Ligands 1a Research Articles

Copper(II)-containing C2-symmetric bistetracarboline amides in enantioselective Henry reactions

A series of new C2-symmetric chiral diamides were synthesized from l-tryptophan and used as chiral ligands chelated with Cu(II) in enantioselective Henry reactions. Ligand 4a with CuCl2·2H2O (5%) showed effective catalytic efficiency in Henry reaction. High yields (up to 99%) and excellent enantioselectivities (up to 98%) were achieved for both aromatic and aliphatic aldehyde substrates.

Abstract 3441: Suppression of colorectal cancer cell proliferation is associated with modulation of Wnt pathway signaling components by Resveratrol

Abstract Our previous studies showed that modulation of cell cycle-regulating genes by Resveratrol (RV) is directly correlated with suppression of colorectal cancer (CRC) cell proliferation. The Wnt pathway, which consists of the canonical pathway (CAN) and non-canonical pathways (N-CAN) is an intricate ensemble of signaling components involved with cellular processes including proliferation and differentiaion. Some cell cycle regulating genes are downstream targets of the Wnt pathway. The CAN utilizes β-catenin whereas the N-CAN pathways are activated independent of β-catenin. The CAN and the N-CAN are antagonistic and modulate each other's activities. Few studies have been conducted to determine the effect of naturopathic and nutritional supplements (NNS) such as RV on the Wnt pathway in human cancers. The aim of this study was to determine whether suppression of CRC cell proliferation by RV is related to modulation of Wnt pathway components. CRC cells derived from surgical specimens (n=3) were treated with RV (5ug/ml) for 72h. Cell proliferation was determined using MTS assay and gene expression was performed using commercially available quantitative RT-PCR Wnt pathway gene expression arrays. RV treatment resulted in a significant decrease of CRC cell proliferation (52% inhibition; p<0.005) compared to untreated cells. The suppression of CRC cell proliferation by RV was correlated with modulation of both CAN and N-CAN components. The CAN components modulated significantly (p<0.05 or greater) by RV included ligand 10A (3.6 fold increase), the receptor frizzled 7 and the transcription factor TCF7L1 (2.2 and 2.6 fold decrease respectively) compared to untreated cells. The N-CAN components modulated significantly by RV were ligands 7A and 11 (2.9 and 2.5 fold increase respectively), and dishevelled-binding CAN antagonist NKD1 (2.5 fold increase) relative to untreated CRC cells. This study demonstrates that RV modulates expression of multiple components of the CAN and N-CAN pathways in CRC cells. The collective effect appears to favor N-CAN activation leading to retardation of the CAN pathway. Thus, upregulation of CAN ligand 10A is expected to be countered by the observed increase in N-CAN Wnt ligands 7A and 11, as well as CAN antagonist NKD1. This observation is consistent with our previous demonstration of the effects of RV on regulation of cell cycle gene expression in CRC leading to inhibition of cellular proliferation. Given the excellent tolerance profile of NNS such as RV, the capacity of such agents to modulate the Wnt pathway and particularly the N-CAN in favor of inhibition of tumor proliferation, offers the opportunity to investigate the effects of chronic administration of these agents on tumor growth and progression in patients. Citation Format: Irshad Ali, Adriana Rosales, Donald P. Braun. Suppression of colorectal cancer cell proliferation is associated with modulation of Wnt pathway signaling components by Resveratrol. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3441. doi:10.1158/1538-7445.AM2014-3441

Bimetallic nickel complexes supported by 2,5-bis(phosphine)-1,4-hydroquinonate ligands. Structural, electrochemical and theoretical investigations

