Antiplasmodial and cytotoxic activities of the constituents of Turraea robusta and Turraea nilotica.

ETHNOPHARMACOLOGICAL RELEVANCE: Turraea robusta and Turraea nilotica are African medicinal plants used for the treatment of a wide variety of diseases, including malaria. The genus Turraea is rich in limonoids and other triterpenoids known to possess various biological activities. MATERIALS AND METHODS: From the stem bark of T. robusta six compounds, and from various parts of T. nilotica eleven compounds were isolated by the use of a combination of chromatographic techniques. The structures of the isolated compounds were elucidated using NMR and MS, whilst the relative configuration of one of the isolated compounds, toonapubesin F, was established by X-ray crystallography. The antiplasmodial activities of the crude extracts and the isolated constituents against the D6 and W2 strains of Plasmodium falciparum were determined using the semiautomated micro dilution technique that measures the ability of the extracts to inhibit the incorporation of (G-(3)H, where G is guanine) hypoxanthine into the malaria parasite. The cytotoxicity of the crude extracts and their isolated constituents was evaluated against the mammalian cell lines African monkey kidney (vero), mouse breast cancer (4T1) and human larynx carcinoma (HEp2). RESULTS: The extracts showed good to moderate antiplasmodial activities, where the extract of the stem bark of T. robusta was also cytotoxic against the 4T1 and the HEp2 cells (IC50<10 µg/ml). The compounds isolated from these extracts were characterized as limonoids, protolimonoids and phytosterol glucosides. These compounds showed good to moderate activities with the most active one being azadironolide, IC50 2.4 ± 0.03 µM and 1.1 ± 0.01 µM against the D6 and W2 strains of Plasmodium falciparum, respectively; all other compounds possessed IC50 14.4-40.5 µM. None of the compounds showed significant cytotoxicity against vero cells, yet four of them were toxic against the 4T1 and HEp2 cancer cell lines with piscidinol A having IC50 8.0 ± 0.03 and 8.4 ± 0.01 µM against the 4T1 and HEp2 cells, respectively. Diacetylation of piscidinol A resulted in reduced cytotoxicity. CONCLUSION: From the medicinal plants T. robusta and T. nilotica, twelve compounds were isolated and characterized; two of the isolated compounds, namely 11-epi-toonacilin and azadironolide showed good antiplasmodial activity with the highest selectivity indices.

Absolute Asymmetric Synthesis: Viedma Ripening of [Co(bpy)3](2+) and Solvent-Free Oxidation to [Co(bpy)3](3.).

Syntheses of [Co(bpy)3](2+) yield racemic solutions because the Δ- and Λ-enantiomers are stereochemically labile. However, crystallization and attrition-enhanced deracemization can give homochiral crystal batches of either handedness in quantitative yield. Subsequently, solvent-free oxidation with bromine vapour fixes the chirality because [Co(bipy)3](3+) does not enantiomerize in solution at ambient temperature. This combination of Viedma ripening and the labile/inert Co(II)/Co(III) couple constitutes a convenient method of absolute asymmetric synthesis.

Spontaneous Generation of Chirality in Simple Diaryl Ethers.

We studied the spontaneous formation of chiral crystals of four diaryl ethers, 3-phenoxybenzaldehyde, 1; 1,3-dimethyl-2-phenoxybenzene, 2; di(4-aminophenyl) ether, 3; and di(p-tolyl) ether, 4. Compounds 1, 3, and 4 form conformationally chiral molecules in the solid state, while the chirality of 2 arises from the formation of supramolecular helices. Compound 1 is a liquid at ambient temperature, but 2-4 are crystalline, and solid-state CD-spectroscopy showed that they could be obtained as optically active bulk samples. It should be noted that the optical activity arise upon crystallization, and no optically active precursors were used. Indeed, even commercial samples of 3 and 4 were found to be optically active, giving evidence for the ease at which total spontaneous resolution may occur in certain systems.

Absolute asymmetric synthesis of a tetrahedral silver complex.

Even though the isolation of tetrahedral stereoisomers usually presents a synthetic challenge, a highly enantioenriched tetrahedral silver complex could be easily accessed by either crystallization or Viedma ripening. The overall preparation may be regarded as an example of absolute asymmetric synthesis. Experimental results indicate that both crystallization and Viedma ripening follow a similar cluster-controlled mechanism.

Absolute asymmetric synthesis: protected substrate oxidation.

