ORCID Profile
0000-0003-0637-4225
Current Organisation
University of Bristol
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Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00576K
Abstract: Designed binaphthyl-based, cationic peptidomimetic antimicrobials targeting C. difficile , incorporating a click-derived 1,2,3-triazole ester isostere at the C-terminus MICs of 4 μg mL −1 against three human isolates of C. difficile .
Publisher: American Chemical Society (ACS)
Date: 23-09-2015
Abstract: The reaction between 1,4-di-Grignard reagents and phosphonous(III) dichlorides is a classical method for the direct synthesis of phospholanes. Reported here is an extension of this approach to the preparation of value-added, annulated phospholane oxides, achieved through the combination of carbocyclic-fused di-Grignard reagents and readily available phosphonic(V) dichlorides. The procedure is amenable to (benz)annulation at both the 2,3- and 3,4-positions of the phospholane ring, and a variety of aliphatic, cyclic and aryl P-electrophiles are tolerated in reasonable to excellent yields.
Publisher: American Chemical Society (ACS)
Date: 16-06-2023
Publisher: American Chemical Society (ACS)
Date: 18-08-2023
DOI: 10.1021/JACS.3C06570
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.EJMECH.2019.02.068
Abstract: Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C. difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 μg/mL against methicillin-resistant Staphylococcus aureus and 8 μg/mL against C. difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 μg/mL), Pseudomonas aeruginosa (8 μg/mL) and Klebsiella pneumoniae (16 μg/mL) additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized hiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.
Publisher: American Chemical Society (ACS)
Date: 08-05-2013
DOI: 10.1021/OL4010646
Abstract: An enantioconvergent Friedel-Crafts alkylation of indoles with donor-acceptor cyclopropanes is described. The reaction is catalyzed by pybox•MgI2 and proceeds via a type I dynamic kinetic asymmetric transformation (DyKAT).
Publisher: American Chemical Society (ACS)
Date: 07-08-2014
DOI: 10.1021/OL502164B
Abstract: The chiral pool-derived 1,1'-ditosyl-2,2'-biaziridine has been established as a valuable building block for the ergent synthesis of enantiopure vicinal diamines. Efficient procedures for the regioselective ring opening of the biaziridine with oxygen, sulfur, nitrogen, and carbon nucleophiles are described. The strategic use of nucleophiles bearing pendant functionality allows further elaboration of the acyclic products to a variety of 2,2'-bicyclic-embedded diamines. Desymmetrization of the biaziridine has also been accomplished via the selective monoaddition of organocuprates.
Publisher: Elsevier BV
Date: 06-2015
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C0CC04045B
Abstract: The first two syntheses of chiral 2,2'-biindoline are reported either in five steps from 2,2'-bioxirane, or three steps from 2,2'-biaziridine, both with exceptional enantiopurity.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB01638J
Abstract: Thirty two new binaphthyl-based, oxazole and thiazole peptidomimetics were prepared, which showed antibacterial activity (MICs 1–16 μg mL −1 ) against both Gram positive and negative isolates.
Publisher: American Chemical Society (ACS)
Date: 27-05-2022
Publisher: Elsevier
Date: 2021
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.EJMECH.2019.02.013
Abstract: Synthetic small molecular antimicrobial peptidomimetics represent a promising new class of potential antibiotics due to their membrane-disrupting ability and their decreased propensity for bacterial resistance. A library of 43 mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics was designed and synthesized based upon previously established lead biarylpeptidomimetics and a known pharmacophore. A reliable, facile and modular synthetic pathway allowed for the efficient synthesis of multiple unique scaffolds which were subjected to ergent derivatization to furnish the hiphilic compounds. In vitro testing revealed enhanced antibacterial efficacy against a range of pathogenic bacteria, including bacterial isolates with methicillin, vancomycin, daptomycin, or multi-drug resistance. Preliminary time-kill kinetics and membrane-disruption assays revealed a likely membrane-active mechanism for the tested peptidomimetics. An optimal balance between hydrophobicity and cationic charge was found to be essential for reduced cytotoxicity/haemolysis (i.e. membrane selectivity) and enhanced Gram-negative activity. The cationic biaryl hiphile 81 was identified as a potent, broad-spectrum peptidomimetic with activity against Gram-positive (methicillin-resistant Staphylococcus aureus - MIC = 2 μg/mL) and Gram-negative (Escherichia coli - MIC = 4 μg/mL) pathogenic bacteria.
