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Tris-(2-pyridylmethyl)amines (TPA or TPMA) are polipyrydine-based ligands extensively used in catalysis and supramolecular chemistry due their capability to form stable tetradentate complexes with a large variety of metals. The unsubstituted ligand, which is also commercially available, can be synthesised by consecutive alkylation of a picoline or by reductive amination of a pyridine aldehyde. In this article, we report a novel synthetic method which opens to the post-functionalisation of these ligands in the benzylic position. This novel derivatization strategy, beside providing synthetic access to novel structures and functions, has been used to prepare a series of metal complexes which have been tested in photochemical hydrogen evolution.
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Electron-rich pyridines with π donor groups at the para position play an important role as nucleophiles in organocatalysis, but their ligand properties and utilization in coordination chemistry have received little attention. Herein, we report the synthesis of two electron-rich pyridines 1 and 2 bearing N-heterocyclic imine groups at the para position and explore their coordination chemistry. Experimental and computational methods were used to assess the donor ability of the new pyridines showing that they are stronger donors than aminopyridines and guanidinyl pyridines, and that the nature of the N-heterocyclic backbone has a strong influence on the pyridine donor strength. Coordination compounds with Lewis acids including the CO2, SO2, BCl3 and PdII ions were synthesized and characterized. Despite the ambident character of the new pyridines, coordination preferentially occurs at the pyridine-N atom. Methyl transfer experiments reveal that 1 and 2 can act as demethylation reagents.
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A 9-step synthetic route to a protected form of the C3-epimer of virenose from D-fucose is described. C3-epi-virenose is the carbohydrate unit of the bioactive polyketide elsamicin B and part of the carbohydrate unit of elsamicin A. The developed route enabled preparation of anomerically activated forms of this unique C6-deoxy sugar, including derivatives with 1-acetyl, 1-acetylthio, 1-trichloroacetimidate, 1-bromo, and 1-fluoro substituents.
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Chartspiroton is a recently discovered naphthoquinone natural product that features a spiro-fused benzofuran lactone. We report its first synthesis via an 11-step linear sequence. The sterically hindered tetra-ortho-substituted biaryl subunit was installed by base-induced ring expansion of a readily available 1,3-indandione. This step also liberated the fully substituted naphthalene core unit at the same time. The unique spiro-fused benzofuran lactone of the natural product was constructed via late-stage oxidation of an advanced naphthoquinone.
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Lix MoS2 is not only a lithium battery material, but is also an important precursor for the synthesis of MoS2 nanomaterials. Current syntheses of MoS2 , such as in n-butyllithium/LiBH4 or electrochemically, are not satisfying in terms of defined stoichiometry and crystallinity, so an accurate experimental crystal structure determination of this important and widely used material has been long awaited. A high-pressure/high-temperature synthesis yielded highly crystalline 1T''-Lix MoS2 (x=1, 1.333). 1T''-LiMoS2 crystallizes in the space group P 1 â¾ $\bar 1$ with a=6.2482(3)â Å, b=6.6336(3)â Å, c=6.7480(3)â Å, α=119.321(2)°, ß=90.010(2)° and γ=90.077(2)°. The arrangement of Mo atoms within the b-c-plane confirmed a predicted Peierls distortion. A similar atom distribution pattern to that of Mo is also observed for the lithium atoms. Calculation of bond valence site energies gave an activation barrier of 1.244â eV for 2D lithium-ion migration. For x=1.333, a phase-pure synthesis was achieved.
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We present a comprehensive account on our efforts behind the recently published synthesis of waixenicin A. Our approach for constructing the dihydropyran ring relied on an Achmatowicz rearrangement. For the assembly of the nine-membered ring, four distinct strategies were investigated. Our initial attempts using radical-based addition/fragmentation reactions targeting the C7-C11 bond proved unsuitable for accessing the 6/9-bicycle. By employing anionic fragmentation conditions at the furfuryl alcohol stage, we successfully reached a 5/9-bicycle. However, subsequent ring-expansion was unsuccessful. Alternative approaches, such as Nozaki-Hiyama-Kishi or Heck reactions to connect the C6-C7 bond, also encountered difficulties, with no nine-membered ring formation observed. Our first breakthrough came from our attempts to install the C5-C6 bond via an intramolecular alkylation. Surprisingly, subsequent functional group modifications proved unexpectedly challenging, necessitating a redesign of our synthetic route. Drawing from all our investigations, we concluded that construction of the C9-C10 bond would enable efficient nine-membered ring alkylation and would facilitate the installation of the desired substitution pattern along the southern periphery. Exploration of this strategy yielded further surprises but ultimately led to the successful synthesis of waixenicin A and 9-deacetoxy-14,15-deepoxyxeniculin. For the latter compound, a bioinspired one-step rearrangement to xeniafauranol A was achieved.
