Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin: Creation of an unnatural analogue with improved anticancer properties.

A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin (1) and variecolactone (2) was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues (5-7). Analysis of the compounds' anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities, 5 was associated with significantly reduced toxic side effects in cancer-bearing mice, indicating its potentially broader therapeutic window. Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.

Tellurolate: an effective Te-atom transfer reagent to prepare the triad of group 5 metal bis(tellurides).

We show in this work how lithium tellurolate Li(X)nTeCH2SiMe3 (X = THF, n = 1, 1; X = 12-crown-4, n = 2, 2), can serve as an effective Te-atom transfer reagent to all group 5 transition metal halide precursors irrespective of the oxidation state. Mononuclear and bis(telluride) complexes, namely (PNP)M(Te)2 (M = V; Nb, 3; Ta, 4; PNP- = N[2-PiPr2-4-methylphenyl]2), are reported herein including structural and spectroscopic data. Whereas the known complex (PNP)V(Te)2 can be readily prepared from the trivalent precursor (PNP)VCl2, two equiv. of tellurolate, and elemental Te partially solubilized with PMe3, complex 3 can also be similarly obtained following the same procedure but with or without a reductant, Na/NaCl. Complex 4 on the other hand is formed from the addition of four equiv. of tellurolate to (PNP)TaF4. Having access to a triad of (PNP)M(Te)2 systems for group 5 metals has allowed us to compare them using a combination of theory and spectroscopy including Te-L1 edge XANES data.

Accelerating σ-Bond Metathesis at Sn(II) Centers.

Molecular main-group hydride catalysts are attractive as cheap and Earth-abundant alternatives to transition-metal analogues. In the case of the latter, specific steric and electronic tuning of the metal center through ligand choice has enabled the iterative and rational development of superior catalysts. Analogously, a deeper understanding of electronic structure-activity relationships for molecular main-group hydrides should facilitate the development of superior main-group hydride catalysts. Herein, we report a modular Sn-Ni bimetallic system in which we systematically vary the ancillary ligand on Ni, which, in turn, tunes the Sn center. This tuning is probed using Sn L1 XAS as a measure of electron density at the Sn center. We demonstrate that increased electron density at Sn centers accelerates the rate of σ-bond metathesis, and we employ this understanding to develop a highly active Sn-based catalyst for the hydroboration of CO2 using pinacolborane. Additionally, we demonstrate that engineering London dispersion interactions within the secondary coordination sphere of Sn allows for further rate acceleration. These results show that the electronics of main-group catalysts can be controlled without the competing effects of geometry perturbations and that this manifests in substantial reactivity differences.

Mechanistic insights into hormesis induced by erythromycin in the marine alga Thalassiosira weissflogii.

Erythromycin (ERY) is a typical macrolide antibiotic with large production and extensive use on a global scale. Detection of ERY in both freshwaters and coaster seawaters, as well as relatively high ecotoxicity of ERY have been documented. Notably, hormesis has been reported on several freshwater algae under ERY stress, where growth was promoted at relatively lower exposures but inhibited at higher treatment levels. On the contrary, there is limited information of ERY toxicity in marine algae, hampering the risk assessment on ERY in the coaster waters. The presence of hormesis may challenge the current concept of dose-response adopted in chemical risk assessment. Whether and how exposure to ERY can induce dose-dependent toxicity in marine algae remain virtually unknown, especially at environmentally relevant concentrations. The present study used a model marine diatom Thalassiosira weissflogii (T. weissflogii) to reveal its toxicological responses to ERY at different biological levels and decipher the underlying mechanisms. Assessment of multiple apical endpoints shows an evident growth promotion following ERY exposure at an environmentally relevant concentration (1 µg/L), associated with increased contents reactive oxygen species (ROS) and chlorophyll-a (Chl-a), activated signaling pathways related to ribosome biosynthesis and translation, and production of total soluble protein. By contrast, growth inhibition in the 750 and 2500 µg/L treatments was attributed to reduced viability, increased ROS formation, reduced content of total soluble protein, inhibited photosynthesis, and perturbed signaling pathways involved in xenobiotic metabolism, ribosome, metabolism of amino acid, and nitrogen metabolism. Measurements of multiple apical endpoints coupled with de novo transcriptomics analysis applied in the present study, a systems biology approach, can generate detailed mechanistic information of chemical toxicity including dose-response and species sensitivity difference used in environmental risk assessment.

