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Dean J. Tantillo - One of the best experts on this subject based on the ideXlab platform.
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predicting productive binding modes for substrates and carbocation intermediates in terpene synthases bornyl diphosphate synthase as a representative case
ACS Catalysis, 2018Co-Authors: Terrence E Obrien, Steven J Bertolani, Yue Zhang, Justin B Siegel, Dean J. TantilloAbstract:Terpene synthases comprise a family of enzymes that convert acyclic oligo-isoprenyl diphosphates to terpene natural products with complex, polycyclic carbon backbones via the generation and protection of carbocation intermediates. To accommodate this chemistry, terpene synthase active sites generally are lined with alkyl and aromatic, i.e., nonpolar, side chains. Predicting the correct, mechanistically relevant binding modes for entire terpene synthase reaction pathways remains an unsolved challenge. Here, we describe a method for identifying such modes: TerDockin, a series of protocols to predict the orientation of carbon skeletons of substrates and derived Carbocations relative to the bound diphosphate group in terpene synthase active sites. Using this recipe for bornyl diphosphate synthase, we have predicted binding modes that are consistent with all current experimental observations, including the results of isotope labeling experiments and known stereoselectivity. In addition, the predicted binding m...
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Predicting Productive Binding Modes for Substrates and Carbocation Intermediates in Terpene SynthasesBornyl Diphosphate Synthase As a Representative Case
2018Co-Authors: Terrence E. O’brien, Yue Zhang, Steven J Bertolani, Justin B Siegel, Dean J. TantilloAbstract:Terpene synthases comprise a family of enzymes that convert acyclic oligo-isoprenyl diphosphates to terpene natural products with complex, polycyclic carbon backbones via the generation and protection of carbocation intermediates. To accommodate this chemistry, terpene synthase active sites generally are lined with alkyl and aromatic, i.e., nonpolar, side chains. Predicting the correct, mechanistically relevant binding modes for entire terpene synthase reaction pathways remains an unsolved challenge. Here, we describe a method for identifying such modes: TerDockin, a series of protocols to predict the orientation of carbon skeletons of substrates and derived Carbocations relative to the bound diphosphate group in terpene synthase active sites. Using this recipe for bornyl diphosphate synthase, we have predicted binding modes that are consistent with all current experimental observations, including the results of isotope labeling experiments and known stereoselectivity. In addition, the predicted binding modes recapitulate key findings of a seminal study involving more computationally demanding QM/MM molecular dynamics methods on part of this pathway. This work illustrates the value of the TerDockin approach as a starting point for more involved calculations and sets the stage for the rational engineering of this family of enzymes
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mechanistically informed predictions of binding modes for carbocation intermediates of a sesquiterpene synthase reaction
Chemical Science, 2016Co-Authors: Terrence E Obrien, Dean J. Tantillo, Steven J Bertolani, Justin B SiegelAbstract:Sesquiterpenoids comprise a class of terpenoid natural products with thousands of compounds that are highly diverse in structure, generally containing a polycyclic carbon backbone that is constructed by a sesquiterpene synthase. Decades of experimental and computational studies have demonstrated that these enzymes generate a carbocation in the active site, which undergoes a series of structural rearrangements until a product is formed via deprotonation or nucleophile attack. However, for the vast majority of these enzymes the productive binding orientation of the intermediate Carbocations has remained unclear. In this work, a method that combines quantum mechanics and computational docking is used to generate an all-atom model of every putative intermediate formed in the context of the enzyme active site for tobacco epi-aristolochene synthase (TEAS). This method identifies a single pathway that links the first intermediate to the last, enabling us to propose the first high-resolution model for the reaction intermediates in the active site of TEAS, and providing testable predictions.
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Dynamic behavior of rearranging Carbocations - implications for terpene biosynthesis.
Beilstein journal of organic chemistry, 2016Co-Authors: Stephanie R. Hare, Dean J. TantilloAbstract:This review describes unexpected dynamical behaviors of rearranging Carbocations and the modern computational methods used to elucidate these aspects of reaction mechanisms. Unique potential energy surface topologies associated with these rearrangements have been discovered in recent years that are not only of fundamental interest, but also provide insight into the way Nature manipulates chemical space to accomplish specific chemical transformations. Cautions for analyzing both experimental and theoretical data on carbocation rearrangements are included throughout.
