Catalytic Nitrene Transfer by an FeIV-Imido Complex Generated by a Comproportionation Process

Nitrene transfer reactions have emerged as one of the most powerful and versatile ways to insert an amine function to various kinds of hydrocarbon substrates. However, the mechanisms of nitrene generation have not been studied in depth albeit their formation is taken for granted in most cases without definitive evidence of their occurrence. In the present work, we compare the generation of tosylimido iron species and NTs transfer from Fe^II and Fe^III precursors where the metal is embedded in a tetracarbene macrocycle. Catalytic nitrene transfer to reference substrates (thioanisole, styrene, ethylbenzene and cyclohexane) revealed that the same active species was at play, irrespective of the ferrous versus ferric nature of the precursor. Through combination of spectroscopic (UV-visible, Mössbauer), ESI-MS and DFT studies, an Fe^IV tosylimido species was identified as the catalytically active species and was characterized spectroscopically and computationally. Whereas its formation from the Fe^II precursor was expected by a two-electron oxidative addition, its formation from an Fe^III precursor was unprecedented. Thanks to a combination of spectroscopic (UV-visible, EPR, Hyscore and Mössbauer), ESI-MS and DFT studies, we found that, when starting from the Fe^III precursor, an Fe^III tosyliodinane adduct was formed and decomposed into an Fe^V tosylimido species which generated the catalytically active Fe^IV tosylimide through a comproportionation process with the Fe^III precursor.     

Sensitive CE-MS method for monitoring of riociguat and desmethylriociguat levels in human serum

Riociguat is novel antihypertensive drug for treatment of pulmonary hypertension. As such, it is still being tested in many clinical and pharmacokinetic trials. Existing methods that determine serum riociguat and desmethylriociguat (DMR) are based solely on liquid chromatography with mass spectrometry. Therefore, we present a novel capillary electrophoresis with mass spectrometry method (CE-MS) for their determination in human serum as alternative method for ongoing trials. Complete resolution of both analytes was achieved by means of pH optimization of ammonium formate background electrolytes that are fully compatible with ESI/MS detection. Simple liquid-liquid extraction was used as sample pretreatment. The calibration dependence of the method was linear (in the range of 10–1000 ng/mL), with adequate accuracy (90.1–114.9%) and precision (13.4%). LOD and LOQ were arbitrarily set at 10 ng/mL for both analytes. Clinical applicability was validated using serum samples from patients treated with riociguat in pharmacokinetic study and the results corresponded with reference HPLC-MS/MS values. Capillary electrophoresis proved to be sensitive and selective tool for the analysis of riociguat and DMR.     

Silver(I) Complexes of Two Flexible Bis-phospholane Ligands: Metallamacrocycles,Polymeric Chains,and Metallacryptands

In a 2:2 reaction with silver(I) chloride or bromide, 1,5-bis(1-phospholano)pentane ( 1a ) afforded frame-like macrocyclic structures, with intra- ( 2 , Cl) or intermolecular ( 3 , Br) halido bridges. In contrast, 1,7-bis(1-phospholano)heptane ( 1b ) formed coordination polymers 4a (Cl) and 4b (Br) with bridging bis-phospholane and halido ligands. A unique paddle wheel-type metallacryptand structure 5 was obtained from 1a and silver(I) bromide in a 2:3 reaction (M:L). All complexes were fully characterized by NMR, IR spectroscopy, mass spectrometry, and X-ray crystallography.     

Dynamics of Bacteriorhodopsin in the Dark-Adapted State from Solution Nuclear Magnetic Resonance Spectroscopy

To achieve efficient proton pumping in the light-driven proton pump bacteriorhodopsin (bR), the protein must be tightly coupled to the retinal to rapidly convert retinal isomerization into protein structural rearrangements. Methyl group dynamics of bR embedded in lipid nanodiscs were determined in the dark-adapted state, and were found to be mostly well ordered at the cytosolic side. Methyl groups in the M145A mutant of bR, which displays only 10 % residual proton pumping activity, are less well ordered, suggesting a link between side-chain dynamics on the cytosolic side of the bR cavity and proton pumping activity. In addition, slow conformational exchange, attributed to low frequency motions of aromatic rings, was indirectly observed for residues on the extracellular side of the bR cavity. This may be related to reorganization of the water network. These observations provide a detailed picture of previously undescribed equilibrium dynamics on different time scales for ground-state bR.     

Vinylic MIDA Boronates: New Building Blocks for the Synthesis of Aza‐Heterocycles

A two‐step synthesis of structurally diverse pyrrole‐containing bicyclic systems is reported. ortho‐Nitro‐haloarenes coupled with vinylic N‐methyliminodiacetic acid (MIDA) boronates generate ortho‐vinyl‐nitroarenes, which undergo a “metal‐free” nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex “drug‐like” molecules. Interestingly, an ortho‐nitro‐allylarene derivative furnished a cyclic β‐aminophosphonate motif.     

Iodine(III)‐Catalyzed Rearrangements of Imides: A Versatile Route to α,α‐Dialkylated α‐Hydroxy Carboxylamides

A tertiary hydroxy group α to a carboxyl moiety comprises a key structural motif in many bioactive substances. With the herein presented metal‐free rearrangement of imides triggered by hypervalent λ³‐iodane, an easy and selective way to gain access to such a compound class, namely α,α‐disubstituted‐α‐hydroxy carboxylamides, was established. Their additional methylene bromide side chain constitutes a useful handle for rapid diversification, as demonstrated by a series of further functionalizations. Moreover, the in situ formation of an iodine(III) species under the reaction conditions was proven. Our findings clearly corroborate that hypervalent λ³‐benziodoxolones are involved in these organocatalytic reactions.     

Modular Synthetic Approach to Carboranyl‒Biomolecules Conjugates

The development of novel, tumor-selective and boron-rich compounds as potential agents for use in boron neutron capture therapy (BNCT) represents a very important field in cancer treatment by radiation therapy. Here, we report the design and synthesis of two promising compounds that combine meta-carborane, a water-soluble monosaccharide and a linking unit, namely glycine or ethylenediamine, for facile coupling with various tumor-selective biomolecules bearing a free amino or carboxylic acid group. In this work, coupling experiments with two selected biomolecules, a coumarin derivative and folic acid, were included. The task of every component in this approach was carefully chosen: the carborane moiety supplies ten boron atoms, which is a tenfold increase in boron content compared to the l-boronophenylalanine (l-BPA) presently used in BNCT; the sugar moiety compensates for the hydrophobic character of the carborane; the linking unit, depending on the chosen biomolecule, acts as the connection between the tumor-selective component and the boron-rich moiety; and the respective tumor-selective biomolecule provides the necessary selectivity. This approach makes it possible to develop a modular and feasible strategy for the synthesis of readily obtainable boron-rich agents with optimized properties for potential applications in BNCT.