Multigenerational impacts of EE2 on reproductive fitness and immune competence of marine medaka.

Estrogenic endocrine disrupting chemicals (EEDC) have been suspected to impact offspring in a transgenerational manner via modifications of the germline epigenome in the directly exposed generations. A holistic assessment of the concentration/ exposure duration-response, threshold level, and critical exposure windows (parental gametogenesis and embryogenesis) for the transgenerational evaluation of reproduction and immune compromise concomitantly will inform the overall EEDC exposure risk. We conducted a multigenerational study using the environmental estrogen, 17α-ethinylestradiol (EE2), and the marine laboratory model fish Oryzias melastigma (adult, F0) and their offspring (F1-F4) to identify transgenerationally altered offspring generations and phenotype persistence. Three exposure scenarios were used: short parental exposure, long parental exposure, and a combined parental and embryonic exposure using two concentrations of EE2 (33ng/L, 113ng/L). The reproductive fitness of fish was evaluated by assessing fecundity, fertilization rate, hatching success, and sex ratio. Immune competence was assessed in adults via a host-resistance assay. EE2 exposure during both parental gametogenesis and embryogenesis was found to induce concentration/ exposure duration-dependent transgenerational reproductive effects in the unexposed F4 offspring. Furthermore, embryonic exposure to 113 ng/L EE2 induced feminization of the directly exposed F1 generation, followed by subsequent masculinization of the F2 and F3 generations. A sex difference was found in the transgenerationally impaired reproductive output with F4 females being sensitive to the lowest concentration of EE2 (33 ng/L) upon long-term ancestral parent exposure (21 days). Conversely, F4 males were affected by ancestral embryonic EE2 exposure. No definitive transgenerational impacts on immune competence were identified in male or female offspring. In combination, these results indicate that EEDCs can be transgenerational toxicants that may negatively impact the reproductive success and population sustainability of fish populations.

Direct Reduction of NO to N2O by a Mononuclear Nonheme Thiolate Ligated Iron(II) Complex via Formation of a Metastable {FeNO}7 Complex.

Addition of NO to a nonheme dithiolate-ligated iron(II) complex, FeII(Me3TACN)(S2SiMe2) (1), results in the generation of N2O. Low-temperature spectroscopic studies reveal a metastable six-coordinate {FeNO}7 intermediate (S = 3/2) that was trapped at -135 °C and was characterized by low-temperature UV-vis, resonance Raman, EPR, Mössbauer, XAS, and DFT studies. Thermal decay of the {FeNO}7 species leads to the evolution of N2O, providing a rare example of a mononuclear thiolate-ligated {FeNO}7 that mediates NO reduction to N2O without the requirement of any exogenous electron or proton sources.

Stereoselective insertion of cyclopropenes into Mg-Mg bonds.

The reaction of cyclopropenes with compounds containing Mg-Mg bonds is reported. 1,2-Dimagnesiation occurs exclusively by syn-addition to the least hindered face of the alkene forming a single diastereomeric product. DFT calculations support a concerted and stereoselective mechanism. These findings shed new light on the stereochemistry of reactions involving magnesium reagents.

Heterobimetallic µ2-halocarbyne complexes.

