Electron-poor hemilabile dicationic palladium NHC complexes - synthesis, structure and catalytic activity.

We present a new class of dicationic palladium NHC complexes with two carbene ligands bearing different aryl substituents and a hemilabile pyrimidyl group. They can either be synthesized from the imidazolium salts via the silver transmetalation route to a halide-free palladium(ii) precursor or by direct deprotonation by palladium acetate. For four complexes we could determine their solid-state structures by X-ray diffraction experiments. Insight gained by NMR spectroscopy and DFT calculations revealed that in solution the two potentially bidentate ligands interchange between chelating and non-chelating coordination modes. The preference of these coordination modes is governed by the steric influence of the different ligands. The complexes were shown to be active catalysts for the hydroarylation of alkynes, and their performance was rationalized by DFT calculations.

Synthesis, characterization and application of organorhenium(vii) trioxides in metathesis reactions and epoxidation catalysis.

Four novel organorhenium(vii) oxides of the type L-ReO3 are presented: [4-(trifluoromethyl)phenyl]trioxorhenium 1b, [4-(trifluoromethoxy)phenyl]trioxorhenium 2b, [4-(trifluoromethyl)tetrafluorophenyl]trioxorhenium(THF) 3b·THF and (2,2,6,6-tetramethylpiperidin-1-yl)trioxorhenium 5. As intermediate products, the novel diarylzinc compounds bis[4-(trifluoromethoxy)phenyl]zinc 2a and bis[2,6-bis(trifluoromethyl)phenyl]zinc 4a were prepared. The properties and structure of 1b-5 were studied by means of 1H, 13C, 19F and 17O NMR, IR, MS, TGA and elemental analysis. Due to the strong Lewis acidity of the Re(vii) centres crystal structures of complexes 1b and 2b were obtained as THF adducts 1b·THF and 2b·THF. Complexes 1b, 2b, 3b·THF and 5 have been examined as catalysts in olefin epoxidation using cis-cyclooctene as a model substrate. Epoxide yields of around 80% and TOFs >1300 h-1 can be obtained with 1b, 2b and 3b·THF using TBHP as an oxidant in CDCl3 at 55 °C, exceeding the only reported catalytically active aryl trioxorhenium complex xylyltrioxorhenium (XTO). Moreover, 1b shows catalytic activity in the self-metathesis of 1-hexene with good yields using Et2AlCl as a co-catalyst. Additionally, 1b and 5 were found to be efficient catalysts for the ring-opening metathesis polymerization (ROMP) of norbornene. Polynorbornene with high molecular weight can be obtained in good yields at room temperature using RnAlCl3-n as a co-catalyst. 5 is the first example of an amido trioxorhenium(vii) complex active in olefin metathesis.

Synthesis and Neurotrophic Activity Studies of Illicium Sesquiterpene Natural Product Analogues.

Neurotrophic natural products hold potential as privileged structures for the development of therapeutic agents against neurodegeneration. However, only a few studies have been conducted to investigate a common pharmacophoric motif and structure-activity relationships (SARs). Here, an investigation of structurally more simple analogues of neurotrophic sesquiterpenes of the illicium family is presented. A concise synthetic route enables preparation of the carbon framework of (±)-Merrilactone A and (±)-Anislactone A/B on a gram scale. This has allowed access to a series of structural analogues by modification of the core structure, including variation of oxidation levels and alteration of functional groups. In total, 15 derivatives of the natural products have been synthesized and tested for their neurite outgrowth activities. Our studies indicate that the promising biological activity can be retained by structurally simpler natural product analogues, which are accessible by a straightforward synthetic route.

Gd-TEMDO: Design, Synthesis, and MRI Application.

A simple Ugi tetrazole multicomponent reaction allows the synthesis of a novel macrocyclic cyclen derivative with four appendant tetrazole arms in just two steps in excellent yields. This ligand, called TEMDO, turns out to have a high complexation affinity with lanthanoid metals. Here we describe the design, synthesis, solid-state structure, binding constant, and some MRI applications of the Gd-TEMDO complex as the first example of a congeneric family of oligo-amino tetrazoles.

