-throughput kinetic analysis for target-directed covalent ligand discovery, Angewandte Chemie, Vol: 57, Pages: 5257-5261, ISSN: 1521-3757

Cysteine-­reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-­quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-­reactive compounds. Here we describe quantitative irreversible tethering(qIT), a general method for screening cysteine-­reactive small moleculesbased upon the maximization of kinetic selectivity. We apply this method prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-­selective allosteric (type IV) kinase inhibitor whose novel mode-­of-­action could be exploited therapeutically.

Journal article

Mann D, Armstrong A, Craven G, Matthies Set al., 2018, (WO2018033753) ASSAY, PCT/GB2017/052456

The present invention relates to a method of measuring the rate of reaction between a target molecule and a ligand candidate, ligands of interest identified according to this method and drugs developed from such ligands. The present invention also relates to a method of measuring the rate of reaction between a thiol and a molecule capable of reacting with said thiol.

Patent

Grant E, Pan Y, Richardson J, Martinelli JR, Armstrong A, Galindo A, Adjiman CSet al., 2018, Multi-Objective Computer-Aided Solvent Design for Selectivity and Rate in Reactions, Computer Aided Chemical Engineering, Pages: 2437-2442

© 2018 Elsevier B.V. A hybrid empirical computer-aided methodology to design the solvent for a reaction, incorporating both selectivity and rate, is presented. A small initial set of diverse solvents is used, for which experimental, in situ kinetic data are obtained. A surrogate model is utilized to correlate the reaction kinetics with solvent properties and a computer-aided molecular design (CAMD) multi-objective optimization problem is then formulated to identify solvents with improved performance compared with the initial solvent set. This methodology is applied to an S N Ar reaction of 2,4-difluoroacetophenone with pyrrolidine, which demonstrates an interesting effect of solvent on both the selectivity of the ortho-:para-substitution ratio and the overall rate of the reaction. A set of Pareto optimal solutions is identified, highlighting the trade-off between reaction rate and selectivity.

Book chapter

Armstrong A, Ces O, Compte RV, 2017, All aboard for chemistry, CHEMISTRY & INDUSTRY, Vol: 81, Pages: 14-15, ISSN: 0009-3068

Journal article

Sung S, Sale D, Braddock DC, Armstrong A, Brenan C, Davies RPet al., 2016, Mechanistic studies on the copper-catalyzed N-arylation of alkylamines promoted by organic soluble ionic bases, ACS Catalysis, Vol: 6, Pages: 3965-3974, ISSN: 2155-5435

Experimental studies on the mechanism of copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a Cu(I) catalyst and the organic base tetrabutylphosphonium malonate (TBPM). The use of TBPM led to high reactivity and high conversion rates in the coupling reaction, as well as obviating any mass transfer effects. The often commonly employed O,O-chelating ligand 2-acetylcyclohexanone was surprisingly found to have a negligible effect on the reaction rate, and on the basis of NMR, calorimetric, and kinetic modeling studies, the malonate dianion in TBPM is instead postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic analysis (RPKA) methods show the reaction rate to have a dependence on all of the reaction components in the concentration range studied, with first-order kinetics with respect to [amine], [aryl halide], and [Cu]total. Unexpectedly, negative first-order kinetics in [TBPM] was observed. This negative rate dependence in [TBPM] can be explained by the formation of an off-cycle copper(I) dimalonate species, which is also argued to undergo disproportionation and is thus responsible for catalyst deactivation. The key role of the amine in minimizing catalyst deactivation is also highlighted by the kinetic studies. An examination of the aryl halide activation mechanism using radical probes was undertaken, which is consistent with an oxidative addition pathway. On the basis of these findings, a more detailed mechanistic cycle for the C–N coupling is proposed, including catalyst deactivation pathways.

Journal article

Byrne B, Alguel Y, Scull NJ, Craven G, Armstrong A, Iwata S, Diallinas G, Amillis S, Capaldi S, Cameron AD, Lambrinidis G, Mikros Eet al., 2016, Structure of eukaryotic purine/Hþ symporter UapA suggests a role for homodimerization in transport activity, Nature Communications, Vol: 7, ISSN: 2041-1723

The uric acid/xanthine H+ symporter, UapA, is a high-affinity purine transporter from the filamentous fungus Aspergillus nidulans. Here we present the crystal structure of a genetically stabilized version of UapA (UapA-G411VΔ1–11) in complex with xanthine. UapA is formed from two domains, a core domain and a gate domain, similar to the previously solved uracil transporter UraA, which belongs to the same family. The structure shows UapA in an inward-facing conformation with xanthine bound to residues in the core domain. Unlike UraA, which was observed to be a monomer, UapA forms a dimer in the crystals with dimer interactions formed exclusively through the gate domain. Analysis of dominant negative mutants is consistent with dimerization playing a key role in transport. We postulate that UapA uses an elevator transport mechanism likely to be shared with other structurally homologous transporters including anion exchangers and prestin.

