A method was developed to synthesize macrocyclic trihydroxamate siderophores using optimized Yamaguchi macrolactonization conditions. The natural ability of siderophores to bind iron(III) was exploited to template the reactions and allowed for rapid reaction rates, high product conversions, and the formation of large macrolactone rings up to 35 atoms. An X-ray structure of a 33-membered macrolactone siderophore-Fe(III) complex is presented.
A survey of individual specimens of northern Papua New Guinea derived Cacospongia mycofijiensis has yielded novel sesquiterpenes, aignopsanoic acid A (1), methyl aignopsanoate A (2), and isoaignopsanoic acid A (3). The structures and absolute configurations of 1–3 were established using NMR data, X-ray crystallography results, and an analysis of CD properties. Two of these metabolites, 1 and 2, were moderately active against Trypanosoma brucei, the parasite responsible for sleeping sickness.
Two different oxygen-ligated cobalt porphyrins have been synthesized and the solid-state structures have been determined at several temperatures. The solid-state structures provide insight into the dynamics of Co–O2 rotation and correlation with protecting group disorder. [Co(TpivPP)(1-EtIm)(O2)] (TpivPP = picket fence porphyrin) is prepared by oxygenation of [Co(TpivPP)(1-EtIm)2] in benzene solution. The structure at room temperature has the oxygen ligand within the ligand binding pocket and disordered over four sites and the trans imidazole is disordered over two sites. The structure at 100 K, after the crystal has been carefully annealed to yield a reversible phase change, is almost completely ordered. The phase change is reversed upon warming the crystal to 200 K, whereupon the oxygen ligand is again disordered but with quite unequal populations. Further warming to 300 K leads to greater disorder of the oxygen ligands with nearly equal O2 occupancies at all four positions. The disorder of the t-butyl groups of the protecting pickets is correlated with rotation of the O2 around the Co–O(O2) bond. [Co(TpivPP)(2-MeHIm)(O2)] is synthesized by a solid-state oxygenation reaction from the five-coordinate precursor [Co(TpivPP)(2-MeHIm)]. Exposure to 1 atm of O2 leads to incomplete oxygenation, however, exposure at 5 atm yields complete oxygenation. Complete oxygenation leads to picket disorder whereas partial (40%) oxygenation does not. Crystallinity is retained on complete degassing of oxygen in the solid, and complete ordering of the pickets is restored. The results should provide basic information needed to better model M–O2 dynamics in protein environments.
The title compound, C23H21NO3S, represents one of the few examples of a 5-substituted indole with a toluenesulfonyl group bonded to the N atom. The benzyl group adopts a synclinal geometry with respect to the indole ring [dihedral angle = 59.95 (4)°], while the tolyl ring is oriented close to perpendicular to the indole ring, making a dihedral angle of 81.85 (3)°. The indole N atom exhibits a slight pyramidalization.
Gram-negative bacteria have evolved an elaborate process for the recycling of their cell wall, which is initiated in the periplasmic space by the action of lytic transglycosylases. The product of this reaction, β-D-N-acetylglucosamine-(1→4)-1,6-anhydro-β-D-N-acetylmuramyl-L-Ala-γ-D-Glu-meso-DAP-D-Ala-D-Ala (compound 1), is internalized to begin the recycling events within the cytoplasm. The first step in the cytoplasmic recycling is catalyzed by the NagZ glycosylase, which cleaves in a hydrolytic reaction the N-acetylglucosamine glycosidic bond of metabolite 1. The reactions catalyzed by both the lytic glycosylases and NagZ are believed to involve oxocarbenium transition species. We describe herein the synthesis and evaluation of four iminosaccharides as possible mimetics of the oxocarbenium species, and disclose one as a potent (compound 3, Ki = 300 ± 15 nM) competitive inhibitor of NagZ.
Iminosaccharide; NagZ; MltB; Peptidoglycan; β-Lactam
bioorganic chemistry; biological activity; bacteria; spores; carbohydrates
The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ~100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC90 = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds.
