ORCID Profile
0000-0002-6495-5282
Current Organisation
University of Newcastle Australia
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Structural Chemistry and Spectroscopy | Characterisation of Biological Macromolecules | Medicinal and Biomolecular Chemistry | Biologically Active Molecules
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences |
Publisher: American Chemical Society (ACS)
Date: 21-04-2022
DOI: 10.26434/CHEMRXIV-2022-H2PDS
Abstract: The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA) as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a click-linked bullvalene core, hence exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding D-Ala-D-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, inferring the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.
Publisher: Wiley
Date: 15-06-2023
Abstract: We present the synthesis of 1,1‐bis(fluorosulfonyl)‐2‐(pyridin‐1‐ium‐1‐yl)ethan‐1‐ide, a bench‐stable precursor to ethene‐1,1‐disulfonyl difluoride (EDSF). The novel SuFEx reagent, EDSF, is demonstrated in the preparation of 26 unique 1,1‐bissulfonylfluoride substituted cyclobutenes via a cycloaddition reaction. The regioselective click cycloaddition reaction is rapid, straightforward, and highly efficient, enabling the generation of highly functionalized 4‐membered ring (4MR) carbocycles. These carbocycles are valuable structural motifs found in numerous bioactive natural products and pharmaceutically relevant small molecules. Additionally, we showcase ersification of the novel cyclobutene cores through selective Cs 2 CO 3 ‐activated SuFEx click chemistry between a single S−F group and an aryl alcohol, yielding the corresponding sulfonate ester products with high efficiency. Finally, density functional theory calculations offer mechanistic insights about the reaction pathway.
Publisher: American Chemical Society (ACS)
Date: 18-06-2020
Publisher: American Chemical Society (ACS)
Date: 20-11-2019
DOI: 10.1021/ACS.ORGLETT.9B03737
Abstract: Substituted bullvalenes are dynamic shape-shifting molecules that exist within complex reaction networks. Herein, we report the synthesis of di- and trisubstituted bullvalenes and investigate their dynamic properties. Trisubstituted bullvalenes share a common major isomer which shows kinetic metastability. A survey of the thermodynamic and kinetic landscapes through computational analysis together with kinetic simulation provides a map of the internal dynamics of these systems.
Publisher: Wiley
Date: 27-02-2018
Publisher: AIP Publishing
Date: 19-04-2021
DOI: 10.1063/5.0045115
Abstract: Cyclodextrins have a erse range of applications, including as supramolecular hosts, as enzyme active-site analogs, in improving drug solubility and delivery, and in molecular selection. We have investigated their ability to form stable complexes with bullvalenes, unusual organic cage molecules that spontaneously interconvert between numerous degenerate isomers. The shape-shifting nature of substituted bullvalenes raises the potential for dynamic adaptive binding to biological targets. We tested whether β- and γ-cyclodextrins can capture particular bullvalene isomers and whether the preferred binding mode(s) differ between isomers. We first applied our computational host–guest interaction potential energy profiling to determine the best binding mode(s) of unsubstituted bullvalene and each isomer of methylenehydroxybullvalene to β- and γ-cyclodextrin. Subsequent molecular dynamics simulations of the predicted host–guest complexes showed that while unsubstituted bullvalene has a single, albeit ill-defined, binding mode with either cyclodextrin, each isomer of methylenehydroxybullvalene has two possible modes of binding to β-cyclodextrin but only a single, nebulous mode of binding to γ-cyclodextrin. Experimental determination of the binding free energy of each methylenehydroxybullvalene–cyclodextrin complex showed that methylenehydroxybullvalene is more likely to bind to β-cyclodextrin than to γ-cyclodextrin, despite its smaller cavity. Together, our results suggest that β-cyclodextrin, but not γ-cyclodextrin, shows promise for conformational capture of mono-substituted bullvalenes. More broadly, our computational pipeline should prove useful for rapid characterization of cyclodextrin host–guest complexes, avoiding the need for costly synthesis of guest molecules that are unlikely to bind stably, as well as providing detailed atomic-level insight into the nature of complexation.
