Synthesis of Functionalized Tetrasubstituted Allenes by the Addition of Bis(trimethylsilyl)ketene Acetals to Ynones Catalyzed by Gold(I).

We have developed a straightforward and rapid methodology for the synthesis of tetrasubstituted allenes bearing carboxylic acids in the 1,3-position through the gold(I)-catalyzed nucleophilic addition of bis(trimethylsilyl)ketene acetals to ynones. The reaction was evaluated with several substrates, and 21 allenes were obtained in moderate to good yields. Using DFT calculations, we studied the mechanism of the reaction, which suggested a nucleophilic 1,4-addition pathway. The potential of allenes to act as a source of highly functionalized lactones was also explored.

Stereoelectronic interactions are too weak to explain the molecular conformation in solid state of cis-2-tert-butyl-5-(tert-butylsulfonyl)-1,3-dioxane.

cis-2-tert-Butyl-5-(tert-butylsulfonyl)-1,3-dioxane (cis-1) exhibits a high degree of eclipsing in the H-C5-S-C segment in the solid state, the origin of which remains unexplained. The eclipsed conformation that corresponds to an energetic minimum in the solid state practically corresponds to a rotational transition state in solution, which allows an approach to understand transitions states. The difference in the enthalpy of sublimation ΔsubH between cis-1 and the more stable trans-1 is 8.40 kcal mol-1, lets to consider that the intermolecular interactions in the crystalline structure must be responsible for the conformational effect observed in the solid state. The study of the experimental electron density of cis-1 in solid state allowed to establish that CH⋯OS intermolecular interaction is the main contribution to the observed eclipsing. The charge density analysis was also performed using the quantum theory of atoms in molecules to evaluate the nature and relevance of the intermolecular interactions in the crystal structure.

First Gallium and Indium Crystal Structures of Curcuminoid Homoleptic Complexes: All-Different Ligand Stereochemistry and Cytotoxic Potential.

The crystal structure determination of metal complexes of curcuminoids is a relevant topic to assess their unequivocal molecular structure. We report herein the first two X-ray crystal structures of homoleptic metal complexes of a curcuminoid, namely Dimethoxycurcumin (DiMeOC), with gallium and indium. Such successful achievement can be attributed to the suppression of interactions from the phenolic groups, which favor an appropriate molecular setup, rendering Dimethoxycurcumin gallium ((DiMeOC)2-Ga) and Dimethoxycurcumin indium ((DiMeOC)3-In) crystals. Surprisingly, the conformation of ligands in the crystal structures shows differences in each metal complex. Thus, the ligands in the (DiMeOC)2-Ga complex show two different conformers in the two molecules of the asymmetric unit. However, the ligands in the (DiMeOC)3-In complex exhibit three different conformations within the same molecule of the asymmetric unit, constituting the first such case described for an ML3 complex. The cytotoxic activity of the (DiMeOC)2-Ga complex is 4-fold higher than cisplatin against the K562 cell line and has comparable activity towards U251 and PC-3 cell lines. Interestingly, this complex exhibit three times lesser toxicity than cisplatin and even slightly lesser cytotoxicity than curcumin itself.

Homoleptic Complexes of Heterocyclic Curcuminoids with Mg(II) and Cu(II): First Conformationally Heteroleptic Case, Crystal Structures, and Biological Properties.

We report herein the synthesis and characterization of three heterocyclic curcuminoid ligands and their homoleptic metal complexes with magnesium and copper. Thus, N-methyl-2-pyrrolecarboxaldehyde, Furan-2-carboxaldehyde, and 2-Thiophenecarboxaldehyde were condensed with 2,4-pentanedione-boron trioxide complex. The first N-methyl-2-pyrrole curcuminoid and its Mg(II) complex are reported. All curcuminoid ligands and their corresponding metal complexes were characterized by infrared spectroscopy (IR), liquid state nuclear magnetic resonance (LSNMR), electron paramagnetic resonance (EPR), mass spectrometry (MS) and single crystal X-ray diffraction (SCXRD). The ThiopheneCurc-Cu (9) constitutes the first case of a "conformationally-heteroleptic" complex. The unique six-peaks star arrangement for the ThiopheneCurc ligand derived from the supramolecular description is reported. The metal complexes of FuranCurc-Mg (5) and ThiopheneCurc-Cu (9) have a good antioxidant effect (IC50 = 11.26 ± 1.73 and 10.30 ± 0.59 µM), three and two times higher than their free ligands respectively. Additionally, (5) shows remarkable cytotoxicity against colon cancer adenocarcinoma cell line HCT-15, comparable to that of cisplatin, with a negligible toxic effect in vitro towards a healthy monkey kidney cell line (COS-7).