Three new conglomerates incorporating bidentate sulfide ligands coordinated by Ru(II) centers have been prepared. Total spontaneous resolution by slow crystallization gives highly enantioenriched crystal batches, which are used in enantioselective oxidation of the sulfide ligands to give chiral sulfoxide complexes with >98 % ee. All relevant stereoisomers have been characterized by single-crystal X-ray diffraction, CD spectroscopy, and chiral HPLC. If the ligand range can be extended to monodentate sulfides, a large-scale and recyclable process for enantioselective oxidation of sulfides can be designed.

A versatile dinucleating ligand containing sulfonamide groups.

Copper, iron, and gallium coordination chemistries of the new pentadentate bis-sulfonamide ligand 2,6-bis(N-2-pyridylmethylsulfonamido)-4-methylphenol (psmpH3) were investigated. PsmpH3 is capable of varying degrees of deprotonation, and notably, complexes containing the fully trideprotonated ligand can be prepared in aqueous solutions using only divalent metal ions. Two of the copper(II) complexes, [Cu2(psmp)(OH)] and [Cu2(psmp)(OAc)2](-), demonstrate the anticipated 1:2 ligand/metal stoichiometry and show that the dimetallic binding site created for exogenous ligands possesses high inherent flexibility since additional one- and three-atom bridging ligands bridge the two copper(II) ions in each complex, respectively. This gives rise to a difference of 0.4 Å in the Cu···Cu distances. Complexes with 2:3 and 2:1 ligand/metal stoichiometries for the divalent and trivalent metal ions, respectively, were observed in [Cu3(psmp)2(H2O)] and [M(psmpH)(psmpH2)], where M = Ga(III), Fe(III). The deprotonated tridentate N-2-pyridylsulfonylmethylphenolato moieties chelate the metal ions in a meridional fashion, whereas in [Cu3(psmp)2(H2O)] the rare µ2-N-sulfonamido bridging coordination mode is observed. In the bis-ligand mononuclear complexes, one picolyl arm of each ligand is protonated and uncoordinated. Magnetic susceptibility measurements on the doubly and triply bridged dicopper(II) complexes indicate strong and medium strength antiferromagnetic coupling interactions, with J = 234 cm(-1) and 115 cm(-1) for [Cu2(psmp)(OH)] and [Cu2(psmp)(OAc)2](-), respectively (in HHDvV =...+JS1S2 convention). The trinuclear [Cu3(psmp)2(H2O)], in which the central copper ion is linked to two flanking copper atoms by two µ2-N-sulfonamido bridges and two phenoxide bridges shows an overall magnetic behavior of antiferromagnetic coupling. This is corroborated computationally by broken-symmetry density functional theory, which for isotropic modeling of the coupling predicts an antiferromagnetic coupling strength of J = 70.5 cm(-1).

Absolute asymmetric synthesis of enantiopure organozinc reagents, followed by highly enantioselective chlorination.

We report the absolute asymmetric synthesis (AAS) of indenylzinc reagents by using total spontaneous resolution followed by enantiospecific conversion into 1-chloroindene. The chiral complex [Zn(dcp)(ind)(tmeda)] (dcp = 2,6-dichlorophenoxy and tmeda = N,N,N',N'-tetramethylethylenediamine) (3) was prepared from the achiral starting materials indene, potassium, zinc chloride, TMEDA, and 2,6-dichlorophenol. The reagent resolved spontaneously on crystallization, and single crystals of 3 react with N-chlorosuccinimide in the presence of benzoquinone in 2-propanol to give 1-chloroindene in >98 % enantiomeric excess. It was found that (R)-3 gave (R)-1-chloroindene upon reaction, indicating an SE 2'-mechanism. Since bulk samples of 3 gave optically active product upon chlorination, total spontaneous resolution must have occurred. This demonstrates that enantiopure products can be obtained through the absolute asymmetric synthesis of organometallic reagents starting from achiral materials. The general absolute asymmetric synthesis (AAS) method offers easy access to both enantiomers and an almost limitless variation in the design of the product.

Hydrogen-bonded network structures in dipyridinium, bis(2-methylpyridinium), bis(3-methylpyridinium) and bis(4-methylpyridinium) dioxidobis(oxydiacetato)uranate(VI).