Publisher: American Chemical Society (ACS)
Date: 24-09-2019
DOI: 10.1021/ACS.ORGLETT.9B03095
Abstract: A concise and ergent strategy for the synthesis of the naphterpin and marinone meroterpenoid families has been developed. The approach features a succession of pericyclic reactions-an aromatic Claisen rearrangement, a retro-6π-electrocyclization, and two Diels-Alder reactions-which facilitated the first total synthesis of naphterpin itself in five steps from 2,5-dimethoxyphenol, alongside similar syntheses of 7-demethylnaphterpin and debromomarinone. Late-stage oxidation and bromination reactions were also investigated, leading to the first total syntheses of naphterpins B and C and isomarinone.
Publisher: Wiley
Date: 14-01-2022
Abstract: A fluxional bis‐monodentate ligand, based on the archetypal shape‐shifting molecule bullvalene, self‐assembles with M 2+ (M=Pd 2+ or Pt 2+ ) to produce a highly complex ensemble of permanently fluxional coordination cages. Metal‐mediated self‐assembly selects for an M 2 L 4 architecture while maintaining shape‐shifting ligand complexity. A second level of simplification is achieved with guest‐exchange the binding of halides within the M 2 L 4 cage mixture results in a convergence to a cage species with all four ligands present as the “B isomer”. Within this confine, the reaction graph of the bullvalene is greatly restricted, but gives rise to a mixture of 38 possible diastereoisomers in rapid exchange. X‐ray crystallography reveals a preference for an achiral form consisting of both ligand enantiomers. Through a combination of NMR spectroscopy and DFT calculations, we elucidate the restricted isomerisation pathway of the permanently fluxional M 2 L 4 assembly.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-04-2023
Abstract: The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d -Ala- d -Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.
Publisher: American Chemical Society (ACS)
Date: 13-12-2022
DOI: 10.1021/ACS.ORGLETT.1C03984
Abstract: The fluxional structure of bullvalene is expanded by the discovery of a [5,5]-sigmatropic rearrangement of dialkenyl substituted derivatives. This gives rise to tetrahydro-1,8-ethenoheptalenes (THEH), representing the first ex les of this tricyclic scaffold. Variation of the substitution pattern alters the product distribution, including one thermodynamically balanced between THEH and bullvalene isomers. DFT calculations are used to explore the thermodynamic landscape and reaction mechanism revealing a pretransition state bifurcation leading to a concerted ambimodal rearrangement pathway.
Publisher: Wiley
Date: 31-01-2018
Abstract: Herein we detail a practical synthesis of bullvalene and a variety of mono- and disubstituted analogues through cobalt-catalysed [6+2] cycloaddition of cyclooctatetraene to alkynes, followed by photochemical di-π-methane rearrangement. The application of isomer-network analysis, coupled with quantum-chemical calculations, provides a powerful automated tool for predicting the properties of bullvalene isomer networks.
Publisher: American Chemical Society (ACS)
Date: 29-09-2015
DOI: 10.1021/JACS.5B07445
Abstract: The [n]radialenes are a unique family of fundamental [n]-membered carbocyclic structures with radiating alkenes, which have attracted significant synthetic and theoretical attention. Whereas [3]-, [4]-, and [6]radialenes have been prepared and studied, all efforts to synthesize the five-membered ring compound have thus far met with failure. Here we describe the first synthesis of the fundamental hydrocarbon [5]radialene, C10H10. Our approach was a departure from previous radialene syntheses in that it utilized a low-temperature decomplexation of a stable organometallic compound, rather than high-temperature elimination or rearrangement. Our strategy was guided by analysis of previous radialene syntheses, which indicated rapid decomposition in oxygen, and ab initio calculations, which revealed an extraordinary susceptibility of [5]radialene to undergo Diels-Alder dimerization olymerization. The origin of this susceptibility was traced to a small distortion energy associated with the formation of the transition structure geometry from the relaxed reactant monomers and to a narrow HOMO-LUMO gap.
