Development of a new experimental NMR strategy for covalent cysteine protease inhibitors screening: toward enhanced drug discovery.

In the development of antiviral drugs, proteases and polymerases are among the most important targets. Cysteine proteases, also known as thiol proteases, catalyze the degradation of proteins by cleaving peptide bonds using the nucleophilic thiol group of cysteine. As part of our research, we are examining how cysteine, an essential amino acid found in the active site of the main protease (Mpro) enzyme in SARS-CoV-2, interacts with electrophilic groups present in ethacrynic acid (EA) and compounds 4, 6, and 8 to form sulfur-carbon bonds. Nuclear magnetic resonance (NMR) spectroscopy was used to monitor the reaction rate between cysteine and Michael acceptors. We found that the inhibitory activity of these compounds towards Mpro is correlated to their chemical reactivity toward cysteine. This approach may serve as a valuable tool in drug development for detecting potential covalent inhibitors of Mpro and other cysteine proteases.

Unlocking the Potential of Deep Eutectic Solvents for C-H Activation and Cross-Coupling Reactions: A Review.

Green chemistry principles have underpinned the development of deep eutectic solvents (DESs). In this brief overview, we discuss the potential of DESs as a greener alternative to volatile organic solvents for cross-coupling and C-H activation reactions in organic chemistry. DESs offer numerous benefits, such as easy preparation, low toxicity, high biodegradability, and the potential to replace volatile organic compounds. The ability of DESs to recover the catalyst-solvent system enhances their sustainability. This review highlights recent advances and challenges in utilizing DESs as a reaction media, as well as the impact of physicochemical properties on the reaction process. Several types of reactions are studied to highlight their effectiveness at promoting C-C bond formation. Aside from demonstrating the success of DESs in this context, this review also discusses the limitations and future prospects of DESs in organic chemistry.

High pressure promoted dearomatization of nitroarenes by [4+2] cycloadditions with silyloxydienes.

Simple nitroarenes such as nitronaphthalenes and nitroquinolines smoothly undergo dearomatizing [4+2] cycloadditions with silyloxydienes under 16 kbar. Highly functionalized 3-dimensional polycyclic adducts bearing a tetrasubstituted carbon centre at the ring junction are obtained in one step from simple raw materials. This unprecedented dearomative Diels-Alder process is performed at room temperature without any chemical promoter, illustrating the exceptional role of high pressure as a physical promoter.

Bonding analysis in ytterbium(II) distannyl and related tetryls.

The syntheses of the ytterbium(II) distannyl [Yb{Sn(SiMe3)3}2·(thf)4] (Yb-Sn) and of its digermyl analogue [Yb{Ge(SiMe3)3}2·(thf)3] (Yb-Ge) are presented. The compounds were characterised by multinuclear high-resolution solution NMR spectroscopy, including 171Yb NMR, and by X-ray diffraction crystallography. The bonding and electronic properties of the two complexes, along with those of the known ytterbium(II) disilyl derivative [Yb{Si(SiMe3)3}2·(thf)3] (Yb-Si) and those of the congeneric calcium distannyl [Ca{Sn(SiMe3)3}2·(thf)4] (Ca-Sn), were investigated in detail by DFT calculations. This analysis points at a primarily ionic Yb-tetrel bonding, with a small covalent contribution, attributed principally to the 5d(Yb) participation. This weak covalent character is found to be larger for the distannyl Yb-Sn than for its lighter Si- and Ge-derivatives. The covalent component is also found to be greater in Yb-Sn than in Ca-Sn, due to the availability of the 5d(Yb) orbitals for bonding.

Metal-metal bonded alkaline-earth distannyls.

The first families of alkaline-earth stannylides [Ae(SnPh3)2·(thf) x ] (Ae = Ca, x = 3, 1; Sr, x = 3, 2; Ba, x = 4, 3) and [Ae{Sn(SiMe3)3}2·(thf) x ] (Ae = Ca, x = 4, 4; Sr, x = 4, 5; Ba, x = 4, 6), where Ae is a large alkaline earth with direct Ae-Sn bonds, are presented. All complexes have been characterised by high-resolution solution NMR spectroscopy, including 119Sn NMR, and by X-ray diffraction crystallography. The molecular structures of [Ca(SnPh3)2·(thf)4] (1'), [Sr(SnPh3)2·(thf)4] (2'), [Ba(SnPh3)2·(thf)5] (3'), 4, 5 and [Ba{Sn(SiMe3)3}2·(thf)5] (6'), most of which crystallised as higher thf solvates than their parents 1-6, were established by XRD analysis; the experimentally determined Sn-Ae-Sn' angles lie in the range 158.10(3)-179.33(4)°. In a given series, the 119Sn NMR chemical shifts are slightly deshielded upon descending group 2 from Ca to Ba, while the silyl-substituted stannyls are much more shielded than the phenyl ones (δ 119Sn/ppm: 1', -133.4; 2', -123.6; 3', -95.5; 4, -856.8; 5, -848.2; 6', -792.7). The bonding and electronic properties of these complexes were also analysed by DFT calculations. The combined spectroscopic, crystallographic and computational analysis of these complexes provide some insight into the main features of these unique families of homoleptic complexes. A comprehensive DFT study (Wiberg bond index, QTAIM and energy decomposition analysis) points at a primarily ionic Ae-Sn bonding, with a small covalent contribution, in these series of complexes; the Sn-Ae-Sn' angle is associated with a flat energy potential surface around its minimum, consistent with the broad range of values determined by experimental and computational methods.