The Homoleptic Curcumin-Copper Single Crystal (ML2): A Long Awaited Breakthrough in the Field of Curcumin Metal Complexes.

The first single crystal structure of the homoleptic copper (II) ML2 complex (M=Cu (II), L = curcumin) was obtained and its structure was elucidated by X-ray diffraction showing a square planar geometry, also confirmed by EPR. The supramolecular arrangement is supported by C-H···O interactions and the solvent (MeOH) plays an important role in stabilizing the crystal packing Crystallinity was additionally assessed by XRD patterns. The log P value of the complex (2.3 ± 0.15) was determined showing the improvement in water solubility. The cytotoxic activity of the complex against six cancer cell lines substantially surpasses that of curcumin itself, and it is particularly selective against leukemia (K562) and human glioblastoma (U251) cell lines, with similar antioxidant activity to BHT. This constitutes the first crystal structure of pristine curcumin complexed with a metal ion.

Effect of the nO → π*C═O Interaction on the Conformational Preference of 1,3-Diketones: A Case Study of Riolozatrione Derivatives.

The cyclopropane ring-opening reaction of riolozatrione, a natural product obtained from Jatropha dioica, afforded a 2,2-disubstituted 1,3-cyclohexandione displaying an alkyl methyl ether group at position 5. The conformational analysis of this product showed a high preference for the trans-diaxial conformation in both solution and solid state. Such conformation was possible from the noncovalent intramolecular nX → π*C═O interactions (X = an element having an unshared electron pair), allowing the determination of the interaction energies. Since the nX → π*C═O interactions can be regarded as additive, the energy values ranged from 4.52 to 6.51 kcal mol-1 for each carbonyl group with a strong dependency on the interatomic distances. The rigorous analysis of the electron density in the topological theory of atoms in molecules framework clearly shows that the origin of O-C═O interactions are through the nO → π*C═O electron transfer mechanism. Such interactions are slightly weaker than a canonical hydrogen bond but seemingly stronger than a van der Waals interaction. This interaction must be considered as a stereoelectronic effect due the electronic transfer between the interacting groups, which are limited by their relative stereochemistry and can be represented by a bond-no bond interaction, causing the pyramidalization of the carbonyl, which is the charge acceptor group.

Hydrogen-Bonded Crystalline Molecular Machines with Ultrafast Rotation and Displacive Phase Transitions.

Two new crystalline rotors 1 and 2 assembled through N-H⋅⋅⋅N hydrogen bonds by using halogenated carbazole as stators and 1,4-diaza[2.2.2]bicyclooctane (DABCO) as the rotator, are described. The dynamic characterization through 1 H T1 relaxometry experiments indicate very low rotational activation barriers (Ea ) of 0.67 kcal mol-1 for 1 and 0.26 kcal mol-1 for 2, indicating that DABCO can reach a THz frequency at room temperature in the latter. These Ea values are supported by solid-state density functional theory computations. Interestingly, both supramolecular rotors show a phase transition between 298 and 250 K, revealed by differential scanning calorimetry and single-crystal X-ray diffraction. The subtle changes in the crystalline environment of these rotors that can alter the motion of an almost barrierless DABCO are discussed here.

Non-Cytotoxic Dibenzyl and Difluoroborate Curcuminoid Fluorophores Allow Visualization of Nucleus or Cytoplasm in Bioimaging.

