I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[26802]
Open Access
Abstract: Prediction of the outcome of ring opening of small organic rings under cationic conditions can be challenging due to the intermediacy of nonclassical carbocations. For example, the solvolysis of cyclobutyl or cyclopropylmethyl derivatives generates up to four products on nucleophilic capture or elimination via cyclopropylcarbinyl and bicyclobutonium ions. Here, we show that such reaction outcomes can be controlled by subtle changes to the structure of nonclassical carbocation. Using bicyclo[1.1.0]butanes as cation precursors, the regio- and stereochemistry of ring opening is shown to depend on the degree and nature of the substituents on the cationic intermediates. Reaction outcomes are rationalized using computational models, resulting in a flowchart to predict product formation from a given cation precursor.
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Jan 2024
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[26802]
Open Access
Abstract: Despite their hydrophobic surfaces with localized π-holes and rigid well-defined architectures providing a scaffold for preorganizing binding motifs, fullerenes remain unexplored as potential supramolecular host platforms for the recognition of anions. Herein, we present the first example of the rational design, synthesis, and unique recognition properties of novel fullerene-functionalized halogen-bonding (XB) heteroditopic ion-pair receptors containing cation and anion binding domains spatially separated by C60. Fullerene spatial separation of the XB donors and the crown ether complexed potassium cation resulted in a rare example of an artificial receptor containing two anion binding sites with opposing preferences for hard and soft halides. Importantly, the incorporation of the C60 motif into the heteroditopic receptor structure has a significant effect on the halide binding selectivity, which is further amplified upon K+ cation binding. The potassium cation complexed fullerene-based receptors exhibit enhanced selectivity for the soft polarizable iodide ion which is assisted by the C60 scaffold preorganizing the potent XB-based binding domains, anion−π interactions, and the exceptional polarizability of the fullerene moiety, as evidenced from DFT calculations. These observations serve to highlight the unique properties of fullerene surfaces for proximal charged guest binding with potential applications in construction of selective molecular sensors and modulating the properties of solar cell devices.
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Dec 2023
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I03-Macromolecular Crystallography
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Diamond Proposal Number(s):
[23459]
Open Access
Abstract: Epoxides are an established class of electrophilic alkylating agents that react with nucleophilic protein residues. We report αβ,α′β′-diepoxyketones (DEKs) as a new type of mechanism-based inhibitors of nucleophilic cysteine enzymes. Studies with the L,D-transpeptidase LdtMt2 from Mycobacterium tuberculosis and the main protease from SARS-CoV-2 (Mpro) reveal that following epoxide ring opening by a nucleophilic cysteine, further reactions can occur, leading to irreversible alkylation.
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Oct 2023
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I03-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Lennart
Brewitz
,
Yu
Nakashima
,
Sonia K.
Piasecka
,
Eidarus
Salah
,
Sally C.
Fletcher
,
Anthony
Tumber
,
Thomas P.
Corner
,
Tristan J.
Kennedy
,
Giorgia
Fiorini
,
Armin
Thalhammer
,
Kirsten E.
Christensen
,
Mathew L.
Coleman
,
Christopher J.
Schofield
Diamond Proposal Number(s):
[23459]
Open Access
Abstract: Jumonji-C domain-containing protein 5 (JMJD5) is a 2-oxoglutarate (2OG)-dependent oxygenase that plays important roles in development, circadian rhythm, and cancer through unclear mechanisms. JMJD5 has been reported to have activity as a histone protease, as an Nε-methyl lysine demethylase, and as an arginine residue hydroxylase. Small-molecule JMJD5-selective inhibitors will be useful for investigating its (patho)physiological roles. Following the observation that the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylic acid (2,4-PDCA) is a 2OG-competing JMJD5 inhibitor, we report that 5-aminoalkyl-substituted 2,4-PDCA derivatives are potent JMJD5 inhibitors manifesting selectivity for JMJD5 over other human 2OG oxygenases. Crystallographic analyses with five inhibitors imply induced fit binding and reveal that the 2,4-PDCA C5 substituent orients into the JMJD5 substrate-binding pocket. Cellular studies indicate that the lead compounds display similar phenotypes as reported for clinically observed JMJD5 variants, which have a reduced catalytic activity compared to wild-type JMJD5.
