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Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e. g., a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9-azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9-azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1-azahomocubane., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

In contrast to their molybdenum dependent relatives, tungsten enzymes operate at significantly lower redox potentials, and in some cases they can carry out reversible redox transformations of their substrates and products. Still, the electrochemical properties of W enzymes have received much less attention than their Mo relatives. Herein we analyse the tungsten enzyme aldehyde oxidoreductase (AOR) from the mesophilic bacterium Aromatoleum aromaticum which has been immobilised on a glassy carbon working electrode. This generates a functional system that electrochemically oxidises a wide variety of aromatic and aliphatic aldehydes in the presence of the electron transfer mediators benzyl viologen, methylene blue or dichlorophenol indophenol. Simulation of the cyclic voltammetry has enabled a thorough kinetic analysis of the system, which reveals that methylene blue acts as a two-electron acceptor. In contrast, the other two mediators act as single electron oxidants. The different electrochemical driving forces imparted by these mediators also lead to significantly different outer sphere electron transfer rates with AOR. This work shows that electrocatalytic aldehyde oxidation can be achieved at a low applied electrochemical potential leading to an extremely energy efficient catalytic process., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Enzyme-catalyzed reaction cascades play an increasingly important role for the sustainable manufacture of diverse chemicals from renewable feedstocks. For instance, dehydratases from the ilvD/EDD superfamily have been embedded into a cascade to convert glucose via pyruvate to isobutanol, a platform chemical for the production of aviation fuels and other valuable materials. These dehydratases depend on the presence of both a Fe-S cluster and a divalent metal ion for their function. However, they also represent the rate-limiting step in the cascade. Here, catalytic parameters and the crystal structure of the dehydratase from Paralcaligenes ureilyticus (PuDHT, both in presence of Mg 2+ and Mn 2+ ) were investigated. Rate measurements demonstrate that the presence of stoichiometric concentrations Mn 2+ promotes higher activity than Mg 2+ , but at high concentrations the former inhibits the activity of PuDHT. Molecular dynamics simulations identify the position of a second binding site for the divalent metal ion. Only binding of Mn 2+ (not Mg 2+ ) to this site affects the ligand environment of the catalytically essential divalent metal binding site, thus providing insight into an inhibitory mechanism of Mn 2+ at higher concentrations. Furthermore, in silico docking identified residues that play a role in determining substrate binding and selectivity. The combined data inform engineering approaches to design an optimal dehydratase for the cascade., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

There is an urgent global need for the development of novel therapeutics to combat the rise of various antibiotic-resistant superbugs. Enzymes of the branched-chain amino acid (BCAA) biosynthesis pathway are an attractive target for novel anti-microbial drug development. Dihydroxy-acid dehydratase (DHAD) is the third enzyme in the BCAA biosynthesis pathway. It relies on an Fe-S cluster for catalytic activity and has recently also gained attention as a catalyst in cell-free enzyme cascades. Two types of Fe-S clusters have been identified in DHADs, i.e. [2Fe-2S] and [4Fe-4S], with the latter being more prone to degradation in the presence of oxygen. Here, we characterise two DHADs from bacterial human pathogens, Staphylococcus aureus and Campylobacter jejuni (SaDHAD and CjDHAD). Purified SaDHAD and CjDHAD are virtually inactive, but activity could be reversibly reconstituted in vitro (up to ∼19,000-fold increase with k cat as high as ∼6.7 s -1 ). Inductively-coupled plasma-optical emission spectroscopy (ICP-OES) measurements are consistent with the presence of [4Fe-4S] clusters in both enzymes. N-isopropyloxalyl hydroxamate (IpOHA) and aspterric acid are both potent inhibitors for both SaDHAD (K i =7.8 and 51.6 μM, respectively) and CjDHAD (K i =32.9 and 35.1 μM, respectively). These compounds thus present suitable starting points for the development of novel anti-microbial chemotherapeutics., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The tigliane ring system, which encompasses iconic members such as phorbol and TPA, is widely renowned due to numerous observations of displaying potent biological activity, and subsequent use as mainstream biochemical tools. Traditionally, naturally occurring phorboids are regarded as tumor promotors through PKC activation, although in recent times more highly oxidized natural derivatives have been identified as anti-tumor agents. In the view that only limited synthetic investigations toward skeletal stereochemical modification have been undertaken, non-natural systems could be useful for a better understanding of the tigliane pharmacophore via interrogation of cellular sensitivity. In this context the concise construction of a number of highly functionalized non-natural D-ring inverted phorbol esters were synthesized, via a rhodium-catalyzed [4+3] cycloaddition, and biologically evaluated using a range of cancer cell lines. The biological results highlight the notion that subtle changes in structure have dramatic effects on potency. Furthermore, although the non-natural derivatives did not outcompete the natural systems in the PKC-activation sensitive MCF7 cancer cell line, they outperformed in other cancer cell lines (MM96L and CAL27). This observation strongly suggested an alternate mode of action not involving activation of PKC, but instead involves thiol addition as indicated by glutathione addition and NF-κB reporter activity., (© 2020 Wiley-VCH GmbH.)