The coordination chemistries of several 2,5-bis(phosphine)-1,4-hydroquinones, (2,5-bis(PiPr2)-3,6-difluoro-1,4-hydroquinone (1a), 2,5-bis(PiPr2)-1,4-hydroquinone (1b), (2,5-bis(PPh2)-3,6-difluoro-1,4-hydroquinone (1c), and 2,5-bis(PPh2)-1,4-hydroquinone (1d)) were investigated. Reactions of these ligands 1a–d with excess (∼2.5) of bis(cyclopentadienide)nickel, and in case of 1a, with bis(pentamethylcyclopentadienide)nickel, resulted in the formation of bimetallic nickel complexes 2a–d and 3a, where both [P,O] chelating pockets of the ligands were occupied by CpNi or Cp∗Ni moieties, respectively. Cyclic voltammetric (CV) scans on complexes 2a–d contained a common feature of two reversible/quasi-reversible waves and one irreversible redox event. Complex [2a][PF6] was isolated by the oxidation of 2a with ferrocenium hexafluorophosphate. Spectroscopic, structural, and synthetic studies were carried out in order to elucidate the nature of these redox processes. Our results suggest that the reversible and quasi-reversible redox events are ligand-based processes (hydroquinone/semiquinone/quinone), while the irreversible process was assigned as metal-based. These conclusions were supported by additional experimental data and by theoretical calculations. Investigations of chemical reactivity showed that cyclopentadienide ligands in complexes 2a–d can be displaced from the metal centers upon reactions with o-aminothiophenol. One of these derivatives, 4a, containing capping [N,S] o-aminothiophenolate ligands was isolated and fully characterized. A CV scan of complex 4a contained one reversible wave and an irreversible wave at higher potentials. The assignment is complicated by the proton transfer processes accompanying the electron transfer events. Complexes 1a, 2a–c, [2a][PF6] and 4a were characterized by single crystal X-ray diffraction experiments.

ChemInform Abstract: The Synthesis of Chiral Amino Diol Tridentate Ligands and Their Enantioselective Induction During the Addition of Diethylzinc to Aldehydes.

Abstract A series of C2-symmetric chiral amino diol tridentate ligands 3a–g were prepared from achiral bulky organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared C2-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enantioselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired configuration during the preparation of the ligand.

Synthesis of chiral 1,3-bis(1-(diarylphosphoryl)ethyl)-benzenes via Ir-catalyzed double asymmetric hydrogenation of bis(diarylvinylphosphine oxides)

A class of chiral 1,3-bis(diarylphosphinoethyl)benzenes, which are key intermediates for the synthesis of PCP-type chiral pincer ligands, were prepared in high diastereomeric ratios and excellent ee values via double asymmetric hydrogenation of the corresponding bis(diarylvinylphosphine oxide) substrates using a SpinPhox/Ir(I) complex as the catalyst. The hydrogenation product 5a was readily transformed into the corresponding borane-protected chiral PCP-type pincer ligand 7a with high enantiomeric excess, exemplifying a viable synthetic route to optically active chiral PCP pincer ligands.

Selective formation of gold(I) bis-phospholane macrocycles, polymeric chains, and nanotubes.

A series of highly flexible bis-phospholane ligands 3a-g with 5-11 methylene groups in the backbone was synthesized and fully characterized by mass spectrometry and NMR ((1)H, (13)C, (31)P) and IR spectroscopy. Gold bis-phospholane macrocycles containing 16 ([Au2Cl2(μ-3a)2], 4), 20 ([Au2Cl2(μ-3c)2], 5), 24 ([Au2Cl(μ-3e)2]Cl, 6), and 28 ([Au2Cl2(μ-3g)2], 7) atoms in the ring were obtained in one step from [AuCl(tht)] (tht = tetrahydrothiophene) and 3a,c,e,g in excellent yield. In addition, three polymers resulting from aurophilic interactions, i.e., zigzag chains in [Au2Cl2(μ-3b)]x (8) and nanotubes in [Au2Cl2(μ-3d)]x (9) and [Au2Cl2(μ-3f)]x (10), with Au···Au distances of 309.41(2), 330.24(6), and 335.82(3) pm, respectively, were obtained. Halide abstraction of 4-7 with AgBF4 led to macrocycles [Au2(μ-3a)2](BF4)2 (11), [Au2(μ-3c)2](BF4)2 (12), [Au2(μ-3e)2](BF4)2 (13), and [Au2(μ-3g)2](BF4)2 (14). In 12, the monomers are connected by strong aurophilic interactions (Au···Au 296.57(1) pm) in the solid state with formation of a polymeric chain. All complexes were fully characterized by NMR ((1)H, (13)C, (31)P) and IR spectroscopy, mass spectrometry, and X-ray diffraction.

1,1-P–OP Ligands with P-Stereogenic Phosphino Groups in Asymmetric Hydrogenations and Hydroformylations

A new series of narrow-bite-angle phosphine–phosphite (1,1-P–OP) ligands (3a–d) has been efficiently prepared from the enantiopure (SP)-tert-butyl(hydroxymethyl)methylphosphino borane complex 1, a crucial intermediate. The catalytic performance of the ligands in Rh-mediated asymmetric hydrogenations and hydroformylations is described. The corresponding rhodium complexes provided excellent efficiencies (full conversion in all cases) and high enantioselectivities (up to 98% ee) for the asymmetric hydrogenation of structurally diverse functionalized alkenes. Furthermore, rhodium catalysts derived from these 1,1-P–OP ligands were highly active and gave excellent regioselectivities (branched/linear product ratios of up to 97/3) and moderate enantioselectivities in the hydroformylation of different terminal olefins.

