Enantiopure Phospha[1]ferrocenophanes: Textbook Examples of Through-Space Nuclear Spin-Spin Coupling.

Three enantiopure phospha[1]ferrocenophanes (2R ) equipped with either a phenyl, an isopropyl, or a tert-butyl group at the bridging phosphorus atom were synthesized by a salt-metathesis approach in isolated yields between 52 and 63 %. The chirality in these strained sandwich compounds stems from the planar-chiral ferrocene moiety, which is symmetrically equipped with two iPr groups adjacent to phosphorus. Surprisingly, all three phospha[1]ferrocenophanes show an uncommon through-space nuclear 1 H-31 P coupling. As a result of the embedded symmetry, these new compounds are ideal examples to differentiate between through-space and through-bond coupling mechanisms in NMR spectroscopy.

Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes.

The effectiveness of utilizing N-Bn-N-Boc-α-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-α-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones. A Felkin-Anh model can be used to rationalize the observed diastereoselectivity.

Chiral bora[1]ferrocenophanes: syntheses, mechanistic insights, and ring-opening polymerizations.

A series of new boron-bridged [1]ferrocenophanes ([1]FCPs) was prepared by salt-metathesis reactions between enantiomerically pure dilithioferrocenes and amino(dichloro)boranes (Et2 NBCl2 , iPr2 NBCl2 , or tBu(Me3 Si)NBCl2 ). The dilithioferrocenes were prepared in situ by lithium-bromine exchange from the respective planar-chiral dibromides (Sp ,Sp )-[1-Br-2-(HR2 C)H3 C5 ]2 Fe (R=Me or Et). In most of the cases, mixtures of the targeted [1]FCPs 4 and the unwanted 1,1'-bis(boryl)ferrocenes 5 were formed. The product ratio depends on the bulkiness of the amino group, the speed of addition of the amino(dichloro)borane, the alkyl group on Cp rings, and in particular on the reaction temperature. The formation of strained [1]FCPs is strongly favored by increased reaction temperatures. Secondly, CHEt2 groups at Cp rings favored the formation of the targeted [1]FCPs stronger than CHMe2 groups. These discoveries open up new possibilities to further suppress the formation of unwanted byproducts by a careful choice of the reaction temperature and through tailoring the bulkiness of CHR2 groups on ferrocene. Thermal ring-opening polymerizations of selected boron-bridged [1]FCPs gave metallopolymers with a Mw of 10 kDa (GPC).

Tautomerism and metal complexation of 2-acylmethyl-2-oxazolines: a combined synthetic, spectroscopic, crystallographic and theoretical treatment.

A synthetic, structural and theoretical investigation into the solid-state, solution and gas phase structure(s) of six 2-acylmethyl-4,4-dimethyl-2-oxazolines is reported. Four of these materials, viz.α-[(4,5-dihydro-4,4-dimethyl-2-oxazolyl)methylene]benzenemethanol (3a), α-[(4,5-dihydro-4,4-dimethyl-2-oxazolyl)methylene]-(4-nitrobenzene)methanol (3b), 1-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-3,3-dimethyl-1-buten-2-ol (3d) and (E)-1-phenyl-2-((3aR)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-ylidene)ethanone (3f) have been characterised in the solid-state by single crystal X-ray diffraction studies. These data represent the first solid-state structural studies of this class of compounds and details the first synthesis and full characterisation of chiral derivative 3f. All four of these materials are shown to exist in the solid phase in the enamine tautomeric form (e.g., 3a is best described as 2-[4,4-dimethyl-2-oxazolidinylidene]-1-phenylethanone) and it is suggested (NMR, IR) that this isomeric form is likely also retained in solution (e.g., CDCl3) as the more stable isomer. An investigation of the relative gas phase stabilities of the three possible (i.e., the (Z)-enol, keto and enamine) isomers of all five compounds by DFT at the B3LYP/6-311G(d) level of theory confirms the latter as the most stable form. The energy differences between the enamine and keto tautomers have been calculated to be the lowest for derivative 3d. These results are compared and contrasted with the previously reported NMR studies of such compounds which have identified the keto form as being a minor (albeit solution) tautomer. Equilibrium solution tautomer distributions for 3d are found to be solvent dependent. The protonated form of 3a, isolated as the HSO4(-) salt (i.e.4a), has been further characterised in the solid state by single crystal X-ray diffraction. These data represent the first example of a protonated oxazoline to be structurally elucidated and confirms that upon protonation, the keto (oxazoline) tautomer is the energetically favoured form in the solid-state. This observation is further supported by DFT studies for the gas phase protonated forms of such materials. Further DFT (B3LYP/6-311G(d)) calculations employing the SM8 or SMD solvation models were then applied to address the observed solution isomeric distribution for 3d; these results corroborate the gas phase theoretical treatment and also yield values that predict the higher solution stability of the enamine form as observed, although they fail to account for the existence of the keto form as a minor solution state tautomer. To access the availability of an enol-form, via hypothetical de-protonation to the enolate, compound 3a was treated with hydrated Cu(NO3)2 in EtOH solution. The resulting isolated green-coloured product (5), the first metal derivative of this entire class of ligands, is best described (IR, X-ray diffraction) as a coordinated enolate complex, i.e., Cu(3a-H)2. Complex 5 crystallizes in the P21/c space group with four molecules in the unit cell. The coordination geometry around the formal Cu(2+) metal centre is determined to be highly distorted square planar in nature (τ4 = 0.442). TD-DFT is used to give a reasonable explanation for the intensity of the absorbance band observed in the visible region for solutions of 5. These latter experiments strongly suggest that the title class of compounds may have considerable potential as ligands in coordination chemistry and/or metal-mediated catalysis.

