Enantioselective total synthesis of (-)-kibdelone C

The kibdelones are aromatic polyketide natural products featuring isoquinolinone and tetrahydroxanthone ring systems. They display potent cytotoxicity toward a range of human cancer cell lines. Here, we present an enantioselective total synthesis of kibdelone C that utilizes a Shi epoxidation to establish the absolute and relative stereochemistry, an acid-catalyzed cyclization to form the tetrahydroxanthone, and a C-H arylation to complete the hexacyclic skeleton.     

Aziridine-mediated ligation and site-specific modification of unprotected peptides

A synthesis of aziridine-containing peptides via the Cu(II)-promoted coupling of unprotected peptide thioacids and N-H aziridine-2-carbonyl peptides is reported. The unique reactivity of the resulting N-acylated aziridine-2-carbonyl peptides facilitates their subsequent regioselective and stereoselective nucleophilic ring-opening to give unprotected peptides that are specifically modified at the ligation site. The aziridine-mediated peptide ligation concept is exemplified using H(2)O as the nucleophile, producing a Xaa-Thr linkage (where Xaa can be an epimerizable and hindered amino acid). The overall process is compatible with a variety of unprotected amino acid functionality, most notably the N-terminal and Lys side chain amines.     

Supported-nanoparticle heterogeneous catalyst formation in contact with solution: kinetics and proposed mechanism for the conversion of Ir(1,5-COD)Cl/γ-Al2O3 to Ir(0)(~900)/γ-Al2O3

A current goal in heterogeneous catalysis is to transfer the synthetic, as well as developing mechanistic, insights from the modern revolution in nanoparticle science to the synthesis of supported-nanoparticle heterogeneous catalysts. In a recent study (Mondloch, J. E.; Wang, Q.; Frenkel, A. I.; Finke, R. G. J. Am. Chem. Soc. 2010, 132, 9701-9714), we initialized tests of the global hypothesis that quantitative kinetic and mechanistic studies, of supported-nanoparticle heterogeneous catalyst formation in contact with solution, can provide synthetic and mechanistic insights that can eventually drive improved syntheses of composition-, size-, and possibly shape-controlled catalysts. That study relied on the development of a well-characterized Ir(1,5-COD)Cl/γ-Al(2)O(3) precatalyst, which, when in contact with solution and H(2), turns into a nonaggregated Ir(0)(~900)/γ-Al(2)O(3) supported-nanoparticle heterogeneous catalyst. The kinetics of the Ir(1,5-COD)Cl/γ-Al(2)O(3) to Ir(0)(~900)/γ-Al(2)O(3) conversion were followed and fit by a two-step mechanism consisting of nucleation (A → B, rate constant k(1)) followed by autocatalytic surface growth (A + B → 2B, rate constant k(2)). However, a crucial, but previously unanswered question is whether the nucleation and growth steps occur primarily in solution, on the support, or possibly in both phases for one or more of the catalyst-formation steps. The present work investigates this central question for the prototype Ir(1,5-COD)Cl/γ-Al(2)O(3) to Ir(0)(~900)/γ-Al(2)O(3) system. Solvent variation-, γ-Al(2)O(3)-, and acetone-dependent kinetic data, along with UV-vis spectroscopic and gas-liquid-chromatography (GLC) data, are consistent with and strongly supportive of a supported-nanoparticle formation mechanism consisting of Ir(1,5-COD)Cl(solvent) dissociation from the γ-Al(2)O(3) support (i.e., from Ir(1,5-COD)Cl/γ-Al(2)O(3)), solution-based nucleation from that dissociated Ir(1,5-COD)Cl(solvent) species, fast Ir(0)(n) nanoparticle capture by γ-Al(2)O(3), and then subsequent solid-oxide-based nanoparticle growth from Ir(0)(n)/γ-Al(2)O(3) and with Ir(1,5-COD)Cl(solvent), the first kinetically documented mechanism of this type. Those data disprove a solid-oxide-based nucleation and growth pathway involving only Ir(1,5-COD)Cl/γ-Al(2)O(3) and also disprove a solution-based nanoparticle growth pathway involving Ir(1,5-COD)Cl(solvent) and Ir(0)(n) in solution. The present mechanistic studies allow comparisons of the Ir(1,5-COD)Cl/γ-Al(2)O(3) to Ir(0)(~900)/γ-Al(2)O(3) supported-nanoparticle formation system to the kinetically and mechanistically well-studied, Ir(1,5-COD)·P(2)W(15)Nb(3)O(62)(8-) to Ir(0)(~300)·(P(2)W(15)Nb(3)O(62)(8-))(n)(-8n) solution-based, polyoxoanion-stabilized nanoparticle formation and stabilization system. That comparison reveals closely analogous, solution Ir(1,5-COD)(+) or Ir(1,5-COD)Cl-mediated, mechanisms of nanoparticle formation. Overall, the hypothesis supported by this work is that these and analogous studies hold promise of providing a way to transfer the synthetic and mechanistic insights, from the modern revolution in nanoparticle synthesis and characterization in solution, to the rational, mechanism-directed syntheses of solid oxide-supported nanoparticle heterogeneous catalysts, also in contact with solution.     