Four complexes containing the [UO(2)(oda)(2)](2-) anion (oda is oxydiacetate) are reported, namely dipyridinium dioxidobis(oxydiacetato)uranate(VI), (C(5)H(6)N)(2)[U(C(4)H(4)O(5))(2)O(2)], (I), bis(2-methylpyridinium) dioxidobis(oxydiacetato)uranate(VI), (C(8)H(8)N)(2)[U(C(4)H(4)O(5))(2)O(2)], (II), bis(3-methylpyridinium) dioxidobis(oxydiacetato)uranate(VI), (C(8)H(8)N)(2)[U(C(4)H(4)O(5))(2)O(2)], (III), and bis(4-methylpyridinium) dioxidobis(oxydiacetato)uranate(VI), (C(8)H(8)N)(2)[U(C(4)H(4)O(5))(2)O(2)], (IV). The anions are achiral and are located on a mirror plane in (I) and on inversion centres in (II)-(IV). The four complexes are assembled into three-dimensional structures via N-H...O and C-H...O interactions. Compounds (III) and (IV) are isomorphous; the [UO(2)(oda)(2)](2-) anions form a porous matrix which is nearly identical in the two structures, and the cations are located in channels formed in this matrix. Compounds (I) and (II) are very different from (III) and (IV): (I) forms a layered structure, while (II) forms ribbons.

catena-Poly[[bis(acetylacetonato-kappa2O,O')cobalt(II)]-mu-1,3-di-4-pyridylpropane-kappa2N:N']: a one-dimensional coordination polymer capable of forming clathrates with prochiral aldehydes.

The title compound, [Co(C5H7O2)2(C13H14N2)]n, forms a coordination polymer in which the Co(II) centre is located on an inversion centre and the 1,3-di-4-pyridylpropane ligand is located on a twofold axis. The polymeric chains are parallel and are held together by weak intermolecular C-H...O interactions. The complex is intended as a possible host for prochiral aldehydes and ketones, and one clathrate was isolated with p-tolylaldehyde.

Dipyridinium dichromate: an achiral compound forming chiral crystals.

The title compound, (C(5)H(6)N)(2)[Cr(2)O(7)], crystallizes in one of the Sohncke space groups, viz. P2(1)2(1)2(1). Crystallization of dipyridinium dichromate is thus an example of spontaneous formation of a chiral crystal structure from achiral molecules. The dichromate anion adopts a virtually eclipsed achiral conformation, and the crystal structure is held together primarily by N-H...O and C-H...O interactions. The possibility of using dipyridinium dichromate as a reagent in enantioselective synthesis is discussed.

Diphenyldipyridinezinc(II): partial spontaneous resolution of an organometallic reagent.

The title compound, [Zn(C(6)H(5))(2)(C(5)H(5)N)(2)], (I), forms conformationally chiral molecules residing on a twofold axis. The molecules are stacked along c, and these stacks are associated by edge-to-face pi-pi interactions. Crystals of (I) belong to the Sohncke space group P2(1)2(1)2 and the crystal lattice of (I) is chiral. The crystal batch that was examined consisted of a mixture of enantiomerically pure crystals and crystals twinned by inversion.

A different approach to enantioselective organic synthesis: absolute asymmetric synthesis of organometallic reagents.

Voilà, optical activity: Both enantiomers of 1-chloroindene have been synthesized in high selectivity from solely achiral starting materials, and without using optically active catalysts (see scheme). These symmetry-breaking syntheses provide a proof-of-concept for a new approach to asymmetric synthesis. NCS=N-chlorosuccinimide.

Investigation of commercial sodium cacodylate trihydrate: penta-mu-aqua-disodium(I) bis(dimethylarsenate) and di-mu-aqua-bis[triaquasodium(I)] bis(dimethylarsenate).

Crystals from commercial samples of sodium cacodylate trihydrate, NaO2As(CH3)2 x 3 H2O, were analyzed by single-crystal X-ray diffraction and two phases were identified, viz. penta-mu-aqua-disodium(I) bis(dimethylarsenate), {[Na2(H2O)5](C2H6AsO2)2}n, (I), and di-mu-aqua-bis[triaquasodium(I)] bis(dimethylarsenate), [Na2(H2O)8](C2H6AsO2)2, (II). Both (I) and (II) form layered structures in which hydrated Na+ ions form layers in the ab plane, the cacodylate ions being located in between the layers. In (I), the two non-equivalent Na+ ions (located at twofold axes) and the three non-equivalent aqua ligands (one of which also lies on a twofold axis) form infinite polymeric layers, but in (II), layers of discrete centrosymmetric [Na2(H2O)8]2+ ions are present. One of the commercial samples analyzed contained almost exclusively crystals of the tetrahydrate (II), while another sample consisted of a mixture of the two phases.

Slow atmospheric oxidation of diphenylzinc: di-mu-phenoxido-bis[(diethyl ether)phenylzinc(II)].