Bis(imino)carbazolate lead(II) fluoride and related halides.

The versatility of a bulky bis(imino)carbazolate ligand in lead(ii) chemistry is illustrated by the synthesis of a soluble, heteroleptic lead(ii) fluoride and several halide (Cl, Br and I), amide and hydrocarbyl congeners. All complexes have been structurally authenticated, and a full set of 207Pb NMR data is discussed.

Spatially encoded diffusion-ordered NMR spectroscopy of reaction mixtures in organic solvents.

Diffusion-ordered NMR spectroscopy (DOSY) is a powerful method for the analysis of mixtures. Classic DOSY methods require several minutes of acquisition, and we show here that DOSY experiments can be recorded in less than one second for the challenging case of solution mixtures in low-viscosity solvents. The proposed method relies on a spatial encoding of the diffusion dimension, for which convection-compensation and spectral-selection strategies are introduced. The method is illustrated with the analysis of a reaction mixture, and more accurate estimates of the diffusion coefficients are obtained.

A Combined 1 H/6 Li†NMR DOSY Strategy Finally Uncovers the Structure of Isopropyllithium in THF.

Despite its common use in synthesis, the structure of isopropylliyhium in THF has never been determined, a dimer being generally proposed but not supported. This paper fills this data gap through a sophisticated NMR study that shows that, in THF at low-temperature, isopropyllithium is in the form of a 1:2 mixture of a trisolvated monomer and a disolvated dimer in equilibrium. The presence of the monomer, never evoked before, together with a hypo-solvation of the dimer hinted by DFT calculations, provides a rational explanation to the remarkable reactivity of this organolithium reagent in ethereal solvents.

Correction: Achieving high resolution and optimizing sensitivity in spatial frequency encoding NMR spectroscopy: from theory to practice.

Correction for 'Achieving high resolution and optimizing sensitivity in spatial frequency encoding NMR spectroscopy: from theory to practice' by Bertrand Plainchont et al., Phys. Chem. Chem. Phys., 2016, 18, 22827-22839.

Achieving high resolution and optimizing sensitivity in spatial frequency encoding NMR spectroscopy: from theory to practice.

A detailed analysis of NMR spectra acquired based on spatial frequency encoding is presented. A theoretical model to simulate gradient encoded pulses is developed in order to describe the spatial properties of the NMR signals that are locally created throughout the sample. The key features that affect the efficiency of the slice selection process during excitation as well as refocusing pulses are investigated on a model ABX spin system, both theoretically and experimentally. It is shown that the sensitivity and resolution of the pure shift and J-edited experiments based on a spatial frequency encoding can be optimized to a point where high-resolution techniques based on a spatial frequency encoding approach show optimal performance compared to other methods.

Radical Cyclisation of α-Halo Aluminium Acetals: A Mechanistic Study.

α-Bromo aluminium acetals are suitable substrates for Ueno-Stork-like radical cyclisations affording γ-lactols and acid-sensitive methylene-γ-lactols in high yields. The mechanistic study herein sets the scope and limitation of this reaction. The influence of the halide (or chalcogenide) atom X (X=Cl, Br, I, SPh, SePh) in the precursors α-haloesters, as well as influence of the solvent and temperature was studied. The structure of the aluminium acetal intermediates resulting from the reduction of the corresponding α-haloesters has been investigated by low-temperature (13) C-INEPT diffusion-ordered NMR spectroscopy (DOSY) experiments and quantum calculations, providing new insights into the structures of these thermally labile intermediates. Oxygen-bridged dimeric structures with a planar Al2 O2 ring are proposed for the least hindered aluminium acetals, while monomeric structures seem to prevail for the most hindered species. A comparison against the radical cyclisation of aluminium acetals derived from allyl and propargyl alcohols with the parent Ueno-Stork has been made at the BHandHLYP/6-311++G(d,p) level of theory, highlighting mechanistic similarities and differences.