| 1. |
- Daver, Henrik, et al.
(författare)
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Theoretical Study of Phosphodiester Hydrolysis and Transesterification Catalyzed by an Unsymmetric Biomimetic Dizinc Complex
- 2016
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 55:4, s. 1872-1882
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Tidskriftsartikel (refereegranskat)abstract
- Density functional theory calculations have been used to investigate the reaction mechanisms of phosphodiester hydrolysis and transesterification catalyzed by a dinuclear zinc complex of the 2-(N-isopropyl-N-((2-pyridyl)methyl)-aminomethyl)-6-(N-(carboxylmethyl)-N-((2-pyridyl)methyl)amino-methyl)-4-methylphenol (IPCPMP) ligand, mimicking the active site of zinc phosphotriesterase. The substrates bis(2,4)-dinitrophenyl phosphate (BDNPP) and 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) were employed as analogues of DNA and RNA, respectively. A number of different mechanistic proposals were considered, with the active catalyst harboring either one or two hydroxide ions. It is concluded that for both reactions the catalyst has only one hydroxide bound, as this option yields lower overall energy barriers. For BDNPP hydrolysis, it is suggested that the hydroxide acts as the nucleophile in the reaction, attacking the phosphorus center of the substrate. For HPNP transesterification, on the other hand, the hydroxide is proposed to act as a Bronsted base, deprotonating the alcohol moiety of the substrate, which in turn performs the nucleophilic attack. The calculated overall barriers are in good agreement with measured rates. Both reactions are found to proceed by essentially concerted associative mechanisms, and it is demonstrated that two consecutive catalytic cycles need to be considered in order to determine the rate-determining free energy barrier.
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| 2. |
- Georgieva, Polina, et al.
(författare)
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Quantum Chemical Modeling of Enzymatic Reactions : The Case of Histone Lysine Methyltransferase
- 2010
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Ingår i: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 31:8, s. 1707-1714
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Tidskriftsartikel (refereegranskat)abstract
- Quantum chemical cluster models of enzyme active sites are today an important and powerful tool in the study of various aspects of enzymatic reactivity. This methodology has been applied to a wide spectrum of reactions and many important mechanistic problems have been solved. Herein, we report a systematic study of the reaction mechanism of the histone lysine methyltransferase (HKMT) SET7/9 enzyme, which catalyzes the methylation of the N-terminal histone tail of the chromatin structure. In this study, HKMT SET7/9 serves as a representative case to examine the modeling approach for the important class of methyl transfer enzymes. Active site models of different sizes are used to evaluate the methodology. In particular, the dependence of the calculated energies on the model size, the influence of the dielectric medium, and the particular choice of the dielectric constant are discussed. In addition, we examine the validity of some technical aspects, such as geometry optimization in solvent or with a large basis set, and the use of different density functional methods.
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| 3. |
- Georgieva, Polina, et al.
(författare)
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The reaction mechanism of phenylethanolamine N-methyltransferase : A density functional theory study
- 2009
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Ingår i: Biochimica et Biophysica Acta - Proteins and Proteomics. - : Elsevier BV. - 1570-9639 .- 1878-1454. ; 1794:12, s. 1831-1837
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Tidskriftsartikel (refereegranskat)abstract
- Hybrid density functional theory methods were used to investigate the reaction mechanism of human phenylethanolamine N-methyltransferase (hPNMT). This enzyme catalyzes the S-adenosyl-L-methionine-dependent conversion of norepinephrine to epinephrine, which constitutes the terminal step in the catecholamine biosynthesis. Several models of the active site were constructed based on the X-ray structure. Geometries of the stationary points along the reaction path were optimized and the reaction barrier and energy were calculated and compared to the experimental values. The calculations demonstrate that the reaction takes place via an S(N)2 mechanism with methyl transfer being rate-limiting, a suggestion supported by mutagenesis studies. Optimal agreement with experimental data is reached using a model in which both active site glutamates; are protonated. Overall, the mechanism of hPNMT is more similar to those of catechol O-methyltransferase and glycine N-methyltransferase than to that of guanidinoacetate N-methyltransferase in which methyl transfer is coupled to proton transfer.