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Lifetimes of Carbocations encountered along reaction coordinates for terpene formation
Chemical Science, 2014Co-Authors: Ryan P. Pemberton, Dean J. TantilloAbstract:The lifetimes of secondary Carbocations proposed to occur along reaction coordinates for terpene-forming carbocation rearrangements were estimated from direct dynamics simulations using density functional theory. Classical secondary Carbocations supported by bicyclo[2.2.1] and bicyclo[2.2.2] frameworks have distinct characteristic lifetimes, ca. 40 and 90 fs, respectively. The fusion of additional rings to these frameworks was found to have little effect on these lifetimes, despite altering the potential energy surfaces for rearrangement. Inherent dynamical tendencies of secondary Carbocations are shown to be manipulable by alkylation and enforced intermolecular interactions.
Hansullrich Siehl - One of the best experts on this subject based on the ideXlab platform.
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quantum chemical study of solvent and substituent effects on the 1 5 hydride shift in 2 6 dimethyl 2 heptyl cations
Journal of Physical Chemistry A, 2006Co-Authors: Valerije Vrcek, Ivana Vinkovic Vrcek, Hansullrich SiehlAbstract:The mechanism of the degenerate 1,5-hydride shift in 2,6-dimethyl-2-heptyl cations has been investigated using ab initio MP2 and density functional theory (DFT) hybrid (B3LYP) calculations. The potential-energy profile for the 1,5-hydride shift consists of three minima corresponding to two equivalent acyclic Carbocations and one symmetrically μ-hydrido-bridged carbocation, while two equivalent unsymmetrically hydrido-bridged Carbocations were located as transition-state structures. The calculated relative energy differences between acyclic Carbocations and symmetrically μ-hydrido-bridged structure are significantly affected by introduction of alkyl and (CH2)n-substituents at the C4 position of the 2,6-dimethyl-2-heptyl cation structure. DFT self-consistent isodensity polarizable continuum method (SCI-PCM) and MP2 PCM continuum methods have been used to calculate the effect of solvation on geometries and relative energies of the species involved in the 1,5-hydride shift. It is found that relative energies ...
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quantum chemical study of solvent and substituent effects on the 1 5 hydride shift in 2 6 dimethyl 2 heptyl cations
The Journal of Physical Chemistry, 2006Co-Authors: Valerije Vrcek, Ivana Vinkovic Vrcek, Hansullrich SiehlAbstract:The mechanism of the degenerate 1, 5-hydride shift in 2, 6-dimethyl-2-heptyl cations has been investigated using ab initio MP2 and density functional theory (DFT) hybrid (B3LYP) calculations. The potential-energy profile for the 1, 5-hydride shift consists of three minima corresponding to two equivalent acyclic Carbocations and one symmetrically -hydrido-bridged carbocation, while two equivalent unsymmetrically hydrido-bridged Carbocations were located as transition-state structures. The calculated relative energy differences between acyclic Carbocations and symmetrically -hydrido-bridged structure are significantly affected by introduction of alkyl and (CH2)n-substituents at the C4 position of the 2, 6-dimethyl-2-heptyl cation structure. DFT self-consistent isodensity polarizable continuum method (SCI-PCM) and MP2 PCM continuum methods have been used to calculate the effect of solvation on geometries and relative energies of the species involved in the 1, 5-hydride shift. It is found that relative energies of acyclic and -hydrido-bridged carbocation structures as well as the energy barriers for 1, 5-hydride shifts are in accord with experimental data if solvation effects are taken into account.
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quantum chemical study of degenerate hydride shifts in acyclic tertiary Carbocations
Journal of Physical Chemistry A, 2002Co-Authors: Ivana Vinkovic Vrcek, Valerije Vrcek, Hansullrich SiehlAbstract:Quantum chemical calculations were carried out to study the mechanism of degenerate 1,2-, 1,3-, and 1,4-hydride shifts in acyclic tertiary Carbocations 2,3-dimethyl-2-butyl, 2,4-dimethyl-2-pentyl, and 2,5-dimethyl-2-hexyl. Stable structures and transition structures were calculated at the B3LYP and MP2 levels using the 6-31G(d) and 6-311G(d,p) basis sets. The potential energy profile for these degenerate hydride shifts has global minima potential wells that correspond to the two interchanging open-chain carbocation structures and a high lying local minimum corresponding to the symmetrically hydrido-bridged intermediates. Unsymmetrically hydrido-bridged Carbocations were located as transition structures. The calculated energy barriers (at the MP4/6-311G(d,p)//MP2/6-311G(d,p) level) for 1,2-, 1,3-, and 1,4-hydride shift are 3.9, 4.2, and 7.5 kcal/mol, respectively. The trend of the calculated energy barriers agrees with the experimentally observed values. Electron correlation using MP2/6-311G(d,p) is superi...