The halocarbyne complexes [M(CX)(CO)2(Tp*)] (M = Mo, W; X = Cl, Br; Tp* = hydrotris(dimethylpyrazolyl)borate) react with [AuCl(SMe2)], [Pt(η2-H2CCH2)(PPh3)2] or [Pt(η2-nbe)3] (nbe = norbornene) to furnish rare examples of µ2-halocarbyne complexes [MAu(µ2-CX)Cl(CO)2(Tp*)], [MPt(µ2-CCl)(CO)2(PPh3)2(Tp*)] and [W2Pt(µ2-CCl)2(CO)4(Tp*)2]. The complex [WPt(µ2-CCl)(CO)2(PPh3)2(Tp*)] spontaneously rearranges to the µ2-carbido complex [WPt(µ2-C)Cl(CO)2(PPh3)2(Tp*)] during silica-gel chromatography. One phosphine ligand of [WPt(µ2-CCl)(CO)2(PPh3)2(Tp*)] is readily substituted by CO to afford [WPt(µ2-CCl)(CO)3(PPh3)(Tp*)]. These µ2-halocarbyne complexes have been interrogated by spectroscopic, crystallographic and computational methods, the latter by reference to data for terminal halocarbyne precursors [M(CX)(CO)2(Tp*)].

Functionalization and Hydrogenation of Carbon Chains Derived from CO.

Selective reactions that combine H2 , CO and organic electrophiles (aldehyde, ketones, isocyanide) to form hydrogenated C3 and C4 carbon chains are reported. These reactions proceed by CO homologation mediated by [W(CO)6 ] and an aluminum(I) reductant, followed by functionalization and hydrogenation of the chain ends. A combination of kinetics (rates, KIEs) and DFT calculations has been used to gain insight into a key step which involves hydrogenation of a metallocarbene intermediate. These findings expand the extremely small scope of systems that combine H2 and CO to make well-defined products with complete control over chain length and functionality.

Study of synergistic disinfection by UVC and positive/negative air ions for aerosolized Escherichia coli, Salmonella typhimurium, and Staphylococcus epidermidis in ventilation duct flow.

The efficacy of the in-duct application of ultraviolet waveband C (UVC) emitting at 254 nm wavelength and air ions against aerosolized bacteria was studied in a full-scale 9-m long ventilation duct. Combined positive and negative ion polarities (bipolar ions) and combined UVC and ions were tested. The UVC was generated by a mercury-type UVC lamp and air ions were generated by positive and negative polarity ionizers. Escherichia coli (E. coli), Salmonella typhimurium (S. typhimurium), and Staphylococcus epidermidis (S. epidermidis)were tested at a concentration of 108 to 109 cells in 50 ml of sterilized distilled water. The case in which the positive ionizer was placed first, followed by the negative ionizer, demonstrated significantly higher disinfection efficiencies for E. coli (p = 0.007) and S. typhimurium (p < 0.001), but lower efficiency for S. epidermidis (p = 0.01) than the reversed sequence. The combination of UVC (3.71 J/m2 ) and air ions (1.13 × 1012  ions/m3 for positive ions and 8.00 × 1011  ions/m3 for negative ions) led to higher inactivation than individual disinfection agents operating under the same dose. A synergetic inactivation effect was observed for S. epidermidis under the combined UVC and positive ion case, while the combined UVC and negative ion case showed significant synergy effects for E. coli and S. typhimurium.

Reactions of aluminium(i) with transition metal carbonyls: scope, mechanism and selectivity of CO homologation.

Over the past few decades, numerous model systems have been discovered that create carbon-carbon bonds from CO. These reactions are of potential relevance to the Fischer-Tropsch process, a technology that converts syngas (H2/CO) into mixtures of hydrocarbons. In this paper, a homogeneous model system that constructs carbon chains from CO is reported. The system exploits the cooperative effect of a transition metal complex and main group reductant. An entire reaction sequence from C1 → C2 → C3 → C4 has been synthetically verified. The scope of reactivity is broad and includes a variety of transition metals (M = Cr, Mo, W, Mn, Re, Co), including those found in industrial heterogeneous Fischer-Tropsch catalysts. Variation of the transition metal fragment impacts the relative rate of the steps of chain growth, allowing isolation and structural characterisation of a rare C2 intermediate. The selectivity of carbon chain growth is also impacted by this variable; two distinct isomers of the C3 carbon chain were observed to form in different ratios with different transition metal reagents. Based on a combination of experiments (isotope labelling studies, study of intermediates) and calculations (DFT, NBO, ETS-NOCV) we propose a complete mechanism for chain growth that involves defined reactivity at both transition metal and main group centres.

