Thorium–ligand multiple bonds via reductive deprotection of a trityl group

Reaction of [Th(I)(NR₂)₃] (R = SiMe₃) (2) with KECPh₃ (E = O, S) affords the thorium chalcogenates, [Th(ECPh₃)(NR₂)₃] (3, E = O; 4, E = S), in moderate yields. Reductive deprotection of the trityl group from 3 and 4 by reaction with KC₈, in the presence of 18-crown-6, affords the thorium oxo complex, [K(18-crown-6)][Th(O)(NR₂)₃] (6), and the thorium sulphide complex, [K(18-crown-6)][Th(S)(NR₂)₃] (7), respectively. The natural bond orbital and quantum theory of atoms-in-molecules approaches are employed to explore the metal–ligand bonding in 6 and 7 and their uranium analogues, and in particular the relative roles of the actinide 5f and 6d orbitals.     

A dual catalytic strategy for carbon–phosphorus cross-coupling via gold and photoredox catalysis

A new method for the P-arylation of aryldiazonium salts with H-phosphonates via dual gold and photoredox catalysis is described. The reaction proceeds smoothly at room temperature in the absence of base and/or additives, and offers an efficient approach to arylphosphonates. The reaction is proposed to proceed through a photoredox-promoted generation of an electrophilic arylgold(iii) intermediate that undergoes coupling with the H-phosphonate nucleophile.     

Can acyclic conformational control be achieved via a sulfur–fluorine gauche effect?

The gauche conformation of the 1,2-difluoroethane motif is known to involve stabilising hyperconjugative interactions between donor (bonding, σ_C–H) and acceptor (antibonding, σ*C–F) orbitals. This model rationalises the generic conformational preference of F–C_β–C_α–X systems (φ_FCCX ≈ 60°), where X is an electron deficient substituent containing a Period 2 atom. Little is known about the corresponding Period 3 systems, such as sulfur and phosphorus, where multiple oxidation states are possible. Conformational analyses of β-fluorosulfides, -sulfoxides and -sulfones are disclosed here, thus extending the scope of the fluorine gauche effect to the 3rd Period (F–C–C–S(O)_n; φ_FCCS ≈ 60°). Synergy between experiment and computation has revealed that the gauche effect is only pronounced in structures bearing an electropositive vicinal sulfur atom (S⁺–O^–, SO₂).     

Highly bent crystals formed by restrained π-stacked columns connected via alkylene linkers with variable conformations

A reproducible formation of strongly bent crystals was accomplished by structurally restraining macrocyclic π-conjugated molecules. The model π-units consist of two 9,10-bis(2-thienylethynyl)anthracenes with a strong propensity for stacking, which are connected in a macrocyclic fashion via two alkylene linkers. The correlation between the crystalline morphology and the macrocyclic structures restrained by a variety of flexible alkylene linker combinations was systematically studied. Bent crystals were obtained only with specific alkylene linkers of appropriate chain length. The alkylene linkers can adopt different conformations in the crystal packing, so as to fill voids within the macrocycle. The ability to form several similar molecular structures with different alkylene conformations gives rise to contaminations of different crystalline phases within a single crystal, and it is these phase contaminations which are responsible for the bending of the crystals.     

Synthesis of a novel polycyclic ring scaffold with antimitotic properties via a selective domino Heck–Suzuki reaction

The synthesis of a previously undescribed sp³-rich 6-5-5-6 tetracyclic ring scaffold using a palladium catalysed domino Heck–Suzuki reaction is reported. This reaction is high-yielding, selective for the domino process over the direct Suzuki reaction and tolerant towards a variety of boronic acids. The novel scaffold can also be accessed via domino Heck–Stille and radical cyclisations. Compounds based around this scaffold were found to be effective antimitotic agents in a human cancer cell line. Detailed phenotypic profiling showed that the compounds affected the congression of chromosomes to give mitotic arrest and apoptotic cell death. Thus, a novel structural class of antimitotic agents that does not disrupt the tubulin network has been identified.     