The preparation and characterization of a mixed-valence π-cation radical derivative of an iron(III) oxochlorinato complex is reported. The new complex has been synthesized by the one-electron oxidation of a pair of [Fe(oxoOEC)(Cl)] molecules to form the dimeric cation [Fe(oxoOEC)(Cl)]+2. The cation has been characterized by an X-ray analysis, Mössbauer spectroscopy, UV-vis and near-IR spectroscopy, and magnetic susceptibility measurements from 6–300 K. The crystal structure shows that the two rings have a smaller overlap area that those of the formally related nickel and copper octaethylporphyrinateethylporphinate derivatives, reflecting the larger steric congestion at the periphery in part of the oxochlorin rings. The Mössbauer data is consistent with two equivalent iron(III) centers. The unpaired electron is delocalized over the two oxochlorin rings and mediates a strong antiferromagnetic interaction between the high-spin iron(III) centers.
The title compound, C15H13NO, has two crystallographically independent molecules in the asymmetric unit which differ principally in the periplanar angle formed by the benzene and pyridine rings [41.41 (3) and 17.92 (5)°]. The molecules exhibit an E conformation between the keto group with respect to the olefin double bond.
The asymmetric unit of the title compound, [Nd2(C6H5COO)5Cl(C4H8O2)]·2.5C4H8O2, consists of two NdIII ions bridged by one Cl− ion, five benzoate ions and one coordinating 1,4-dioxane molecule. One NdIII ion is nine-coordinate, with a very distorted monocapped square-antiprismatic geometry. It is coordinated by two chelating carboxylate groups, three monodentate carboxylate groups, one chloride ion and one dioxane molecule. A second independent NdIII ion is eight-coordinated in a distorted square-antiprismatic geometry by one chelating carboxylate group, five monodentate carboxylate groups and one chloride ion. The chains of the extended structure are parallel to the crystallographic b axis. There is a small amount of void space which is filled with five disordered dioxane solvent molecules per unit cell. The intensity contribution of the disordered solvent molecules was removed by applying the SQUEEZE procedure in PLATON [Spek (2009). Acta Cryst. D65, 148–155].
Magnesium metal is an ideal rechargeable battery anode material because of its high volumetric energy density, high negative reduction potential and natural abundance. Coupling Mg with high capacity, low-cost cathode materials such as electrophilic sulphur is only possible with a non-nucleophilic electrolyte. Here we show how the crystallization of the electrochemically active species formed from the reaction between hexamethyldisilazide magnesium chloride and aluminum trichloride enables the synthesis of a non-nucleophilic electrolyte. Furthermore, crystallization was essential in the identification of the electroactive species, [Mg2(μ-Cl)3·6THF]+, and vital to improvements in the voltage stability and coulombic efficiency of the electrolyte. X-ray photoelectron spectroscopy analysis of the sulphur electrode confirmed that the electrochemical conversion between sulphur and magnesium sulfide can be successfully performed using this electrolyte.
Magnesium is an ideal rechargeable battery anode material, but coupling it with a low-cost sulphur cathode, requires a non-nucleophilic electrolyte. Kim et al. prepare a non-nucleophilic electrolyte from hexamethyldisilazide magnesium chloride and aluminium trichloride, and show its compatibility with a sulphur cathode.
3-Deoxy-3-fluoro-d-glucopyranose crystallizes from acetone to give a unit cell containing two crystallographically independent molecules. One of these molecules (at site A) is structurally homogeneous and corresponds to 3-deoxy-3-fluoro-β-d-glucopyranose, C6H11FO5, (I). The second molecule (at site B) is structurally heterogeneous and corresponds to a mixture of (I) and 3-deoxy-3-fluoro-α-d-glucopyranose, (II); treatment of the diffraction data using partial-occupancy oxygen at the anomeric center gave a high-quality packing model with an occupancy ratio of 0.84:0.16 for (II):(I) at site B. The mixture of α- and β-anomers at site B appears to be accommodated in the lattice because hydrogen-bonding partners are present to hydrogen bond to the anomeric OH group in either an axial or equatorial orientation. Cremer–Pople analysis of (I) and (II) shows the pyranosyl ring of (II) to be slightly more distorted than that of (I) [θ(I) = 3.85 (15)° and θ(II) = 6.35 (16)°], but the general direction of distortion is similar in both structures [ϕ(I) = 67 (2)° (B
C1,C4) and ϕ(II) = 26.0 (15)° (C3
C1); B = boat conformation and TB = twist-boat conformation]. The exocyclic hydroxymethyl (–CH2OH) conformation is gg (gauche–gauche) (H5 anti to O6) in both (I) and (II). Structural comparisons of (I) and (II) to related unsubstituted, deoxy and fluorine-substituted monosaccharides show that the gluco ring can assume a wide range of distorted chair structures in the crystalline state depending on ring substitution patterns.
