Modeling Complex Ligands for High Oxidation State Catalysis: Titanium Hydroamination with Unsymmetrical Ligands.

A method for modeling high oxidation state catalysts is used on precatalysts with unsymmetrical and symmetrical bidentate ligands to get a more detailed understanding of how changes to ancillary ligands affect the hydroamination of alkynes catalyzed by titanium. To model the electronic donor ability, the ligand donor parameter (LDP) was used, and to model the steric effects, percent buried volume (% Vbur) was employed. For the modeling study, 7 previously unpublished unsymmetrical Ti(XX')(NMe2)2 precatalysts were prepared, where XX' is a chelating ligand with pyrrolyl/indolyl linkages. The rates of these unsymmetrical and 10 previously reported symmetrical precatalysts were used with the model kobs = a + b(LDP)1 + c(LDP)2 + d(% Vbur)1 + e(% Vbur)2, where a-e were found through least-squares refinement. The model suggests that (1) the two attachment points of the bidentate ligand XX' are in different environments on the metal (e.g., axial and equatorial in a trigonal bipyramidal or square pyramidal structure), (2) the position of the unsymmetrical ligand on the metal is determined by the electronics of the ligand rather than the sterics, and (3) that one side of the chelating ligand's electronics strongly influences the rate, while the other side's sterics more strongly influences the rate. From these studies, we were able to generate catalysts fitting to this model with rate constants larger than the fastest symmetrical catalyst tested.

A rare isocyanide derived from an unprecedented neutral yttrium(ii) bis(amide) complex.

A room temperature stable complex formulated as Y(NHAr*)2 has been prepared, where Ar* = 2,6-(2,4,6-(iPr)3C6H2)C6H3, by KC8 reduction of ClY(NHAr*)2. Based on EPR evidence, Y(NHAr*)2 is an example of a d1 Y(ii) complex with significant delocalization of the unpaired electron density from the metal to the ligand. The isolation of molecular divalent metal complexes is challenging for rare earth elements such as yttrium. In fact, stabilization of the divalent state requires judicious ligand design that allows the metal center to be coordinatively saturated. Divalent rare earth elements tend to be reactive towards various substrates. Interestingly, Y(NHAr*)2 reacts as a radical donor towards t BuNC to generate an unusual yttrium isocyanide complex, CNY(NHAr*)2, based on spectroscopic evidence and single-crystal X-ray diffraction data.

Exploring structural effects in a new class of NRF2 inhibitors.

NRF2 is a transcription factor that controls the cellular response to various stressors, such as reactive oxygen and nitrogen species. As such, it plays a key role in the suppression of carcinogenesis, but constitutive NRF2 expression in cancer cells leads to resistance to chemotherapeutics and promotes metastasis. As a result, inhibition of the NRF2 pathway is a target for new drugs, especially for use in conjunction with established chemotherapeutic agents like carboplatin and 5-fluorouracil. A new class of NRF2 inhibitors has been discovered with substituted nicotinonitriles, such as MSU38225. In this work, the effects on NRF2 inhibition with structural changes were explored. Through these studies, we identified a few compounds with as good or better activity than the initial hit but with greatly improved solubility. The syntheses involved a variety of metal-catalyzed reactions, including titanium multicomponent coupling reactions and various Pd and Cu coupling reactions. In addition to inhibiting NRF2 activity, these new compounds inhibited the proliferation and migration of lung cancer cells in which the NRF2 pathway is constitutively activated.

Synthesis, structure, properties, and cytotoxicity of a (quinoline)RuCp+ complex.

