Photoredox-Mediated Hydrogen Isotope Exchange Reactions of Amino-Acids,Peptides, and Peptide-Derived Drugs

Hydrogen isotopically labelled compounds are essential diagnostic tools in drug research and development, as they provide vital information about the biological metabolism of drug candidates and their metabolites. Herein we report a photoredox-initiated hydrogen atom transfer (HAT) protocol which efficiently and selectively introduces deuterium or tritium at C(sp³)−H bonds, utilizing heavy water (D₂O or T₂O) as the hydrogen isotope source, and a guanidine base. This protocol has been successfully applied to the incorporation of deuterium in several amino acids (lysine, glycine and proline) and small peptides. Finally, the method has been applied to tritium, because tritium-labelled peptides are essential for application in biological experiments, such as ligand-binding assays, or absorption, distribution, metabolism, and excretion (ADME) studies.     

Near-Infrared Light Triggered-Release in Deep Brain Regions Using Ultra-photosensitive Nanovesicles

Remote and minimally-invasive modulation of biological systems with light has transformed modern biology and neuroscience. However, light absorption and scattering significantly prevents penetration to deep brain regions. Herein, we describe the use of gold-coated mechanoresponsive nanovesicles, which consist of liposomes made from the artificial phospholipid Rad-PC-Rad as a tool for the delivery of bioactive molecules into brain tissue. Near-infrared picosecond laser pulses activated the gold-coating on the surface of nanovesicles, creating nanomechanical stress and leading to near-complete vesicle cargo release in sub-seconds. Compared to natural phospholipid liposomes, the photo-release was possible at 40 times lower laser energy. This high photosensitivity enables photorelease of molecules down to a depth of 4 mm in mouse brain. This promising tool provides a versatile platform to optically release functional molecules to modulate brain circuits.     

Inducing Propeller Chirality in Triaryl Boranes with Chiral Amines

Stabilization of chiral propeller conformations in triaryl compounds is challenging due to generally low racemization barriers. Nonetheless, it was recently found that chiral conformational preferences can be induced to triaryl boranes by incorporating point-chiral alkylether chains to the aryl blades and subsequently locking the structure with ammonia. A four-point interaction, meaning that the cooperative effects of Lewis-adduct formation and three hydrogen bonds, was proposed as stabilizing mechanism. Herein, it was shown that three such strong interactions suffice to introduce a preferential propeller handedness. Although DFT calculations predict no noteworthy preferences for either P- or M-chiral propellers for some of the investigated triarylborane–amine adducts that were prepared with chiral primary amines, vibrational circular dichroism (VCD) spectroscopic characterizations revealed that there is indeed a measurable excess of one propeller handedness. Furthermore, the steric demand of the amine was found to play a key role in the induction process and especially in preventing blade rotations.     

One-Step Synthesis and Schlenk-Type Equilibrium of Cyclopentadienylmagnesium Bromides

In the in situ Grignard metalation method (iGMM), the addition of bromoethane to a suspension of magnesium turnings and cyclopentadienes [C₅H₆ (HCp), C₅H₅-Si(iPr)₃ (HCp^TIPS)] in diethyl ether smoothly yields heteroleptic [(Et₂O)Mg(Cp^R)(μ-Br)]₂ (Cp^R=Cp ( 1 ), Cp^TIPS ( 2 )). The Schlenk equilibrium of 2 in toluene leads to ligand exchange and formation of homoleptic [Mg(Cp^R)₂] ( 3 ) and [(Et₂O)MgBr(μ-Br)]₂ ( 4 ). Interfering solvation and aggregation as well as ligand redistribution equilibria hamper a quantitative elucidation of thermodynamic data for the Schlenk equilibrium of 2 in toluene. In ethereal solvents, mononuclear species [(Et₂O)₂Mg(Cp^TIPS)Br] ( 2’ ), [(Et₂O)_nMg(Cp^TIPS)₂] ( 3’ ), and [(Et₂O)₂MgBr₂] ( 4’ ) coexist. Larger coordination numbers can be realized with cyclic ethers like tetrahydropyran allowing crystallization of [(thp)₄MgBr₂] ( 5 ). The interpretation of the temperature-dependency of the Schlenk equilibrium constant in diethyl ether gives a reaction enthalpy ΔH and reaction entropy ΔS of −11.5 kJ mol⁻¹ and 60 J mol⁻¹, respectively.     

Testing for Hermite Rank in Gaussian Subordination Processes

Statistical inference for time series with long-range dependence is often based on the assumption of Gaussian subordination X_t = G(Z_t). Although the Hermite rank m of G plays an essential role for statistical inference in these situations, the question of estimating m or of testing hypotheses about the Hermite rank has not been addressed in the literature. In this article, a method is introduced for testing H₀: m = 1 against H₁: m > 1. This allows for deciding whether inference based on the usual assumption of m = 1 is appropriate. Simulations and data examples illustrate the method.     

Experimental and Computational Mechanistic Studies of the β-Diketiminatoiron(II)-Catalysed Hydroamination of Primary Aminoalkenes

A comprehensive mechanistic study by means of complementary experimental and computational approaches of the exo-cyclohydroamination of primary aminoalkenes mediated by the recently reported β-diketiminatoiron(II) complex B is presented. Kinetic analysis of the cyclisation of 2,2-diphenylpent-4-en-1-amine ( 1 a ) catalysed by B revealed a first-order dependence of the rate on both aminoalkene and catalyst concentrations and a primary kinetic isotope effect (KIE) (k_H/k_D) of 2.7 (90 °C). Eyring analysis afforded ΔH^≠=22.2 kcal mol⁻¹, ΔS^≠=−13.4 cal mol⁻¹ K⁻¹. Plausible mechanistic pathways for competitive avenues of direct intramolecular hydroamination and oxidative amination have been scrutinised computationally. A kinetically challenging proton-assisted concerted N−C/C−H bond-forming non-insertive pathway is seen not to be accessible in the presence of a distinctly faster σ-insertive pathway. This operative pathway involves 1) rapid and reversible syn-migratory 1,2-insertion of the alkene into the Fe−N_amido σ bond at the monomer {N^N}Fe^II amido compound; 2) turnover-limiting Fe−C σ bond aminolysis at the thus generated transient {N^N}Fe^II alkyl intermediate and 3) regeneration of the catalytically competent {N^N}Fe^II amido complex, which favours its dimer, likely representing the catalyst resting state, through rapid cycloamine displacement by substrate. The collectively derived mechanistic picture is consonant with all empirical data obtained from stoichiometric, catalytic and kinetics experiments.