Detection of 5-methylcytosine and 5-hydroxymethylcytosine in DNA via host–guest interactions inside α-hemolysin nanopores

Cytosine methylation and hydroxymethylation are both important epigenetic modifications of DNA in mammalian cells. Therefore, profiling DNA (hydroxy)methylation across the genome is vital for understanding their roles in gene regulation. Here, we report a nanopore-based approach for quick and reliable detection of 5-methylcytosine and 5-hydroxymethylcytosine in DNA at the single-molecule level. The single-stranded DNA containing 5-methylcytosine or 5-hydroxymethylcytosine was first selectively modified on the epigenetic base to attach a host–guest complex. Threading of the modified DNA molecules through α-hemolysin nanopores causes unbinding of the host–guest complex and generates highly characteristic current signatures. Statistical analysis of the signature events affords quantitative information about 5-methylcytosine and 5-hydroxymethylcytosine in DNA. Our results suggest that other DNA modifications could also be detected with the developed method. Furthermore, we anticipate our nanopore sensing strategy to be generally useful in biochemical analysis and to find applications in the early diagnosis of diseases.     

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C₆H₄–COO^–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C₅H₅)₂Ti{OC(O)-4-C₆H₄-P(Ph₂)AuCl}₂] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.     

Unveiling the nature of supramolecular crown ether–C60 interactions

A series of exTTF-(crown ether)₂ receptors, designed to host C₆₀, has been prepared. The size of the crown ether and the nature of the heteroatoms have been systematically changed to fine tune the association constants. Electrochemical measurements and transient absorption spectroscopy assisted in corroborating charge transfer in the ground state and in the excited state, leading to the formation of radical ion pairs featuring lifetimes in the range from 12 to 21 ps. To rationalize the nature of the exTTF-(crown ether)₂·C₆₀ stabilizing interactions, theoretical calculations have been carried out, suggesting a synergetic interplay of donor–acceptor, π–π, n–π and CH···π interactions, which is the basis for the affinity of our novel receptors towards C₆₀.     

Stereoselective radical C–H alkylation with acceptor/acceptor-substituted diazo reagents via Co(ii)-based metalloradical catalysis

Co(ii)-based metalloradical catalysis has, for the first time, been successfully applied for asymmetric intramolecular C–H alkylation of acceptor/acceptor-substituted diazo reagents. Through the design and synthesis of a new D ₂-symmetric chiral amidoporphyrin as the supporting ligand, the Co(ii)-based metalloradical system, which operates at room temperature, is capable of 1,5-C–H alkylation of α-methoxycarbonyl-α-diazosulfones with a broad range of electronic properties, providing the 5-membered sulfolane derivatives in high yields with excellent diastereoselectivities and enantioselectivities. In addition to complete chemoselectivity toward allylic and allenic C–H bonds, the Co(ii)-based metalloradical catalysis for asymmetric C–H alkylation features a remarkable degree of functional group tolerance.     

A carbon–carbon hybrid – immobilizing carbon nanodots onto carbon nanotubes

The thrust of this work is to integrate small and uniformly sized carbon nanodots (CNDs) with single-walled carbon nanotubes (SWCNT) of different diameters as electron donors and electron acceptors, respectively, and to test their synergetic interactions in terms of optoelectronic devices. CNDs (denoted pCNDs, where p indicates pressure) were prepared by pressure-controlled microwave decomposition of citric acid and urea. pCNDs were immobilized on single-walled carbon nanotubes by wrapping the latter with poly(4-vinylbenzyl trimethylamine) (PVBTA), which features positively charged ammonium groups in the backbone. Negatively charged surface groups on the CNDs lead to attractive electrostatic interactions. Ground state interactions between the CNDs and SWCNTs were confirmed by a full-fledged photophysical investigation based on steady-state and time-resolved techniques. As a complement, charge injection into the SWCNTs upon photoexcitation was investigated by ultra-short time-resolved spectroscopy.     

Tylosin polyketide synthase module 3: stereospecificity,stereoselectivity and steady-state kinetic analysis of β-processing domains via diffusible,synthetic substrates

