Application of a Palladium-Catalyzed C-H Functionalization/Indolization Method to Syntheses of cis-Trikentrin†A and Herbindole†B.

We describe herein formal syntheses of the indole alkaloids cis-trikentrin A and herbindole B from a common meso-hydroquinone intermediate prepared by a ruthenium-catalyzed [2+2+1+1] cycloaddition that has not been used previously in natural product synthesis. Key steps include a sterically demanding Buchwald-Hartwig amination as well as a unique C(sp(3) )-H amination/indole formation. Studies toward a selective desymmetrization of the meso-hydroquinone are also reported.

Magnetic Anisotropy in Functionalized Bipyridyl Cryptates.

The magnetic properties of molecular lanthanoid complexes are very important for a variety of scientific and technological applications, with the unique magnetic anisotropy being one of the most important features. In this context, a very rigid tris(bipyridine) cryptand was synthesized with a primary amine functionality for future bioconjugation. The magnetic anisotropy was investigated for the corresponding paramagnetic ytterbium cryptate. With the use of a combination of density functional theory calculations and lanthanoid-induced NMR shift analysis, the magnetic susceptibility tensor was determined and compared to the unfunctionalized cryptate analogue. The size and orientation of the axial and rhombic tensor components show remarkably great resilience toward the decrease of local symmetry around the metal and anion exchange in the inner coordination sphere. In addition, the functionalized ytterbium cryptate also exhibits efficient near-IR luminescence.

Synthesis, spectroscopic properties, and photoinduced CO-release studies of functionalized ruthenium(II) polypyridyl complexes: versatile building blocks for development of CORM-peptide nucleic acid bioconjugates.

A series of ruthenium(II) dicarbonyl complexes of formula [RuCl2(L)(CO)2] (L = bpy(CH3,CH3) = 4,4'-dimethyl-2,2'-bipyridine, bpy(CH3,CHO) = 4'-methyl-2,2'-bipyridine-4-carboxyaldehyde, bpy(CH3,COOH) = 4'-methyl-2,2'-bipyridine-4-carboxylic acid, CppH = 2-(pyridin-2-yl)pyrimidine-4-carboxylic acid, dppzcH = dipyrido[3,2-a:2',3'-c]phenazine-11-carboxylic acid), and [RuCl(L)(CO)2](+) (L = tpy(COOH) = 6-(2,2':6',2″-terpyridine-4'-yloxy)hexanoic acid) has been synthesized. In addition, a high-yield synthesis of a peptide nucleic acid (PNA) monomer containing the 2-(pyridin-2-yl)pyrimidine ligand was also developed, and this compound was used to prepare the first Ru(II) dicarbonyl complex, [RuCl2(Cpp-L-PNA)(CO)2],(Cpp-L-PNA = tert-butyl-N-[2-(N-9-fluorenylmethoxycarbonyl)aminoethyl]-N-[6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoyl]glycinate) attached to a PNA monomer backbone. Such metal-complex PNA-bioconjugates are attracting profound interest for biosensing and biomedical applications. Characterization of all complexes has been undertaken by IR and NMR spectroscopy, mass spectrometry, elemental analysis, and UV-vis spectroscopy. Investigation of the CO-release properties of the Ru(II) complexes in water/dimethyl sulfoxide (49:1) using the myoglobin assay showed that they are stable under physiological conditions in the dark for at least 60 min and most of them even for up to 15 h. In contrast, photoinduced CO release was observed upon illumination at 365 nm, the low-energy shoulder of the main absorption maximum centered around 300 nm, establishing these compounds as a new class of PhotoCORMs. While the two 2,2'-bipyridine complexes release 1 equiv of CO per mole of complex, the terpyridine, 2-(2'-pyridyl)pyrimidine, and dipyrido[3,2-a:2',3'-c]phenazine complexes are less effective CO releasers. Attachment of the 2-(2'-pyridyl)pyrimidine complex to a PNA backbone as in [RuCl2(Cpp-L-PNA)CO2] did not significantly change the spectroscopic or CO-release properties compared to the parent complex. Thus, a novel class of Ru(II)-based PhotoCORMs has been established which can be coupled to carrier delivery vectors such as PNA to facilitate cellular uptake without loss of the inherent CORM properties of the parent compound.

Understanding the quenching effects of aromatic C-H- and C-D-oscillators in near-IR lanthanoid luminescence.

Several series of selectively deuterated 2,2'-bipyridine-based cryptates with the near-IR emissive lanthanoids Pr, Nd, Er, and Yb are reported. The structural and luminescence properties of these complexes have been comprehensively investigated. A combination of experimental techniques (X-ray crystallography, lanthanoid-induced NMR shift analysis, luminescence, vibrational near-IR absorption) and theoretical concepts has been applied with a focus on nonradiative deactivation through multiphonon relaxation of lanthanoid excited states by aromatic, high-energy C-(H/D) oscillators. It is shown that the characteristics for the overtones of these vibrational modes deviate substantially from harmonic oscillators and that anharmonicity within a local-mode Morse model is an essential parameter for any accurate description. The spectral overlap integrals (SOIs) of lanthanoid electronic states with aromatic C-(H/D) overtones are evaluated quantitatively for different lanthanoid/oscillator combinations and the implications for luminescence enhancement through deuteration is discussed. Simple Gaussian functions are proposed as appropriate mathematical forms for the empirical approximation of SOIs.