α-Amino Acid-Isosteric α-Amino Tetrazoles.

The synthesis of all 20 common natural proteinogenic and 4 otherα-amino acid-isosteric α-amino tetrazoles has been accomplished, whereby the carboxyl group is replaced by the isosteric 5-tetrazolyl group. The short process involves the use of the key Ugi tetrazole reaction followed by deprotection chemistries. The tetrazole group is bioisosteric to the carboxylic acid and is widely used in medicinal chemistry and drug design. Surprisingly, several of the common α-amino acid-isosteric α-amino tetrazoles are unknown up to now. Therefore a rapid synthetic access to this compound class and non-natural derivatives is of high interest to advance the field.

2,30-Bis(10H-indole) heterocycles: New p53/MDM2/MDMX antagonists.

The protein­protein interaction of p53 and MDM2/X is a promising non genotoxic anticancer target. A rapid and efficient methodology was developed to synthesize the 2,30-bis(10H-indole) heterocyclic scaffold 2 as ester, acid and amide derivatives. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and HSQC experiments, indicating good inhibition and a perfect starting point for further optimizations.

Multiple Multidentate Halogen Bonding in Solution, in the Solid State, and in the (Calculated) Gas Phase.

The binding properties of neutral halogen-bond donors (XB donors) bearing two multidentate Lewis acidic motifs toward halides were investigated. Employing polyfluorinated and polyiodinated terphenyl and quaterphenyl derivatives as anion receptors, we obtained X-ray crystallographic data of the adducts of three structurally related XB donors with tetraalkylammonium chloride, bromide, and iodide. The stability of these XB complexes in solution was determined by isothermal titration calorimetry (ITC), and the results were compared to X-ray analyses as well as to calculated binding patterns in the gas phase. Density functional theory (DFT) calculations on the gas-phase complexes indicated that the experimentally observed distortion of the XB donors during multiple multidentate binding can be reproduced in 1:1 complexes with halides, whereas adducts with two halides show a symmetric binding pattern in the gas phase that is markedly different from the solid state structures. Overall, this study demonstrates the limitations in the transferability of binding data between solid state, solution, and gas phase in the study of complex multidentate XB donors.

Toward new organometallic architectures: synthesis of carbene-centered rhodium and palladium bisphosphine complexes. stability and reactivity of [PC(BIm)PRh(L)][PF6] pincers.

In this article, we report the synthesis of a tridentate carbene-centered bisphosphine ligand precursor and its complexes. The developed four-step synthetic strategy of a new PC(BIm)P pincer ligand represents the derivatization of benzimidazole in the first and third positions by (diphenylphosphoryl)methylene synthone, followed by phosphine deprotection and subsequent insertion of a noncoordinating anion. The obtained ligand precursor undergoes complexation, with PdCl2 and [µ-OCH3Rh(COD)]2 smoothly forming the target organometallics [PC(BIm)PPdCl][PF6] and [PC(BIm)PRh(L)][PF6] under mild hydrogenation conditions. A more detailed study of the rhodium complexes [PC(BIm)PRh(L)][PF6] reveals significant thermal stability of the PC(BIm)PRh moiety in the solid state as well as in solution. The chemical behavior of 1,3-bis(diphenylphosphinomethylene)benzimidazol-2-ylrhodium acetonitrile hexafluorophosphate has been screened under decarbonylation, hydrogenation, and hydroboration reaction conditions. Thus, the PC(BIm)PRh(I) complex is a sufficiently stable compound, with the potential to be applied in catalysis.

Mechanistic Investigations of the Stereoselective Rare Earth Metal-Mediated Ring-Opening Polymerization of ß-Butyrolactone.