1st row transition metal aluminylene complexes: preparation, properties and bonding analysis.

The synthesis and spectroscopic characterisation of eight new first-row transition metal (M = Cr, Mn, Fe, Co, Cu) aluminylene complexes is reported. DFT and ab initio calculations have been used to provide detailed insight into the metal-metal bond. The σ-donation and π-backdonation properties of the aluminylene ligand are evaluated via NBO and ETS-NOCV calculations. These calculations reveal that these ligands are strong σ-donors but also competent π-acceptors. These properties are not fixed but vary in response to the nature of the transition metal centre, suggesting that aluminylene fragments can modulate their bonding to accommodate both electron-rich and electron-poor transition metals. Ab initio DLPNO-CCSD(T) calculations show that dispersion plays an important role in stabilising these complexes. Both short-range and long-range dispersion interactions are identified. These results will likely inform the design of next-generation catalysts based on aluminium metalloligands.

Group 11 Borataalkene Complexes: Models for Alkene Activation.

A series of linear late transition metal (M=Cu, Ag, Au and Zn) complexes featuring a side-on [B=C]- containing ligand have been isolated and characterised. The [B=C]- moiety is isoelectronic with the C=C system of an alkene. Comparison across the series shows that in the solid-state, deviation between the η2 and η1 coordination mode occurs. A related zinc complex containing two [B=C]- ligands was prepared as a further point of comparison for the η1 coordination mode. The bonding in these new complexes has been interrogated by computational techniques (QTAIM, NBO, ETS-NOCV) and rationalised in terms of the Dewar-Chatt-Duncanson model. The combined structural and computational data provide unique insight into catalytically relevant linear d10 complexes of Cu, Ag and Au. Slippage is proposed to play a key role in catalytic reactions of alkenes through disruption and polarisation of the π-system. Through the preparation and analysis of a consistent series of group 11 complexes, we show that variation of the metal can impact the coordination mode and hence substrate activation.

Chemoselective C-C σ-Bond Activation of the Most Stable Ring in Biphenylene*.

The chemoselective cleavage of a six-membered aromatic ring in biphenylene is reported using an aluminum(I) complex. This type of selectivity is unprecedented. In every example of transition metal mediated C-C σ-bond activation reported to date, the reaction occurs at the central four-membered ring of biphenylene. Insight into the origin of chemoselectivity was obtained through a detailed mechanistic analysis (isolation of an intermediate, DFT studies, activation strain analysis). In conclusion, the divergent reactivity can be attributed to differences in both the symmetry and radial extension of the frontier molecular orbitals of the aluminum(I) fragment compared to that of common transition metal fragments.

Cooperative strategies for CO homologation.

Recent approaches in which at least two metal or main-group centres are involved in the homologation of CO are reviewed. We have characterised the strategies into three broad areas: (i) the reductive homologation of atmospheric CO at a metal or main group centre (ii) the reductive homologation of metal-carbonyl CO units and (iii) reductive homologation of CO with M-M, B-Li, Si[double bond, length as m-dash]Si, and B[triple bond, length as m-dash]B bonds.

Activation and Functionalization of C-C σ Bonds of Alkylidene Cyclopropanes at Main Group Centers.

Aluminum(I) and magnesium(I) compounds are reported for the C-C σ-bond activation of strained alkylidene cyclopropanes. These reactions result in the formal addition of the C-C σ bond to the main group center either at a single site (Al) or across a metal-metal bond (Mg-Mg). Mechanistic studies suggest that rather than occurring by a concerted oxidative addition, these reactions involve stepwise processes in which substrate binding to the main group metal acts as a precursor to α- or ß-alkyl migration steps that break the C-C σ bond. This mechanistic understanding is used to develop the magnesium-catalyzed hydrosilylation of the C-C σ bonds of alkylidene cyclopropanes.