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Platinum-based chemotherapeutics are a cornerstone in the treatment of many malignancies. However, their dose-limiting side effects have rooted efforts to develop new drug candidates with higher selectivity for tumor tissues and less problematic side effects. Here, we developed a cytotoxic platinum(II) complex based on Zeise's salt, containing the nonsteroidal anti-inflammatory drug acetylsalicylic acid and alanine as ligands (4). The previously developed complex (5) displayed high reactivity against sulfur-containing biomolecules; therefore, we put the focus on the optimization of the structure regarding its stability. Different amino acids were used as biocompatible chelating ligands to achieve this aim. Differences in the coordination sphere caused pronounced changes in the stability of Zeise-type precursors 1-3. Coordination with l-Ala through N in the trans position to ethylene showed the most promising results and was employed to stabilize 5. As a result, complex 4 showed improved stability and cytotoxicity, outperforming both 5 and 1.
Assuntos
Antineoplásicos , Platina , Platina/química , Aminoácidos , Antineoplásicos/farmacologia , Antineoplásicos/química , Quelantes/farmacologia , Aspirina/farmacologia , Aspirina/química , LigantesRESUMO
The impact of methoxy and hydroxyl groups at the salicylidene moiety of chlorido[N,N'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) complexes was evaluated on human MDA-MB 231 breast cancer and HL-60 leukemia cells. Methoxylated complexes (C1-C3) inhibited proliferation, migration, and metabolic activity in a concentration-dependent manner following the rank order: C2 > C3 > C1. In particular, C2 was highly cytotoxic with an IC50 of 4.2 µM which was 6.6-fold lower than that of cisplatin (IC50 of 27.9 µM). In contrast, hydroxylated complexes C4-C6 were almost inactive up to the highest concentration tested due to lack of cellular uptake. C2 caused a dual mode of cell death, ferroptosis, and necroptosis, whereby at higher concentrations, ferroptosis was the preferred form. Ferroptotic morphology and the presence of ferrous iron and lipid reactive oxygen species proved the involvement of ferroptosis. C2 was identified as a promising lead compound for the design of drug candidates inducing ferroptosis.
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Antineoplásicos , Ferro , Humanos , Antineoplásicos/química , Morte Celular , Linhagem Celular Tumoral , Etilenodiaminas/farmacologia , Etilenodiaminas/química , Ferro/química , Complexos de Coordenação/químicaRESUMO
We report the synthesis of 17 molybdenum and tungsten complexes supported by the ubiquitous BDI ligand framework (BDI = ß-diketiminate). The focal entry point is the synthesis of four molybdenum and tungsten(V) BDI complexes of the general formula [MO(BDIR)Cl2] [M = Mo, R = Dipp (1); M = W, R = Dipp (2); M = Mo, R = Mes (3); M = W, R = Mes (4)] synthesized by the reaction between MoOCl3(THF)2 or WOCl3(THF)2 and LiBDIR. Reactivity studies show that the BDIDipp complexes are excellent precursors toward adduct formation, reacting smoothly with dimethylaminopyridine (DMAP) and triethylphosphine oxide (OPEt3). No reaction with small phosphines has been observed, strongly contrasting the chemistry of previously reported rhenium(V) complexes. Additionally, the complexes 1 and 2 are good precursors for salt metathesis reactions. While 1 can be chemically reduced to the first stable example of a Mo(IV) BDI complex 15, reduction of 2 resulted in degradation of the BDI ligand via a nitrene transfer reaction, leading to MAD (4-((2,6-diisopropylphenyl)imino)pent-2-enide) supported tungsten(V) and tungsten(VI) complexes 16 and 17. All reported complexes have been thoroughly studied by VT-NMR and (heteronuclear) NMR spectroscopy, as well as UV-vis and EPR spectroscopy, IR spectroscopy, and X-ray diffraction analysis.
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Zeise's salt derivatives of the potassium trichlorido[η2-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl3/ASA-But-PtCl3 derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl3 and ASA-But-PtCl3 interfere with the arachidonic acid cascade as part of their mode of action to reduce the growth of COX-1/2-expressing tumor cells. With the aim to increase the antiproliferative activity by strengthening the inhibitory potency against COX-2, F, Cl, or CH3 substituents were introduced into the acetylsalicylic acid (ASA) moiety. Each structural modification improved COX-2 inhibition. Especially compounds with F substituents at ASA-But-PtCl3 reached the maximum achievable inhibition of about 70% already at 1 µM. The PGE2 formation in COX-1/2-positive HT-29 cells was suppressed by all F/Cl/CH3 derivatives, indicating COX inhibitory potency in cellular systems. The CH3-bearing complexes showed the highest cytotoxicity in COX-1/2-positive HT-29 cells with IC50 values of 16-27 µM. In COX-negative MCF-7 cells, they were 2-3-fold less active. These data clearly demonstrate that it is possible to increase the cytotoxicity of ASA-Prop-PtCl3 and ASA-But-PtCl3 derivatives by enhancing COX-2 inhibition.