Dysphania is an abundant genus of plants, many of which are endemic to the Australian continent, occurring primarily in arid and temperate zones. Despite their prevalence, very few investigations into the phytochemistry of native Dysphania have been undertaken. Described herein, is the isolation and elucidation of two enantiomeric diastereomers of humulene diepoxide C from D. kalpari and D. rhadinostachya, of which unassigned diastereomers of humulene diepoxide C have been previously reported as components in beer brewed from aged hops. In addition, two (+)-humulene diepoxiols (humulene diepoxiol C-I and C-II) were isolated from D. rhadinostachya. Analysis of Chinook hops oil confirmed the presence of both humulene diepoxide C-I and C-II as trace components, and in turn enabled GC-MS peak assignment to the relative stereochemistry. Anticancer assays did not reveal any significant activity for the (+)-humulene diepoxides. Antifungal assays showed good activity against a drug-resistant strain of C. auris, with MIC 50 values of 8.53 and 4.91 μm obtained for (+)-humulene diepoxide C-I and C-II, respectively., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

5-(2-Oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) is a natural product formed during bacterial synthesis of vitamin B2. It potently activates mucosal associated invariant T (MAIT) cells and has immunomodulatory, inflammatory, and anticancer properties. This highly polar and unstable compound forms a remarkably stable Schiff base with a lysine residue in major histocompatibility complex class I-related protein (MR1) expressed in antigen-presenting cells. Inspired by the importance of the ribityl moiety of 5-OP-RU for binding to both MR1 and the T cell receptor (TCR) on MAIT cells, each OH was removed in silico. DFT calculations and MD simulations revealed a very stable hydrogen bond between the C3'-OH and uracil N1H, which profoundly restricts flexibility and positioning of each ribityl-OH, potentially impacting their interactions with MR1 and TCR. By using deoxygenation strategies and kinetically controlled imine formation, four monodeoxyribityl and four monohydroxyalkyl analogues of 5-OP-RU were synthesised as new tools for probing T cell activation mechanisms., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report the first electrochemical study of a lanthanoid-dependent methanol dehydrogenase (Eu-MDH) from the acidophilic verrucomicrobial methanotroph Methylacidiphilum fumariolicum SolV with its own physiological cytochrome c GJ electron acceptor. Eu-MDH harbours a redox active 2,7,9-tricarboxypyrroloquinoline quinone (PQQ) cofactor which is non-covalently bound but coordinates trivalent lanthanoid elements including Eu 3+ . Eu-MDH and the cytochrome were co-adsorbed with the biopolymer chitosan and cast onto a mercaptoundecanol (MU) monolayer modified Au working electrode. Cyclic voltammetry of cytochrome c GJ reveals a well-defined quasi-reversible Fe III/II redox couple at +255 mV vs. NHE at pH 7.5 and this response is pH independent. The reversible one-electron response of the cytochrome c GJ transforms into a sigmoidal catalytic wave in the presence of Eu-MDH and its substrates (methanol or formaldehyde). The catalytic current was pH-dependent and pH 7.3 was found to be optimal. Kinetic parameters (pH dependence, activation energy) obtained by electrochemistry show the same trends as those obtained from an artificial phenazine ethosulfate/dichlorophenol indophenol assay., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The scope and limitations of Eaton's rhodium(I)-catalyzed valence isomerization of cubane to cyclooctatetraene (COT) were investigated in the context of functional group tolerability, multiple substitution modes and the ability of cubane-alcohols to undergo one-pot tandem Ley-Griffith Wittig reactions in the absence of a transition metal catalyst., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The electrochemically driven catalysis of the complex molybdoenzyme steroid C25 dehydrogenase (S25DH) from the β-Proteobacterium Sterolibacterium denitrificans is reported. S25DH catalyses the oxygen-independent regioselective hydroxylation of the tertiary C25 atom of sterols and also their derivatives. Cholest-4-en-3-one is a native substrate for S25DH, which produces 25-hydroxycholest-4-en-3-one as a product of catalytic turnover. Cholecalciferol (vitD 3 ) is also a substrate. S25DH was immobilised on a modified gold working electrode with the co-adsorbent chitosan. The complexes ferricyanide ([Fe(CN) 6 ] 3- ) and ferrocenium methanol (FM + ) are effective artificial electron acceptors from S25DH and act as mediators of electron transfer between the electrode and the enzyme. 