Synthesis and structure–activity relationship studies in serotonin 5-HT4 receptor ligands based on a benzo[de][2,6]naphthridine scaffold

A small series of serotonin 5-HT4 receptor ligands has been designed from flexible 2-methoxyquinoline compounds 7a,b by applying the conformational constraint approach. Ligands 7a,b and the corresponding conformationally constrained analogues 8a–g were synthesized and their interactions with the 5-HT4 receptor were examined by measuring both binding affinity and the ability to promote or inhibit receptor–G protein coupling. Ester derivative 7a and conformationally constrained compound 8b were demonstrated to be the most interesting compounds showing a nanomolar 5-HT4R affinity similar to that shown by reference ligands cisapride (1) and RS-23,597-190 (4). The result was rationalized by docking studies in term of high similarity in the binding modalities of flexible 7a and conformationally constrained 8b. The intrinsic efficacy of some selected ligands was determined by evaluating the receptor–G protein coupling and the results obtained demonstrated that the nature and the position of substituents play a critical role in the interaction of these ligands with their receptor.

Imidazolidinium ferrate complexes: Synthesis and catalytic properties

Abstract The new well-defined and air stable anionic iron complexes bearing an imidazolidinium ligand (2a–d) have been synthesized and characterized by elemental analysis and single-crystal X-ray diffraction studies. Starting from FeBr2, [imidazolidinium][FeBr4] complexes 2a and 2b were prepared. The reaction of imidazolidinium chlorides with Fe(OAc)2, followed by a recrystallization in the air led to bis(imidazolidinium) μ-oxido-bis[trichloroferrate(III)] complexes 2c and 2d. The catalytic activity of these novel complexes has been evaluated in the cross-coupling reactions of alkyl halides with Grignard reagents.

Palladium(II)‐N‐heterocyclic carbene complexes: synthesis, characterization and catalytic application

N‐Heterocyclic carbenes (NHCs) are of great importance and are powerful ligands for transition metals. A new series of sterically hindered benzimidazole‐based NHC ligands (LHX) (2a, 2b, 2c, 2d, 2e, 2f), silver–NHC complexes (3a, 3b, 3c, 3d, 3e, 3f) and palladium–NHC complexes (4a, 4b, 4c, 4d, 4e, 4f) have been synthesized and characterized using appropriate spectroscopic techniques. Studies have focused on the development of a more efficient catalytic system for the Suzuki coupling reaction of aryl chlorides. Catalytic performance of Pd–NHC complexes and in situ prepared Pd(OAc)2/LHX catalysts has been investigated for the Suzuki cross‐coupling reaction under mild reaction conditions in aqueous N,N‐dimethylformamide (DMF). These complexes smoothly catalyzed the Suzuki–Miyaura reactions of electron‐rich and electron‐poor aryl chlorides. Copyright © 2014 John Wiley & Sons, Ltd.

Oxorhenium(V) complexes with naphtholate-oxazoline ligands in the catalytic epoxidation of olefins

Four oxorhenium(V) complexes 3a–d equipped with naphtholate-oxazoline based ligands 2a–d have been prepared and characterized by NMR, IR and mass spectroscopy as well as elemental analysis. Ligands 2a–d were prepared in a two-step procedure from commercially available starting materials. Ligands 2a–b and 2c–d are regioisomers to each other regarding the position of the –OH group and oxazoline moiety on the naphthol ring. Reaction of 2a–d with (NBu4)[ReOCl4] in methanol under reflux gave oxorhenium(V) complexes 3a–d of the type [ReOCl(L)2] as green solids in acceptable to good yields. The molecular structures of complexes 3b and 3d have been determined via single crystal X-ray diffraction analysis and both display a distorted octahedral geometry. Complexes 3a–d are active catalysts for the epoxidation of cyclooctene with tert-butylhydroperoxide (TBHP) showing moderate conversions between 41% and 65%.

