Chemoenzymatic Hunsdiecker-Type Decarboxylative Bromination of Cinnamic Acids.

In this contribution, we report chemoenzymatic bromodecarboxylation (Hunsdiecker-type) of α,ß-unsaturated carboxylic acids. The extraordinarily robust chloroperoxidase from Curvularia inaequalis (CiVCPO) generated hypobromite from H2O2 and bromide, which then spontaneously reacted with a broad range of unsaturated carboxylic acids and yielded the corresponding vinyl bromide products. Selectivity issues arising from the (here undesired) addition of water to the intermediate bromonium ion could be solved by reaction medium engineering. The vinyl bromides so obtained could be used as starting materials for a range of cross-coupling and pericyclic reactions.

Structure of the Reductase Domain of a Fungal Carboxylic Acid Reductase and Its Substrate Scope in Thioester and Aldehyde Reduction.

The synthesis of aldehydes from carboxylic acids has long been a challenge in chemistry. In contrast to the harsh chemically driven reduction, enzymes such as carboxylic acid reductases (CARs) are considered appealing biocatalysts for aldehyde production. Although structures of single- and didomains of microbial CARs have been reported, to date no full-length protein structure has been elucidated. In this study, we aimed to obtain structural and functional information regarding the reductase (R) domain of a CAR from the fungus Neurospora crassa (Nc). The NcCAR R-domain revealed activity for N-acetylcysteamine thioester (S-(2-acetamidoethyl) benzothioate), which mimics the phosphopantetheinylacyl-intermediate and can be anticipated as the minimal substrate for thioester reduction by CARs. The determined crystal structure of the NcCAR R-domain reveals a tunnel that putatively harbors the phosphopantetheinylacyl-intermediate, which is in good agreement with docking experiments performed with the minimal substrate. In vitro studies were performed with this highly purified R-domain and NADPH, demonstrating carbonyl reduction activity. The R-domain was able to accept not only a simple aromatic ketone but also benzaldehyde and octanal, which are typically considered to be the final product of carboxylic acid reduction by CAR. Also, the full-length NcCAR reduced aldehydes to primary alcohols. In conclusion, aldehyde overreduction can no longer be attributed exclusively to the host background.

Biocatalytic Aromaticity-Breaking Epoxidation of Naphthalene and Nucleophilic Ring-Opening Reactions.

Aromatic hydroxylation reactions catalyzed by heme-thiolate enzymes proceed via an epoxide intermediate. These aromatic epoxides could be valuable building blocks for organic synthesis giving access to a range of chiral trans-disubstituted cyclohexadiene synthons. Here, we show that naphthalene epoxides generated by fungal peroxygenases can be subjected to nucleophilic ring opening, yielding non-racemic trans-disubstituted cyclohexadiene derivates, which in turn can be used for further chemical transformations. This approach may represent a promising shortcut for the synthesis of natural products and APIs.

New antimicrobial metabolites from the medicinal herb Artemisia herba-Alba.

Artemisia herba-alba is widely used in traditional medicines for the treatment of several diseases. From the aerial parts organic extract of A. herba-alba, two new compounds, 1,3,8-trihydroxyeudesm-4-en-7α,11ßH-12,6α-olide (1) and 5-ß-​D-​glucopyranosyloxy​-​7-methoxy-​6H-​benzopyran-​2-​one (2), respectively, together with five known metabolites: 3α,8ß-dihydroxygermacr-4(15),9(10)-dien-7ß,11αH,12,6α-olide (3), 1ß,8α-dihydroxy-11α,13-dihydrobalchanin (4), 11-epiartapshin (5), tomenin (6) and benzoic acid, p-​(ß-​D-​glucopyranosyloxy)​-​methyl ester (7), were isolated and identified. The chemical structures were proven depending upon spectroscopic analysis, including 1 D/2D NMR as and ESI-MS. Compound 1 inhibited Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus. Compounds 2 and 3 exhibited antibacterial activity against both gram-positive and gram-negative bacteria.

Photobiocatalytic synthesis of chiral secondary fatty alcohols from renewable unsaturated fatty acids.

En route to a bio-based chemical industry, the conversion of fatty acids into building blocks is of particular interest. Enzymatic routes, occurring under mild conditions and excelling by intrinsic selectivity, are particularly attractive. Here we report photoenzymatic cascade reactions to transform unsaturated fatty acids into enantiomerically pure secondary fatty alcohols. In a first step the C=C-double bond is stereoselectively hydrated using oleate hydratases from Lactobacillus reuteri or Stenotrophomonas maltophilia. Also, dihydroxylation mediated by the 5,8-diol synthase from Aspergillus nidulans is demonstrated. The second step comprises decarboxylation of the intermediate hydroxy acids by the photoactivated decarboxylase from Chlorella variabilis NC64A. A broad range of (poly)unsaturated fatty acids can be transformed into enantiomerically pure fatty alcohols in a simple one-pot approach.