Curcumin, the most important secondary metabolite isolated from Curcuma longa, is known for its numerous purported therapeutic properties and as a natural dye. Herein, based on curcumin's intrinsic fluorescence, a search for improved curcumin-based fluorophores was conducted. Within the set of semi-synthetic curcumin derivatives i.e. mono (1), di (2), tri (3), tetra (4) benzylated and dibenzyl-fluoroborate (5), the fluorescence properties of 2 and 5 in solution outstood with a two-fold quantum yield compared to curcumin. Furthermore, all benzylated derivatives showed a favorable minimal cytotoxic activity upon screening at 25 µM against human cancer and non-tumoral COS-7 cell lines, with a reduction of its cytotoxic effect related to the degree of substitution. Fluorophores 2 and 5 are versatile bioimaging tools, as revealed by Confocal Fluorescence Microscopy (CFM), and showed permeation of living cell membranes of astrocytes and astrocytomas. When 2 is excited with a 405- (blue) or 543-nm (green) laser, it is possible to exclusively and intensively visualize the nucleus. However, the fluorescence emission fades as the laser wavelength moves towards the red region. In comparison, 5 allows selective visualization of cytoplasm when a 560-nm laser is used, showing emission in the NIR region, while it is possible to exclusively observe the nucleus at the blue region with a 405-nm laser.

Labdanes, Withanolides, and Other Constituents from Physalis nicandroides.

Chemical investigation of the aerial parts (except fruits and calixes) of Physalis nicandroides var. attenuata led to the isolation of a series of new labdane-type diterpenoids, including the closely related compounds 1-3, the labdane glucosides 4 and 5, a mixture of the epimeric alcohols 6 and 7, and one labdanetriol, isolated as its tri-O-acetyl derivative 9. In addition, three new withanolides (14-16) and six known compounds were isolated. The structures of these compounds were elucidated by analysis of their spectroscopic data and chemical transformations, and those of compounds 1, 4, and 16 were confirmed by X-ray diffraction analysis of the natural product (1) and of the corresponding acetyl derivatives 4a and 16a. Fourteen of these compounds were assayed for their in vitro inhibitory activity against yeast α-glucosidase and acetylcholinesterase enzymes. The results were negative in both cases, except for compound 3a that marginally inhibited the activity of acetylcholinesterase with an IC50 value of 64.4 µM.

Amarisolide F, an Acylated Diterpenoid Glucoside and Related Terpenoids from Salvia amarissima.

Nine terpenoids were isolated from the leaves and flowers of Salvia amarissima, including a new acylated diterpenoid glucoside, amarisolide F (1), a new neo-clerodane diterpenoid, amarissinin D (2), which was isolated as an acetyl derivative (2a), and four known diterpenoids. The structure of amarisolide F (1) was elucidated by NMR and MS data analyses, as well as its methanolysis products 7 and 8, which also constituted new diterpenoids, named amarissinin E and 8- epi-amarissinin E, respectively. The absolute configuration of compound 7 was established by single-crystal X-ray diffraction. The cytotoxicity and anti-MDR effect of 1 in three phenotypes of the MCF-7 cell lines were assayed. Compound 1 was 2-3.6-fold more active than amarissinins A (3) and B (4), but several orders of magnitude less active than teotihuacanin (6) and reserpine.

A New Family of Homoleptic Copper Complexes of Curcuminoids: Synthesis, Characterization and Biological Properties.

We report herein the synthesis and crystal structures of five new homoleptic copper complexes of curcuminoids. The scarcity of reports of homoleptic complex structures of curcuminoids is attributed to the lack of crystallinity of such derivatives, and therefore, their characterization by single crystal X-ray diffraction is rare. The ligand design suppressing the phenolic interaction by esterification or etherification has afforded a significant increase in the number of known crystal structures of homoleptic metal complexes of curcuminoids revealing more favorable crystallinity. The crystal structures of the present new copper complexes show four-fold coordination with a square planar geometry. Two polymorphs were found for DiBncOC-Cu when crystallized from DMF. The characterization of these new complexes was carried out using infrared radiation (IR), nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and single crystal X-ray diffraction (SCXRD) and the antioxidant and cytotoxic activity of the obtained complexes was evaluated.

Multifunctional Fischer Aminocarbene Complexes as Hole or Electron Transporting Layers in Organic Solar Cells.