Fine‐Tunable Tris(triazolyl)methane Ligands for Copper(I)‐ Catalyzed Azide–Alkyne Cycloaddition Reactions

AbstractThe preparation of a small library of modular tris(triazolyl)methane ligands for copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reactions is reported. The synthesis of the first generation ligand, tris(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methanol (1a), suitable for work in aqueous systems, is reported at the 50–100 mmol scale through a one‐stage, environmentally benign procedure. One‐stage procedures for the synthesis of tris(aryltriazolyl)methanol structures (1b, phenyl; 1c, para‐trifluoromethylphenyl; 1d, para‐methoxyphenyl) designed for electronic fine‐tuning of catalytic properties, and of 1a‐derived ethers 2c (OBn) and 2d (OMe), designed for CuAAC reactions in organic solvents, are also reported. The complete set of ligands (1a–d, 2c–d) has been tested in the reaction of phenylacetylene with benzyl azide in six different solvents (water, hexane, toluene, dichloromethane, tetrahydrofuran, and acetonitrile), and this has allowed the identification of 1b, 1c and 2c as the ligands depicting the highest tolerance to changes in solvent polarity within the considered family. The comparative performance of ligands 1b–d and 2c in the cycloaddition of a small family of alkynes with benzyl azide in two very different reaction media (1:1 t‐BuOH/H2O and toluene) has been studied as a guide for catalyst selection in specific applications. The applicability of 1c in CuAAC reactions involving functional substrates in toluene has been explored under thermal and microwave‐accelerated (tandem azide formation plus CuAAC reaction) reaction conditions.magnified image

SAR study on arylmethyloxyphenyl scaffold: Looking for a P-gp nanomolar affinity

Starting from the previously developed P-gp ligands 1a and 1b (EC50 = 0.25 μM and 0.65 μM, respectively), new arylmethyloxyphenyl derivatives have been synthesized as P-gp modulators in order to investigate: (i) the effect of small electron-donor groups (OMe) (5–11), (ii) the effect of the replacement of methoxy groups with an electron-withdrawal substituent (Cl) on C-ring (13) (iii) the effect induced by the replacement of C-ring with heteroaromatic cycles such as thiophene and pyrimidine (13, 15, 16), (iv) the effect induced by molecular constriction on C ring (14, 17, 18) on P-gp modulating activity. The results demonstrated that P-gp inhibition potency is strongly correlated to the number of methoxy groups in the A-ring whereas the methoxylation of C-ring seems to poorly affect P-gp activity. The best result was found for compound 10 that displays a nanomolar affinity (EC50 = 7.1 nM) towards P-gp pump and, in the meantime lacks of activity against MRP1 pump.

The synthesis of chiral amino diol tridentate ligands and their enantioselective induction during the addition of diethylzinc to aldehydes

A series of C2-symmetric chiral amino diol tridentate ligands 3a–g were prepared from achiral bulky organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared C2-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enantioselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired configuration during the preparation of the ligand.

Synthesis and chemical–optical characterization of novel two-photon fluorescent borinates derived from Schiff bases

Herein is reported the synthesis and characterization of eight borinates (2a–h) prepared from the reaction of the corresponding bidentate imine ligands (1a–h) and diphenylborinic acid. All compounds were characterized by MS, IR and NMR spectroscopies whereas the molecular structures of derivatives 2c and 2e were also studied by X-ray diffraction analysis that corroborated the presence of a tetra-coordinated boron atom. In addition, the linear and nonlinear optical (NLO) characterization of these molecules having D–π–CN+–π–D and D–π–CN+–π–A electronic systems was performed, i.e., the third-order nonlinear optical responses were measured by using the two-photon excited fluorescence and the third-harmonic generation (χ3 determination) techniques. The borinates showed two-photon absorption (2PA) effect in solution under femtosecond excitation: 2g and 2h having D–π–CN+–π–A architecture showed the largest 2PA cross-sections (σ2PA) values at 760 nm: 124 and 174 GM (1 GM = 10−50 cm4 s), respectively, while the values for 2e and 2f that possess D–π–CN+–π–D structure were 12 and 37 GM. The χ3 values, with nanosecond excitation, were of the order of 10−12 esu at 1200 nm.

Synthesis of Esomeprazole through Asymmetric Oxidation

N,N'-dicyclohexyl-D-tartaric diamide 2a andN,N'-di-[(R)-inda-D-tartaric diamide 2b were prepared through the reaction of diethyl-D-tartrate with cyclohexylamine and (R)-(-)-1-aminoindan, respectively. The two compounds coordinated with isopropyl titanate (Ti (O-iPr)4), were used as catalyst in the asymmetric oxidation of pyrmetazol 3 with cumene hydroperoxide (CHP) as oxidant. The results revealed that both the catalytic systems derived from ligand 2a and 2b with Ti (O-iPr)4showed good catalytic activity and enantioselectivity in the synthesis of esomeprazole. Under the optimized conditions, the yield reached 91%, 91% and the enantio excess (ee) was up to 87% , 89%.

