Profiling withanolide A for therapeutic targets in neurodegenerative diseases.

To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-κB, TRα, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.

Antiprotozoal Isoprenoids from Salvia hydrangea.

Fractionation of the n-hexane extract of Salvia hydrangea afforded seven isoprenoids including six new compounds (1-6) and salvadione A (7). Their structures were established by comprehensive spectroscopic and spectrometric data analysis (1D and 2D NMR, HRMS). The absolute configuration of salvadione A (7) was established by single-crystal X-ray diffraction analysis with Cu/Kα radiation. In addition, the absolute configuration of all compounds was determined by electronic circular dichroism spectroscopy. A biosynthetic pathway for the formation of the scaffold of 1 is proposed. The antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum was determined, and cytotoxicity was assessed in rat myoblast L6 cells. Perovskone C (2) exhibited good activity against P. falciparum (IC50 0.6 µM) and a selectivity index of 62.2.

Chiral Bifunctional Phosphine-Carboxylate Ligands for Palladium(0)-Catalyzed Enantioselective C-H Arylation.

Previous enantioselective Pd0 -catalyzed C-H activation reactions proceeding via the concerted metalation-deprotonation mechanism employed either a chiral ancillary ligand, a chiral base, or a bimolecular mixture thereof. This study describes the development of new chiral bifunctional ligands based on a binaphthyl scaffold which incorporates both a phosphine and a carboxylic acid moiety. The optimal ligand provided high yields and enantioselectivities for a desymmetrizing C(sp2 )-H arylation leading to 5,6-dihydrophenanthridines, whereas the corresponding monofunctional ligands showed low enantioselectivities. The bifunctional system proved applicable to a range of substituted dihydrophenanthridines, and allowed the parallel kinetic resolution of racemic substrates.

Domino Pd0 -Catalyzed C(sp3 )-H Arylation/Electrocyclic Reactions via Benzazetidine Intermediates.

The Pd0 -catalyzed C(sp3 )-H arylation of 2-bromo-N-methylanilides leads to unstable benzazetidine intermediates that rearrange to benzoxazines through 4π electrocyclic ring-opening and 6π electrocyclization. The introduction of a bulky, non-activatable amide group on the nitrogen atom was key to favor the challenging reductive elimination step and disfavor undesired reaction pathways.

Mixed-Valent Molecular Triple Deckers.

Two phenothiazine (PTZ) moieties were connected via naphthalene spacers to a central arene to result in stacked PTZ-arene-PTZ structure elements. Benzene and tetramethoxybenzene units served as central arenes mediating electronic communication between the two PTZ units. Based on cyclic voltammetry, UV/Vis-NIR absorption, EPR spectroscopy, and computational studies, the one-electron oxidized forms of the resulting compounds behave as class II organic mixed-valence species in which the unpaired electron is partially delocalized over both PTZ units. The barrier for intramolecular electron transfer depends on the nature of the central arene sandwiched between the two PTZ moieties. These are the first examples of rigid organic mixed-valent triple-decker compounds with possible electron-transfer pathways directly across a stacked structure, and they illustrate the potential of oligo-naphthalene building blocks for long-range electron transfer and a future molecular electronics technology.

Intramolecular Light-Driven Accumulation of Reduction Equivalents by Proton-Coupled Electron Transfer.

The photochemistry of a molecular pentad composed of a central anthraquinone (AQ) acceptor flanked by two Ru(bpy)32+ photosensitizers and two peripheral triarylamine (TAA) donors was investigated by transient IR and UV-vis spectroscopies in the presence of 0.2 M p-toluenesulfonic acid (TsOH) in deaerated acetonitrile. In ∼15% of all excited pentad molecules, AQ is converted to its hydroquinone form (AQH2) via reversible intramolecular electron transfer from the two TAA units (τ = 65 ps), followed by intermolecular proton transfer from TsOH (τ ≈ 3 ns for the first step). Although the light-driven accumulation of reduction equivalents occurs through a sequence of electron and proton transfer steps, the resulting photoproduct decays via concerted PCET (τ = 4.7 µs) with an H/D kinetic isotope effect of 1.4 ± 0.2. Moreover, the reoxidation of AQH2 seems to take place via a double electron transfer step involving both TAA+ units rather than sequential single electron transfer events. Thus, the overall charge-recombination reaction seems to involve a concerted proton-coupled two-electron oxidation of AQH2. The comparison of experimental data obtained in neat acetonitrile with data from acidic solutions suggests that the inverted driving-force effect can play a crucial role for obtaining long-lived photoproducts resulting from multiphoton, multielectron processes. Our pentad provides the first example of light-driven accumulation of reduction equivalents stabilized by PCET in artificial molecular systems without sacrificial reagents. Our study provides fundamental insight into how light-driven multielectron redox chemistry, for example the reduction of CO2 or the oxidation of H2O, can potentially be performed without sacrificial reagents.