A new series of Fischer carbenes have been synthetized and examined as hole-transporting or electron-transporting layers (HTLs or ETLs) in the fabrication of organic solar cells (OSCs). The synthesis of three Fischer aminocarbene complexes with the general formula [Cr(CO)5{C(NHCH2)Ar}] (Ar = 2-pyridyl (3a), 3-pyridyl (3b) and 4-pyridyl (3c)) is reported. The molecular structure of complex 3b has been confirmed by X-ray analysis. In order to study the possible applications of the three Fischer aminocarbenes in OSCs, thin films of these complexes were prepared using a vacuum deposition process. These organometallic films were chemically and morphologically characterized by IR spectroscopy, SEM, AFM and XRD. According to the IR and Tauc analysis, the vacuum deposition process generates thin films free of impurities with an activation energy of 4.0, 2.7 and 2.1 eV for 3a, 3b y 3c, respectively. The UV-vis spectra of the amorphous aminocarbene films show that they are practically transparent to the visible radiation of the electromagnetic spectrum. This is due to the fact that their absorption is located mainly in the ultraviolet range. Two OSCs with bulk-heterojunction configuration were manufactured in order to prove the use of the aminocarbenes as ETL o HTL. The aminocarbene [Cr(CO)5{C(NHCH2) 4-pyridyl}] (3c) proved to be suitable as ETL with a fill factor (FF) of 0.23 and a short circuit current density (JSC) of 1.037 mA/cm².

neo-Clerodane Diterpenoids from Salvia polystachya Stimulate the Expression of Extracellular Matrix Components in Human Dermal Fibroblasts.

Eleven neo-clerodane diterpenoids (1-11) including the new analogues 1, 2, and 10, and 3',5,6,7-tetrahydroxy-4'-methoxyflavone (12) were isolated from the aerial parts of Salvia polystachya. Polystachyne G (1) and 15-epi-polystachyne G (2) were isolated as an epimeric mixture, containing a 5-hydroxyfuran-2(5H)-one unit in the side chain at C-12 of the neo-clerodane framework. Polystachyne H (10) contains a 1(10),2-diene moiety and a tertiary C-4 hydroxy group. The structures of these compounds were established by analysis of their NMR spectroscopic and MS spectrometric data. The absolute configurations of compounds 3, 4, and 10 were determined through single-crystal X-ray diffraction analysis. The antibacterial, antifungal, and phytotoxic activities of the diterpenoids were determined. In addition, the stimulatory effect of the expression of extracellular matrix components of nine of the isolates (1-8 and 11) was assayed. Compounds 1-4, 8, and 11 increased the expression of the genes codifying for type I, type III, and type V collagens and for elastin.

Cadinane-Type Sesquiterpenoids from Heterotheca inuloides: Absolute Configuration and Anti-inflammatory Activity.

Eight cadinane-type sesquiterpenoids (1-8) together with some triterpenoids, flavonoids, and sterols were isolated from the aerial parts of Heterotheca inuloides. The structures of the new compounds (1-4) were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis. The structures of the new (1-3) and the known (5-7) sesquiterpenoids were confirmed by X-ray crystallography. The absolute configurations of metabolites 2-5 were determined by comparing their experimental and calculated electronic circular dichroism spectra and confirmed via refinement of the Flack parameter using anomalous X-ray scattering from the oxygen atoms and chemical correlation methods. The sesquiterpenoids were evaluated for their anti-inflammatory potential by applying the TPA-induced mouse ear edema model. The results revealed that some of these metabolites exhibit moderate anti-inflammatory activity. At a dose of 228 µg/ear compound 1 showed 43.14 ± 8.09% inhibition on ear edema, indicating an IC50 > 228 µg/ear.

Structure elucidation of a new isoflavone by exclusive use of ¹H NMR measurements.