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Aug 2023
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[20876]
Open Access
Abstract: Cyclic porphyrin oligomers have been studied as models for photosynthetic light-harvesting antenna complexes and as potential receptors for supramolecular chemistry. Here, we report the synthesis of unprecedented β,β-directly linked cyclic zinc porphyrin oligomers, the trimer (CP3) and tetramer (CP4), by Yamamoto coupling of a 2,3-dibromoporphyrin precursor. Their three-dimensional structures were confirmed by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray diffraction analyses. The minimum-energy geometries of CP3 and CP4 have propeller and saddle shapes, respectively, as calculated using density functional theory. Their different geometries result in distinct photophysical and electrochemical properties. The smaller dihedral angles between the porphyrin units in CP3, compared with CP4, result in stronger π-conjugation, splitting the ultraviolet–vis absorption bands and shifting them to longer wavelengths. Analysis of the crystallographic bond lengths indicates that the central benzene ring of the CP3 is partially aromatic [harmonic oscillator model of aromaticity (HOMA) 0.52], whereas the central cyclooctatetraene ring of the CP4 is non-aromatic (HOMA –0.02). The saddle-shaped structure of CP4 makes it a ditopic receptor for fullerenes, with affinity constants of (1.1 ± 0.4) × 105 M–1 for C70 and (2.2 ± 0.1) × 104 M–1 for C60, respectively, in toluene solution at 298 K. The formation of a 1:2 complex with C60 is confirmed by NMR titration and single-crystal X-ray diffraction.
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May 2023
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[20876]
Open Access
Abstract: We report that phthalimides may be cyclized using a Mukaiyama-type aldol coupling to give variously substituted fused lactam (1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one) systems. This novel process shows a high level of regioselectivity for o-substituted phthalimides, dictated by steric and electronic factors, but not for m-substituted phthalimides. The initial aldol adduct is prone to elimination, giving 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones, and the initial cyclisation can be conducted in such a way that aldol cyclisation-elimination is achievable in a one-pot approach. The 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones possess cross conjugation and steric effects which significantly influence the reactivity of several functional groups, but conditions suitable for epoxidation, ester hydrolysis and amide formation, and reduction, which provide for ring manipulation, were identified. Many of the derived lactam systems, and especially the eliminated systems, show low solubility, which compromises biological activity, although in some cases, antibacterial and cytotoxic activity was found, and this new class of small molecule provides a useful skeleton for further elaboration and study.
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Dec 2022
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Ysobel R.
Baker
,
Cameron
Thorpe
,
Jinfeng
Chen
,
Laura M.
Poller
,
Lina
Cox
,
Pawan
Kumar
,
Wooi F.
Lim
,
Lillian
Lie
,
Graham
Mcclorey
,
Sven
Epple
,
Daniel
Singleton
,
Michael A.
Mcdonough
,
Jack S.
Hardwick
,
Kirsten E.
Christensen
,
Matthew J. A.
Wood
,
James P.
Hall
,
Afaf H.
El-Sagheer
,
Tom
Brown
Diamond Proposal Number(s):
[18069, 23459]
Open Access
Abstract: Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3′-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.