Collective Syntheses of Icetexane Natural Products Based on Biogenetic Hypotheses.

A divergent synthesis of 10 icetexane natural products based on a proposed biogenetic cationic ring expansion of a reduced carnosic acid derivative is described. Of these icetexanes, (+)-salvicanol, (-)-cyclocoulterone, (-)-coulterone, (-)-obtusinone D, and (-)-obtusinone E have been synthesized for the first time. In addition, the hypothesis for the non-enzymatic biogenesis of benzo[1,3]dioxole natural products has been experimentally investigated. Additional experimental evidence for the abiotic formation of the methylenedioxy unit is provided, as photolysis of the quinone (+)-komaroviquinone resulted in the formation of the [1,3]dioxole-containing natural product (-)-cyclocoulterone and (+)-komarovispirone.

Intramolecular Inverse Electron-Demand [4 + 2] Cycloadditions of Ynamides with Pyrimidines: Scope and Density Functional Theory Insights.

4-Aminopyridines are valuable scaffolds for the chemical industry in general, from life sciences to catalysis. We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in continuous mode in superheated toluene, to overcome the limited scalability of MW reactions, results in a notable production increase compared to batch mode. Finally, density functional theory investigations shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA sequence.

Spin-Delocalization in a Helical Open-Shell Hydrocarbon.

Neutral open-shell molecules, in which spin density is delocalized through a helical conjugated backbone, hold promise as models for investigating phenomena arising from the interplay of magnetism and chirality. Apart from a handful of examples, however, the chemistry of these compounds remains largely unexplored. Here, we examine the prospect of extending spin-delocalization over a helical backbone in a model compound naphtho[3,2,1-no]tetraphene, the first helically chiral open-shell hydrocarbon, in which one benzene ring is fused to [5]helicene, forming a phenalenyl subunit. The unpaired electron in this molecule is delocalized over the entire helical core composed of six rings, albeit in a nonuniform fashion, unlike in phenalenyl. In the case of a monosubstituted derivative, the uneven spin-distribution results in a selective σ-dimer formation in solution, as confirmed by 2D NMR spectroscopy. In contrast, the dimerization process is suppressed entirely when four substituents are installed to sterically hinder all reactive positions. The persistent nature of the tetrasubstituted derivative allowed its characterization by EPR, UV-vis, and CD spectroscopies, validating spin-delocalization through a chiral backbone, in accord with DFT calculations. The nonuniform spin-distribution, which dictates the selectivity of the σ-dimer formation, is rationalized by evaluating the aromaticity of the resonance structures that contribute to spin-delocalization.

Formal Total Synthesis of (-)-Jiadifenolide and Synthetic Studies toward seco-Prezizaane-Type Sesquiterpenes.

Synthetic studies toward highly oxygenated seco-prezizaane sesquiterpenes are reported, which culminated in a formal total synthesis of the neurotrophic agent (-)-jiadifenolide. For the construction of the tricyclic core structure, an unusual intramolecular and diastereoselective Nozaki-Hiyama-Kishi reaction involving a ketone as electrophilic coupling partner was developed. In addition, synthetic approaches toward the related natural product (2R)-hydroxy-norneomajucin, featuring a Mn-mediated radical cyclization for the tricycle assembly and a regioselective OH-directed C-H activation are presented.

Charge Transfer Pathways in Three Isomers of Naphthalene-Bridged Organic Mixed Valence Compounds.

Naphthalene was substituted at different positions with two identical triarylamine moieties to result in species which are mixed-valence compounds in their one-electron oxidized forms. They were investigated by cyclic voltammetry, optical absorption, EPR spectroscopy, X-ray crystallography, and DFT calculations. When the two redox-active triarylamine moieties are connected to the 2- and 6-positions of the naphthalene bridge, their electronic communication is significantly stronger than when they are linked to the 1- and 5-positions, and this can be understood on the basis of a simple through-bond charge transfer pathway model. However, this model fails to explain why electronic communication between triarylamine moieties in the 1,5- and 1,8-isomers is similarly strong, indicating that through-space charge transfer pathways play an important role in the latter. In particular, charge transfer in the 1,8-isomer is likely to occur between the triarylamino C atoms in α-position to the naphthalene linker because the respective atoms are only about 3 Å apart from each other, and because they carry significant spin density in the one-electron oxidized forms of triarylamines. This particular through-space charge transfer pathway might be generally important in molecular structures based on the 1,8-disubstituted naphthalene pillaring motif.

Stereoselective Arene-Forming Aldol Condensation: Synthesis of Configurationally Stable Oligo-1,2-naphthylenes.