A rare example of a structurally characterized metal quinoline complex was prepared using a non-covalent quinoline-based proteasome inhibitor (Quin1), and a related complex bearing an inactive quinoline ligand (Quin2) was also synthesized. The quinolines are prepared by a one-pot procedure involving titanium-catalyzed alkyne iminoamination and are bound to ruthenium by reaction with CpRu(NCMe)3+ PF6- in CH2Cl2. The arene of the quinoline is η6-bonded to the ruthenium metal center. The kinetics of quinoline displacement were investigated, and reactivity with deuterated solvents follows the order acetonitrile > DMSO > water. Quinolines with more methyl groups on the arene are more kinetically stable, and RuCp(Quin1)+ PF6- (1), which has two methyl groups on the arene, is stable for days in DMSO. In contrast, a very similar complex (2) made with Quin2 having no methyl groups on the arene was readily displaced by DMSO. Both 1 and 2 are stable in 9 : 1 water/DMSO for days with no measurable displacement of the quinoline. The cytotoxicity of the quinolines, their CpRu+-complexes, and CpRu(DMSO)3+ PF6- was investigated towards two multiple myeloma cell lines: MC/CAR and RPMI 8226. To determine whether the activity of the complexes was related to the nature of the quinoline ligands, two structurally similar quinoline ligands with vastly different biological properties were investigated. Quin1 is a cytotoxic proteasome inhibitor, whereas Quin2 is not a proteasome inhibitor and showed no discernable cytotoxicity. The ruthenium complexes showed poor cellular proteasome inhibition. However, both 1 and 2 showed good cytotoxicity towards RPMI 8226 and MC/CAR, with 1 being slightly more cytotoxic. For example, 1 has a CC50 = 2 µM in RPMI 8226, and 2 has a CC50 = 5 µM for the same cell line. In contrast, CpRu(DMSO)3+ PF6- was quite active towards MC/CAR with CC50 = 2.8 µM but showed no discernible cytotoxicity toward RPMI 8226. The mechanism of action responsible for the observed cytotoxicity is not known, but the new Ru(Cp)(Quin)+ PF6- complexes do not cross-link DNA as found for platinum-based drugs. It is concluded that the Ru(Cp)(Quin)+ PF6- complexes remain intact in the cellular assays and constitute a new class of cytotoxic metal complexes.

Substituted pyridines from isoxazoles: scope and mechanism.

Treatment of isoxazoles with enamines leads to an inverse electron-demand hetero-Diels-Alder reaction that produces substituted pyridines in the presence of TiCl4(THF)2 and titanium powder. The reaction is highly regioselective with only a single isomer of the product observed by GC/MS and tolerant of many common functional groups. The transformation was examined computationally, and it was found that TiCl4 (or a similar Lewis acid) likely acts to catalyze the reaction. After the initial [4 + 2]-cycloaddition, the oxaza-[2.2.1]-bicycle produced likely ring opens before amine loss to give an N-oxide. The pyridine is then obtained after reduction with TiCl4 and titanium powder.

A Novel Nrf2 Pathway Inhibitor Sensitizes Keap1-Mutant Lung Cancer Cells to Chemotherapy.

The nuclear factor erythroid-2-related factor 2 (Nrf2)-Keap1-ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU38225. By inhibiting production of antioxidants, MSU38225 increases the level of reactive oxygen species (ROS) when cells are stimulated with tert-butyl hydroperoxide (tBHP). MSU38225 also inhibits the growth of human lung cancer cells in both two-dimensional cell culture and soft agar. Cancer cells addicted to Nrf2 are more susceptible to MSU38225 for suppression of cell proliferation. MSU38225 also sensitizes human lung cancer cells to chemotherapies both in vitro and in vivo Our results suggest that MSU38225 is a novel Nrf2 pathway inhibitor that could potentially serve as an adjuvant therapy to enhance the response to chemotherapies in patients with lung cancer.

Catalyst design insights from modelling a titanium-catalyzed multicomponent reaction.

High oxidation state transition metal catalysis touches our daily lives through bulk chemical production, e.g. olefin polymerization, and through specialty chemical reactions common in organic synthesis, e.g. the Sharpless asymmetric epoxidation and olefin dihydroxylation. Our group has been expanding the reaction chemistry of titanium(iv) to produce a host of nitrogen-based heterocycles via multicomponent coupling reactions. One such multicomponent coupling reaction discovered in our laboratory is iminoamination, involving an amine, an alkyne, and an isonitrile. However, the experimental modeling of high oxidation state reactions lags far behind that of low oxidation state systems, where a great deal is known about ligands, their donor properties and how their structures affect catalysis. As a result, we have developed an experimental method for determining the donor abilities of anionic ligands on high oxidation state systems, which is based on the chromium(vi) nitride system NCr(NiPr2)2X, where X = the ligand being interrogated. The parameters obtained are simply called ligand donor parameters (LDP). In this contribution, a detailed optimization of the Ti(NMe2)2(dpm)-catalyzed iminoamination reaction was carried out, where dpm = 5,5-dimethyldipyrrolylmethane. During the course of these studies, dimeric {Ti(µ-N-tolyl)(dpm)}2 was isolated, which is proposed as the resting state of the catalyst. To destabilize this resting state, a more electron-rich bis(aryloxide) catalyst system was investigated. The more electron-rich system is somewhat more active for iminoamination under some conditions; however, the catalyst is prone to disproportionation. A study of heteroleptic titanium complexes revealed that the disproportionation equilibrium constant can be effectively modeled as a function of the square of the difference in LDP between the ligands, (ΔLDP)2. Using this methodology, one can estimate the stability of titanium complexes toward disproportionation.