Chemoenzymatic Halocyclization of 4-Pentenoic Acid at Preparative Scale.

The scale-up of chemoenzymatic bromolactonization to 100 g scale is presented, together with an identification of current limitations. The preparative-scale reaction also allowed for meaningful mass balances identifying current bottlenecks of the chemoenzymatic reaction.

Chemoenzymatic Halocyclization of γ,δ-Unsaturated Carboxylic Acids and Alcohols.

Invited for this month's cover is the group of Prof. Dr. Frank Hollmann at Delft University of Technology in the Netherlands. The Front Cover shows the vanadium-dependent haloperoxidase from the marine organism Curcuvaria inaequalis, which efficiently activates halides as hypohalites that can then initiate spontaneous halo-lactonization and halo-etherification reactions. The Communication itself is available at 10.1002/cssc.201902240.

Chemoenzymatic Halocyclization of γ,δ-Unsaturated Carboxylic Acids and Alcohols.

A chemoenzymatic method for the halocyclization of unsaturated alcohols and acids by using the robust V-dependent chloroperoxidase from Curvularia inaequalis (CiVCPO) as catalyst has been developed for the in situ generation of hypohalites. A broad range of halolactones and cyclic haloethers are formed with excellent performance of the biocatalyst.

A Photoenzymatic NADH Regeneration System.

A photoenzymatic NADH regeneration system was established. The combination of deazariboflavin as a photocatalyst with putidaredoxin reductase enabled the selective reduction of NAD+ into the enzyme-active 1,4-NADH to promote an alcohol dehydrogenase catalysed stereospecific reduction reaction. The catalytic turnover of all the reaction components was demonstrated. Factors influencing the efficiency of the overall system were identified.

Endothelial dysfunction marker YKL-40 is elevated in male patients with idiopathic infertility.

Metabolic syndrome represents a collection of cardiovascular risk factors, including overweight, hypertension, dyslipidemia and impaired glucose metabolism, with insulin resistance. In recent years, the potential relationship between metabolic syndrome and male factor infertility has been studied. As endothelial dysfunction is the hallmark of metabolic syndrome, the aim of this work was to assess serum levels of YKL-40 as a marker of endothelial dysfunction in male patients with idiopathic infertility. The study revealed that YKL-40 levels were elevated in patients than controls denoting that endothelial dysfunction might play a role in the pathogenesis of idiopathic infertility and that YKL-40 as a marker of endothelial dysfunction could be a useful marker of idiopathic infertility.

Synthesis, Spectral Characterization, SEM, Antimicrobial, Antioxidative Activity Evaluation, DNA Binding and DNA Cleavage Investigation of Transition Metal(II) Complexes Derived from a tetradentate Schiff base bearing thiophene moiety.

A novel series of Co(II), Ni(II), Cu(II) and Zn(II) mononuclear complexes have been synthesized involving a potentially tetradentate Schiff base ligand, which was obtained by condensation of 2-aminophenol with 2,5-thiophene-dicarboxaldehyde. The complexes were synthesized via reflux reaction of methanolic solution of the appropriate Schiff base ligand with one equivalent of corresponding metal acetate salt. Based on different techniques including micro analysis, FT-IR, NMR, UV-Vis, ESR, ESI-mass and conductivity measurements, four-coordinated geometry was assigned for all complexes. Spectroscopic data have shown that, the reported Schiff base coordinated to metal ions as a dibasic tetradentate ligand through the phenolic oxygen and the azomethine nitrogen. The antimicrobial activities of the parent ligand and its complexes were investigated by using the agar disk diffusion method. Antioxidation properties of the novel complexes were investigated and it was found that all the complexes have good radical scavenging properties. The binding of complexes to calf thymus DNA (CT-DNA) was investigated by absorption, emission and viscosity measurements. Binding studies have shown that all the complexes interacted with CT-DNA via intercalation mode and the binding affinity varies with relative order as Cu(II) complex > Co(II) complex > Zn(II) complex > Ni(II) complex. Furthermore, DNA cleavage properties of the metal complexes were also investigated. The results suggested the possible utilization of novel complexes for pharmaceutical applications.