The leaves of Piscidia carthagenensis provided new 7,2',5'-trimethoxy-3',4'-methylenedioxyisoflavone (1), admixed with known 6,7-dimethoxy-3',4'-methylenedioxyisoflavone (2), and 5,4'-dihydroxy-7,2',5'-trimethoxyisoflavone (3), which were separated by extensive fractional solubillization. Selective irradiation of the H-5 "singlet" of 2 allowed distinction of the two methoxy group signals, whose chemical shift difference is only 0.004 ppm (1.2 Hz at 300 MHz). The (1)H and (13)C NMR data of 3 were assigned with the aid of HETCOR and gHMBC measurements. Although 1 looked inhomogeneous in the solid state, its solution structure followed from (1)H NMR measurements, where it looked homogeneous. To clarify the solid state aspect and confirm the structure of 1, two types of crystals were mechanically separated and subjected to single crystal X-ray diffraction measurements. This study revealed polymorphism because of the concomitant presence of orthorhombic and triclinic crystals, but showed no atropisomerism. The structure of 3 was also verified by X-ray diffraction crystallography.

5,10-seco-neo-clerodanes and neo-clerodanes from Salvia microphylla.

Two new 5,10-seco-neo-clerodanes, salvimicrophyllins A and B (1 and 2), and two new neo-clerodanes, salvimicrophyllins C and D (3 and 4), were isolated from the leaves and flowers of Salvia microphylla. The structures of these compounds were elucidated mainly by analysis of their NMR spectroscopic and mass spectrometric data. The relative configurations of the salvimicrophyllins were determined by analysis of NOESY spectra and ECD curves, and the relative configuration of compound 2 was confirmed by single-crystal X-ray diffraction crystallography.

Well-defined Cu(I) complexes based on [N,P]-pyrrole ligands catalyzed a highly endoselective 1,3-dipolar cycloaddition.

We herein report the synthesis and catalytic application of a new family of dinuclear Cu(I) complexes based on [N,P]-pyrrole ligands. The Cu(I) complexes (4a-d) were obtained in good yields and their catalytic properties were evaluated in the1,3-dipolar cycloaddition of azomethine ylides and electron-deficient alkenes. The air-stable complexes 4a-d exhibited high endo-diasteroselectivity to obtain substituted pyrrolidines, and the catalytic system showed excellent reactivity and wide substitution tolerance.

An enantioselective approach to furanoeremophilanes: (+)-9-oxoeuryopsin.

An enantioselective total synthesis of the furanoeremophilane sesquiterpene (+)-9-oxoeuryopsin 1 is reported. The synthesis involves as a key step a copper(II) triflate catalyzed tandem asymmetric conjugate addition of AlMe3 to 2-methyl-2-cyclohexen-1-one with the Feringa (S,R,R)-phosphoramidite binaphthol ligand, followed by aldol condensation of the resulting aluminum enolate with 4-methyl-3-furaldehyde 4. This tandem transformation has not been previously reported with a 2-substituted-2-cyclohexen-1-one. Conventional functional group manipulations completed the synthesis.

Three new coordination geometries of homoleptic Zn complexes of curcuminoids and their high antiproliferative potential.

To our previously reported first crystal structure of a homoleptic zinc curcuminoid complex with square pyramidal geometry, we add herein three new geometries of homoleptic type complexes i.e. octahedral, trigonal-pyramidal, and trigonal-bipyramidal. Octahedral geometry was observed in the new pseudo-polymorph of the DAC-Zn complex resulting from crystallization in DMF, while square-pyramidal geometry was obtained in DMSO. Improving crystallinity involved suppressing the phenolic interactions by etherification and esterification. The complete characterization of these complexes was carried out using SCXRD, IR, MS, EA, liquid, and solid-state NMR. Moreover, the cytotoxic activity of all complexes was evaluated. The IC50 values for the DiMeOC-Zn (7) complex were 8 or 22 times higher than for cisplatin in the U251 and HCT-15 cell lines, indicating a high antiproliferative and therapeutic potential.

Unreported ent-rosane diterpenes from Croton niveus Jacq. (Euphorbiaceae). Cytotoxic activity and docking studies.

From the bioactive extract of the euphorbiaceous Croton niveus Jacq., three previously unreported ent-rosane diterpenes have been isolated and characterized by conventional methods, in addition to the known compounds lupeol, cajucarinolide and some phytosterols. Two of the ent-rosane diterpenes displayed activity against HCT-15 and PC-3 cancer cell lines, and the results of docking calculations of these compounds with NF-κB and STAT3 receptors agreed with the proposed mode of action of diterpenes against PC-3 cells.