The title compound, [Zn2(C6H5)2(C6H5O)2(C4H10O)2], was isolated from a solution of diphenylzinc in diethyl ether that had been exposed to air. The molecules are dinuclear, with a distorted tetrahedral coordination geometry around the Zn atoms and with molecules situated about a crystallographic inversion centre. Molecules associate via three sets of C-H...pi(arene) interactions, leading to a network structure.

Degradation of silicone grease by Grignard reagents: bis(mu-dimethylphenylsilanolato-kappa2O:O)bis[bromido(diethyl ether)magnesium(II)].

The title compound, [Mg2Br2(C8H11OSi)2(C4H10O)2], was obtained by slow dissolution of silicone grease in a diethyl ether solution of phenylmagnesium bromide. The molecules lie about inversion centres and do not display any short intermolecular interactions. There are only a handful of crystal structures of triorganosiloxomagnesium complexes reported previously, and the structure also illustrates the type of species that may be present in solution after accidental contact of Grignard reagents with silicon grease.

In search of conformationally chiral square-planar complexes: dichloridobis(2-methoxypyridine-kappaN)copper(II).

The title compound, [CuCl2(C6H7NO)2], was synthesized during a study of conformationally chiral square-planar coordination compounds. The coordination geometry deviates from the square-planar geometry generally adopted by copper(II) chloride complexes with pyridine ligands towards a tetrahedral arrangement of ligands. The complex is conformationally chiral but crystallizes in a centrosymmetric space group with both enantiomers present in the unit cell.

Total spontaneous resolution of chiral covalent networks from stereochemically labile metal complexes.

Stereochemically labile copper and zinc complexes with the N,N'-dimethylethylenediamine ligand (dmeda) have been shown to be promising precursors for the total spontaneous resolution of chiral covalent networks. (N,N')-[Cu(NO3)2(dmeda)]infinity crystallises as a conglomerate and yields either enantiopure (R,R)-1 or enantiopure (S,S)-1. A mixed-valence copper(I/II) complex, [{Cu(II)Br2(dmeda)}3(Cu(I)Br)2]infinity (2), which crystallises as a pair of interpenetrating chiral (10,3)-a nets, is formed from CuBr, CuBr2 and dmeda. One net contains ligands with solely (R,R) configuration and exhibits helices with (P) configuration while the other has solely (S,S)-dmeda ligands and gives rise to a net in which the helices have (M) configuration. The whole crystalline arrangement is racemic, because the interpenetrating chiral nets are of opposite handedness. With zinc chloride (R,S)-[ZnCl(dmeda)2]2[ZnCl4] (3) is obtained, which is a network structure, although not chiral. Total spontaneous resolution of stereochemically labile metal complexes formed from achiral or racemic building blocks is suggested as a viable route for the preparation of covalent chiral networks. Once the absolute structure of the compound has been determined by X-ray crystallography, a quantitative determination of the enantiomeric excess of the bulk product can be undertaken by means of solid-state CD spectroscopy.

Absolute asymmetric synthesis of stereochemically labile aldehyde helicates and subsequent chirality transfer reactions.

Helical complexes formed between aluminum tris(2,6-diphenylphenoxide) (ATPH) and five different aldehydes have been prepared and structurally characterized by X-ray diffraction. It was found that [Al(OC6H3Ph2)3PhCHO] (2), [Al(OC6H3Ph2)3(4-CH3C6H4CHO)] (3), [Al(OC6H3Ph2)3(4-tBuC6H4CHO)] (4), and [Al(OC6H3Ph2)3(p-CH3OC6H4CHO)] (5) all crystallize as conglomerates, while crystals of [Al(OC6H3Ph2)3(o-CH3OC6H4CHO)] (6) are racemic. Supramolecular CH/pi interactions between molecules in crystals of 2-5 that enable stereochemical information to be mediated in three dimensions have been identified and explain the high frequency of conglomerate formation among ATPH helicates. Since 2-5 are stereochemically labile and thus enantiomerize rapidly in solution, the conglomerates can be resolved by crystallization-induced asymmetric transformation. The determination of the enantiomeric excess (ee) in solid samples of stereochemically labile molecules is not trivial, but solid-state CD spectroscopic data, anomalous dispersion data, and the ee values in alkylation reactions all indicate that preferential crystallization of 2-5 yields an essentially enantiopure product. Thus the preparation of 2-5 constitute new examples of absolute asymmetric synthesis. The helical chirality can be transferred (and thus trapped) to alcohols (with ee values of up to 16%) in crystal-to-crystal reactions with achiral organometallic reagents.