Rapid chemoenzymatic route to glutamate transporter inhibitor l-TFB-TBOA and related amino acids.

The complex amino acid (l-threo)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (l-TFB-TBOA) and its derivatives are privileged compounds for studying the roles of excitatory amino acid transporters (EAATs) in regulation of glutamatergic neurotransmission, animal behavior, and in the pathogenesis of neurological diseases. The wide-spread use of l-TFB-TBOA stems from its high potency of EAAT inhibition and the lack of off-target binding to glutamate receptors. However, one of the main challenges in the evaluation of l-TFB-TBOA and its derivatives is the laborious synthesis of these compounds in stereoisomerically pure form. Here, we report an efficient and step-economic chemoenzymatic route that gives access to enantio- and diastereopure l-TFB-TBOA and its derivatives at multigram scale.

Triclinic and monoclinic polymorphs of meso-(E,E)-1,1'-[1,2-bis(4-chlorophenyl)ethane-1,2-diyl]bis(phenyldiazene): the high-yield synthesis of an unexpected product, concomitant polymorphism and configurational disorder.

Pyrazolidine-3,5-diones and their derivatives exhibit a wide range of biological activities. Seeking to explore the effect of combining a hydrocarbyl ring substituent, as present in sulfinpyrazone (used to treat gout), with a chlorinated aryl ring, as present in muzolimine (a diuretic), we explored the reaction between 1-phenylpyrazolidine-3,5-dione and 4-chlorobenzaldehyde under mildly basic conditions in the expectation of producing the simple condensation product 4-(4-chlorobenzylidene)-1-phenylpyrazolidine-3,5-dione. However, the reaction product proved to be meso-(E,E)-1,1'-[1,2-bis(4-chlorophenyl)ethane-1,2-diyl]bis(phenyldiazene), C26H20Cl2N4, and a tentative mechanism is proposed. Crystallization from ethanol produces two concomitant polymorphs, i.e. a triclinic form, (I), in the space group P-1, and a monoclinic form, (II), in the space group C2/c. In both polymorphs, the molecules lie across centres of inversion, but in (II), the molecules are subject to whole-molecule disorder equivalent to configurational disorder with occupancies of 0.6021 (19) and 0.3979 (19). There are no hydrogen bonds in the crystal structure of polymorph (I), but the molecules of polymorph (II) are linked by C-H...π(arene) hydrogen bonds into complex chains, which are further linked into sheets by C-H...N interactions.

The interplay of solvation, molecular conformation and supramolecular assembly in 1,1'-({[(ethane-1,2-diyl)dioxy](1,2-phenylene)}bis(methanylylidene))bis(thiosemicarbazide) and its N,N-dimethylformamide disolvate.

The wide diversity of applications of thiosemicarbazones and bis(thiosemicarbazones) has seen them used as anticancer and antitubercular agents, and as ligands in metal complexes designed to act as site-specific radiopharmaceuticals. Molecules of 1,1'-({[(ethane-1,2-diyl)dioxy](1,2-phenylene)}bis(methanylylidene))bis(thiosemicarbazide) {alternative name: 2,2'-[ethane-1,2-diylbis(oxy)]dibenzaldehyde bis(thiosemicarbazide)}, C18H20N6O2S2, (I), lie across twofold rotation axes in the space group C2/c, with an O-C-C-O torsion angle of -59.62 (13)° and a trans-planar arrangement of the thiosemicarbazide fragments relative to the adjacent aryl rings. The molecules of (I) are linked by N-H...S hydrogen bonds to form sheets containing R(2)4(38) rings and two types of R(2)2(8) ring. In the N,N-dimethylformamide disolvate, C18H20N6O2S2·2C3H7NO, (II), the independent molecular components all lie in general positions, but one of the solvent molecules is disordered over two sets of atomic sites having occupancies of 0.839 (3) and 0.161 (3). The O-C-C-O torsion angle in the ArOCH2CH2OAr component is -75.91 (14)° and the independent thiosemicarbazide fragments both adopt a cis-planar arrangement relative to the adjacent aryl rings. The ArOCH2CH2OAr components in (II) are linked by N-H...S hydrogen bonds to form deeply puckered sheets containing R(2)2(8), R(2)4(8) and two types of R(2)2(38) rings, and which contain cavities which accommodate all of the solvent molecules in the interior of the sheets. Comparisons are made with some related compounds.

A Novel Fluorescent Optode for Recognition of Zn(2+) ion Based on N,N(')-bis-(1-Hydroxypheylimine)2,5-Thiophenedicarobxaldehyde (HPTD) Schiff Base.