Journal article

Bures Amat J, Blackmond DG, armstrong A, Explaining Anomalies in Enamine Catalysis: “Downstream Species” as a New Paradigm for Stereocontrol, Accounts of Chemical Research, ISSN: 1520-4898

Journal article

Armstrong A, Pullin RDC, Scutt JN, 2015, Tertiary Amine Promoted Aziridination: Preparation of NH-Aziridines from Aliphatic ,-Unsaturated Ketones, SYNLETT, Vol: 27, Pages: 151-155, ISSN: 0936-5214

trans-NH-Aziridines were prepared from aliphatic α,β-unsaturated ketones using a tertiary amine promoted reaction via in situ generated N,N-ylides. Through use of modified conditions the reaction proved to be applicable for the diastereoselective aziridination of a range of enolisable aliphatic α,β-unsaturated ketones of varying substitution patterns.

Journal article

Sung S, Braddock DC, Armstrong A, Brennan C, Sale D, White AJP, Davies RPet al., 2015, Synthesis, Characterisation and Reactivity of Copper(I) Amide Complexes and Studies on Their Role in the Modified Ullmann Amination Reaction, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 21, Pages: 7179-7192, ISSN: 0947-6539

Journal article

Allen CE, Curran PR, Brearley AS, Boissel V, Sviridenko L, Press NJ, Stonehouse JP, Armstrong Aet al., 2015, Efficient and Facile Synthesis of Acrylamide Libraries for Protein-Guided Tethering, ORGANIC LETTERS, Vol: 17, Pages: 458-460, ISSN: 1523-7060

Journal article

Bures J, Dingwall P, Armstrong A, Blackmond DGet al., 2014, Rationalization of an Unusual Solvent-Induced Inversion of Enantio-meric Excess in Organocatalytic Selenylation of Aldehydes, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 53, Pages: 8700-8704, ISSN: 1433-7851

Journal article

Armstrong A, Emmerson DPG, Milner HJ, Sheppard RJet al., 2014, [2,3]-Sigmatropic Rearrangement of Allylic Selenimides: Strategy for the Synthesis of Peptides, Peptidomimetics, and N-Aryl Vinyl Glycines, JOURNAL OF ORGANIC CHEMISTRY, Vol: 79, Pages: 3895-3907, ISSN: 0022-3263

Journal article

Armstrong A, Pullin RDC, Jenner CR, Foo K, White AJP, Scutt JNet al., 2014, Tertiary amine-promoted enone aziridination: investigations into factors influencing enantioselective induction, TETRAHEDRON-ASYMMETRY, Vol: 25, Pages: 74-86, ISSN: 0957-4166

Journal article

Armstrong A, Boto RA, Dingwall P, Contreras-Garcia J, Harvey MJ, Mason NJ, Rzepa HSet al., 2014, The Houk-List transition states for organocatalytic mechanisms revisited, CHEMICAL SCIENCE, Vol: 5, Pages: 2057-2071, ISSN: 2041-6520

Journal article

Armstrong A, Braddock DC, Jones AX, Clark Set al., 2013, Catalytic asymmetric bromolactonization reactions using (DHQD)(2)PHAL-benzoic acid combinations, TETRAHEDRON LETTERS, Vol: 54, Pages: 7004-7008, ISSN: 0040-4039

Journal article

Struebing H, Ganase Z, Karamertzanis PG, Siougkrou E, Haycock P, Piccione PM, Armstrong A, Galindo A, Adjiman CSet al., 2013, Computer-aided molecular design of solvents for accelerated reaction kinetics, NATURE CHEMISTRY, Vol: 5, Pages: 952-957, ISSN: 1755-4330

Journal article

Collins JC, Armstrong A, Chapman KL, Cordingley HC, Jaxa-Chamiec AA, Judd KE, Mann DJ, Scott KA, Tralau-Stewart CJ, Low CMRet al., 2013, Prospective use of molecular field points in ligand-based virtual screening: efficient identification of new reversible Cdc25 inhibitors, MEDCHEMCOMM, Vol: 4, Pages: 1148-1155, ISSN: 2040-2503

Journal article

Burés J, Armstrong A, Blackmond DG, 2013, The interplay of thermodynamics and kinetics in dictating organocatalytic reactivity and selectivity, Pure and Applied Chemistry, Pages: 1-1, ISSN: 0033-4545

Journal article

Nonoo RH, Armstrong A, Mann DJ, 2012, Kinetic Template-Guided Tethering of Fragments, CHEMMEDCHEM, Vol: 7, Pages: 2082-2086, ISSN: 1860-7179

Journal article

Armstrong A, Ferguson A, 2012, Synthesis and ring openings of cinnamate-derived N-unfunctionalised aziridines, BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, Vol: 8, Pages: 1747-1752, ISSN: 1860-5397

