Development and validation of a liquid chromatography–tandem mass spectrometry method for the simultaneous analysis of androgens,estrogens, glucocorticoids and progestagens in human serum

We present a liquid chromatography tandem mass spectrometry method for the simultaneous analysis of 16 endogenous steroids (androgens, estrogens, glucocorticoids and progestogens) in human serum. Samples (250 μl of matrix) were extracted with t-butylmethyl ether prior to LC–MS/MS analysis. The chromatographic separation was achieved on a reversed-phase column using a methanol–water gradient. The HPLC was coupled to a triple quadrupole mass spectrometer equipped with an electrospray ionization source with acquisition in multiple reaction monitoring mode. The method was validated using surrogate matrices and human serum samples. The specificity of the method was confirmed for all of the considered steroids; linearity was also assessed (R² > 0.99, lack-of-fit test) in the ranges of concentrations investigated. The lower limits of quantification were in the range 10–400 pg/ml depending on the target steroid. Accuracy was in the range 85–115% for all target steroids except for the lower limit of quantitation levels where it was 80–120%. The extraction recovery was always >65%. No significant matrix effects were observed. To test the reliability of the method, the analysis of serum samples collected from 10 healthy subjects (5 M/5F) was performed. The present method can be used to identify the trajectories of deviation from the concentration normality ranges applied to disorders of the gonadal and adrenal axes.     

A Buchwald–Hartwig Protocol to Enable Rapid Linker Exploration of Cereblon E3-Ligase PROTACs**

A palladium-catalysed Buchwald–Hartwig amination for lenalidomide-derived aryl bromides was optimised using high throughput experimentation (HTE). The substrate scope of the optimised conditions was evaluated for a range of alkyl- and aryl- amines and functionalised aryl bromides. The methodology allows access to new cereblon-based bifunctional proteolysis targeting chimeras with a reduced step count and improved yields.     

Group 6 Oxyfluoro-Anion Salts of [XeF5]+ and [Xe2F11]+: Syntheses and Structures of [XeF5][M2O2F9] (M=Mo,W), [Xe2F11][M′OF5] (M′=Cr,Mo, W), [XeF5][HF2]⋅CrOF4, and [XeF5][WOF5]⋅XeOF4

The reactions of the fluoride-ion donor, XeF₆, with the fluoride-ion acceptors, M′OF₄ (M′=Cr, Mo, W), yield [XeF₅]⁺ and [Xe₂F₁₁]⁺ salts of [M′OF₅]⁻ and [M₂O₂F₉]⁻ (M=Mo, W). Xenon hexafluoride and MOF₄ react in anhydrous hydrogen fluoride (aHF) to give equilibrium mixtures of [Xe₂F₁₁]⁺, [XeF₅]⁺, [(HF)_nF]⁻, [MOF₅]⁻, and [M₂O₂F₉]⁻ from which the title salts were crystallized. The [XeF₅][CrOF₅] and [Xe₂F₁₁][CrOF₅] salts could not be formed from mixtures of CrOF₄ and XeF₆ in aHF at low temperature (LT) owing to the low fluoride-ion affinity of CrOF₄, but yielded [XeF₅][HF₂]⋅CrOF₄ instead. In contrast, MoOF₄ and WOF₄ are sufficiently Lewis acidic to abstract F⁻ ion from [(HF)_nF]⁻ in aHF to give the [MOF₅]⁻ and [M₂O₂F₉]⁻ salts of [XeF₅]⁺ and [Xe₂F₁₁]⁺. To circumvent [(HF)_nF]⁻ formation, [Xe₂F₁₁][CrOF₅] was synthesized at LT in CF₂ClCF₂Cl solvent. The salts were characterized by LT Raman spectroscopy and LT single-crystal X-ray diffraction, which provided the first X-ray crystal structure of the [CrOF₅]⁻ anion and high-precision geometric parameters for [MOF₅]⁻ and [M₂O₂F₉]⁻. Hydrolysis of [Xe₂F₁₁][WOF₅] by water contaminant in HF solvent yielded [XeF₅][WOF₅]⋅XeOF₄. Quantum-chemical calculations were carried out for M′OF₄, [M′OF₅]⁻, [M′₂O₂F₉]⁻, {[Xe₂F₁₁][CrOF₅]}₂, [Xe₂F₁₁][MOF₅], and {[XeF₅][M₂O₂F₉]}₂ to obtain their gas-phase geometries and vibrational frequencies to aid in their vibrational mode assignments and to assess chemical bonding.     

Dearomatization of 3-Nitroindoles with Highly γ-Functionalized Allenoates in Formal (3+2) Cycloadditions

3-Nitroindoles are easily reacted with highly substituted γ-allenoates in the presence of a commercially available phosphine catalyst. For instance, allenoates derived from biomolecules such as amino and deoxycholic acids are combined for the first time with 3-nitroindole. The corresponding dearomatized (3+2) tricyclic cycloadducts are obtained as α-regioisomers exclusively. DFT computations shed light on this multi-step reaction mechanism and on the selectivities observed in the sequence.     

Photoinduced Mo−CN Bond Breakage in Octacyanomolybdate Leading to Spin Triplet Trapping

The photoinduced properties of the octacoordinated complex K₄Mo^IV(CN)₈⋅2 H₂O were studied by theoretical calculations, crystallography, and optical and magnetic measurements. The crystal structure recorded at 10 K after blue light irradiation reveals an heptacoordinated Mo(CN)₇ species originating from the light-induced cleavage of one Mo−CN bond, concomitant with the photoinduced formation of a paramagnetic signal. When this complex is heated to 70 K, it returns to its original diamagnetic ground state, demonstrating full reversibility. The photomagnetic properties show a partial conversion into a triplet state possessing significant magnetic anisotropy, which is in agreement with theoretical studies. Inspired by these results, we isolated the new compound [K(crypt-222)]₃[Mo^IV(CN)₇]⋅3 CH₃CN using a photochemical pathway, confirming that photodissociation leads to a stable heptacyanomolybdate(IV) species in solution.