Unusual cationic trinuclear nickel clusters incorporating oxazolines or N,N,N',N'-tetramethylethylene-1,2-diamine: applications in olefin polymerization.

The synthesis and characterization of two rare examples of the nickel(II)-containing trinuclear clusters of the general formula µ(3)-halido-µ(3)-hydroxotris(µ-halido)tris(L) trinickel(II) halide [halide = Cl (2), Br (3); L = 4,4-dimethyl-2-(o-anilinyl)-2-oxazoline] are described. These materials are compared and contrasted to the "parent" chloride salt (1) of this series (L = N,N,N',N'-tetramethylethylene-1,2-diamine and halide = Cl) and its congeners; 2 and 3 represent the first oxazoline-containing clusters of this structural class. Both 1 and 2 are shown to be active catalysts for the polymerization of olefins (styrene, methyl methacrylate, etc.) using a stoichiometric equivalent of methylaluminoxane as the copromoter, a situation that gives good yields of syndiotactic rich polymers. Density functional theory (B3LYP/6-31G*/LANL2DZ) is employed to hypothesize the likely origin of the activity demonstrated by these compounds.

Cyclo-linopeptide A methanol solvate.

Crystals of the title compound, C(57)H(85)N(9)O(9)·CH(4)O, the methanol solvate of a nine peptide polypeptide, cyclo-(Pro-Pro-Phe-Phe-Leu-Ile-Ile-Leu-Val), were obtained after separation of the cyclic peptide from flax oil. The cyclo-linopeptide A (CLP-A) mol-ecules are linked in chains along the a axis by N-H⋯O hydrogen bonds. Each methanol O atom is hydrogen bonded to one O atom and two N-H groups in the same CLP-A mol-ecule. There are a total of eight hydrogen bonds in each CLP-A-MeOH unit.

Synthesis and characterization of aluminum- and gallium-bridged [1.1]chromarenophanes and [1.1]molybdarenophanes.