Electronic and Structural Comparisons between Iron(II/III) and Ruthenium(II/III) Imide Analogs.

To examine structural and electronic differences between iron and ruthenium imido complexes, a series of compounds was prepared with different phosphine basal sets. The starting material for the ruthenium complexes was Ru(NAr/Ar*)(PMe3)3 (Ru1/Ru1*), where Ar = 2,6-(iPr)2C6H3 and Ar* = 2,4,6-(iPr)3C6H2, which were prepared from cis-RuCl2(PMe3)4 and 2 equiv of LiNHAr/Ar*. The starting materials for the iron complexes were the analogous Fe(NAr/Ar*)(PMe3)3 species (Fe1/Fe1*), which were not isolated but could be generated in situ from FeCl2, PMe3, and LiNHAr/Ar*. With both iron and ruthenium, the PMe3 starting materials underwent phosphine replacement with chelating ligands to give new group 8 imido complexes in the +2 oxidation state. Addition of 1,2-bis(diphenylphosphino)ethane (dppe) to M1/M1* gave Ru(NAr/Ar*)(PMe3)(dppe) and Fe(NAr/Ar*)(PMe3)(dppe). Addition of 1,2-bis(dimethylphosphino)ethane (dmpe) provided Ru(NAr/Ar*)(dmpe)2. A triphos ligand, {P(Me)2CH2}3SitBu (tP3), was also examined. Addition of tP3 to Fe1 provided Fe(NAr)(tP3) (Fe4), but a similar reaction with Ru1 only gave intractable materials. Oxidation of Fe4 with AgSbF6 gave {Fe(NAr)(tP3)}+SbF6- (Fe4a). Oxidation of Ru2 with AgSbF6 gave the unstable cation {Ru(NAr)(PMe3)(dppe)}+, which dimerized in the presence of acetonitrile via C-C bond formation at the aryl group C4 positions, affording {Ru(NAr)(PMe3)(NCMe)(dppe)}2+. This suggested that there was substantial radical character in the imide π system on oxidation and that an aromatic group substituted at the 4-position might provide greater stability. The cations {Fe(NAr*)(PMe3)(dppe)}+ (Fe2a*), {Ru(NAr*)(PMe3)(dppe)}+ (Ru2a*), and Fe4a were examined by EPR spectroscopy, which suggested differences in electronic structure depending on the metal and ligand set. CASPT2 calculations on model systems for Ru2a* and Fe2a* suggested that the large differences in electronic structure are related to the energy gap between the π-antibonding HOMO and the π-bonding HOMO-1. Both the geometry of the phosphines, which is slightly different between the iron and ruthenium analogs, and the metal center seem to contribute to this energetic difference.

A silica-supported titanium catalyst for heterogeneous hydroamination and multicomponent coupling reactions.

Highly dehydrated silica gel, SiO2700, gave a material with a total surface hydroxyl density of 0.31 ± 0.05 mmol g-1, 0.9 ± 0.1 Si-OH sites per nm2. Treatment of this material with Ti(NMe2)4 gave Ti(NMe2)3/SiO2700, which is 1.50% ± 0.07 Ti, where the titanium is bound to the surface, on average, through a single O-Si-Ti linkage. This material was tested for its properties as a catalyst for C-N bond forming reactions and was found to be a competent alkyne hydroamination and iminoamination catalyst. For iminoamination, which is the 3-component coupling of an alkyne, primary amine, and isonitrile, this heterogeneous catalyst was able to carry out some catalyses faster than previously reported homogeneous catalysts with lower catalyst loadings. The material is also a catalyst for the addition of aniline to dicyclohexylcarbodiimide to form a substituted guanidine. In addition, a known quinoline with biological activity was prepared using the heterogeneous catalyst in a one-pot procedure using half the catalyst loading of the previously reported synthesis.