Publisher: American Chemical Society (ACS)
Date: 29-11-2019
DOI: 10.26434/CHEMRXIV.10732838.V1
Abstract: Boronate ester bullvalenes are now accessible in two to four operationally simple steps. This unlocks late-stage ersification through Suzuki cross-coupling reactions to give mono-, di-, and tri-substituted bullvalenes. Moreover, a linchpin strategy enables pre-programmed installation of two different substituents. Analysis of solution phase isomer distributions and single crystal X-ray structures reveals that isomer preference in the crystal lattice is due to general shape selectivity.
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2SC20130E
Publisher: American Chemical Society (ACS)
Date: 11-02-2020
DOI: 10.1021/JACS.9B12930
Publisher: American Chemical Society (ACS)
Date: 06-10-2020
Publisher: American Chemical Society (ACS)
Date: 17-10-2017
DOI: 10.1021/ACS.ORGLETT.7B02665
Abstract: The use of tetrachloroethylene spiked with tetramethylsilane as a solvent for routine NMR analysis has been evaluated. Excellent quality spectra are reliably obtained, comparable to s les run in chloroform-d. Validation of this method is presented, together with the spectral data of commonly encountered trace impurities. In addition, NMR analysis for the concentration determination of organometallic reagents has been simplified using double-walled NMR tubes using a calibrated external reference solution within a hermetically sealed chamber.
Publisher: Wiley
Date: 26-08-2011
Abstract: [3]Dendralene and [4]dendralene are converted smoothly into tricarbonyliron complexes. The structures of four complexes analyzed by DFT and single-crystal X-ray analysis show that, in contrast to free hydrocarbons, complexed dendralenes prefer a roughly in-plane conformation. The complexes are stable towards Fe(CO)(3) group migration up to 150 °C. The synthetic value of Fe(CO)(3) complexation in the dendralene series is demonstrated through a variety of selective synthetic manipulations (Diels-Alder reaction, dipolar cycloaddition, Simmons-Smith cyclopropanation, dihydroxylation, olefin cross metathesis) that are not achievable by direct transformation of the free hydrocarbons. Application to the synthesis of a previously unreported, highly reactive linear/cross-conjugated hydrocarbon is also described.
Publisher: Springer Science and Business Media LLC
Date: 21-09-0008
Publisher: American Chemical Society (ACS)
Date: 16-04-2015
DOI: 10.1021/ACS.ORGLETT.5B00604
Abstract: Indolynes are converted into previously unprecedented indole building blocks by platinum(0)-catalyzed insertion into a symmetrically substituted boron-boron bond. The two boron sites in these indoles must be differentiated in a subsequent step, and the 6,7-bis[(pinacolato)boryl]indole was shown to undergo site-selective Suzuki-Miyaura cross-coupling with perfect C7 selectivity. The net reaction is the regioselective installation of two different substituents in the C6 and C7 positions of a 6,7-indolyne precursor.
Publisher: American Chemical Society (ACS)
Date: 04-11-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0SC04553E
Abstract: Cycloadditions of deuterium-labeled 1,3-butadiene with monosubstituted alkenic dienophiles challenge the widespread assumption of endo -selectivity in prototypical Diels–Alder reactions.
Publisher: Wiley
Date: 14-07-2022
Abstract: Structurally unique natural products pose biosynthetic puzzles whose solution can inspire new chemical reactions. Herein, we propose a unified biosynthetic pathway towards some complex meroterpenoids—the hyperireflexolides, biyoulactones, hybeanones and hypermonones. This hypothesis led to the discovery of uncatalyzed, intramolecular carbonyl‐ene reactions that are spontaneous at room temperature. We also developed an anionic cascade reaction featuring an α‐hydroxy‐β‐diketone rearrangement and an intramolecular aldol reaction to access four distinct natural product scaffolds from a common intermediate.
Publisher: Wiley
Date: 27-02-2018
Publisher: American Chemical Society (ACS)
Date: 17-03-2014
DOI: 10.1021/JO500458Y
Abstract: An examination of Diels-Alder reactions of furan-containing analogues of dendralenes has revealed complex and fascinating reaction sequences, which chart the inherent site and stereoselectivity of these processes and give rapid access to structures of high molecular complexity.