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The reactivities of halido[1,3-diethyl-4,5-diphenyl-1H-imidazol-2-ylidene]gold(I) (chlorido (5), bromido (6), iodido (7)), bis[1,3-diethyl-4,5-diphenyl-1H-imidazol-2-ylidene]gold(I) (8), and bis[1,3-diethyl-4,5-diphenyl-1H-imidazol-2-ylidene]dihalidogold(III) (chlorido (9), bromido (10), iodido (11)) complexes against ingredients of the cell culture medium were analyzed by HPLC. The degradation in the RPMI 1640 medium was studied, too. Complex 6 quantitatively reacted with chloride to 5, while 7 showed additionally ligand scrambling to 8. Interactions with non-thiol containing amino acids could not be detected. However, glutathione (GSH) reacted immediately with 5 and 6 yielding the (NHC)gold(I)-GSH complex 12. The most active complex 8 was stable under in vitro conditions and strongly participated on the biological effects of 7. The gold(III) species 9-11 were completely reduced by GSH to 8 and are prodrugs. All complexes were tested for inhibitory effects in Cisplatin-resistant cells, as well as against cancer stem cell-enriched cell lines and showed excellent activity. Such compounds are of utmost interest for the therapy of drug-resistant tumors.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos de Bifenilo , Técnicas de Cultura de Células , Ouro/química , Hidrocarbonetos Halogenados/químicaRESUMO
We present a concise asymmetric total synthesis (5-8â steps) of nine sesquiterpenoid alkaloids featuring four different tetra-/pentacyclic scaffolds. To this end, a novel, bioinspired indole N-terminated cationic tricyclization has been developed, enabling the divergent synthesis of greenwayodendrines and polysin. Subtle variation of the C2-substituted indole cyclization precursor allowed switching between indole N- and C-termination. For the latter, a subsequent Witkop oxidation enabled conversion of the cyclopentene-fused indole into the eight-membered benzolactam to directly furnish the family of greenwaylactams. In addition, a diastereomeric C-termination product has been elaborated to provide access to polyveoline.
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The use of chiroptical techniques in combination with stereodynamic probes is becoming one of the leading strategies for chiral sensing. While in most of the reported studies circular dichroism (CD) is the adopted spectroscopic technique, examples regarding the use of vibrational CD (VCD), circularly polarized luminescence (CPL), and Raman optical activity (ROA) are emerging as innovative tools. In this communication, an anthracene-decorated tris(2-pyridylmethyl)amine zinc complex (TPMA) is reported for its capability to act as a chiral sensor using either CD or fluorescence detected circular dichroism (FDCD). The latter technique offers the unique possibility to determine the enantiomeric excess of a series of carboxylic acids at sensor concentrations down to 0.1 µM. Limitations and possibilities opened by the use of this methodology, in particular regarding the specificity of the probe in the presence of another contaminant, are discussed.
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The first asymmetric total synthesis of the Xenia diterpenoid waixenicin A, a potent and highly selective TRPM7 inhibitor, is reported. The characteristic trans-fused oxabicyclo[7.4.0]tridecane ring system was constructed via a diastereoselective conjugate addition/trapping sequence, followed by an intramolecular alkylation to forge the 9-membered ring. While a ß-keto sulfone motif enabled efficient ring-closure, the subsequent radical desulfonylation suffered from (E)/(Z)-isomerization of the C7/C8-alkene. Conducting the sequence with a trimethylsilylethyl ester allowed for a fluoride-mediated decarboxylation that proceeded without detectable isomerization. The acid-labile enol acetal of the delicate dihydropyran core was introduced at an early stage and temporarily deactivated by a triflate function. The latter was critical for the introduction of the side chain. Diverting from a common late-stage intermediate provided access to waixenicin A and 9-deacetoxy-14,15-deepoxyxeniculin. A high-yielding base-mediated dihydropyran-cyclohexene rearrangement of 9-deacetoxy-14,15-deepoxyxeniculin led to xeniafaraunol A in one step.
