Gold(I) Phosphine Derivatives with Improved Selectivity as Topically Active Drug Leads to Overcome 5-Nitroheterocyclic Drug Resistance in Trichomonas vaginalis.

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.

Conformational twisting of a formate-bridged diiridium complex enables catalytic formic acid dehydrogenation.

We previously reported that iridium complex 1a enables the first homogeneous catalytic dehydrogenation of neat formic acid and enjoys unusual stability through millions of turnovers. Binuclear iridium hydride species 5a, which features a provocative C2-symmetric geometry, was isolated from the reaction as a catalyst resting state. By synthesizing and carefully examining the catalytic initiation of a series of analogues to 1a, we establish here a strong correlation between the formation of C2-twisted iridium dimers analogous to 5a and the reactivity of formic acid dehydrogenation: an efficient C2 twist appears unique to 1a and essential to catalytic reactivity.

A prolific catalyst for dehydrogenation of neat formic acid.

Formic acid is a promising energy carrier for on-demand hydrogen generation. Because the reverse reaction is also feasible, formic acid is a form of stored hydrogen. Here we present a robust, reusable iridium catalyst that enables hydrogen gas release from neat formic acid. This catalysis works under mild conditions in the presence of air, is highly selective and affords millions of turnovers. While many catalysts exist for both formic acid dehydrogenation and carbon dioxide reduction, solutions to date on hydrogen gas release rely on volatile components that reduce the weight content of stored hydrogen and/or introduce fuel cell poisons. These are avoided here. The catalyst utilizes an interesting chemical mechanism, which is described on the basis of kinetic and synthetic experiments.

Synthesis and Characterization of Dimethylbis(2-pyridyl)borate Nickel(II) Complexes: Unimolecular Square-Planar to Square-Planar Rotation around Nickel(II).

The syntheses of novel dimethylbis(2-pyridyl)borate nickel(II) complexes 4 and 6 are reported. These complexes were unambiguously characterized by X-ray analysis. In dichloromethane solvent, complex 4 undergoes a unique square-planar to square-planar rotation around the nickel(II) center, for which activation parameters of ΔH⧧ = 12.2(1) kcal mol-1 and ΔS⧧ = 0.8(5) eu were measured via NMR inversion recovery experiments. Complex 4 was also observed to isomerize via a relatively slow ring flip: ΔH⧧ = 15.0(2) kcal mol-1; and ΔS⧧ = -4.2(7) eu. DFT studies support the experimentally measured rotation activation energy (cf. calculated ΔH⧧ = 11.1 kcal mol-1) as well as the presence of a high-energy triplet intermediate (ΔH = 8.8 kcal mol-1).

Chemistry of trans-resveratrol with singlet oxygen: [2+2] addition, [4+2] addition, and formation of the phytoalexin moracin M.

Resveratrol (1) reacts with singlet oxygen by two major pathways: A [2+2] cycloaddition forming a transient dioxetane that cleaves into the corresponding aldehydes and a [4+2] cycloaddition forming an endoperoxide that, upon heating, undergoes a rearrangement to moracin M. The rate constant by which singlet oxygen is removed by 1 (k(T)) was determined by time-resolved infrared luminescence spectroscopy to be 1.5 × 10(6) M(-1) sec(-1) in CD(3)OD, smaller than previously reported values. Chemical reaction accounts for ca. 25% of k(T).

Photooxidation of mixed aryl and biarylphosphines.

Arylphosphines and dialkylbiarylphosphines react with singlet oxygen to form phosphine oxides and phosphinate esters. For mixed arylphosphines, the most electron-rich aryl group migrates to form the phosphinate, while for dialkylbiarylphosphines migration of the alkyl group occurs. Dialkylbiarylphosphines also yield arene epoxides, especially in electron-rich systems. Phosphinate ester formation is increased at high temperature, while protic solvents increase the yield of epoxide. The product distribution provides evidence for Buchwald's recent conformational model for the aerobic oxidation of dialkylbiarylphosphines.

Phosphadioxirane: a peroxide from an ortho-substituted arylphosphine and singlet dioxygen.

We prepared the primary adduct for the reaction of singlet dioxygen (1O2) with an arylphosphine by using the sterically hindered arylphosphine tris(o-methoxyphenyl)phosphine. The resulting phosphadioxirane has a dioxygen molecule triangularly bound to the phosphorus atom. Olefin trapping experiments show that the phosphadioxirane can undergo nonradical oxygen atom-transfer reactions. Under protic conditions, two different intermediates are formed during the reaction of singlet dioxygen with tris(o-methoxyphenyl)phosphine, namely, the corresponding hydroperoxy arylphosphine and a hydroxy phosphorane. Experiments with other arylphosphines possessing different electronic and steric properties demonstrate that the relative stability of the tris(o-methoxyphenyl)phosphadioxirane is due to both steric and electronic effects.