Journal article

Bures J, Armstrong A, Blackmond DG, 2012, Curtin-Hammett Paradigm for Stereocontrol in Organocatalysis by Diarylprolinol Ether Catalysts, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 134, Pages: {6741-6750}-{6741-6750}, ISSN: 0002-7863

Detailed mechanistic study of two reactions catalyzed by diarylprolinol ether catalysts, the conjugate addition of aldehydes to nitro-olefins and the alpha-chlorination of aldehydes, leads to the proposal that the stereochemical outcome in these cases is not determined by the transition state of the step in which the stereogenic center is formed from enamine attack on the electrophile but instead is correlated with the relative stability and reactivity of diastereomeric intermediates downstream in the catalytic cycle. This combination of kinetic and thermodynamic factors illustrates a remarkable Curtin-Hammett scenario that can result in either an enhancement or an erosion of the selectivity that would be predicted by the transition state for enamine attack on the electrophile. Evidence is offered to suggest that this concept may represent a general phenomenon for pyrrolidine-based catalysts lacking an acidic directing proton. Implications for catalyst and reaction design are discussed.

Journal article

Bures J, Armstrong A, Blackmond DG, 2012, Kinetic correlation between aldehyde/enamine stereoisomers in reactions between aldehydes with alpha-stereocenters and chiral pyrrolidine-based catalysts, CHEMICAL SCIENCE, Vol: 3, Pages: {1273-1277}-{1273-1277}, ISSN: 2041-6520

The formation of enamines between aldehydes with alpha-stereocenters and pyrrolidine-based catalysts that lack an acidic proton is examined by kinetic and spectroscopic studies. The reaction exhibits “kinetic stereospecificity” in that each enantiomer of the aldehyde initially reacts to form a specific enamine stereoisomer, prior to thermodynamic equilibration of the E and Z enamines. For the case of prolinate catalysts, each of the stereoisomeric enamines is correlated with a specific stereoisomeric oxazolidinone. The reactions of E and Z enamines with electrophiles such as DEAD lead to products of opposite stereochemistry. The product enantioselectivity observed depends on the extent to which the E and Z enamines are pre-equilibrated prior to reaction with the electrophile. General implications for selectivity in organocatalytic reactions are discussed.

Journal article

Armstrong A, Deacon N, Donald C, 2011, Enantioselective Synthesis of alpha-Aminophosphonates via Organocatalytic Sulfenylation and [2,3]-Sigmatropic Sulfimide Rearrangement, SYNLETT, Pages: 2347-2350, ISSN: 0936-5214

Journal article

Hein JE, Bures J, Lam Y-H, Hughes M, Houk KN, Armstrong A, Blackmond DGet al., 2011, Enamine Carboxylates as Stereodetermining Intermediates in Prolinate Catalysis, ORGANIC LETTERS, Vol: 13, Pages: {5644-5647}-{5644-5647}, ISSN: 1523-7060

Experimental and computational studies probing the nature of Intermediates in the alpha-amination of aldehydes catalyzed by prolinate salts support an enamine carboxylate intermediate in the stereodetermining step.

Journal article

Hein JE, Armstrong A, Blackmond DG, 2011, Kinetic profiling of prolinate-catalyzed α-amination of aldehydes., Org Lett, Vol: 13, Pages: 4300-4303

Deconvolution of the role of off-cycle species from the desired catalytic cycle leads to an optimized protocol for the prolinate-catalyzed amination of aldehydes. The scope of complex reaction networks will be greatly broadened by understanding ancillary rate processes that influence the productive catalytic pathway.

Journal article

Hein JE, Armstrong A, Blackmond DG, 2011, Kinetic Profiling of Prolinate-Catalyzed alpha-Amination of Aldehydes, ORGANIC LETTERS, Vol: 13, Pages: 4300-4303, ISSN: 1523-7060

Journal article

Bures J, Armstrong A, Blackmond DG, 2011, Mechanistic Rationalization of Organocatalyzed Conjugate Addition of Linear Aldehydes to Nitro-olefins, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 133, Pages: {8822-8825}-{8822-8825}, ISSN: 0002-7863

Kinetic studies of the conjugate addition of propanal to nitrostyrene catalyzed by diarylprolinol ethers reveal that formation of the product iminium species is rate-determining and is promoted by both the reaction product and acid additives. The beneficial role of a dominant cyclobutane intermediate in maintaining high stereoselectivity is highlighted. This mechanistic understanding led to the design of highly productive reaction protocols.

Journal article

Armstrong A, Emmerson DPG, 2011, Enantioselective Synthesis of alpha-Alkyl, alpha-Vinyl Amino Acids via [2,3]-Sigmatropic Rearrangement of Selenimides, ORGANIC LETTERS, Vol: 13, Pages: 1040-1043, ISSN: 1523-7060

Journal article

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