A theoretical study of the mechanism of the desymmetrization of cyclic meso-anhydrides by chiral amino alcohols

The alcoholysis of cyclic meso-anhydrides catalyzed by β-amino alcohols has been investigated with DFT quantum mechanics to determine the mechanism of this reaction. Both nucleophilic catalysis and general base catalysis pathways are explored for methanol-induced ring opening of an anhydride catalyzed by a chiral amino alcohol. The nucleophilic pathway involves a late transition state with a high energy barrier. In this mechanism, methanolysis is expected to take place following the amine-induced ring opening of the anhydride. In the base-catalyzed mechanism, methanol attack on one carbonyl group of the meso-anhydride is assisted by the β-amino alcohol; the amine functionality abstracts the methanol proton. The chiral amino alcohol also catalyzes the reaction by stabilizing the oxyanion that forms upon ring opening of the anhydride by hydrogen bonding with its alcoholic moiety. Both stepwise and concerted pathways have been studied for the general base catalysis route. Transition structures for both are found to be lower in energy than in the nucleophilic mechanism. Overall this study has shed light on the mechanism of the β-amino alcohol-catalyzed alcoholysis of cyclic meso-anhydrides, showing that the nucleophilic pathway is approximately 100 kJ mol−1 higher in energy than the general base pathwa

Dissociation of HNO3 in water revisited : experiment and theory

Nitric acid dissociation in water is studied as a function of concentration, employing experimental techniques (1H NMR spectroscopy and calorimetry), quantum chemical methods (B3LYP and PBE functionals for molecular clusters) and molecular dynamics simulations (the PBE-D3 functional for solutions under periodic boundary conditions). The extent of dissociation, via proton transfer to a neighboring water molecule, as a function of concentration is studied computationally for molecular nitric acid clusters HNO3(H2O)x (x = 1–8), as well as periodic liquids (HNO3 mole fractions of 0.19 and 0.5, simulated at T = 300 K and 450 K). Despite the simple nature of these structural models, their computed and simulated average 1H chemical shifts compare well with the experimental measurements in this study. Finally, the measured and calculated chemical shifts have shown reasonable relationships with the enthalpy change upon mixing of this binary complex.Peer reviewe

Towards the elucidation of the deamidation mechanism of asparaginyl residues in peptides and proteins

La déamidation des protéines est un thème de grand intérêt qui a été le sujet de nombreuses études théoriques et expérimentales. La déamidation est un processus non-enzymatique et spontané qui convertit les résidus asparagines dans les protéines en acides aspartiques. Le changement de charge aboutit à des changements temporels de conformation dans les protéines et a été associé à la dégradation des protéines et au phénomène de vieillissement. Dans ce manuscrit, certains aspects mécanistiques de ce processus ont été étudiés et de nombreuses mises à jour ont été obtenues sur les mécanismes potentiels amenant à la déamidation. Ces mécanismes et leurs énergies sont présentés en détail. Une autre destinée possible des résidus asparagines, la coupure de la chaîne principale, est introduite et comparée au mécanisme de déamidation. Enfin, des tentatives pour comprendre l'effet des résidus adjacents dans la déamidation des asparagines sont élaborées et plusieurs idées pour un futur travail sont soulignés.Deamidation of proteins is a topic of wide interest that has been subject to experimental and theoretical studies. Deamidation is a nonenzymatic and spontaneous process that converts asparagine residues in proteins into aspartic acid. The change in charge leads to time-dependent conformational changes in proteins and has been associated with protein degradation and ageing. In this manuscript, certain mechanistic aspects of this process have been investigated and many insights have been attained on potential mechanisms leading to deamidation. These mechanisms and their energetics have been presented in detail. Another potential fate of asparagine residues, backbone cleavage, has been introduced and compared with the deamidation mechanism. Finally, attempts to understand the effect of neighboring residues on Asn deamidation have been elaborated and several ideas for future work have been outlined.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Hybrid usage of computational tools in drug synthesis

We describe several computational methodologies used in aiding the chemical synthesis of drugs. We first summarize quantum mechanical approaches that weigh thermodynamical and kinetic factors in selecting the possible pathways during synthesis. The two major problems encountered in computational approaches are the efficient sampling of the conformational space and the incorporation of solvent effect into the system of interest. Thus, conformational search methodologies of small to medium sized molecules, with emphasis on cyclic molecules, are reviewed. Also, the analysis of the solvent effect on the synthesis of drug molecules and yield, using continuum methodologies as well as molecular dynamics, is discussed. How results from these studies are in turn fed back into detailed quantum mechanical calculations with supermolecules of solvent and reaction site are outlined. It is shown that the usage of several computational techniques hand-in-hand provides a plethora of information that may be utilized during the actual synthesis of drug molecules

A computational approach to the synthesis of dirithromycin

Dirithromycin is a macrolide antibiotic derived from erythromycin A. Dirithromycin is synthesized by the condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)-acetaldehyde. To gain insight into the synthesis, the condensation mechanism has been analyzed computationally by the AM1 method in the gas phase. First, the formation of the Schiff bases of dirithromycin and epidirithromycin from 9(S)-erythromycylamine and 2-(2-methoxyethoxy)-acetaldehyde were modeled. Then, the tautomerization of the Schiff bases to dirithromycin and epidirithromycin were considered. Finally, the epimerization of the Schiff base of epidirithromycin to the Schiff base of dirithromycin was investigated. Our results show that, even though carbinolamine forms faster for epidirithromycin than the corresponding structure for dirithromycin, dirithromycin is the major product of the synthesis

Theoretical study of selective methylation in the synthesis of azithromycin

Azithromycin is a 15-membered macrolide antibiotic which is active in vitro against clinically important gram-negative bacteria. In this study, the selectivity of the methylation mechanism was analyzed computationally on the 2'-OCbz-3'-NMeCbz derivative of azithromycin in vacuum and in DMF. We have shown that the methylation of the hydroxy group on C-6 is energetically unfavorable compared to the other hydroxy groups in vacuum; the softness values further showed that the C-6 anion is not reactive towards CH3I in the methylation mechanism. To understand the effect of the solvent on the methylation process, detailed molecular dynamics simulations were performed in DMF using the anions at the C-4", C-6, C-11 and C-12 positions. We find the conformations of the anions not to be affected by the presence of the solvent. The radial distribution functions of the solvent molecules around the O- of the anions demonstrate that DMF molecules cluster around the C-6 anion. The relative strength of the anion-solvent interactions reveal that the solvent molecules provide the largest stabilization to the C-6 anion and prevent the methylation at this position. The latter descriptor was found to be an important factor in explaining the experimentally observed selectivity towards the methylation of the C-4", C-6, C-11 and C-12 anions