Anomalous reversal of C-H and C-D quenching efficiencies in luminescent praseodymium cryptates.

A series of selectively deuterated praseodymium cryptates has been synthesized. Their luminescence lifetimes in solution range from 150 to 595 ns for the (1)D(2) → (3)F(4) transition. Global fitting of the nonradiative deactivation rate differences of the isotopologic C-(H/D) oscillators revealed that aromatic C-D overtones anomalously quench the luminescence more than C-H vibrations. This is explained by the dominance of Franck-Condon overlap factors that greatly favor C-D oscillators, which are in almost ideal resonance with the relevant energy gap (1)D(2)-(1)G(4) of praseodymium.

Dependence of the photophysical properties on the number of 2,2'-bipyridine units in a series of luminescent europium and terbium cryptates.

The luminescence properties of a series of lanthanoid cryptates with an increasing number of 2,2'-bipyridine units have been investigated for the lanthanoids Eu and Tb in aqueous solution. The trends in important parameters that influence the photophysics in these complexes have been determined. With increasing bipyridine content, an increase is observed for the intersystem crossing efficiencies and the number of inner-sphere water molecules. In contrast, a decrease is found in the same direction for overall quantum yields, triplet energies, and sensitization efficiencies.

Quantification of C-H quenching in near-IR luminescent ytterbium and neodymium cryptates.

Two series of selectively deuterated cryptates with the lanthanoids Yb and Nd have been synthesized, and the luminescence lifetimes for the corresponding near-IR emission bands have been measured. Global fitting of these lifetime data combined with structural analysis allows for the accurate quantification of the contributions of individual C-H oscillators groups in the ligand to the nonradiative deactivation rates of the emissive lanthanoid states.

A [4+2] mixed ligand approach to ruthenium DNA metallointercalators [Ru(tpa)(N-N)](PF(6))(2) using a tris(2-pyridylmethyl)amine (tpa) capping ligand.

A series of five tris(2-pyridylmethyl)amine (tpa) ruthenium complexes [Ru(tpa)(N-N)](PF(6))(2) with N-N=bpy (2,2'-bipyridine), phen (1,10-phenanthroline), dpq (dipyrido[3,2-d:2',3'-f]quinoxaline), dppz (dipyrido[3,2-a;2',3'-c]phenazine), and dppn (4,5,9,16-tetraazadibenzo[a,c]naphthacene) was prepared and characterized by NMR, UV-Visible (UV/Vis), and fluorescence spectroscopy as well as cyclic voltammetry. Structures optimized with density functional theory methods (DFT, BP86, TZVP) without constraints show C(1) symmetry while in solution, the (1)H and (13)C NMR spectra are in accordance with an average C(s) symmetry. This is thought to be due to a low energy barrier for flipping of the equatorial pyridine ring from one side of the N-N plane to the other. The electronic structure of the compounds was studied with DFT and a change in the highest occupied molecular orbital (HOMO) character from Ru t(2g) for the bpy, phen, and dpq to N-N ligand-based for the dppz and dppn complexes was found. TDDFT calculations showed dominant N-N-based intra-ligand charge transfer (ILCT) transitions in the latter two complexes mixed with metal-to-ligand charge transfer (MLCT) bands found for all five compounds. DNA binding of the complexes was studied with UV/Vis titrations, the fluorescent ethidium bromide displacement assay, and CD spectroscopy. The affinity increases with the aromatic surface area of of the bidentate N-N ligand in the order bpy<

[N,N'-Bis(salicylidene)-1,2-phenylenediamine]metal complexes with cell death promoting properties.

We developed N,N'-bis(salicylidene)-1,2-phenylenediamine (salophene, 1) as a chelating agent for metal ions such as Mn(II/III), Fe(II/III), Co(II), Ni(II), Cu(II), and Zn(II). The resulting complexes, from which owing to the carrier ligand a selective mode of action is assumed, were tested for antiproliferative effects on the MCF-7 breast cancer cell line. The cytotoxicity in this assay depended on the nature of the transition metal used. Iron complexes in oxidation states +II and +III (3, 4) strongly reduced cell proliferation in a concentration-dependent manner, whereas, e.g., the manganese analogues 5 and 6 were only marginally active. Therefore, the [N,N'-bis(salicylidene)-1,2-phenylenediamine]iron(II/III) complexes 3 and 4 were selected for studies on the mode of action. Both complexes possessed high activity against various tumor cells, for instance, MDA-MB-231 mammary carcinoma cells as well as HT-29 colon carcinoma cells. They were able to generate reactive oxygen species, showed DNA binding, and induced apoptosis. Exchange of 1 by N,N'-bis(salicylidene)-1,2-cyclohexanediamine (saldach, 2) yielding complexes 7 and 8 reduced the in vitro effects drastically. An unequivocal mode of action cannot be deduced from these results, but it seems to be very likely that cell death is caused by interference with more than one intracellular target.