Poly(3-hydroxybutyrate) (PHB) is produced by numerous bacteria as carbon and energy reserve storage material. Whereas nature only produces PHB in its strictly isotactic (R) form, homogeneous catalysis, when starting from racemic (rac) ß-butyrolactone (BL) as monomer, can in fact produce a wide variety of tacticities. The variation of the metal center and the surrounding ligand structure enable activity as well as tacticity tuning. However, no homogeneous catalyst exists to date that is easy to modify, highly active, and able to produce PHB with high isotacticities from rac-ß-BL. Therefore, in this work, the reaction kinetics of various 2-methoxyethylamino-bis(phenolate) lanthanide (Ln=Sm, Tb, Y, Lu) catalysts are examined in detail. The order in monomer and catalyst are determined to elucidate the reaction mechanism and the results are correlated with DFT calculations of the catalytic cycle. Furthermore, the enthalpies and entropies of the rate-determining steps are determined through temperature-dependent in situ IR measurements. Experimental and computational results converge in one specific mechanism for the ring-opening polymerization of BL and even allow us to rationalize the preference for syndiotactic PHB.

Leuckart-Wallach Route Toward Isocyanides and Some Applications.

Isocyanide-based multicomponent reactions (IMCR) are among the most important chemical reactions to efficiently generate molecular diversity and have found widespread use in industry and academia. Generally, isocyanides are synthesized in 1-2 steps starting from primary amines. Here, we provide experimental detail on an alternative approach toward formamides and, thus, isocyanides via the Leuckart-Wallach reaction in an improved variation. The resulting >50 synthesized and characterized formamides are useful starting materials for IMCR, as well as other chemistries. The advantage of using the Leuckart-Wallach pathway to formamides and isocyanides is the lower price, on average, of the starting materials, as well as their differential and complementary structural diversity, as compared to the primary amine pathway.

Mechanistic Aspects of a Highly Active Dinuclear Zinc Catalyst for the Co-polymerization of Epoxides and CO2.

The dinuclear zinc complex reported by us is to date the most active zinc catalyst for the co-polymerization of cyclohexene oxide (CHO) and carbon dioxide. However, co-polymerization experiments with propylene oxide (PO) and CO2 revealed surprisingly low conversions. Within this work, we focused on clarification of this behavior through experimental results and quantum chemical studies. The combination of both results indicated the formation of an energetically highly stable intermediate in the presence of propylene oxide and carbon dioxide. A similar species in the case of cyclohexene oxide/CO2 co-polymerization was not stable enough to deactivate the catalyst due to steric repulsion.

Rational synthesis and characterization of dimolybdenum(II) compounds bearing ferrocenyl-containing ligands toward modulation of electronic coupling.

Three novel cis-to-trans-converted dimolybdenum(II) complexes, trans-[Mo2(O2C-Fc)2(DPPX)2][BF4]2 {2a-2c; DPPX = DPPA [N,N-bis(diphenylphosphino)amine], DPPM [1,1-bis(diphenylphosphino)methane], and DPPE [1,2-bis(diphenylphosphino)ethane], respectively}, were synthesized through the insertion of bulky diphosphine ligands, which force a permanent trans arrangement, as evidenced by X-ray crystallography and density functional theory calculations. All compounds were characterized by means of NMR, UV-vis, and IR spectroscopy as well as thermogravimetry-mass spectrometry measurements. Interestingly, uncommon UV-vis transitions and oxidation sequences were observed compared to previously reported ones. As verified by electrochemical measurements, all synthesized complexes show two separate one-electron-redox processes assigned to subsequent oxidations of the two redox-active ferrocenecarboxylate ligands, with a split of ca. 70 mV. This behavior reveals electronic interaction between the two equatorially trans-positioned ferrocenyl units. The presented work provides new insights into the rational synthesis of electronically coupled trans-coordinated Mo2 systems, paving the way toward the design of linear multicenter redox-active oligomers.

MCR synthesis of a tetracyclic tetrazole scaffold.

Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds.

Square-planar ruthenium(II) complexes: control of spin state by pincer ligand functionalization.