A novel fluorescent sensing film has been proposed for sensitive determination of Zn(2+) ion in EtOH-HEPES buffer solution (20 mM HEPES, 50:50, v/v, pH 7.0). The novel sensor based on incorporating a novel qaudridentate Schiff base N,N(')-bis-(1-hydroxypheylimine)2,5-thiophenedicarobxaldehyde (HPTD) as ionophore in the plasticized PVC membrane containing bis(2-ethylhexyl)sebecate (DOS) as plasticizer. The novel optode membrane works on the basis of a cation-exchange mechanism and shows a significant fluorescent emission enhancement on exposure to HEPES buffer solution of pH 7.0 containing Zn(2+) ion. Under optimal conditions, the proposed sensing film displays a linear range of 1.0 × 10(-12) to 8.6 × 10(-4) M with a limit of detection 5.3 × 10(-13) M. The response characteristics of the sensor including reversibility, reproducibility, response time and lifetime are discussed in detail. The optode membrane has been applied to determine Zn(2+) in various real water samples.

Crystal structure of 3-amino-1-(4-hy-droxy-phen-yl)-1H-benzo[f]chromene-2-carbo-nitrile.

In the title compound, C20H14N2O2, the hy-droxy-benzene ring is almost perpendicular to the mean plane of the naphthalene ring system, making a dihedral angle of 85.56 (4)°. The 4H-pyran ring fused with the naphthalene ring system has a flattened boat conformation. In the crystal, O-H⋯N and N-H⋯O hydrogen bonds link the mol-ecules into a supra-molecular layer in the bc plane; N-H⋯π inter-actions also contribute to this arrangement. The layers are linked by weak by C-H⋯π and π-π [inter-centroid separation = 3.8713 (7) Å] inter-actions.

Crystal structure of 2-amino-7-hy-droxy-4-(4-hy-droxy-phen-yl)-4H-chromene-3-carbo-nitrile.

In the title compound, C16H12N2O3, the chromene ring system is nearly planar [maximum deviation from the mean plane = 0.057 (1) Å], and is almost perpendicular to the benzene ring, with a dihedral angle of 85.29 (5)°. In the crystal, mol-ecules are linked by classical N-H⋯O, O-H⋯O and O-H⋯N hydrogen bonds, and weak C-H⋯O hydrogen bonds, forming a three-dimensional supra-molecular network. Furthermore, a weak π-π stacking inter-action is observed; the centroid-to-centroid distance is 3.7260 (7) Å.

Crystal structure of 3-amino-1-(4-meth-oxy-phen-yl)-1H-benzo[f]chromene-2-carbo-nitrile.

In the title compound, C21H16N2O2, the meth-oxy-benzene ring is almost perpendicular to the mean plane of the naphthalene ring system, making a dihedral angle of 83.62 (5)°. The 4H-pyran ring fused with the naphthalene ring system is almost planar [maximum deviation = 0.033 (1) Å]. In the crystal, mol-ecules are linked into inversion dimers by pairs of N-H⋯N hydrogen bonds. N-H⋯O hydrogen bonds connect the dimers, forming a helical supra-molecular chain along the a-axis direction. The crystal packing also features C-H⋯π inter-actions.

Crystal structure of 3-amino-1-(4-chloro-phen-yl)-1H-benzo[f]chromene-2-carbo-nitrile.

In the title compound, C20H13ClN2O, the chloro-benzene ring is almost perpendicular to the mean plane of the naphthalene ring system, making a dihedral angle of 81.26 (8)°. The 4H-pyran ring fused with the naphthalene ring system has a flattened boat conformation. In the crystal, N-H⋯N hydrogen bonds generate chains along the b-axis direction. Further N-H⋯N hydrogen bonds link these chains into sheets parallel to (010). The crystal packing also features C-H⋯π inter-actions. The crystal studied was an inversion twin with a 0.557 (16):0.443 (16) domain ratio.

Crystal structure of 2-amino-4-phenyl-4H-benzo[h]chromene-3-carbo-nitrile.

In the title compound, C20H14N2O, the plane of the phenyl ring is almost normal to that of the naphthalene ring system, forming a dihedral angle of 83.15 (8)°. The 4H-pyran ring fused with the naphthalene ring system has a flattened boat conformation. In the crystal, mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers with an R 2 (2)(12) ring motif. The dimers are connected by C-H⋯π inter-actions, forming supra-molecular chains along [010].