4-Deoxy-4-fluoro-β-d-glucopyranose, C6H11FO5, (I), crystallizes from water at room temperature in a slightly distorted 4
1 chair conformation. The observed chair distortion differs from that observed in β-d-glucopyranose [Kouwijzer, van Eijck, Kooijman & Kroon (1995 ▶). Acta Cryst. B51, 209–220], (II), with the former skewed toward a B
C3,O5 (boat) conformer and the latter toward an O5
C2 (twist–boat) conformer, based on Cremer–Pople analysis. The exocyclic hydroxymethyl group conformations in (I) and (II) are similar; in both cases, the O—C—C—O torsion angle is ∼−60° (gg conformer). Intermolecular hydrogen bonding in the crystal structures of (I) and (II) is conserved in that identical patterns of donors and acceptors are observed for the exocyclic substituents and the ring O atom of each monosaccharide. Inspection of the crystal packing structures of (I) and (II) reveals an essentially identical packing configuration.
The title complex, aqua[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](η4-cycloocta-1,5-diene)rhodium(I) tetrafluoridoborate, [Rh(C8H12)(C27H36N2)(H2O)]BF4, exihibits a square-planar geometry around the Rh(I) atom, formed by a bidentate cycloocta-1,5-diene (cod) ligand, an N-heterocylcic carbene and an aqua ligand. The complex is cationic and a BF4
− anion balances the charge. The structure exists as a hydrogen-bonded dimer in the solid state, formed via interactions between the aqua ligand H atoms and the BF4
− F atoms.
A complete, isostructural series of complexes with La-Lu (except Pm) with the ligand TREN-1,2-HOIQO has been synthesized and structurally characterized by means of single-crystal X-ray analysis. All complexes are 1D-polymeric species in the solid state, with the lanthanide being in an eight-coordinate, distorted trigonal-dodecahedral environment with a donor set of eight unique oxygen atoms. This series constitutes the first complete set of isostructural complexes from La-Lu (without Pm) with a ligand of denticity greater than two. The geometric arrangement of the chelating moieties slightly deviates across the lanthanide series, as analyzed by a shape parameter metric based on the comparison of the dihedral angles along all edges of the coordination polyhedron. The apparent lanthanide contraction in the individual Ln-O bond lengths deviates considerably from the expected quadratic decrease that was found previously in a number of complexes with ligands of low denticity. The sum of all bond lengths around the trivalent metal cation, however, is more regular, showing an almost ideal quadratic behavior across the entire series. The quadratic nature of the lanthanide contraction is derived theoretically from Slater’s model for the calculation of ionic radii. In addition, the sum of all distances along the edges of the coordination polyhedron show exactly the same quadratic dependence as the Ln-X bond lengths. The universal validity of this coordination sphere contraction, concomitant with the quadratic decrease in Ln-X bond lengths, was confirmed by reexamination of four other, previously published series of lanthanide complexes. Due to the importance of multidentate ligands for the chelation of rare-earth metals, this result provides a significant advance for the prediction and rationalization of the geometric features of the corresponding lanthanide complexes, with great potential impact for all aspects of lanthanide coordination.
The temperature dependence of the crystalline phase of (nitrosyl)(tetraphenylporphinato)-cobalt(II), [Co(TPP)(NO)], has been explored over the temperature range of 100–250 K by X-ray diffraction experiments. The crystalline complex is found in the tetragonal crystal system at higher temperatures and in the triclinic crystal system at lower temperatures. In the tetragonal system, the axial ligand is strongly disordered, with the molecule having crystallographically required 4/m symmetry, leading to eight distinct positions of the single nitrosyl oxygen atom. The phase transition to the triclinic crystal system leads to a partial ordering with the molecule now having inversion symmetry and disorder of the axial nitrosyl ligand over only two positions. At an intermediate temperature near the transition point, a transition structure in which the ordering observed at lower temperatures is only partially complete has been characterized. The increase in ordering allows subtle molecular geometry features to be observed. The transition of the reversible phase change begins at about 195 K. This transition has been confirmed by both X-ray diffraction studies and a differential scanning calorimetry study.