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Dynamic covalent chemistry (DCC) has, in recent years, provided valuable tools to synthesize molecular architectures of increasing complexity. We have also taken advantage of imine DCC chemistry to prepare TPMA-based supramolecular cages for molecular recognition applications. However, the versatility of this approach has as a major drawback the intrinsic hydrolytic lability of imines, which hampers some applications. We present herein a synthetic strategy that combines the advantages of a thermodynamic-driven formation of a supramolecular structure using imine chemistry, together with the possibility to synthetize chiral hydrolytically stable structures through a [3,3]-sigmatropic rearrangement. A preliminary mechanistic analysis of this one-pot synthesis and the scope of the reaction are also discussed.
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The title compound, [Mn(C7H7)(C6H5O2)]PF6 or [(Cht)Mn(Cp'CO2H)]PF6, with Cht = cyclo-hepta-trienyl and Cp' = C5H4, is an air-stable, purple, heteroleptic, cationic sandwich complex with manganese in oxidation state +I and π-coordinating cyclo-hepta-trienyl and cyclo-penta-dienyl ligands. The latter ligand carries the carb-oxy-lic acid functionality. This 'tromancenium-8-carb-oxy-lic acid' with hexa-fluorido-phosphate as counter-ion represents a rare case of a cationic carb-oxy-lic acid. Structurally, this organometallic carb-oxy-lic acid displays the common motif of planar Osp 2â¯H-Osp 3/Osp 3-Hâ¯Osp 2 hydrogen-bonded carb-oxy-lic acid dimers with anti-oriented metallocenyl moieties, the cationic charge of which is balanced by octa-hedrally shaped hexa-fluorido-phosphate anions. Positional disorder is observed in the cyclo-hepta-trienyl ring and the PF6 - anion.
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Building on studies of monoclinic Li3SiNO2, a polymorph, ß-Li3SiNO2, with a previously unknown structure type was synthesized. The ß-phase crystallizes in the orthorhombic space group Pbca (no. 61) with lattice parameters of a = 18.736(2), b = 11.1267(5), c = 5.0897(3) Å, and a cell volume of V = 1057.2(1) Å3. Using high-temperature solid-state reactions in sealed tantalum tubes, it was possible to obtain high purity samples (<5 wt% of side phase LiSi2N3 according to Rietveld analysis) containing exclusively one or the other polymorph, depending solely on the cooling rate. In contrast to the monoclinic phase, orthorhombic ß-Li3SiNO2 additionally contains a third layer and shows a layer-sequence of the type ABCB. Doped with the activator ion Eu2+, the new polymorph exhibits an intense yellow emission (λmax = 586 nm, fwhm = 89 nm, 0.33 eV, 2650 cm-1) under irradiation with UV to blue light. Hence, the structural difference between the two polymorphs goes along with a significant blue-shift of 16 nm. The results from single-crystal diffraction and single-grain luminescence measurements were confirmed by Rietveld analysis of bulk samples and powder luminescence data.
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Cobaltocenium carbaldehyde (formylcobaltocenium) hexafluoridophosphate, a long sought-after functionalized cobaltocenium salt, is accessible from cobaltocenium carboxylic acid by a three-step synthetic sequence involving (i) chlorination to the acid chloride, (ii) copper-borohydride reduction to the hydroxymethyl derivative, and (iii) Dess-Martin oxidation to the title compound. Due to the strongly electron-withdrawing cationic cobaltocenium moiety, no standard aldehyde reactivity is observed. Instead, nucleophilic addition followed by haloform-type cleavage prevails, thereby ruling out common useful aldehyde derivatization. One-electron reduction of cobaltocenium carbaldehyde hexafluoridophosphate affords the deep-blue, isolable cobaltocene carbaldehyde 19-valence-electron radical whose spin density is located fully at cobalt and not at the formyl carbon atom. 1H/13C NMR, IR, EPR spectroscopy, high-resolution mass spectrometry, cyclic voltammetry, single crystal structure analysis (XRD), and density functional theory are applied to characterize these unusual formyl-cobaltocenium/cobaltocene compounds.
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1,4-Diphosphabarrelenes are bicyclic diphosphines relevant, for example, for the generation of polymetallic coordination compounds. However, current synthetic protocols either suffer from low yields or require multiple reaction steps. Herein, we report the one-step synthesis of pyrrole-based 1,4-diphosphabarrelenes that are obtained in very good yields from the reaction of 1,2,5-trimethylpyrrole with 1,2-bis(dichlorophosphino)ethane or 1,2-bis(dichlorophosphino)benzene. The new caged diphosphines are strong donor ligands and act as bridging ligand in nickel(0), rhodium(I), iridium(I) and copper(I) coordination compounds.