A photochemical route to a square planar, ruthenium(iv)-bis(imide).

The square planar, ruthenium(iv) bis(imide) trans-Ru(NAr)2(PMe3)2 can be prepared photochemically from a Ru(ii) tetrazene. Additionally, we report reactivity of the Ru(iv) bis(imide) species, similar to that of the osmium derivative. Attempts to change both imide group and phosphine substituents are presented, which led to alternative reactivity.

Synthesis and Characterization of a Neutral U(II) Arene Sandwich Complex.

Reduction of IU(NHAriPr6)2 (AriPr6 = 2,6-(2,4,6-iPr3C6H2)2C6H3) results in a rare example of a U(II) complex, U(NHAriPr6)2, and the first example that is a neutral species. Here, we show spectroscopic and magnetic studies that suggest a 5f46d0 valence electronic configuration for uranium, along with characterization of related U(III) complexes.

Quantifying ligand effects in high-oxidation-state metal catalysis.

Catalysis by high-valent metals such as titanium(IV) impacts our lives daily through reactions like olefin polymerization. In any catalysis, optimization involves a careful choice of not just the metal but also the ancillary ligands. Because these choices dramatically impact the electronic structure of the system and, in turn, catalyst performance, new tools for catalyst development are needed. Understanding ancillary ligand effects is arguably one of the most critical aspects of catalyst optimization and, while parameters for phosphines have been used for decades with low-valent systems, a comparable system does not exist for high-valent metals. A new electronic parameter for ligand donation, derived from experiments on a high-valent chromium species, is now available. Here, we show that the new parameters enable quantitative determination of ancillary ligand effects on catalysis rate and, in some cases, even provide mechanistic information. Analysing reactions in this way can be used to design better catalyst architectures and paves the way for the use of such parameters in a host of high-valent processes.

Substituted quinolines as noncovalent proteasome inhibitors.

Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4µM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.

A complex with nitrogen single, double, and triple bonds to the same chromium atom: synthesis, structure, and reactivity.

A nitrogen-based analogue of the Schrock and Clark "yl-ene-yne" complex, W(CBu t )(CHBu t )(CH2Bu t )(dmpe), has been prepared. The new complex is the nitrido, imido, amido anion [NCr(NPh)(NPri2)2]-, which was structurally characterized with the [K(crypt-2.2.2)]+ counterion. The "Cr-N 1-2-3" complex was prepared from NCr(NHPh)(NPri2)2, which exists as this nitrido-amido tautomer, rather than the bis(imido) Cr(NH)(NPh)(NPri2)2. By selection of electrophile, the nitrido-imido salt K[NCr(NPh)(NPri2)2] can undergo reaction at either the imido or the nitrido to form unusual examples of nitrido or bis(imido) complexes.

Heterogeneity correction for intensity-modulated frameless SRS in pituitary and cavernous sinus tumors: a retrospective study.