Structurally well-defined oligomers are fundamental for the functionality of natural molecular systems and key for the design of synthetic counterparts. Herein, we describe a strategy for the efficient synthesis of individual stereoisomers of 1,2-naphthylene oligomers by iterative building block additions and consecutive stereoselective arene-forming aldol condensation reactions. The catalyst-controlled atropoenantioselective and the substrate-controlled atropodiastereoselective aldol condensation reaction provide structurally distinct ter- and quaternaphthalene stereoisomers, which represent configurationally stable analogues of otherwise stereodynamic, helically shaped ortho-phenylenes.

Cethrene: A Helically Chiral Biradicaloid Isomer of Heptazethrene.

We report the synthesis and properties of "cethrene", the only helically chiral isomer of heptazethrene with a biradicaloid singlet ground state. Cethrene gives a well-resolved EPR spectrum at room temperature and its structure was confirmed by 2D NMR and absorption spectroscopies. Our experiments and calculations show that the helical twist affects its electronic properties and decreases the singlet-triplet energy gap when compared to that of planar heptazethrene. Cethrene undergoes an intramolecular cyclization within several hours at room temperature.

Tuning Helical Chirality in Polycyclic Ladder Systems.

Conceptually and experimentally, a new set of helical model compounds is presented herein that allow correlations between structural features and their expression in the secondary structure to be investigated. A cross-linked oligomer with two strands of mismatching lengths connected in a ladder-type fashion serves as a model system. Compensation for the dimensional mismatch leads to the adoption of a helical arrangement. A strategically placed relay ensures the continuity and uniformity of the helix. Upon exchanging the heteroatomic linkage, the helix responds by increasing or decreasing the torsion of the backbone. Inversion of the relay's substitution pattern causes a distortion of the structure, while maintaining the directionality of the helix. Based on a short synthetic protocol with a modular precursor, four closely related "Geländer" oligomers (Geländer is the German word for bannister) were accessed and fully characterized. XRD analysis for one representative of each helical arrangement and complementary computational studies for the remaining derivatives allowed the impact of the alterations on the secondary structures to be studied. Isolation of pure enantiomers of all new Geländer oligomers provided insight into the racemization kinetics and estimation of the racemization barrier. In silico simulation of the electronic circular dichroism spectra of the model compounds enabled the helicity of the isolated samples to be assigned.

Tetramethoxybenzene is a Good Building Block for Molecular Wires: Insights from Photoinduced Electron Transfer.

Two donor bridge-acceptor molecules with terminal triarylamine and Ru(bpy)3(2+) (bpy = 2,2'-bipyridine) redox partners were synthesized and investigated by cyclic voltammetry, optical absorption, luminescence, and transient absorption spectroscopy. The two dyads differ only by the central bridging unit, which was tetramethoxybenzene (tmb) in one case and unsubstituted phenylene (ph) in the other case. Photoirradiation of the Ru(bpy)3(2+) complex of the two dyads triggers intramolecular electron transfer from the triarylamine to the (3)MLCT-excited metal complex, and this process occurs with time constants of 1.5 and 6.8 ns for the tmb- and ph-bridged dyads, respectively. Thermal electron transfer in the reverse direction then leads to disappearance of the photoproduct with a time constant of 10 ns in both dyads. The faster rate of photoinduced charge transfer in the tmb-bridged dyad can be understood in the framework of a hole-tunneling model in which the electron-rich tmb bridge imposes a more shallow barrier than the less electron-rich ph spacer. Until now tmb-based molecular wires have received very little attention, and alkoxy substituents have been mostly used for improving the solubility of oligo-p-phenylene vinylene (OPV) and oligo-p-phenylene ethynylene (OPE) wires. Our study illustrates how four alkoxy-substituents on a phenylene backbone can have a significant influence on the charge-transfer properties of a molecular wire, and this is relevant in the greater context of a future molecular electronics technology.

Labdane and Clerodane Diterpenoids from Colophospermum mopane.

Five labdane (1-5), an isolabdane (6), and five clerodane diterpenoids (7-11), were isolated from seeds, husks, and leaves of Colophospermum mopane. Compounds 1-3 and 6-9 are new, and their structures were elucidated by means of physical data analysis (1D and 2D NMR, HRESIMS). The absolute configurations of 1, 7, and 10 were determined by single-crystal X-ray diffraction with Cu Kα radiation. For compounds 2 and 6, the absolute configurations were established by the modified Mosher's method and corroborated by comparison of experimental and calculated electronic circular dichroism spectra of their 3-p-bromobenzoate derivatives. The crude extracts and compounds were evaluated for antimicrobial activity. The leaf extract was the most active against Staphylococcus aureus (125 µg/mL). Compound 11 showed the best inhibitory activity, with minimum inhibitory values of 15.6 µg/mL against Escherichia coli and Staphylococcus aureus and 31.3 µg/mL against Enterococcus faecalis.

hERG Channel Inhibitory Daphnane Diterpenoid Orthoesters and Polycephalones A and B with Unprecedented Skeletons from Gnidia polycephala.

