Ag2O versus Cu2O in the Catalytic Isomerization of Coordinated Diaminocarbenes to Formamidines: A Theoretical Study

DFT theoretical calculations for the Ag2O-induced isomerization process of diaminocarbenes to formamidines, coordinated to Mn(I), have been carried out. The reaction mechanism found involves metalation of an N-H residue of the carbene ligand by the catalyst Ag2O and the formation of a key transition state showing a μ-η2:η2 coordination of the formamidinyl ligand between manganese and silver, which allows a translocation process of Mn(I) and silver(I) ions between the carbene carbon atom and the nitrogen atom, before the formation of the formamidine ligand is completed. Calculations carried out using Cu2O as a catalyst instead of Ag2O show a similar reaction mechanism that is thermodynamically possible, but highly unfavorable kinetically and very unlikely to be observed, which fully agrees with experimental results.

Tetraalkyl Hydroxymethylene-bisphosphonate and Dialkyl 1-Diphenylphosphinoyl-1-hydroxy-ethylphosphonate Derivatives by the Pudovik Reaction and Their Rearranged Products

The reaction of diethyl α-oxoethylphosphonate and diethyl oxobenzylphosphonate with diethyl phosphite, dimethyl phosphite, and diphenylphosphine oxide affords, depending on the substrates and conditions (nature and quantity of the amine catalyst, temperature, and solvent), the Pudovik adduct and/or the corresponding >P(O)–CH–O–P(O)< product formed by rearrangement. The nature of the substituent on the central carbon atom (a methyl or phenyl group) influences the inclination for the rearrangement. The asymmetric products (either adducts or rearranged species) with different P(O)Y functions (Y = RO or Ph) exhibit interesting NMR features.

Harnessing the ambiphilicity of silyl nitronates in a catalytic asymmetric approach to aliphatic β3-amino acids

Nitronate anions, formally generated by α-deprotonating the corresponding nitroalkanes, are highly nucleophilic and versatile intermediates in many carbon–carbon bond-forming reactions. In contrast, the corresponding silyl nitronates are ambiphilic and react, at the same carbon atom, with both electrophiles and nucleophiles. However, while their nucleophilicity has been well exploited in catalytic enantioselective reactions with imines and aldehydes, utilizing the electrophilicity of silyl nitronates in asymmetric synthesis has remained elusive. Here we report the facile, efficient and general reactivity of readily available silyl nitronates with silyl ketene acetals, catalysed by highly Lewis-acidic and confined silylium imidodiphosphorimidate catalysts. The products of this reaction, so-called nitroso acetals, are obtained in excellent enantioselectivity and can be easily converted into N-Boc-β3-amino acid esters in a single step.

QSAR, pharmacophore modeling and molecular docking studies to identify structural alerts for some nitrogen heterocycles as dual inhibitor of telomerase reverse transcriptase and human telomeric G-quadruplex DNA

Background Telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA are amongst the favorable target for researchers to discover novel and more effective anticancer agents. To understand and elucidate structure activity relationship and mechanism of inhibition of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA, a QSAR modeling and molecular docking were conducted. Results Two robust QSAR model were obtained which consist of full set QSAR model (R2: 0.8174, CCCtr: 0.8995, Q2loo: 0.7881, Q2LMO: 0.7814) and divided set QSAR model (R2: 0.8217, CCCtr: 0.9021, Q2loo: 0.7886, Q2LMO: 0.7783, Q2-F1: 0.7078, Q2-F2: 0.6865, Q2-F3: 0.7346) for envisaging the inhibitory activity of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA. The analysis reveals that carbon atom exactly at 3 bonds from aromatic carbon atom, nitrogen atom exactly at six bonds from planer nitrogen atom, aromatic carbon atom within 2 A0 from the center of mass of molecule and occurrence of element hydrogen within 2 A0 from donar atom are the key pharmacophoric features important for dual inhibition of TERT and human telomeric G-quadruplex DNA. To validate this analysis, pharmacophore modeling and the molecular docking is performed. Molecular docking analysis support QSAR analysis and revealed that, dual inhibition of TERT and human telomeric DNA is mainly contributed from hydrophobic and hydrogen bonding interactions. Conclusion The findings of molecular docking, pharmacophore modelling, and QSAR are all consistent and in strong agreement. The validated QSAR analyses can detect structural alerts, pharmacophore modelling can classify a molecule's consensus pharmacophore involving hydrophobic and acceptor regions, whereas docking analysis can reveal the mechanism of dual inhibition of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA. The combination of QSAR, pharmacophore modeling and molecular docking may be useful for the future drug design of dual inhibitors to combat the devastating issue of resistance. Graphical abstract

Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes

Organophosphorus compounds with stereogenic phosphorus and carbon atoms have received increasing attention. In this regards, primary phosphines with a stereogenic carbon atom adjacent to the phosphorus atom were synthesized by the reduction in phosphonates and phosphonoselenoates with a binaphthyl group. Their oxidized products, i.e., phosphine oxides with a stereogenic tetrasubstituted carbon atom, were found to undergo BEt3-mediated radical addition to cyclohexene to give P-stereogenic secondary phosphine oxides with a diastereoselectivity of 91:9. The products were characterized by ordinary analytical methods, such as Fourier transform infrared spectroscopy; 1H, 13C, and 31P NMR spectroscopies; and mass spectroscopy. Computational studies on the phosphorus-centered radical species and the obtained product implied that the thermodynamically stable radical and the adduct may be formed as a major diastereomer. The radical addition to a range of alkenes took place in an anti-Markovnikov fashion to give P-stereogenic secondary phosphine oxides. A variety of functional groups in the alkenes were tolerated under the reaction conditions to afford secondary phosphine oxides in moderate yields. Primary phosphines with an alkenyl group, which were generated in situ, underwent intramolecular cyclization to give five- and six-membered cyclic phosphines in high yields after protection by BH3.

Dative behavior of N-heterocyclic carbenes (NHCs) with selenium in Se-NHC compounds

N-heterocyclic carbenes (NHCs) are an eminent class of carbenes having a heterocyclic ring in which a divalent carbon atom is attached directly to a nitrogen atom. In the NHCs, the donation of lone pair is another important research in the dative bonding and not only in NHCs the dative bond plays a functionalized role in the other classes of complex formation like ylidones L → E ← L and carbones L → C ← L. M–NHC bond is L-M sigma-dative bond and NHCs are considered as strong sigma-donor ligands. The clear picture of the M–NHC bond can be better understood by M–NHC pi-interaction. M-L pi interaction is comprised of two steps. One is L → M sigma-donation and M → L π* back bonding. This dative donor nature of NHC and also its behavior in organoselenium is studied through DFT in which it’s optimized structure, bond lengths, molecular vibrations are calculated.

Two Sides of Quantum-Based Modeling of Enzyme-Catalyzed Reactions: Mechanistic and Electronic Structure Aspects of the Hydrolysis by Glutamate Carboxypeptidase

We report the results of a computational study of the hydrolysis reaction mechanism of N-acetyl-l-aspartyl-l-glutamate (NAAG) catalyzed by glutamate carboxypeptidase II. Analysis of both mechanistic and electronic structure aspects of this multistep reaction is in the focus of this work. In these simulations, model systems are constructed using the relevant crystal structure of the mutated inactive enzyme. After selection of reaction coordinates, the Gibbs energy profiles of elementary steps of the reaction are computed using molecular dynamics simulations with ab initio type QM/MM potentials (QM/MM MD). Energies and forces in the large QM subsystem are estimated in the DFT(PBE0-D3/6-31G**) approximation. The established mechanism includes four elementary steps with the activation energy barriers not exceeding 7 kcal/mol. The models explain the role of point mutations in the enzyme observed in the experimental kinetic studies; namely, the Tyr552Ile substitution disturbs the “oxyanion hole”, and the Glu424Gln replacement increases the distance of the nucleophilic attack. Both issues diminish the substrate activation in the enzyme active site. To quantify the substrate activation, we apply the QTAIM-based approaches and the NBO analysis of dynamic features of the corresponding enzyme-substrate complexes. Analysis of the 2D Laplacian of electron density maps allows one to define structures with the electron density deconcentration on the substrate carbon atom, i.e., at the electrophilic site of reactants. The similar electronic structure element in the NBO approach is a lone vacancy on the carbonyl carbon atom in the reactive species. The electronic structure patterns revealed in the NBO and QTAIM-based analyses consistently clarify the reactivity issues in this system.

Through a Glass Darkly—Some Thoughts on Symmetry and Chemistry

This article reviews the development of concepts of chirality in chemistry. The story follows the parallel development of the optical properties of materials and the understanding of chemical structure until the two are fused in the recognition of the tetrahedral carbon atom in 1874. The different types of chiral molecule that have been identified since the first concept of the asymmetric carbon atom are introduced as is the notation used in various disciplines of chemistry to describe the relative or absolute configuration. In the final section, a polemical case for a unified nomenclature is presented.