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Jul 2022
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[26802]
Open Access
Abstract: Herein we disclose a mild protocol for the reductive functionalisation of quinolinium and isoquinolinium salts. The reaction proceeds under transition-metal-free conditions as well as under rhodium catalysis with very low catalyst loadings (0.01 mol %) and uses inexpensive formic acid as the terminal reductant. A wide range of electrophiles, including enones, imides, unsaturated esters and sulfones, β-nitro styrenes and aldehydes are intercepted by the in situ formed enamine species forming a large variety of substituted tetrahydro(iso)quinolines. Electrophiles are incorporated at the C-3 and C-4 position for quinolines and isoquinolines respectively, providing access to substitution patterns which are not favoured in electrophilic or nucleophilic aromatic substitution. Finally, this reactivity was exploited to facilitate three types of annulation reactions, giving rise to complex polycyclic products of a formal [3+3] or [4+2] cycloaddition.
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May 2022
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I19-Small Molecule Single Crystal Diffraction
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Wenjun
Xu
,
Edmund
Leary
,
Sara
Sangtarash
,
Michael
Jirasek
,
M. Teresa
González
,
Kirsten E.
Christensen
,
Lydia
Abellán Vicente
,
Nicolás
Agraït
,
Simon J.
Higgins
,
Richard J.
Nichols
,
Colin J.
Lambert
,
Harry L.
Anderson
Diamond Proposal Number(s):
[20876]
Abstract: Molecules capable of mediating charge transport over several nanometers with minimal decay in conductance have fundamental and technological implications. Polymethine cyanine dyes are fascinating molecular wires because up to a critical length, they have no bond-length alternation (BLA) and their electronic structure resembles a one-dimensional free-electron gas. Beyond this threshold, they undergo a symmetry-breaking Peierls transition, which increases the HOMO–LUMO gap. We have investigated cationic cyanines with central polymethine chains of 5–13 carbon atoms (Cy3+–Cy11+). The absorption spectra and crystal structures show that symmetry breaking is sensitive to the polarity of the medium and the size of the counterion. X-ray crystallography reveals that Cy9·PF6 and Cy11·B(C6F5)4 are Peierls distorted, with high BLA at one end of the π-system, away from the partially delocalized positive charge. This pattern of BLA distribution resembles that of solitons in polyacetylene. The single-molecule conductance is essentially independent of molecular length for the polymethine salts of Cy3+–Cy11+ with the large B(C6F5)4– counterion, but with the PF6– counterion, the conductance decreases for the longer molecules, Cy7+–Cy11+, because this smaller anion polarizes the π-system, inducing a symmetry-breaking transition. At higher bias (0.9 V), the conductance of the shorter chains, Cy3+–Cy7+, increases with length (negative attenuation factor, β = −1.6 nm–1), but the conductance still drops in Cy9+ and Cy11+ with the small polarizing PF6– counteranion.
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Nov 2021
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[20876]
Abstract: Bulky photo-labile masked alkyne equivalents (MAEs) are needed for the synthesis of polyyne polyrotaxanes, as insulated molecular wires and as stabilized forms of the linear polymeric allotrope of carbon, carbyne. We have synthesized a novel MAE based on phenanthrene and compared it with an indane-based MAE. Photochemical unmasking of model compounds was studied at different wavelengths (250 nm and 350 nm), and key products were identified by NMR spectroscopy and X-ray crystallography. UV irradiation at 250 nm leads to unmasking of both MAEs. Irradiation of the phenanthrene system at 350 nm results in quantitative dimerization via [2+2] cycloaddition to form a [3]-ladderane; irradiation of this ladderane at 250 nm generates a dihydrotriphenylene, which can be oxidized easily to a triphenylene. Irradiation of the indane-based MAE at 350 nm in the presence of traces of oxygen forms an endoperoxide and a bisepoxide. Both MAEs have been incorporated into rotaxanes via copper-mediated active metal template Glaser or Cadiot-Chodkiewicz coupling. The identity of the rotaxanes was confirmed by NMR spectroscopy and mass spectrometry. The phenanthrene rotaxane decomposes during attempted photochemical unmasking, whereas photolysis of the indane rotaxane results in unmasking of the polyyne thread to form a rotaxane with a chain of 16 sp-hybridized carbon atoms. This approach opens avenues towards the synthesis of encapsulated carbon allotropes.
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Jun 2020
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