Chiral Cu(ii)-amino alcohol based complexes for asymmetric aza-Henry reaction of N-Ts imines

A series of chiral dimeric ligands 1A–C, 2A–B, 3A–B and 4A derived from (S)/(R) 1,1′-bi(2-naphthol)-bis-aldehyde/piperazine-bis-aldehyde and various aminoalcohols viz., (1R,2S)-(−)-2-aminodiphenylethanol, (1S,2R)-(−)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol and (R)-valinol were synthesized. In situ generated complexes 1A–C–, 2A–B–, 3A–B–, 4A–Cu(II)/Cu(I) of dimeric chiral ligands with different copper salts were used as catalysts for the asymmetric aza-Henry reaction of a variety of N-tosylimines as substrates with different nitroalkanes at RT to afford good yields of aza-Henry products (80% with respect to the imines) with excellent enantioselectivity (ee > 99%) in 24 h with nitromethane and high syn selective products with excellent enantioselectivity with nitroethane. The dimeric chiral Cu(II) complex 1A–Cu(II) retained its performance at the gram level and was expediently recycled for a number of times. The enantio-pure aza-Henry product was further used for the synthesis of (S)-levamisole (an anthelminthic agent) in good yield and ee in three steps.

Novel chiral (salen)Mn(iii) complexes containing a calix[4]arene unit in 1,3-alternate conformation as catalysts for enantioselective epoxidation reactions of (Z)-aryl alkenes

Two new chiral calix[4]arene-salen ligands 1a,b, based on calix[4]arene platforms in 1,3-alternate conformation, have been prepared by a new general synthetic pathway. Their Mn(III) complexes, 3a,b have shown fairly good efficiency in the asymmetric epoxidation of styrene and substituted styrenes, whereas excellent catalytic activity and selectivity were observed with rigid bicyclic alkenes, namely 1,2-dihydro-naphthalene and substituted 2,2'-dimethyl-chromene. The higher catalytic properties of 3a may be ascribed to the more rigid and inherently chiral structure as proved by molecular modelling, NMR spectroscopy and X-ray data of the similarly structured UO2 complexes 2a,b.

Acridone–Pterocarpan Conjugate: A Hybrid Molecular Probe for Recognition of Nucleic Acids

AbstractChemical fusion of a naturally occurring pharmacophore (pterocarpan) with a fluorophore (acridone) by thermally induced cascade sigmatropic rearrangement leads to the formation of a structurally different class of DNA binding ligands. Competitive binding assay in the presence of a classical minor groove binder shows the possibility of DNA minor groove binding by the ligand 4a. High cell viability of the prepared molecular probes was of utility for nuclear staining as well as cell cycle analysis through fluorescence‐activated cell sorting (FACS).

Novel synthesis of palladium (II) complexes derived from 3-arylsydnone-4-carbaldehyde N(4)-phenylthiosemicarbazones and biological activity

The aim of this research is to investigate whether the oxygen atom O(6) in the sydnone ring of 3-arylsydnone-4-carbaldehyde N(4)-phenylthiosemicarbazones (HArSYTSCs, 3a-d) is a good electron donor atom upon metal complexation. Furthermore, ligands 3a-d and the corresponding palladium complexes (Pd(ArSYTSC)Cl, 4a-d) would be expected to find their potent biological activities. The desired palladium complexes 4a-d were first synthesized from thiosemicarbazones 3a-d. Then, the antiproliferative activity of ligands 3a-d and complexes 4a-d were tested against human hepatocellular carcinoma and human cervical epithelioid carcinoma (HeLa) cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl trazolium bromide (MTT) assay. According to X-ray analyses, ligands 3a-d are bonded to the Pd (II) center in an O, N, S-tridentate coordination mode through sydnone carbonyl oxygen O(6), azomethine nitrogen and the thiolate sulfur atom. The carbonyl oxygen of the sydnone ring is found to be a good electron donor site upon metal complexation. Moreover, MTT assay results reveal that the palladium complexes 4a-d have greater antiproliferative activity than 5-fluorouracil. In particular, the complexes exhibit obvious better activity than the corresponding ligands 3a-d against HeLa cell. The results indicate that the synthesized novel palladium complexes have greater antiproliferative activity than both 5-fluorouracil and the corresponding ligands against HeLa cell. Accordingly, the study of sydnonyl complexes bearing anticancer activities may support the development of coordination chemistry.