2-Hydroxypropyl-β-cyclodextrin (HPCD) was employed as a sterol solubiliser, in addition to 2-methoxyethanol. The catalytic activity varied, depending upon the concentration of solubiliser in the reaction mixture. Parallel studies with [Fe(CN) 6 ] 3- as a chemical (as opposed to electrochemical) oxidant coupled to HPLC analysis show that S25DH is capable of oxidising both vitD 3 and its less stable isomer, pre-vitD 3 , and that the former substrate is stabilised by HPCD., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Single crystal structural analysis of [Fe II (tame) 2 ]Cl 2 ⋅MeOH (tame=1,1,1-tris(aminomethyl)ethane) as a function of temperature reveals a smooth crossover between a high temperature high-spin octahedral d 6 state and a low temperature low-spin ground state without change of the symmetry of the crystal structure. The temperature at which the high and low spin states are present in equal proportions is T 1/2 =140 K. Single crystal, variable-temperature optical spectroscopy of [Fe II (tame) 2 ]Cl 2 ⋅MeOH is consistent with this change in electronic ground state. These experimental results confirm the spin activity predicted for [Fe II (tame) 2 ] 2+ during its de novo artificial evolution design as a spin-crossover complex [Chem. Inf., Model: 2015, 55, 1844], offering the first experimental validation of a functional transition-metal complex predicted by such in silico molecular design methods. Additional quantum chemical calculations offer, together with the crystal structure analysis, insight into the role of spin-passive structural components. A thermodynamic analysis based on an Ising-like mean field model (Slichter-Drickammer approximation) provides estimates of the enthalpy, entropy and cooperativity of the crossover between the high and low spin states., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Ley-Griffith tetra-n-propylammonium perruthenate (TPAP) catalyst has been widely deployed by the synthesis community, mainly for the oxidation of alcohols to aldehydes and ketones, but also for a variety of other synthetic transformations (e.g. diol cleavage, isomerizations, imine formation and heterocyclic synthesis). Such popularity has been forged on broad reaction scope, functional group tolerance, mild conditions, and commercial catalyst supply. However, the mild instability of TPAP creates preparation, storage, and reaction reproducibility issues, due to unpreventable slow decomposition. In search of attributes conducive to catalyst longevity an extensive range of novel perruthenate salts were prepared. Subsequent evaluation unearthed a set of readily synthesized, bench stable, phosphonium perruthenates (ATP3 and MTP3) that mirror the reactivity of TPAP, but avoid storage decomposition issues., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first stereocontrolled Cu-catalyzed sequential 1,6/1,4-asymmetric conjugate addition (ACA) of C-metalated hard nucleophiles to cyclic dienones is reported. The use of DiPPAM (diphenylphosphinoazomethinylate) followed by a phosphoramidite as the stereoinducing ligands facilitated both high ee values for the 1,6-ACA and high de values for the 1,4-ACA reaction components, which thus gave enantioenriched 1,3-dialkylated moieties. The absolute configurations were determined by using vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD) spectroscopy, in combination with DFT calculations and X-ray analysis. Interestingly, DFT calculations for the mechanism of enantioselective 1,6-addition by using an unprecedented Cu-Zn bimetallic catalytic system confirmed this attribution. Lastly, exploring intramolecular cyclization avenues for enantioenriched 1,3-dialkylated products provided access to the challenging drimane skeleton., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Gedunin, first isolated in 1960, displays a remarkable range of biological activity, but has yet to receive dedicated synthetic attention from a ground up construction perspective. Presented herein is a successfully executed approach to the fully functionalized ABC ring system of this challengingly complex natural product., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chamaelirium luteum is used in traditional medicine systems and commercial botanical dietary supplements for the treatment of female reproductive health problems. Despite the wide use of this herb, only very limited phytochemical characterisation is available. Our investigation of C. luteum roots led to the isolation of two new steroidal saponins 1 and 2 that contain an unusual aglycone 3. The absolute configurations of these molecules were unable to be determined spectroscopically and thus the total synthesis of 3 was undertaken and achieved in 16 steps and 1.6 % overall yield from pregnenolone. The key step in the synthesis was the stereoselective installation of the side chain at C-17 and C-20, which employed anion-accelerated oxy-Cope methodology. The relative configuration of aglycone 3 was determined by X-ray crystallography of an advanced synthetic intermediate. The absolute configuration was based upon that of the pregnenolone-derived steroidal skeleton and determined to be 23R,24S., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A detailed examination of [4+2] cycloaddition reactions between 1,8-disubstituted cyclooctatetraenes and diazo compounds revealed that 4-phenyl-1,2,4-triazole-3,5-dione (PTAD) reacts to form either 2,3- or 3,4-disubstituted adducts. The product distribution can be controlled by modulating the electron density of the cyclooctatetraene. Unprecedented [4+2] cycloadditions between diisopropyl azodicarboxylate (DIAD) and 1,8-disubstituted cyclooctatetraenes are also described and further manipulation of a resulting cycloadduct uncovered a new pathway to the synthetically challenging bicyclo[4.2.0]octa-2,4-diene family. Variation of the substituents resulted in a range of compounds displaying selective action against different human tumour cell types.