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| 4. |
- Hammar, Peter, 1980-
(författare)
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Quantum Chemical Studies of Mechanisms and Stereoselectivities of Organocatalytic Reactions
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As the field of organocatalysis is growing, it is becoming more important to understand the specific modes of action of these new organic catalysts. Quantum chemistry, in particular density functional theory, has proven very powerful in exploring reaction mechanisms as well as selectivities in organocatalytic reactions, and is the tool used in this thesis. Different reaction mechanisms of several organocatalytic reactions have been examined, and we have been able to exclude various reaction pathways based on the calculated reaction barriers. The origins of stereoselection in a number of reactions have been rationalized. The computational method has generally reproduced the experimental stereoselectivities satisfactorily. The amino acid-catalyzed aldol reaction has previously been established to go through an enamine intermediate. In the first study of this thesis the understanding of this kind of reactions has been expanded to the dipeptide-catalyzed aldol reaction. The factors governing the enantioselection have been studied, showing how the chirality of the amino acids controls the conformation of the transition state, thereby determining the configuration of the product. In the cinchona thiourea-catalyzed Henry reaction two reaction modes regarding substrate binding to the two sites of the catalyst have been investigated, showing the optimal arrangement for this reaction. This enabled the rationalization of the observed stereoselectivity. The hydrophosphination of α,β-unsaturated aldehydes was studied. The bulky substituent of the chiral prolinol-derived catalyst was shown to effectively shield one face of the reactive iminium intermediate, thereby inducing the stereoselectivity. The transfer hydrogenation of imines using Hantzsch esters as hydride source and axially chiral phosphoric acid catalyst has also been explored. A reaction mode where both the Hantzsch ester and the protonated imine are hydrogen bonded to the phosphoric acid is demonstrated to be the preferred mode of action. The different arrangements leading to the two enantiomers of the product are evaluated for several cases, including the hydride transfer step in the reductive amination of α-branched aldehydes via dynamic kinetic resolution. Finally, the intramolecular aldol reaction of ketoaldehydes catalyzed by guanidinebased triazabicyclodecene (TBD) has been studied. Different mechanistic proposals have been assessed computationally, showing that the favoured reaction pathway is catalyzed by proton shuttling. The ability of a range of guanidines to catalyze this reaction has been investigated. The calculated reaction barriers reproduced the experimental reactivities quite well.
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| 5. |
- Marcelli, Tommaso, et al.
(författare)
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Origin of Enantioselectivity in the Organocatalytic Reductive Amination of α-Branched Aldehydes
- 2009
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Ingår i: Advanced Synthesis and Catalysis. - Weinheim : Wiley-VCH Verlag GmbH&Co. KGaA. - 1615-4150 .- 1615-4169. ; 351:4, s. 525-529
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Tidskriftsartikel (refereegranskat)abstract
- The reason for enantioselectivity in thereductive amination of α-branched aldehydes wasinvestigated. The relative energies of all the diastereomeric transition states for hydride transfer of a suitable computational model were calculated at the B3LYP/6-311+(2d,2p) level of theory. Our calculations successfully reproduce and rationalize the experimentally observed stereochemical outcome of the reaction.
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| 6. |
- Bunrit, Anon, et al.
(författare)
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Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer
- 2015
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 137:14, s. 4646-4649
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Tidskriftsartikel (refereegranskat)abstract
- The hydroxyl group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols has been intramolecularly displaced by uncharged O-, N-, and S-centered nucleophiles to yield enantioenriched tetrahydrofuran, pyrrolidine, and tetrahydrothiophene derivatives with phosphinic acid catalysis. The five-membered heterocyclic products are generated in good to excellent yields, with high degree of chirality transfer, and water as the only side-product. Racemization experiments show that phosphinic acid does not promote S(N)1 reactivity. Density functional theory calculations corroborate a reaction pathway where the phosphinic acid operates as a bifunctional catalyst in the intramolecular substitution reaction. In this mechanism, the acidic proton of the phosphinic acid protonates the hydroxyl group, enhancing the leaving group ability. Simultaneously, the oxo group of phosphinic acid operates as a base abstracting the nucleophilic proton and thus enhancing the nucleophilicity. This reaction will open up new atom efficient techniques that enable alcohols to be used as nucleofuges in substitution reactions in the future.
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| 7. |
- Bunrit, Anon, et al.
(författare)
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Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer
- 2016
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Ingår i: Synlett. - : Georg Thieme Verlag KG. - 0936-5214 .- 1437-2096. ; 27:2, s. 173-176
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Tidskriftsartikel (refereegranskat)abstract
- A brief overview of the development of direct substitution of the hydroxyl (OH) group of alcohols in our research group is presented. By applying a BrOnsted acid, an intramolecular substitution of the OH group in stereogenic alcohols with chirality transfer was achieved. Noteworthy, the intramolecular substitution has a wide scope in respect to both the nucleophile and also the nucleofuge. A mechanistic study by both experiments and DFT calculations revealed a unique reaction pathway in which the BrOnsted acid operates in a bifunctional manner to promote an S(N)2-type reaction mechanism.
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| 8. |
- Das, Biswanath, et al.