The synthesis and structural characterization of the first [1.1]chromarenophanes and the first [1.1]molybdarenophanes are described. A salt-metathesis reaction of [2-(Me 2NCH 2)C 6H 4]AlCl 2 with freshly prepared [Cr(LiC 6H 5) 2].TMEDA (TMEDA = N, N, N', N'-tetramethylethylenediamine) resulted in the dialumina[1.1]chromarenophane [{2-(Me 2NCH 2)C 6H 4}Al(eta (6)-C 6H 5) 2Cr] 2 ( 2a). The poor solubility of 2a in organic solvents prompted us to synthesize the new intramolecularly coordinated aluminum- and gallium dichlorides [5- tBu-2-(Me 2NCH 2)C 6H 3]ECl 2 [E = Al ( 3a), Ga ( 3b)] in which the phenyl group was equipped with a tert-butyl group. Salt-metathesis reactions of 3a and 3b, respectively, with freshly prepared [M(LiC 6H 5) 2].TMEDA (M = Cr, Mo) resulted in four new [1.1]metallarenophanes of the general type [{5- tBu-2-(Me 2NCH 2)C 6H 3}E(eta (6)-C 6H 5) 2M] 2 [E = Al, M = Cr ( 4a); E = Ga, M = Cr ( 4b); E = Al, M = Mo ( 5a); E = Ga, M = Mo ( 5b)]. 2a, 4a, b, and 5a, b have been structurally characterized by single-crystal analysis [ 2a.1/2C 6H 12: C 48H 56Al 2Cr 2N 2, monoclinic, P2 1/ c, a = 9.9117(9) A, b = 19.9361(16) A, c = 10.638(2) A, alpha = 90 degrees , beta = 112.322(5) degrees , gamma = 90 degrees , Z = 2; 4a.2C 6H 6: C 62H 72Al 2Cr 2N 2, monoclinic, P2 1/ c, a = 10.9626(9) A, b = 19.3350(18) A, c = 12.4626(9) A, alpha = 90 degrees , beta = 100.756(5) degrees , gamma = 90 degrees , Z = 2; 4b.2C 6H 6: C 62H 72Cr 2Ga 2N 2, monoclinic, P2 1/ c, a = 10.8428(2) A, b = 19.4844(4) A, c = 12.4958(2) A, alpha = 90 degrees , beta = 100.6187 degrees , gamma = 90 degrees , Z = 2; 5a.2C 6H 6: C 62H 72Al 2Mo 2N 2, triclinic, P1, a = 10.4377(4) A, b = 11.6510(4) A, c = 11.6514(4) A, alpha = 73.545(3) degrees , beta = 89.318(2) degrees , gamma = 76.120(2) degrees , Z = 1; 5b.2C 6H 6: C 62H 72Ga 2Mo 2N 2, triclinic, P1, a = 10.3451(5) A, b = 11.6752(6) A, c = 11.6900(5) A, alpha = 73.917(3) degrees , beta = 89.550(3) degrees , gamma = 76.774(2) degrees , Z = 1]. All five [1.1]metallarenophanes 2a, 4a, b, and 5a, b crystallize as anti isomers with both Me 2N donor groups in exo positions ( C i point group symmetry). The new [1.1]metallarenophanes show NMR spectra that can be interpreted as being caused by time-averaged C 2 h symmetrical species, which is consistent with the findings of their molecular structures in the solid state. Variable-temperature (1)H NMR measurements for 4a, b and 5a, b (500 MHz; -90 to 90 degrees C) revealed only peak broadening in the lower temperature range of -70 to -90 degrees C. (1)H NMR saturation transfer difference experiments did not show an expected anti-to-anti isomerization, rendering the new [1.1]metallacyclophanes rigid on the NMR time scale. Electrochemical measurements were performed for 4a, b and 5a, b. However, reproducible cyclic voltammograms could only be obtained for the two gallium species 4b and 5b, revealing the expected weak communication between the two transition-metal atoms in both compounds (class II).

Cytotoxic 3,5-bis(benzylidene)piperidin-4-ones and N-acyl analogs displaying selective toxicity for malignant cells.

A series of 3,5-bis(benzylidene)piperidin-4-ones 1, 1-acryloyl-3,5-bis(benzylidene)piperidin-4-ones 2 and adducts of 2 with sodium 2-mercaptoethanesulfonate (mesna), namely series 3, were prepared as candidate cytotoxic agents. These compounds were examined against neoplastic HSC-2, HSC-4 and HL-60 cells as well as HGF, HPC and HPLF normal cell lines and many of the compounds displayed selective toxicity for malignant cells. The CC50 values of the analogs in series 2 towards the cancer cell lines were mainly submicromolar. The relative potencies, selectivity and logP values were in the order of 2>1>3. The sulfonic acid group of a representative compound in series 3 was replaced by a thiol function to produce 4 leading to substantial increases in cytotoxic potencies and hydrophobicity indicating that the presence of a hydrophilic sulfonic acid group was disadvantageous in terms of potency. Molecular modeling suggested that the superior cytotoxicity of various members of series 1-3 over an acyclic analog 5 may have been due to the greater torsion angles theta1 and theta2 created between the arylidene aryl rings and the adjacent olefinic groups in series 1-3.

N-(2,6-Diisopropyl-phen-yl)formamide.

The title compound, C(13)H(19)NO, exhibits a non-planar structure in which the 2,6-diisopropyl-phenyl ring is tilted at a dihedral angle of 77.4 (1)° with respect to the formamide group. This is the largest dihedral angle known among structurally characterized formamides. The mol-ecules are linked via N-H⋯O hydrogen bonds, forming infinite chains which run along the b-axis directions.

The galla[1]ferrocenophane {[dimeth-yl(2-pyrid-yl)sil-yl]bis-(trimethyl-silyl)methyl-κC,N}(ferrocene-1,1'-di-yl)gallium(III).