iron porphyrinates; Mössbauer spectroscopy; nuclear resonance vibrational spectra NO bonding π vs. σ; NO complexes
The first example of sulfonylation-induced N- to O-acetyl migration of 2-acetamidoethanol derivatives is described. This type of reaction could happen with any 2-acetamidoethanol derivatives under typical sulfonylation conditions (TsCl or MsCl, pyridine) and might be a common side reaction of significance. Furthermore, the results reveal that 2-acetamidoethanol derivatives with sterically encumbered hydroxyl group result in the migration products in high yields. The mechanism of the migration reaction is discussed.
The X-ray characterization of the five-coordinate picket-fence porphyrin complex, [Co(TpivPP)(2-MeHim)], is reported. The complex has the displacement of cobalt from the porphyrin plane = 0.15 Å, and Co–NIm = 2.145 (3) and (Co–Np)av = 1.979(3) Å. This five-coordinate complex, in the presence of dioxygen and excess 2-methylimidazole, undergoes an unanticipated, photoinitiated atropisomerization of the porphyrin ligand, oxidation of cobalt(II) and the formation of the neutral cobalt(III) complex [Co(α,α,β,β-TpivPP)(2-MeHim)(2-MeIm−]. Two distinct examples of this complex have been structurally characterized, both have structural parameters consistent with cobalt(III). The two new Co(III) porphyrin complexes have axial Co–NIm distances ranging from 1.952 to 1.972 Å, but which allow for the distinction between imidazole and imidazolate. An interesting intermolecular hydrogen bonding network is observed that leads to infinite helical chains. UV-vis spectroscopic study suggests that [Co(TpivPP)(2-MeHIm)(O2)] is an intermediate state for the oxidation reaction and the atropisomerization process is photocatalyzed. A reaction route is proposed based on the spectroscopic studies.
Recent reports of potential physiological roles of hydrogen sulfide have prompted interest in heme-sulfide interactions. Heme-H2S and/or heme-HS− interactions could potentially occur during endogenous production, transport, signaling events, and catabolism of H2S. We have investigated the interaction of the hydrosulfide ion (HS−) with iron porphyrinates. UV-vis spectral studies show the formation of [Fe(Por)(SH)]−, [Fe(Por)(SH)2]2−, and the mixed ligand species [Fe(Por)(Im)(SH)]−. UV-vis binding studies of [Fe(OEP)] and [Fe(Tp-OMePP)] (OEP = octaethylporphyrinate, Tp-OMePP = tetra-p-methoxyphenylporphyrinate) with HS− allowed for calculation of formation constants and extinction coefficients of the mono- and bis-HS− complexes. We report the synthesis of the first HS− bound iron(II) porphyrin compounds, [Na(222)][Fe(OEP)(SH)]·0.5C6H6 and [Na(222)][Fe(Tp-OMePP)(SH)]·C6H5Cl (222 = kryptofix-222). Characterization by single-crystal X-ray analysis, mass spectrometry, and Mössbauer and IR spectroscopy are all consistent with that of known sulfur-bound high-spin iron(II) compounds. The Fe–S distances of 2.3929(5) and 2.3887(13) Å are longer than all reported values of [FeII(Por)(SR)]− species. An analysis of porphyrin non-planarity for these derivatives and for all five-coordinate high-spin iron(II) porphyrinate derivatives with an axial anion ligand is presented. In our hands, attempts to synthesize iron(III) HS− derivatives led to iron(II) species.
Easily accessible 2-(2-aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides rearranged to 2,3-dihydro-1H-imidazo[1,2-b]indazoles under mild conditions. The rearrangement appeared to be general, tolerated a wide range of functional groups, and provided access to an as yet unexplored class of heterocycles. Herein we report the characterization of this heterocycles.
The title compound, C7H14N4, represents the first structurally characterized, isolated triazaadamantane. In the crystal structure, weak intermolecular N—H⋯N hydrogen bonds link the molecules into columns about the crystallographic fourfold axis.