Polyketide synthase (PKS) β-processing domains are responsible for much of the stereochemical complexity of polyketide natural products. Although the importance of β-processing domains has been well noted and significantly explored, key stereochemical details pertaining to cryptic stereochemistry and the impact of remote stereogenic centers have yet to be fully discerned. To uncover the inner workings of ketoreductases (KR) and dehydratases (DH) from the tylosin pathway a didomain composed of TylDH3-KR3 was recombinantly expressed and interrogated with full-length tetraketide substrates to probe the impact of vicinal and distal stereochemistry. In vitro product isolation analysis revealed the products of the cryptic KR as d-alcohols and of the DH as trans-olefins. Steady-state kinetic analysis of the dehydration reaction demonstrated a strict stereochemical tolerance at the β-position as d-configured substrates were processed more than 100 times more efficiently than l-alcohols. Unexpectedly, the k _cat/K _M values were diminished 14- to 45-fold upon inversion of remote ε- and ζ-stereocenters. This stereochemical discrimination is predicted to be driven by a combination of allylic A^1,3 strain that likely disfavors binding of the ε-epimer and a loss of electrostatic interactions with the ζ-epimer. Our results strongly suggest that dehydratases may play a role in refining the stereochemical outcomes of preceding modules through their substrate stereospecificity, honing the configurational purity of the final PKS product.     

Mutual stabilisation between MII 4L6 tetrahedra and MIIX4 2– metallate guests

A complex host–guest equilibrium employing metal ions incorporated into both the host and guest is discussed. M^IIX₄ ^2– metallate guests are shown to provide a good size and shape match for encapsulation within the M₄L₆ tetrahedral capsules, facilitating the generation of previously unreported Zn₄L₆ complexes. Displacement of the initial, primary template anion (ZnBr₄ ^2–) by a secondary template anion (ClO₄ ^–) is shown to result in the formation of a pentagonal-prismatic Zn₁₀L₁₅ structure that incorporates both Br^– and ClO₄ ^–. Furthermore, the formation of heterometallic complexes provides direct evidence for metal exchange between the guest and host complex.     

Fe(iv) alkylidenes via protonation of Fe(ii) vinyl chelates and a comparative M?ssbauer spectroscopic study

Treatment of cis-Me₂Fe(PMe₃)₄ with di-1,2-(E-2-(pyridin-2-yl)vinyl)benzene ((bdvp)H₂), a tetradentate ligand precursor, afforded (bdvp)Fe(PMe₃)₂ (1-PMe₃) and 2 equiv. CH₄, via C–H bond activation. Similar treatments with tridentate ligand precursors PhCHNCH₂(E-CHCHPh) ((pipp)H₂) and PhCHN(2-CCMe-Ph) ((pipa)H) under dinitrogen provided trans-(pipp)Fe(PMe₃)₂N₂ (2) and trans-(pipvd)Fe(PMe₃)₂N₂ (3), respectively; the latter via one C–H bond activation, and a subsequent insertion of the alkyne into the remaining Fe–Me bond. All three Fe(ii) vinyl species were protonated with H[BAr^F ₄] to form the corresponding Fe(iv) alkylidene cations, [(bavp)Fe(PMe₃)₂][BAr^F ₄] (4-PMe₃), [(piap)Fe(PMe₃)₃][BAr^F ₄] (5), and [(pipad)Fe(PMe₃)₃][BAr^F ₄] (6). Mössbauer spectroscopic measurements on the formally Fe(ii) and Fe(iv) derivatives revealed isomer shifts within 0.1 mm s^–1, reflecting the similarity in their bond distances.     

In vitro reconstitution of α-pyrone ring formation in myxopyronin biosynthesis

Myxopyronins are α-pyrone antibiotics produced by the terrestrial bacterium Myxococcus fulvus Mx f50 and possess antibacterial activity against Gram-positive and Gram-negative pathogens. They target the bacterial RNA polymerase (RNAP) “switch region” as non-competitive inhibitors and display no cross-resistance to the established RNAP inhibitor rifampicin. Recent analysis of the myxopyronin biosynthetic pathway led to the hypothesis that this secondary metabolite is produced from two separate polyketide parts, which are condensed by the stand-alone ketosynthase MxnB. Using in vitro assays we show that MxnB catalyzes a unique condensation reaction forming the α-pyrone ring of myxopyronins from two activated acyl chains in form of their β-keto intermediates. MxnB is able to accept thioester substrates coupled to either N-acetylcysteamine (NAC) or a specific carrier protein (CP). The turnover rate of MxnB for substrates bound to CP was 12-fold higher than for NAC substrates, demonstrating the importance of protein–protein interactions in polyketide synthase (PKS) systems. The crystal structure of MxnB reveals the enzyme to be an unusual member of the ketosynthase group capable of binding and condensing two long alkyl chains bound to carrier proteins. The geometry of the two binding tunnels supports the biochemical data and allows us to propose an order of reaction, which is supported by the identification of novel myxopyronin congeners in the extract of the producer strain. Insights into the mechanism of this unique condensation reaction do not only expand our knowledge regarding the thiolase enzyme family but also opens up opportunities for PKS bioengineering to achieve directed structural modifications.     