Vibrational frequencies and spectroscopic constants from quartic force fields for cis-HOCO: the radical and the anion

The use of accurate quartic force fields together with vibrational configuration interaction recently predicted gas phase fundamental vibrational frequencies of the trans-HOCO radical to within 4 cm(-1) of experimental results for the two highest frequency modes. Utilizing the same approach, we are providing a full list of fundamental vibrational frequencies and spectroscopic constants for the cis-HOCO system in both radical and anionic forms. Our predicted geometrical parameters of the cis-HOCO radical match experiment and previous computation to better than 1% deviation, and previous theoretical work agrees equally well for the anion. Correspondence between vibrational perturbation theory and variational vibrational configuration interaction for prediction of the frequencies of each mode is strong, better than 5 cm(-1), except for the torsional motion, similar to what has been previously identified in the trans-HOCO radical. Among other considerations, our results are immediately applicable to dissociative photodetachment experiments which initially draw on the cis-HOCO anion since it is the most stable conformer of the anion and is used to gain insight into the portion of the OH + CO potential surface where the HOCO radical is believed to form, and we are also providing highly accurate electron binding energies relevant to these experiments.     

HNO3-NHx, H2SO4-NHx, CH(O)OH-NHx, and CH3C(O)OH-NHx complexes and their role in the formation of condensation nuclei

The formation of sulfuric acid (H(2)SO(4)), nitric acid (HNO(3)), acetic acid (CH(3)C(O)OH), and formic acid (HC(O))H) complexes with ammonia (NH(3)), amidogen radical (NH(2)), and imidogen radical (NH) was studied using natural bond orbital calculations. The equilibrium structures, binding energies, and harmonic frequencies were calculated for each acid-NH(x) complex using hybrid density functional (B3LYP) and second-order M?ller-Plesset perturbation approximation methods with the 6-311++G(3df,3pd) basis set. The results presented here suggest that the effect of NH(2) on the formation of new condensation nuclei will be similar to that of NH(3), but to a lesser degree and confined primarily to complexes with H(2)SO(4) and HNO(3). The NH radical is not expected to play a significant role in the formation of new atmospheric condensation nuclei.     

Experimental characterization of the weakly anisotropic CN X 2Σ+ + Ne potential from IR-UV double resonance studies of the CN-Ne complex

IR-UV double resonance spectroscopy has been used to characterize hindered internal rotor states (n(K) = 0(0), 1(1), and 1(0)) of the CN-Ne complex in its ground electronic state with various degrees of CN stretch (ν(CN)) excitation. Rotationally resolved infrared overtone spectra of the CN-Ne complex exhibit perturbations arising from Coriolis coupling between the closely spaced hindered rotor states (1(1) and 1(0)) with two quanta of CN stretch (ν(CN) = 2). A deperturbation analysis is used to obtain accurate rotational constants and associated average CN center-of-mass to Ne separation distances as well as the coupling strength. The energetic ordering and spacings of the hindered internal rotor states provide a direct reflection of the weakly anisotropic intermolecular potential between CN X (2)Σ(+) and Ne, with only an 8 cm(-1) barrier to CN internal rotation, from which radially averaged anisotropy parameters (V(10) and V(20)) are extracted that are consistent for ν(CN) = 0-3. Complementary ab initio calculation of the CN X (2)Σ(+) + Ne potential using MRCI+Q extrapolated to the complete one-electron basis set limit is compared with the experimentally derived anisotropy by optimizing the radial potential at each angle. Experiment and theory are in excellent accord, both indicating a bent minimum energy configuration and nearly free rotor behavior. Analogous experimental and theoretical studies of the CN-Ne complex upon electronic excitation to the CN B (2)Σ(+) state indicate a slightly more anisotropic potential with a linear CN-Ne minimum energy configuration. The results from these IR-UV double resonance studies are compared with prior electronic spectroscopy and theoretical studies of the CN-Ne system.     