The hERG channel is an important antitarget in safety pharmacology. Several drugs have been withdrawn from the market or received severe usage restrictions because of hERG-related cardiotoxicity. In a screening of medicinal plants for hERG channel inhibition using a two-microelectrode voltage clamp assay with Xenopus laevis oocytes, a dichloromethane extract of the roots of Gnidia polycephala reduced the peak tail hERG current by 58.8 ± 13.4% (n = 3) at a concentration of 100 µg/mL. By means of HPLC-based activity profiling daphnane-type diterpenoid orthoesters (DDOs) 1, 4, and 5 were identified as the active compounds [55.4 ± 7.0% (n = 4), 42.5 ± 16.0% (n = 3), and 51.3 ± 9.4% (n = 4), respectively, at 100 µM]. In a detailed phytochemical profiling of the active extract, 16 compounds were isolated and characterized, including two 2-phenylpyranones (15 and 16) with an unprecedented tetrahydro-4H-5,8-epoxypyrano[2,3-d]oxepin-4-one skeleton, two new DDOs (3 and 4), two new guaiane sesquiterpenoids (11 and 12), and 10 known compounds (1, 2, 5-10, 13, and 14). Structure elucidation was achieved by extensive spectroscopic analysis (1D and 2D NMR, HRMS, and electronic circular dichroism), computational methods, and X-ray crystallography.

Isolation and Total Synthesis of Kirkamide, an Aminocyclitol from an Obligate Leaf Nodule Symbiont.

The new C7N aminocyclitol kirkamide (1) was isolated from leaf nodules of the plant Psychotria kirkii by using a genome-driven (1)H NMR-guided fractionation approach. The structure and absolute configuration were elucidated by HRMS, NMR, and single-crystal X-ray crystallography. An enantioselective total synthesis was developed, which delivered kirkamide (1) on a gram scale in 11 steps and features a Ferrier carbocyclization and a Pd-mediated hydroxymethylation. We propose that kirkamide is synthesized by Candidatus Burkholderia kirkii, the obligate leaf symbiont of Psychotria kirkii. Kirkamide (1) was shown to be toxic to aquatic arthropods and insects, thus suggesting that bacterial secondary metabolites play a protective role in the Psychotria/Burkholderia leaf nodule symbiosis.

On the synthesis, characterization and reactivity of N-heteroaryl-boryl radicals, a new radical class based on five-membered ring ligands.

The synthesis and physical characterization of a new class of N-heterocycle-boryl radicals is presented, based on five membered ring ligands with a N(sp(2) ) complexation site. These pyrazole-boranes and pyrazaboles exhibit a low bond dissociation energy (BDE; BH) and accordingly excellent hydrogen transfer properties. Most importantly, a high modulation of the BDE(BH) by the fine tuning of the N-heterocyclic ligand was obtained in this series and could be correlated with the spin density on the boron atom of the corresponding radical. The reactivity of the latter for small molecule chemistry has been studied through the determination of several reaction rate constants corresponding to addition to alkenes and alkynes, addition to O2 , oxidation by iodonium salts and halogen abstraction from alkyl halides. Two selected applications of N-heterocycle-boryl radicals are also proposed herein, for radical polymerization and for radical dehalogenation reactions.

Photoinduced electron transfer in rhenium(I)-oligotriarylamine molecules.

Two molecular triads with an oligotriarylamine multielectron donor were synthesized and investigated with a view to obtaining charge-separated states in which the oligotriarylamine is oxidized 2-fold. Such photoinduced accumulation of multiple redox equivalents is of interest for artificial photosynthesis. The first triad was comprised of the oligotriarylamine and two rhenium(I) tricarbonyl diimine photosensitizers each of which can potentially accept one electron. In the second triad the oligotriarylamine was connected to anthraquinone, in principle an acceptor of two electrons, via a rhenium(I) tricarbonyl diimine unit. With nanosecond transient absorption spectroscopy (using an ordinary pump-probe technique) no evidence for the generation of 2-fold oxidized oligotriarylamine or 2-fold reduced anthraquinone was found. The key factors limiting the photochemistry of the new triads to simple charge separation of one electron and one hole are discussed, and the insights gained from this study are useful for further research in the area of charge accumulation in purely molecular (nanoparticle-free) systems. An important problem of the rhenium-based systems considered here is the short wavelength required for photoexcitation. In the second triad, photogenerated anthraquinone monoanion is protonated by organic acids, and the resulting semiquinone species leads to an increase in lifetime of the charge-separated state by about an order of magnitude. This shows that the proton-coupled electron transfer chemistry of quinones could be beneficial for photoinduced charge accumulation.