Reactions of an Aluminum(I) Reagent with 1,2-, 1,3-, and 1,5-Dienes: Dearomatization, Reversibility, and a Pericyclic Mechanism.

Addition of the aluminum(I) reagent [{(ArNCMe)2CH}Al] (Ar = 2,6-di-iso-propylphenyl) to a series of cyclic and acyclic 1,2-, 1,3-, and 1,5-dienes is reported. In the case of 1,3-dienes, the reaction occurs by a pericyclic reaction mechanism, specifically a cheletropic cycloaddition, to form aluminocyclopentene-containing products. This mechanism has been examined by stereochemical experiments and DFT calculations. The stereochemical experiments show that the (4 + 1) cycloaddition follows a suprafacial topology, while calculations support a concerted albeit asynchronous pathway in which the transition state demonstrates aromatic character. Remarkably, the substrate scope of the (4 + 1) cycloaddition includes styene, 1,1-diphenylethylene, and anthracene. In these cases, the diene motif is either in part, or entirely, contained within an aromatic ring and reactions occur with dearomatisation of the substrate and can be reversible. In the case of 1,2-cyclononadiene or 1,5-cyclooctadiene, complementary reactivity is observed; the orthogonal nature of the C═C π-bonds (1,2-diene) and the homoconjugated system (1,5-diene) both disfavor a (4 + 1) cycloaddition. Rather, reaction pathways are determined by an initial (2 + 1) cycloaddition to form an aluminocyclopropane intermediate which can in turn undergo insertion of a further C═C π-bond, leading to complex organometallic products that incorporate fused hydrocarbon rings.

Reversible insertion of CO into an aluminium-carbon bond.

A [2.2.1] aluminium metallobicycle is capable of reversibly inserting CO to form a [2.2.2] metallobicycle at 100 °C. Computational studies reveal a highly asynchronous, but concerted, transition state for CO insertion. The coordination of CO to aluminium precedes C-C bond formation. The reversible migratory insertion of CO at aluminium thus mimics well-established transition-metal reactivity.

Carbon Chain Growth by Sequential Reactions of CO and CO2 with [W(CO)6] and an Aluminum(I) Reductant.

The formation of carbon chains by the coupling of CO x ( x = 1 or 2) units on transition metals is a fundamental step relevant to Fischer-Tropsch catalysis. Fischer-Tropsch catalysis produces energy dense liquid hydrocarbons from synthesis gas (CO and H2) and has been a mainstay of the energy economy since its discovery nearly a century ago. Despite detailed studies aimed at elucidating the steps of catalysis, experimental evidence for chain growth (C n → C n+1; n ≥ 2) from the coupling of CO units on metal complexes is, to the best of our knowledge, unprecedented. In this paper, we show that carbon chains can be grown from sequential reactions of CO or CO2 with a transition metal carbonyl complex. By exploiting the cooperative effect of transition and main group metals, we document the first example of chain propagation from sequential coupling of CO units (C1 → C3 → C4), along with the first example of incorporation of CO2 into the growing carbon chain.

An unusual alkylidyne homologation.

The reaction of [W([triple bond, length as m-dash]CH)Br(CO)2(dcpe)] (dcpe = 1,2-bis(dicyclohexylphosphino)ethane) with tBuLi and SiCl4 affords the trichlorosilyl ligated neopentylidyne complex [W([triple bond, length as m-dash]CtBu)(SiCl3)(CO)2(dcpe)]. This slowly reacts with H2O to afford [W([triple bond, length as m-dash]CCH2tBu)Cl3(dcpe)] and ultimately H2C[double bond, length as m-dash]CHtBu via an unprecedented alkylidyne homologation in which coordinated CO is the source of the additional carbon atom with potential relevance to the Fischer-Tropsch process.