Publisher: Elsevier
Date: 2023
Publisher: American Chemical Society (ACS)
Date: 12-06-2019
DOI: 10.1021/ACS.ORGLETT.9B01580
Abstract: Aminobenzaldehydes bearing a pendant 3,5-dinitrophenyl group react thermally with N-substituted α-amino acids to form unprecedented benzoazepine-fused isoindolines. The reaction proceeds via a dearomatization/rearomatization sequence involving an intramolecular (3 + 2)-cycloaddition between the in situ formed azomethine ylide and the dinitroarene. Various glycine derivatives are tolerated as well as branched substrates based on cyclic, α-mono-, and α,α-disubstituted amino acids, giving single diastereomers in many cases. The method is scalable and gives products with a nitro group ready for further manipulation.
Publisher: Georg Thieme Verlag KG
Date: 20-03-2020
Abstract: A diastereoselective palladium-catalyzed dearomative formal (4+2) cycloaddition between vinyl benzoxazinanones and 3-nitroindoles has been developed. This reaction provides a concise route to tetrahydro-5H-indolo[2,3-b]quinolines in excellent yield (up to 94%) and diastereoselectivity (up to :2), with versatile functional handles including vinyl, nitro, and free NH groups.
Publisher: Elsevier BV
Date: 08-2009
Publisher: Wiley
Date: 16-05-2018
Abstract: A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2-aryl, 3-carboxy and 4-amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre-functionalised 4-oxofurans, readily prepared from cinnamate esters via oxa-Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C-3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C-4 relative to the other ring substituents. The resulting compounds, which displayed desirable physical properties as lead-like scaffolds, were derivatised into a small library of 24 compounds, demonstrating their ability to serve as starting points for drug discovery. Ultimately, this chemistry enabled the preparation of 1948 THF-containing compounds for inclusion in the Joint European Compound Library.
Publisher: American Chemical Society (ACS)
Date: 08-06-2021
Publisher: American Chemical Society (ACS)
Date: 07-05-2015
Abstract: The copper-catalyzed ring opening of chiral-pool-derived 1,1'-diBoc-2,2'-biaziridine with Grignard reagents affords enantiopure 2-imidazolidinones in a desymmetrizing, cascade process involving the Boc protecting group. This ergent strategy provides reaction-ready, N-differentiated products and allows two C-C bond constructions concurrent to imidazolidinone formation. A variety of alkyl, cyclic, and aryl Grignard reagents are tolerated in reasonable to good yields.
Publisher: Wiley
Date: 21-08-2018
Publisher: Wiley
Date: 15-05-2018
Abstract: The enantioselective Cu-catalyzed 1,6-boration of (E,E)-α,β,γ,δ-unsaturated ketones is described, which gives homoallylic boronates with high enantiomeric purity and unexpectedly high Z-selectivity. By changing the solvent, the outcome can be altered to give E-allylic boronates.
Publisher: Elsevier BV
Date: 08-2010
Publisher: Elsevier
Date: 2021
Publisher: American Chemical Society (ACS)
Date: 10-02-2022
DOI: 10.1021/JACS.1C11928
Publisher: American Chemical Society (ACS)
Date: 04-12-2017
Abstract: A trans-diastereoselective Pd-catalyzed dearomative [3 + 2] cycloaddition between vinylcyclopropane dicarboxylates and 3-nitroindoles has been developed. The reaction provides densely functionalized cyclopenta[b]indolines with versatile vinyl and nitro-groups. The addition of a halide additive was found to be critical for the diastereoselectivity of the reaction, which is proposed to be a result of a rapid π-σ-π interconversion between the intermediates allowing for Curtin-Hammett control. A switch in diastereoselectivity to afford products with the vinyl and nitro groups cis to each other is observed with a 4-substituted 3-nitroindole.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Steven Wales.