Amphipathic Barbiturates as Mimics of Antimicrobial Peptides and the Marine Natural Products Eusynstyelamides with Activity against Multi-resistant Clinical Isolates.

We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N'-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2-8 µg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum ß-lactamase-carbapenemase production. The guanidine barbiturate 7e (3,5-di-Br) demonstrated promising in vivo antibiotic efficacy in mice infected with clinical isolates of Escherichia coli and Klebsiella pneumoniae using a neutropenic peritonitis model. Mode of action studies showed a strong membrane disrupting effect and was supported by nuclear magnetic resonance and molecular dynamics simulations. The results express how the pharmacophore model of small AMPs and the structure of the marine eusynstyelamides can be used to design highly potent lead peptidomimetics against multi-resistant bacteria.

Cobalt-catalysed alkene hydrogenation: a metallacycle can explain the hydroxyl activating effect and the diastereoselectivity.

Bis(phosphine)cobalt dialkyl complexes have been reported to be highly active in the hydrogenation of tri-substituted alkenes bearing hydroxyl substituents. Alkene substrates containing ether, ester, or ketone substituents show minimal reactivity, indicating an activating effect of the hydroxyl group. The mechanistic details of bis(phosphine)cobalt-catalysed hydrogenation were recently evaluated computationally (X. Ma, M. Lei, J. Org. Chem. 2017, 82, 2703-2712) and a Co(0)-Co(ii) redox mechanism was proposed. However, the activating effect of the hydroxyl substituent and the accompanying high diastereoselectivity were not studied. Here we report a computational study rationalizing the role of the hydroxyl group through a key metallacycle species. The metallacycle is part of a non-redox catalytic pathway proceeding through Co(ii) intermediates throughout. The preference for alcohol over ether substrates and the high diastereoselectivity of terpinen-4-ol hydrogenation are correctly predicted in computations adopting the new pathway, whereas the alternative redox mechanism predicts ethers rather than alcohols to be more reactive substrates. Additional experimental evidence supports the role of the hydroxyl group in the metallacycle mechanism. Our work highlights the importance of employing known substrate preferences and stereoselectivities to test the validity of computationally proposed reaction pathways.

Accurate prediction of emission energies with TD-DFT methods for platinum and iridium OLED materials.

Accurate prediction of triplet excitation energies for transition metal complexes has proven to be a difficult task when confronted with a variety of metal centers and ligand types. Specifically, phosphorescent transition metal light emitters, typically based on iridium or platinum, often give calculated results of varying accuracy when compared to experimentally determined T1 emission values. Developing a computational protocol for reliably calculating OLED emission energies will allow for the prediction of a complex's color prior to synthesis, saving time and resources in the laboratory. A comprehensive investigation into the dependence of the DFT functional, basis set, and solvent model is presented here, with the aim of identifying an accurate method while remaining computationally cost-effective. A protocol that uses TD-DFT excitation energies on ground-state geometries was used to predict triplet emission values of 34 experimentally characterized complexes, using a combination of gas phase B3LYP/LANL2dz for optimization and B3LYP/CEP-31G/PCM(THF) for excitation energies. Results show excellent correlation with experimental emission values of iridium and platinum complexes for a wide range of emission energies. The set of complexes tested includes neutral and charged complexes, as well as a variety of different ligand types.

A computational study of metal-mediated decomposition of nitrene transfer reagents.

Metal-mediated decomposition to form nitrene complexes is investigated by using DFT for prototypical organic azides and iodonium imides used in organic synthesis. Each system exhibited exothermic pathways via formation of cyclic intermediates, which decompose to yield LNi = NX + Y (L = bis-phosphine, NX = nitrene, Y = N2 or IPh). Also, the typical heterotransfer reagents used in organic synthesis show a greater tendency toward triplet nitrene complexes and hence the potential for metal-free reactivity than aliphatic and aromatic substituted versions.

Catalytic tuning of a phosphinoethane ligand for enhanced C-H activation.

Hydrogen atom abstraction (HAA) from 1,4-cyclohexadiene (CD-H) by (dtbpe)Ni(NAr) to form a Ni(I)-amide, (dtbpe)Ni(NHAr), and cyclohexadienyl radical is calculated to be thermodynamically reasonable, DeltaH(HAA)(dtbpe) = -1.3 kcal/mol, dtbpe = bis(di-tert-butylphosphino)ethane, Ar = 2,6-diisopropylphenyl. However, radical rebound to form a metal-bound amine is highly endothermic (DeltaH(reb)(dtbpe) = +25.1 kcal/mol). Analysis of bond enthalpies indicates that weakening of the Ni-N bond (Ni-amide --> Ni-amine) upon radical rebound is not compensated by the weak C-N bond formed. Hence, a ligand was sought that would enhance the metal-amine bond strength while diminishing the metal-amide bond strength. Reaction of (dfmpe)Ni(NAr) with CD-H was thus analyzed, dfmpe = bis(di(trifluoromethyl)phosphino)ethane. While there is a small change in the thermodynamics of HAA (DeltaH(HAA)(dfmpe) = -5.7 kcal/mol), there is a profound change in the rebound step (DeltaH(reb)(dfmpe) = -7.8 kcal/mol) upon replacing dtbpe by dfmpe. Regeneration of the nitrene active species by reaction of ArN3 with the metal-bound product is calculated to be highly exothermic, DeltaH(reg) = -36.7 kcal/mol. Two candidates for a precatalyst, (dfmpe)Ni(COD) and (dfmpe)Ni(bpy), COD = 1,5-cyclooctadiene and bpy = 2,2'-bipyridine, were calculated to undergo highly exothermic reactions with ArN3 to form the nitrene active species. The calculated enthalpic barrier for HAA of CD-H by (dfmpe)Ni(NAr) is 21.3 kcal/mol. Hence, consideration of the computed thermodynamics and kinetics suggests that nickel-nitrenes with fluorinated phosphine supporting ligation are promising candidates for catalytic amination of C-H bonds.