BACKGROUND: Frameless immobilization allows for planning and quality assurance of intensity-modulated radiosurgery (IM-SRS) plans. We tested the hypothesis that IM-SRS planning with uniform tissue density corrections results in dose inaccuracy compared to heterogeneity-corrected algorithms. METHODS: Fifteen patients with tumors of the pituitary or cavernous sinus underwent frameless IM-SRS. Treatment planning CT and MRI scans were obtained and fused to delineate the tumor, optic nerves, chiasm, and brainstem. The plan was developed with static gantry IM-SRS fields using a pencil beam (PB), analytical anisotropic (AAA), and Acuros XB (AXB) algorithms. We evaluated measures of target coverage as well as doses to organs at risk (OAR) for each algorithm. We compared the results of each algorithm in the cases where PTV overlapped OAR (n = 10) to cases without overlapping OAR with PTV (n = 5). Utilizing film dosimetry, we measured the dose distribution for each algorithm through a uniform density target to a rando phantom with non-uniform density of air, tissue, and bone. RESULTS: There was no difference in target coverage measured by DMaxPTV, DMinPTV, D95%PTV, or the isodose surface (IDS) covering 95% of the PTV regardless of algorithm. However, there were differences in dose to OAR. PB predicted higher (p < 0.05) Dmax for the brainstem, chiasm, right optic nerve, and left optic nerve. In cases of PTV overlapping an optic nerve (n = 7), PB was unable to limit dose to 8 Gy while achieving PTV coverage (PB 855 cGy vs. AAA 769 cGy, p = 0.05 vs. AXB 658 cGy, p = 0.03). Within the rando phantom, the PB and AAA algorithms over-estimated the dose delivered in the bone-tissue-air interface of the sinus (+17%), while the AXB algorithm closely predicted the actual dose delivered through the inhomogeneous tissue (+/- 1 % max, p < 0.05). CONCLUSIONS: Patients undergoing frameless SRS benefit from heterogeneity corrected dose plans when the lesion lies in areas of widely varying tissue density and near critical normal structures such as the skull base. Film dosimetry confirms that the AXB dose calculation algorithm more accurately predicts actual dose delivered though tissues of varying densities than PB or AAA dose calculation algorithms.

Titanium-catalyzed multicomponent couplings: efficient one-pot syntheses of nitrogen heterocycles.

Nitrogen-based heterocycles are important frameworks for pharmaceuticals, natural products, organic dyes for solar cells, and many other applications. Catalysis for the formation of heterocyclic scaffolds, like many C-C and C-N bond-forming reactions, has focused on the use of rare, late transition metals like palladium and gold. Our group is interested in the use of Earth-abundant catalysts based on titanium to generate heterocycles using multicomponent coupling strategies, often in one-pot reactions. To be of maximal utility, the catalysts need to be easily prepared from inexpensive reagents, and that has been one guiding principle in the research. For this purpose, a series of easily prepared pyrrole-based ligands has been developed. Titanium imido complexes are known to catalyze the hydroamination of alkynes, and this reaction has been used to advantage in the production of α,ß-unsaturated imines from 1,3-enynes and pyrroles from 1,4-diynes. Likewise, catalyst design can be used to find complexes applicable to hydrohydrazination, coupling of a hydrazine and alkyne, which is a method for the production of hydrazones. Many of the hydrazones synthesized are converted to indoles through Fischer cyclization by addition of a Lewis acid. However, more complex products are available in a single catalytic cycle through coupling of isonitriles, primary amines, and alkynes to give tautomers of 1,3-diimines, iminoamination (IA). The products of IA are useful intermediates for the one-pot synthesis of pyrazoles, pyrimidines, isoxazoles, quinolines, and 2-amino-3-cyanopyridines. The regioselectivity of the reactions is elucidated in some detail for some of these heterocycles. The 2-amino-3-cyanopyridines are synthesized through isolable intermediates, 1,2-dihydro-2-iminopyridines, which undergo Dimroth rearrangement driven by aromatization of the pyridine ring; the proposed mechanism of the reaction is discussed. The IA-based heterocyclic syntheses can be accomplished start to finish (catalyst generation to heterocyclic synthesis) in a single vessel. The catalyst can be formed in situ from commercially available Ti(NMe2)4 and the protonated form of the ligand. Then, the primary amine, alkyne, and isonitrile are added to the flask, and the IA product is synthesized. The volatiles are removed (if necessary), and the next reagent is added. A brief video showing the process for the simple heterocycle 4-phenylpyrazole from phenylacetylene, cyclohexylamine, tert-butylisonitrile, and hydrazine hydrate is included. Further development in this field will unlock new, efficient reactions for the production of carbon-carbon and carbon-nitrogen bonds. As an example of such a process recently discovered, a catalyst for the regioselective production of pyrazoles in a single step from terminal alkynes, hydrazines, and cyclohexylisonitrile is discussed. Using titanium catalysis, many heterocyclic cores can be accessed easily and efficiently. Further, the early metal chemistry described is often orthogonal to late metal-based reactions, which use substrates like aryl halides, silyl groups, boryl groups, and so forth. As a result, earth-abundant and nontoxic titanium can fulfill important roles in the synthesis of useful classes of compounds like heterocycles.