Johan Franzén - One of the best experts on this subject based on the ideXlab platform.
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chiral anion directed asymmetric carbocation catalyzed diels alder reactions
European Journal of Organic Chemistry, 2016Co-Authors: Veluru Ramesh Naidu, Johan FranzénAbstract:In recent years the carbocation has re-emerged as a highly efficient Lewis acid catalyst for a variety of organic transformations. However, the goal of asymmetric carbocation catalysis has so far been out of reach mainly as a result of difficulties associated with the preparation of stable chiral Carbocations. Here, we describe developments towards asymmetric carbocation catalysis based on the concept of chiral-anion-directed catalysis. Chiral tritylium salts can be conveniently prepared in situ by mixing trityl chloride derivatives with chiral phosphonate, phosphoramide, bis(sulfonyl)amide, and bis(sulfuryl)amide silver or sodium salts. It is shown that the bis(sulfuryl)amide/tritylium ion salt catalyzes the Diels–Alder reaction with an up to 53 % enantiomeric excess.
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The Carbocation: A Forgotten Lewis Acid Catalyst
Chemcatchem, 2015Co-Authors: Veluru Ramesh Naidu, Johan FranzénAbstract:A Lewis acid that has received negligible attention as a catalyst is the carbocation. The carbocation is isoelectronic to boron and owes its Lewis acidity to a low-lying empty p(C) orbital. In terms of reactivity and stability Carbocations are very versatile Lewis acids, from the extremely unstable methylium cation to the water-stable tris(N,N-dimethylaniline) methylium ion (crystal violet). Although the Lewis acid properties of Carbocations have been extensively studied since the discovery of the tropolium ion more than 130years ago there is only a handful examples on the application of Carbocations as Lewis acid catalysts. Herein, the research on triarylmethylium (trityl)-cation catalysis is summarized. In light of the reports the trityl ion emerges as a highly efficient and highly versatile Lewis acid catalyst capable of catalyzing different classes of reactions often with high selectivity and low catalyst loadings (for some reactions down to ppm levels).
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Carbocations as Lewis Acid Catalysts: Reactivity and Scope
Advanced Synthesis & Catalysis, 2014Co-Authors: Juho Bah, Veluru Ramesh Naidu, Johannes Teske, Johan FranzénAbstract:The strength of efficient metal-free catalysis will be examined in this thesis. Efforts towards more sustainable processes will be demonstrated through implementation of strategies that meet several of the 12 principles of Green Chemistry.In the first part, a stereoselective total synthesis of multiple alkaloids from the Corynantheine and Ipecac families together with their non-natural analogues will be disclosed. A highly efficient, common synthetic strategy is applied leading to high overall yields starting from easily available starting material. Overall operational simplicity and sustainability have been the main focus. Time-consuming and waste-generating isolations and purifications of intermediates have been minimized, as well as the introduction of protection-group chemistry. Moreover, the first example of the total synthesis of Hydroxydihydrocorynantheol together with its non-natural epimer has been accomplished in multi-gram scale without protection groups and without a single isolation or purification step in high overall yield and diastereoselectivity.In the second part, Carbocations will be presented as highly effective and versatile non-metal Lewis acid catalysts. Lewis acidity-tuning of Carbocations will be introduced and applied in several reactions to suppress competing reactions. Finally, the broad scope of carbocation catalyzed transformations will be exposed.At large, evident progress has been made towards more sustainable chemistry.
Valerije Vrcek - One of the best experts on this subject based on the ideXlab platform.
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quantum chemical study of solvent and substituent effects on the 1 5 hydride shift in 2 6 dimethyl 2 heptyl cations
Journal of Physical Chemistry A, 2006Co-Authors: Valerije Vrcek, Ivana Vinkovic Vrcek, Hansullrich SiehlAbstract:The mechanism of the degenerate 1,5-hydride shift in 2,6-dimethyl-2-heptyl cations has been investigated using ab initio MP2 and density functional theory (DFT) hybrid (B3LYP) calculations. The potential-energy profile for the 1,5-hydride shift consists of three minima corresponding to two equivalent acyclic Carbocations and one symmetrically μ-hydrido-bridged carbocation, while two equivalent unsymmetrically hydrido-bridged Carbocations were located as transition-state structures. The calculated relative energy differences between acyclic Carbocations and symmetrically μ-hydrido-bridged structure are significantly affected by introduction of alkyl and (CH2)n-substituents at the C4 position of the 2,6-dimethyl-2-heptyl cation structure. DFT self-consistent isodensity polarizable continuum method (SCI-PCM) and MP2 PCM continuum methods have been used to calculate the effect of solvation on geometries and relative energies of the species involved in the 1,5-hydride shift. It is found that relative energies ...