Functionalization of the PNP pincer ligand backbone allows for a comparison of the dialkyl amido, vinyl alkyl amido, and divinyl amido ruthenium(II) pincer complex series [RuCl{N(CH2 CH2 PtBu2 )2 }], [RuCl{N(CHCHPtBu2 )(CH2 CH2 PtBu2 )}], and [RuCl{N(CHCHPtBu2 )2 }], in which the ruthenium(II) ions are in the extremely rare square-planar coordination geometry. Whereas the dialkylamido complex adopts an electronic singlet (S=0) ground state and energetically low-lying triplet (S=1) state, the vinyl alkyl amido and the divinyl amido complexes exhibit unusual triplet (S=1) ground states as confirmed by experimental and computational examination. However, essentially non-magnetic ground states arise for the two intermediate-spin complexes owing to unusually large zero-field splitting (D>+200 cm(-1) ). The change in ground state electronic configuration is attributed to tailored pincer ligand-to-metal π-donation within the PNP ligand series.

Toward molecular recognition: three-point halogen bonding in the solid state and in solution.

A well-defined three-point interaction based solely on halogen bonding is presented. X-ray structural analyses of tridentate halogen bond donors (halogen-based Lewis acids) with a carefully chosen triamine illustrate the ideal geometric fit of the Lewis acidic axes of the former with the Lewis basic centers of the latter. Titration experiments reveal that the corresponding binding constant is about 3 orders of magnitude higher than that with a comparable monodentate amine. Other, less perfectly fitting multidentate amines also bind markedly weaker. Multipoint interactions like the one presented herein are the basis of molecular recognition, and we expect this principle to further establish halogen bonding as a reliable tool for solution-phase applications.

A universal isocyanide for diverse heterocycle syntheses.

Novel scaffolds are of uttermost importance for the discovery of functional material. Three different heterocyclic scaffolds easily accessible from isocyanoacetaldehyde dimethylacetal 1 by multicomponent reaction (MCR) are described. They can be efficiently synthesized by a Ugi tetrazole multicomponent reaction of 1. We discuss the synthesis, 3D structures, and other physicochemical properties.

Receptor-bound conformation of cilengitide better represented by its solution-state structure than the solid-state structure.

The X-ray crystal and NMR spectroscopic structures of the peptide drug candidate Cilengitide (cyclo(RGDf(NMe)Val)) in various solvents are obtained and compared in addition to the integrin receptor bound conformation. The NMR-based solution structures exhibit conformations closely resembling the X-ray structure of Cilengitide bound to the head group of integrin αvß3. In contrast, the structure of pure Cilengitide recrystallized from methanol reveals a different conformation controlled by the lattice forces of the crystal packing. Molecular modeling studies of the various ligand structures docked to the αvß3 integrin revealed that utilization of the solid-state conformation of Cilengitide leads-unlike the solution-based structures-to a mismatch of the ligand-receptor interactions compared with the experimentally determined structure of the protein-ligand complex. Such discrepancies between solution and crystal conformations of ligands can be misleading during the structure-based lead optimization process and should thus be taken carefully into account in ligand orientated drug design.

Loop shaped dicarboxylate-bridged dimolybdenum(II) bisphosphine compounds--a rational synthesis.

The reaction of the tetrametallic molecular loop [(CH3CN)6Mo2(OOC-C4H6-COO)]2[BF4]4 (1) (1 equiv.) with 2 equiv. of bis(diphenylphosphino)amine (dppa), 1,2-bis(diphenylphosphino)ethane (dppe) and bis(diphenylphosphino)methane (dppm) in propionitrile leads to the formation of the still tetrametallic complexes [(CH3CH2CN)4(X)Mo2(OOC-C4H6-COO)]2[BF4]4 (X = dppa (2), dppe (3), dppm (4)), also displaying a loop structure. All three complexes are characterized by NMR spectroscopy ((1)H, (11)B, (13)C{(1)H}, (19)F, (31)P{(1)H}), IR spectroscopy, elemental analysis, TG-MS measurements and UV-vis spectroscopy, compounds 2 and 3 additionally by X-ray single crystal diffraction.