Core–shell structured phosphorescent nanoparticles for detection of exogenous and endogenous hypochlorite in live cells via ratiometric imaging and photoluminescence lifetime imaging microscopy

We report a ratiometric phosphorescence sensory system for hypochlorite (ClO^–) based on core–shell structured silica nanoparticles. Two phosphorescent iridium(iii) complexes were immobilised in the inner solid core and outer mesoporous layer of the nanoparticles, respectively. The former is insensitive to ClO^– and thus serves as an internal standard to increase the accuracy and precision, while the latter exhibits a specific and significant luminogenic response to ClO^–, providing high selectivity and sensitivity. Upon exposure to ClO^–, the nanoparticles display a sharp luminescence colour change from blue to red. Additionally, intracellular detection of exogenous and endogenous ClO^– has been demonstrated via ratiometric imaging and photoluminescence lifetime imaging microscopy. Compared to intensity-based sensing, ratiometric and lifetime-based measurements are independent of the probe concentration and are thus less affected by external influences, especially in intracellular applications.     

Copper-catalyzed intermolecular C(sp3)–H bond functionalization towards the synthesis of tertiary carbamates

We describe the development of an intermolecular unactivated C(sp³)–H bond functionalization towards the direct synthesis of tertiary carbamates. The transformation proceeded using a readily available, abundant first-row transition metal catalyst (copper), and isocyanates as the source of the amide moiety. This is a novel strategy for direct transformation of a variety of unactivated hydrocarbon feedstocks to N-alkyl-N-aryl and N,N-dialkyl carbamates without pre-functionalization or installation of a directing group. The reaction had a broad substrate scope with 3° > 2° > 1° site selectivity. The reaction proceeded even on a gram scale, and a corresponding free amine was directly obtained when the reaction was performed at high temperature. Kinetic studies suggested that radical-mediated C(sp³)–H bond cleavage was the rate-determining step.     

Rh-catalyzed desymmetrization of α-quaternary centers by isomerization-hydroacylation

We describe a Rh-catalyzed desymmetrization of all-carbon quaternary centers from α,α-bis(allyl)aldehydes by a cascade featuring isomerization and hydroacylation. This desymmetrization competes with two other novel olefin functionalizations that are triggered by C–H bond activation, including carboacylation and bisacylation. A BIPHEP ligand promotes enantioselective formation of α-vinylcyclopentanones. Mechanistic studies support irreversible and enantioselective olefin-isomerization followed by olefin-hydroacylation.     

Non-equilibrium cobalt(iii) “click” capsules

Cobalt(iii) tetrahedral capsules have been prepared using an assembly-followed-by-oxidation protocol from a cobalt(ii) precursor and a readily derivatizable pyridyl-triazole ligand system. Experiments designed to probe the constitutional dynamics show that these architectures are in a non-equilibrium state. A preliminary investigation into the host–guest chemistry of a water-soluble derivative shows it can bind and differentiate a range of different neutral organic molecules. The stability of this ensemble also permits the study of guest-binding at high salt concentrations.     

Preparation of LiCoPO<Subscript>4</Subscript> powders and films via sol–gel

Lithium intercalation materials are of special interest as cathodes in rechargeable batteries. An uncomplicated sol–gel process has been used for the synthesis of Li–Co phosphates powders and, for the first time, of LiCoPO₄ films. The powders were prepared from aqueous solutions, containing Li, Co and phosphate precursors to which acid citric and ethylene glycol was added, during the drying process at 75 °C. The X-ray diffraction patterns of the prepared powders confirmed the presence of LiCoPO₄ with an olivine-like structure as main phase. The morphological investigations of the powder showed a platelet-like structure with an average grain size of 0.75 μm. The films of LiCoPO₄ were deposited onto ITO glass substrates with the combination of the dip-coating process under the same conditions. Finally, the films were annealed in inert atmosphere at 300 °C. The morphological investigations reveal a smooth and homogeneous surface of the prepared Li–Co phosphate films. The preliminary electrical investigation on the prepared LiCoPO₄ films showed lithium ions electrochemical activity in the range 3.0–4.5 V.