Publisher: Wiley
Date: 20-03-2015
Abstract: A new stereochemical probe for mechanisms at the silicon atom that is based on a deuterium-labeled silolane is synthesized and evaluated. The key synthetic step involves the hydrogenation of a 2,5-dihydrosilole with deuterium gas, giving a complex mixture of isochronic stereoisotopologues. The overall stereochemical imbalance of this mixture is evident in its (2) H NMR spectrum, which provides a good qualitative measure of changes in the configuration at the silicon atom. The technique is rapid, easy to use, and overcomes limitations and biases of traditional methods. The utility of this new procedure is demonstrated by tracking the stereochemical course of several classical reactions as well as contemporary catalytic transformations involving bond formation at the silicon atom.
Publisher: Wiley
Date: 14-01-2010
Publisher: Wiley
Date: 15-06-2023
Abstract: We present the synthesis of 1,1‐bis(fluorosulfonyl)‐2‐(pyridin‐1‐ium‐1‐yl)ethan‐1‐ide, a bench‐stable precursor to ethene‐1,1‐disulfonyl difluoride (EDSF). The novel SuFEx reagent, EDSF, is demonstrated in the preparation of 26 unique 1,1‐bissulfonylfluoride substituted cyclobutenes via a cycloaddition reaction. The regioselective click cycloaddition reaction is rapid, straightforward, and highly efficient, enabling the generation of highly functionalized 4‐membered ring (4MR) carbocycles. These carbocycles are valuable structural motifs found in numerous bioactive natural products and pharmaceutically relevant small molecules. Additionally, we showcase ersification of the novel cyclobutene cores through selective Cs 2 CO 3 ‐activated SuFEx click chemistry between a single S−F group and an aryl alcohol, yielding the corresponding sulfonate ester products with high efficiency. Finally, density functional theory calculations offer mechanistic insights about the reaction pathway.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0SC03073B
Abstract: A new strategy to the endiandric acid natural products is demonstrated by intercepting the 8π/6π/IMDA pericyclic cascade through a tactical anti- vicinal difunctionalisation of cyclooctatetraene.
Publisher: American Chemical Society (ACS)
Date: 10-07-2020
DOI: 10.1021/JACS.0C05286
Publisher: American Chemical Society (ACS)
Date: 16-03-2022
DOI: 10.1021/ACS.ORGLETT.2C00325
Abstract: Synthetic approaches to bicyclo[4.2.0]octadiene natural products frequently employ the synthesis of linear tetraenes to initiate a biosynthetic 8π/6π-electrocyclization cascade. This work forges a functionalized bicyclo[4.2.0]octadiene in two steps from cyclooctatetraene. The versatility of this method is demonstrated through natural product synthesis, including the first total synthesis of kingianic acid A and formal syntheses of kingianins A, D, and F and cryptobeilic acid D ethyl ester. The unexpected formation of an
Publisher: American Chemical Society (ACS)
Date: 16-06-2014
DOI: 10.1021/OM500485M
Publisher: American Chemical Society (ACS)
Date: 14-01-2016
DOI: 10.1021/JACS.5B11889
Abstract: The [n]dendralenes are a family of acyclic hydrocarbons which, by virtue of their ability to rapidly generate structural complexity, have attracted significant recent synthetic attention. [3]Dendralene through [8]dendralene have been previously prepared but no higher member of the family has been reported to date. Here, we describe the first chemical syntheses of the "higher" dendralenes, [9]dendralene through [12]dendralene. We also report a detailed investigation into the spectroscopic properties and chemical reactivity of the complete family of fundamental hydrocarbons, [3]dendralene to [12]dendralene. These studies reveal the first case of diminishing alternation in behavior in a series of related structures. We also report a comprehensive series of computational studies, which trace this d ening oscillatory effect in both spectroscopic measurements and chemical reactivity to conformational preferences.
Publisher: Wiley
Date: 31-01-2018
Start Date: 2021
End Date: 07-2023
Amount: $1,240,000.00
Funder: Australian Research Council
View Funded Activity