Gelatinases (MMP-2 and MMP-9) have been implicated in a number of pathological conditions, including cancer and cardiovascular disease. Hence, small molecule inhibitors of these enzymes are highly sought for use as potential therapeutic agents. 2-(4-Phenoxyphenylsulfonylmethyl)thiirane (SB-3CT) has previously been demonstrated to be a potent and selective inhibitor of gelatinases, however, it is rapidly metabolized because of oxidation at the para position of the phenoxy ring and at the α-position to the sulfonyl group. α-Methyl variants of SB-3CT were conceived to improve metabolic stability and as mechanistic probes. We describe herein the synthesis and evaluation of these structural variants as potent inhibitors of gelatinases. Two (compounds 5b and 5d) among the four synthetic stereoisomers were found to exhibit slow-binding inhibition of gelatinases and MMP-14 (MT1-MMP), which is a hallmark of the mechanism of this class of inhibitors. The ability of these compounds to inhibit MMP-2, MMP-9, and MMP-14 could target cancer tissues more effectively. Metabolism of the newly synthesized inhibitors showed that both oxidation at the α-position to the sulfonyl group and oxidation at the para position of the terminal phenyl ring were prevented. Instead oxidation on the thiirane sulfur is the only biotransformation pathway observed for these gelatinase inhibitors.
enzyme inhibition; gelatinase; metabolism
The title molecule, [Fe(C36H44N4)Cl]·1.5CH2Cl2, is a high-spin square-pyramidal iron(III) porphyrinate with an average value for the equatorial Fe—N bond lengths of 2.065 (3) Å and an axial Fe—Cl distance of 2.2430 (13) Å. The iron cation is displaced by 0.518 (1) Å from the 24-atom mean plane of the porphyrin ring. These values are typical for high-spin iron(III) porphyrinates.
Heme-copper oxidases have a crucial role in energy transduction mechanism, catalyzing the reduction of dioxygen to water. The reduction of dioxygen takes place at the binuclear center, which contains heme a3 and CuB. The X-ray crystal structures have revealed that the C6' of tyrosine 244 (bovine heart numbering) is cross-linked to a nitrogen of histidine 240, a ligand to CuB. The role of the cross-linked tyrosine at the active site still remains unclear. In order to provide insight into the function of the cross-linked tyrosine, we have investigated the spectroscopic and electrochemical properties of chemical analogs of the CuB-His-Tyr site. The analogs, a tridentate histidine-phenol cross-linked ether ligand and the corresponding Cu-containing complex, were previously synthesized in our laboratory (White K. et al.; Chem. Commun. 3252–3254, 2007). Spectrophotometric titrations of the ligand and the Cu-complex indicate a pKA of the phenolic proton of 8.8 and 7.7, respectively. These results are consistent with the cross-linked tyrosine playing a proton delivery role at the cytochrome oxidase active site. The presence of the phenoxyl radical was investigated at low temperature using electron paramagnetic resonance (EPR) and Fourier transform infrared (FT-IR) difference spectroscopy. UV-photolysis of the ligand, without bound copper, generated a narrow g = 2.0047 signal, attributed to the phenoxyl radial. EPR spectra recorded before and after UV photolysis of the Cu-complex showed a g = 2 signal characteristic of oxidized copper, suggesting that the copper is not spin-coupled to the phenoxyl radical. An EPR signal from the phenoxyl radical was not observed in the Cu-complex, either due to spin relaxation of the two unpaired electrons or to masking of the narrow phenoxyl radical signal by the strong copper contribution. Stable isotope (13C) labeling of the phenol ring (C1') Cu-complex, combined with photo-induced difference FT-IR-spectroscopy, revealed bands at 1485 and 1483 cm−1 in the 12C-minus-13C isotope-edited spectra of the ligand and Cu-complex, respectively. These bands are attributed to the radical ν7a' stretching frequency and are shifted to 1468 and 1472 cm−1, respectively, with 13C1' labeling. These results show that a radical is generated in both the ligand and the Cu-complex and support the unambiguous assignment of a vibrational band to the phenoxyl radical ν7a' stretching mode. These data are discussed with respect to a possible role of the cross-linked tyrosine radical in cytochrome oxidase.