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quantum chemical study of solvent and substituent effects on the 1 5 hydride shift in 2 6 dimethyl 2 heptyl cations
The Journal of Physical Chemistry, 2006Co-Authors: Valerije Vrcek, Ivana Vinkovic Vrcek, Hansullrich SiehlAbstract:The mechanism of the degenerate 1, 5-hydride shift in 2, 6-dimethyl-2-heptyl cations has been investigated using ab initio MP2 and density functional theory (DFT) hybrid (B3LYP) calculations. The potential-energy profile for the 1, 5-hydride shift consists of three minima corresponding to two equivalent acyclic Carbocations and one symmetrically -hydrido-bridged carbocation, while two equivalent unsymmetrically hydrido-bridged Carbocations were located as transition-state structures. The calculated relative energy differences between acyclic Carbocations and symmetrically -hydrido-bridged structure are significantly affected by introduction of alkyl and (CH2)n-substituents at the C4 position of the 2, 6-dimethyl-2-heptyl cation structure. DFT self-consistent isodensity polarizable continuum method (SCI-PCM) and MP2 PCM continuum methods have been used to calculate the effect of solvation on geometries and relative energies of the species involved in the 1, 5-hydride shift. It is found that relative energies of acyclic and -hydrido-bridged carbocation structures as well as the energy barriers for 1, 5-hydride shifts are in accord with experimental data if solvation effects are taken into account.
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quantum chemical study of degenerate hydride shifts in acyclic tertiary Carbocations
Journal of Physical Chemistry A, 2002Co-Authors: Ivana Vinkovic Vrcek, Valerije Vrcek, Hansullrich SiehlAbstract:Quantum chemical calculations were carried out to study the mechanism of degenerate 1,2-, 1,3-, and 1,4-hydride shifts in acyclic tertiary Carbocations 2,3-dimethyl-2-butyl, 2,4-dimethyl-2-pentyl, and 2,5-dimethyl-2-hexyl. Stable structures and transition structures were calculated at the B3LYP and MP2 levels using the 6-31G(d) and 6-311G(d,p) basis sets. The potential energy profile for these degenerate hydride shifts has global minima potential wells that correspond to the two interchanging open-chain carbocation structures and a high lying local minimum corresponding to the symmetrically hydrido-bridged intermediates. Unsymmetrically hydrido-bridged Carbocations were located as transition structures. The calculated energy barriers (at the MP4/6-311G(d,p)//MP2/6-311G(d,p) level) for 1,2-, 1,3-, and 1,4-hydride shift are 3.9, 4.2, and 7.5 kcal/mol, respectively. The trend of the calculated energy barriers agrees with the experimentally observed values. Electron correlation using MP2/6-311G(d,p) is superi...
Maria A. Chiacchio - One of the best experts on this subject based on the ideXlab platform.
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pivotal neighboring group participation in substitution versus elimination reactions computational evidence for ion pairs in the thionation of alcohols with lawesson s reagent
European Journal of Organic Chemistry, 2017Co-Authors: Maria A. Chiacchio, Laura Legnani, Pierluigi Caramella, Tomas Tejero, Pedro MerinoAbstract:The mechanism of the thionation of alcohols with Lawesson's reagent was explored through quantum chemical DFT methods. Evidence that Carbocations are involved was found. The mechanism is completely different to that established recently for the thionation of carbonyls. The presence of a phenyl ring at the alcoholic carbon atom exerts a pivotal role in the stability of the carbocation and enables a S–π interaction, which is crucial for favoring thionation instead of undesired elimination. The influence of the solvent was also studied, and elimination is preferred in toluene, whereas substitution leading to thionation is favored in acetonitrile. A clear correlation between solvent polarity and elimination was observed. The study is in complete agreement with the different behavior observed experimentally for primary, secondary, and tertiary alcohols (bearing a phenyl ring or not), and the best conditions for minimizing undesired elimination can be predicted.