The potentially hexadentate mixed-donor cage ligand 1-methyl-8-amino-3,13,16-trithia-6,10,19-triazabicyclo[6.6.6]eicosane (AMME-N(3)S(3)sar; sar=sarcophagine) displays variable coordination modes in a complex with copper(II). In the absence of coordinating anions, the ligand adopts a conventional hexadentate N(3)S(3) binding mode in the complex [Cu(AMME-N(3)S(3)sar)](ClO(4))(2) that is typical of cage ligands. This structure was determined by X-ray crystallography and solution spectroscopy (EPR and NIR UV/Vis). However, in the presence of bromide ions in DMSO, clean conversion to a five-coordinate bromido complex [Cu(AMME-N(3)S(3)sar)Br](+) is observed that features a novel tetradentate (N(2)S(2))-coordinated form of the cage ligand. This copper(II) complex has also been characterized by X-ray crystallography and solution spectroscopy. The mechanism of the reversible interconversion between the six- and five-coordinated copper(II) complexes has been studied and the reaction has been resolved into two steps; the rate of the first is linearly dependent on bromide ion concentration and the second is bromide independent. Electrochemistry of both [Cu(AMME-N(3)S(3)sar)](2+) and [Cu(AMME-N(3)S(3)sar)Br](+) in DMSO shows that upon reduction to the monovalent state, they share a common five-coordinated form in which the ligand is bound to copper in a tetradentate form exclusively, regardless of whether a six- or five-coordinated copper(II) complex is the precursor.

The synthesis, characterization and copper(II) coordination chemistry of three new cyclic peptide ligands, PatJ(1) (cyclo-(Ile-Thr-(Gly)Thz-Ile-Thr-(Gly)Thz)), PatJ(2) (cyclo-(Ile-Thr-(Gly)Thz-(D)-Ile-Thr-(Gly)Thz)), and PatL (cyclo-(Ile-Ser-(Gly)Thz-Ile-Ser-(Gly)Thz)) are reported. All of these cyclic peptides and PatN (cyclo-(Ile-Ser-(Gly)Thz-Ile-Thr-(Gly)Thz)) are derivatives of patellamide A and have a [24]azacrown-8 macrocyclic structure. All four synthetic cyclic peptides have two thiazole rings but, in contrast to patellamide A, no oxazoline rings. The molecular structure of PatJ(1), determined by X-ray crystallography, has a saddle conformation with two close-to-coparallel thiazole rings, very similar to the geometry of patellamide D. The two coordination sites of PatJ(1) with thiazole-N and amide-N donors are each well preorganized for transition metal ion binding. The coordination of copper(II) was monitored by UV/Vis spectroscopy, and this reveals various (meta)stable mono- and dinuclear copper(II) complexes whose stoichiometry was confirmed by mass spectra. Two types of dinuclear copper(II) complexes, [Cu(2)(H(4)L)(OH(2))(n)](2+) (n=6, 8) and [Cu(2)(H(2)L)(OH(2))(n)] (n=4, 6; L=PatN, PatL, PatJ(1), PatJ(2)) have been identified and analyzed structurally by EPR spectroscopy and a combination of spectra simulations and molecular mechanics calculations (MM-EPR). The four structures are similar to each other and have a saddle conformation, that is, derived from the crystal structure of PatJ(1) by a twist of the two thiozole rings. The small but significant structural differences are characterized by the EPR simulations.