The title compound, [GaFe(C(5)H(4))(2)(C(14)H(28)NSi(3))] or [{(2-H(4)C(5)N)Me(2)Si}(Me(3)Si)(2)C]Ga(C(5)H(4))(2)Fe, a galla[1]ferrocenophane, crystallizes with two independent mol-ecules in the asymmetric unit. In these strained sandwich compounds, the angles between the planes of the two π-ligands are 15.4 (2) and 16.4 (2)°, with gallium in a distorted tetrahedral coordination environment.

Bis[2-phenyl-1-(phenyl-iminio)isoindo-line] di-µ-chlorido-bis-[dichloridopalladate(II)] benzene disolvate.

In the title compound, (C(20)H(17)N(2))(2)[Pd(2)Cl(6)]·2C(6)H(6), the dichloride-bridged [Pd(2)Cl(6)](2-) anion lies across an inversion center with each Pd(II) ion in a slightly distorted square-planar environment. In the crystal structure, two cations and an anion are connected via N-H⋯Cl hydrogen bonds between the NH groups of the iminioisoindoline cations and terminal Cl atoms of a hexa-chloridodipalladate(II) anion. The Pd-Cl distance of the terminal chloride engaged in hydrogen bonding is slightly longer than the Pd-Cl distance of the adjacent terminal chloride which is not involved in hydrogen bonding.

Correlations between cytotoxicity and topography of some 2-arylidenebenzocycloalkanones determined by X-ray crystallography.

Three series of 2-arylidenebenzocycloalkanones 1-3 were prepared in order to compare the topography of the molecules with cytotoxicity. These compounds contain two aryl rings whose spatial relationships to each other were influenced by the size of the alicyclic ring and the nature of the substituents in the arylidene aryl rings. All compounds were evaluated against murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. From these results, 1l and 2c,l emerged as useful lead molecules and 1l was shown to significantly inhibit macromolecular DNA, RNA, and protein syntheses in L1210 cells. Various interatomic distances, bond angles, and a torsion angle of 19 representative compounds were determined by X-ray crystallography, and correlations between these data and the cytotoxicity were noted in nearly 40% of the cases examined. Structure-activity relationships revealed that in general, the steric properties of the groups in the arylidene aryl ring, as revealed by measurements of the molar refractivity values, contributed more to bioactivity than the electronic and hydrophobic properties of the aryl substituents. The compounds displayed little murine toxicity, which favors the decision to develop these molecules as cytotoxic and anticancer agents.

Chemical mediators: the remarkable structure and host-selectivity of depsilairdin, a sesquiterpenic depsipeptide containing a new amino acid.

The chemical structure determination of depsilairdin, a highly selective phytotoxin produced by the plant pathogenic fungus Leptosphaeriamaculans/Phoma lingam, is described. The elucidation of the unusual chemical structure used a combination of NMR spectral data and X-ray crystallography. The absolute configuration was established using chemical degradation and synthesis of (3S,6R)-3,6-diisopropyl-2,5-morpholinedione and its (3R,6S) and (3R,6R) stereoisomers. Similar to the fungal pathogen, depsilairdin caused strong lesions only on brown mustard leaves but not on related species. [structure: see text]

Structure, chemistry, and biological activity of pseudophomins A and B, new cyclic lipodepsipeptides isolated from the biocontrol bacterium Pseudomonas fluorescens.

Pseudophomins A and B are cyclic lipodepsipeptides isolated from Pseudomonas fluorescens strain BRG100, a bacterium with potential application for biocontrol of plant pathogens and weeds. Their chemical structures were established by a combination of spectroscopic data, X-ray crystallography, and selective chemical degradation. This unique chemical degradation allowed the unambiguous determination of the absolute configuration of the amino acid residue Leu-1, due to gamma-lactam formation followed by selective cleavage of the adjacent N(8)-C(7) bond. To the best of our knowledge this is the first application of gamma-lactam formation to the determination of absolute configuration of an adjacent amino acid. Pseudophomin B showed higher antifungal activity against the phytopathogens Phoma lingam/Leptosphaeria maculans and Sclerotinia sclerotiorum than pseudophomin A, and is likely to be the main component responsible for the antifungal activity of EtOAc extracts of strain BRG100. By contrast, pseudophomin A showed stronger inhibition of green foxtail (Setaria viridis) root germination than pseudophomin B.

Cytotoxic 1,4-bis(2-oxo-1-cycloalkylmethylene)benzenes and related compounds.

A series of 1,4-bis(2-oxo-1-cycloalkylmethylene)benzenes 2a-c and 4 and a related acyclic analogue 6a were synthesised and converted to the corresponding Mannich bases 3a-c, 5 and 6b. Evaluation of these compounds against murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes revealed that the Mannich bases were more cytotoxic than the corresponding unsaturated ketones. 1,4-bis(3-Dimethylaminomethyl-2-oxo-1-cyclohexylmethylene)benzene dihydrochloride (3a) had lower IC(50) values than melphalan against the four cell lines and was 15 times more potent than this drug when examined against a panel of human tumours.

Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones and related compounds.

A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone (2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones (3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones (4). A cytotoxic evaluation of the compounds in series 1-4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the compounds displayed significant toxicity; the IC(50) values of 54% of the enones were less than 10 microM when all four screens were considered and less than 1 microM for all members of series 3 in the P388 assay. Various correlations were established between the potencies of the compounds in series 1, 3 and 4 and the Hammett sigma, Hansch pi and molecular refractivity constants of the aryl substituents. Several torsion angles and interatomic distances of five representative compounds in series 3 and 4 were determined by X-ray crystallography, some of which contributed to the observed bioactivity. The marked cytotoxicity and lack of murine toxicity of most of the compounds described in this study, as well as their selective toxicity towards different tumour cell lines, revealed that development of the enones 2-4 as novel candidate antineoplastic agents should be pursued.

Cytotoxic 1,3-diarylidene-2-tetralones and related compounds.

A number of 1,3-arylidene-2-tetralones 1, 2 and 4 were synthesised and demonstrated cytotoxic activity towards murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the related 1-arylidene-2-tetralones 3 possessed lower potencies in these screens than the compounds in series 1 and 4. Approximately, half of the compounds were evaluated against a panel of human tumour cell lines. In this screen, most of the enones were more cytotoxic than the established anticancer agent melphalan and some demonstrated selective toxicity towards leukemic and colon cancer cells. The modes of action of representative compounds include interfering with the biosyntheses of nucleic acids and proteins as well as altering redox potentials. The compounds were well tolerated when administered intraperiteonally to mice. Thus these novel enones are promising prototypic molecules due to their potent cytotoxic properties and lack of significant murine toxicity.

Bis-diimidazolylidine complexes of nickel: investigations into nickel catalyzed coupling reactions.

Air and moisture stable homoleptic bis(diimidazolylidine)nickel(II) complexes, ([(diNHC)(2)Ni](2+)) 3a,b and their corresponding silver(I) 4a,b and palladium(II) 5a,b complexes were synthesized and characterized by NMR and single crystal X-ray analysis. The catalytic potential of complex 3a was assessed in Mizoroki-Heck and Suzuki-Miyaura coupling reactions. In the Suzuki-Miyaura coupling reaction, nickel precatalyst 3a was active for the coupling of aryl chlorides as well as aryl fluorides. The analogously synthesized Pd(II) complexes resulted in formation of (diNHC)PdCl(2) species which were not active for the coupling of aryl fluorides. For the Mizoroki-Heck reaction, it was found that aryl iodides could be activated in the absence of nickel or palladium precatalysts when using Na(2)CO(3) or NEt(3) as base while aryl iodides and aryl bromides could be activated in the Suzuki-Miyaura reaction sans precatalyst when K(3)PO(4) was used as base.

Oxazoles revisited: On the nature of binding of benzoxazole and 2-methylbenzoxazole with the zinc and palladium halides.

A synthetic and structural (X-ray) investigation into the bonding modes of benzoxazole (box) and 2-methylbenzoxazole (Mebox) ligands with halide precursors of Zn and Pd has been undertaken to clarify earlier discrepancies concerning the nature of the bonding mode(s) of the two azoles. In four structurally characterised examples, all contain the title ligands in a κ(1)N bonding motif. Calculations at the density functional level (DFT) of theory (B3LYP) confirm the ground state stability of this class of coordination for several hypothetical Pd and Zn (gas phase) compounds. The attempt to obtain suitable crystalline material of PdCl(2)(box)(2) (i.e., 5) leads to substantial complex degradation. One minor product of this process has been identified (X-ray) as the diarylformamidinato complex C(26)H(22)N(4)O(4)Pd, presumably formed via a complex combination of the decomposition products of both free box and 5.

The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones.

This study demonstrated that replacement of the axial protons on the C2 and C6 atoms of various 1-methyl-3,5-bis(benzylidene)-4-piperidones 3 by a dimethylene bridge leading to series 2 lowered cytotoxic potencies. Four compounds 2a and 3a-c emerged as lead molecules based on their toxicity towards different neoplasms and their selective toxicity for malignant rather than normal cells. Some possible reasons for the disparity between the IC(50) values in the two series of compounds are presented based on molecular modeling, logP values and respiration in rat liver mitochondria.