Electron Capture,Collision-Induced,and Electron Capture-Collision Induced Dissociation in Q-TOF

Recently, we demonstrated that a radio-frequency-free electromagnetostatic (rf-free EMS) cell could be retrofitted into a triple quad mass spectrometer to allow electron-capture dissociation (ECD) without the aid of cooling gas or phase-specific electron injection into the cell (Voinov et al., Rapid Commun Mass Spectrom 22, 3087–3088, 2008; Voinov et al., Anal Chem 81, 1238–1243, 2009). Subsequently, we used our rf-free EMS cell in the same instrument platform to demonstrate ECD occurring in the same space and at the same time with collision-induced dissociation (CID) to produce golden pairs and even triplets from peptides (Voinov et al., Rapid Commun Mass Spectrom 23, 3028–3030, 2009). In this report, we demonstrate that ECD and CID product-ion mass spectra can be recorded at high resolution with flexible control of fragmentation processes using a newly designed cell installed in a hybrid Q-TOF tandem mass spectrometer.     

Lung assist device technology with physiologic blood flow developed on a tissue engineered scaffold platform

There is no technology available to support failing lung function for patients outside the hospital. An implantable lung assist device would augment lung function as a bridge to transplant or possible destination therapy. Utilizing biomimetic design principles, a microfluidic vascular network was developed for blood inflow from the pulmonary artery and blood return to the left atrium. Computational fluid dynamics analysis was used to optimize blood flow within the vascular network. A micro milled variable depth mold with 3D features was created to achieve both physiologic blood flow and shear stress. Gas exchange occurs across a thin silicone membrane between the vascular network and adjacent alveolar chamber with flowing oxygen. The device had a surface area of 23.1 cm(2) and respiratory membrane thickness of 8.7 ± 1.2 μm. Carbon dioxide transfer within the device was 156 ml min(-1) m(-2) and the oxygen transfer was 34 ml min(-1) m(-2). A lung assist device based on tissue engineering architecture achieves gas exchange comparable to hollow fiber oxygenators yet does so while maintaining physiologic blood flow. This device may be scaled up to create an implantable ambulatory lung assist device.     

Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program PROTOBUILD

Peroxisome proliferator activated receptors (PPARs) have been shown to have critical roles in fatty acid oxidation, triglyceride synthesis, and lipid metabolism - making them an important target in drug discovery. Here we describe the in silico design, synthesis and in vitro characterisation of a novel series of 2,5-disubstituted indoles as PPARα/γ dual agonists. PPAR activation assays are performed with known agonists diazabenzene (WY14.643), aminopyridine (BRL49653) and bisaryl (L165.041), as positive controls. All the indole compounds synthesized are found to be active PPARα and PPARγ agonists, with particular efficacy from those with 2-naphthylmethyl substitution. This is a useful demonstration of a new de novo design methodology implemented by the protobuild program and its ability to rapidly produce novel modulators for a well characterized drug target.     

Modification of the magnetic properties of a heterometallic wheel by inclusion of a Jahn-Teller distorted Cu(II) ion

An investigation into the physical consequences of including a Jahn-Teller distorted Cu(II) ion within an antiferromagnetically coupled ring, [R(2)NH(2)][Cr(7)CuF(8)((O(2)C(t)Bu)(16))] is reported. Inelastic neutron scattering (INS) and electron paramagnetic resonance (EPR) spectroscopic data are simulated using a microscopic spin Hamiltonian, and show that the two Cr-Cu exchange interactions must be inequivalent. One Cr-Cu exchange is found to be antiferromagnetic and the other ferromagnetic. The geometry of the Jahn-Teller elongation is deduced from these results, and shows that a Jahn-Teller elongation axis must lie in the plane of the Cr(7)Cu wheel; the elongation is not observed by X-ray crystallography, due to positional disorder of the Cu site within the wheel. An electronic structure calculation confirms the structural distortion of the Cu site.