(författare)
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An Unsymmetric Ligand with a N5O2 Donor Set and Its Corresponding Dizinc Complex : A Structural and Functional Phosphoesterase Model
- 2018
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Ingår i: European Journal of Inorganic Chemistry. - : Wiley. - 1434-1948 .- 1099-1948 .- 1099-0682. ; :36, s. 4004-4013
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Tidskriftsartikel (refereegranskat)abstract
- To mimic the active sites of the hydrolytic enzyme zinc phosphotriesterase, a new dinucleating unsymmetric ligand, PICIMP (2-{[2-hydroxy-5-methyl-3-({[(1-methyl-1H-imidazol-2-yl)methyl](pyridin-2-ylmethyl)amino}methyl)benzyl][(1-methyl-1H-imidazol-2-yl)methyl]amino}acetic acid), has been synthesized and characterized. The hydrolytic efficacy of the complex solution (PICIMP/ZnCl2 = 1:2) has been investigated using bis-(2,4-dinitrophenyl)phosphate (BDNPP), a DNA analogue substrate. Speciation studies were undertaken by potentiometric titrations at varying pH for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; these studies reveal that the dinuclear zinc(II) complexes, [Zn-2(PICIMP)](2+) and [Zn-2(PICIMP)(OH)](+) predominate in solution above pH 4. The obtained pK(a) of 7.44 for the deprotonation of water suggests formation of a bridging hydroxide between the two Zn-II ions. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-10.5 have been performed. The cumulative results indicate the hydroxo-bridged dinuclear Zn-II complex [Zn-2(PICIMP)(mu-OH)](+) as the effective catalyst. Density functional theory calculations were performed to investigate the detailed reaction mechanism. The calculations suggest that the bridging hydroxide becomes terminally coordinated to one of the zinc ions before performing the nucleophilic attack in the reaction.
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| 9. |
- Lundberg, Helena, et al.
(författare)
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Mechanistic Elucidation of Zirconium-Catalyzed Direct Amidation
- 2017
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 139:6, s. 2286-2295
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism of the zirconium-catalyzed condensation of carboxylic acids and amines for direct formation of amides was studied using kinetics, NMR spectroscopy, and DFT calculations. The reaction is found to be first order with respect to the catalyst and has a positive rate dependence on amine concentration. A negative rate dependence on carboxylic acid concentration is observed along with S-shaped kinetic profiles under certain conditions, which is consistent with the formation of reversible off-cycle species. Kinetic experiments using reaction progress kinetic analysis protocols demonstrate that inhibition of the catalyst by the amide product can be avoided using a high amine concentration. These insights led to the design of a reaction protocol with improved yields and a decrease in catalyst loading. NMR spectroscopy provides important details of the nature of the zirconium catalyst and serves as the starting point for a theoretical study of the catalytic cycle using DFT calculations. These studies indicate that a dinuclear zirconium species can catalyze the reaction with feasible energy barriers. The amine is proposed to perform a nucleophilic attack at a terminal eta(2)-carboxylate ligand of the zirconium catalyst, followed by a C-O bond cleavage step, with an intermediate proton transfer from nitrogen to oxygen facilitated by an additional equivalent of amine. In addition, the DFT calculations reproduce experimentally observed effects on reaction rate, induced by electronically different substituents on the carboxylic acid.
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| 10. |
- Zhang, Kaiheng, et al.
(författare)
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Solvent Dependency in Stereoselective δ-Lactam Formation of Chiral α-Fluoromalonate Derivatives : Stereodivergent Synthesis of Heterocycles with Fluorine Containing Stereocenters Adjacent to Tertiary Stereocenters
- 2022
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Ingår i: Advanced Synthesis and Catalysis. - : Wiley. - 1615-4150 .- 1615-4169. ; 364:5, s. 958-965
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Tidskriftsartikel (refereegranskat)abstract
- The discovery and investigation of solvent dependency in stereoselective intramolecular amidation of chiral 5-aminofunctionalized-2-fluoromalonate ester derivatives, which gives access to highly functionalized δ-lactams with a quaternary fluorine-containing stereocenter, is disclosed. Experimental work together with density functional theory calculations led to understanding of how to direct and switch the stereochemical outcome of the stereoselective δ-lactam formation. The merging of this solvent-dependent stereoselective switch with asymmetric catalysis and cascade reactions gives access to an unprecedented strategy for stereodivergent synthesis of all possible stereoisomers of fluorine-containing stereocenters adjacent to tertiary stereocenters of a wide range of heterocyclic compounds with 95->99% ee in one-pot. It is also useful for application in total synthesis of fluorine-containing pharmaceuticals.
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