Control Elements in Dynamically Determined Selectivity on a Bifurcating Surface

Thomas, Jacqueline B.; Waas, Jack R.; Harmata, Michael; Singleton, Daniel A.

doi:10.1021/ja802577v

Cited by 155 publications

(138 citation statements)

References 100 publications

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“…Instead, the shape of the PES and resulting dynamical effects will play an important role. 39 For the reaction of 5, the [4+2] adduct 7 is calculated to be 5.2 kcal mol -1 less stable than the [6+4] adduct 6. A possible Cope rearrangement reaction could convert 7 into 6.…”

Section: Solvation Only Has a Minor Effect On The Barriers Of Reactmentioning

confidence: 99%

Transannular [6 + 4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A

Patel

Houk

2015

J. Am. Chem. Soc.

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The transannular [6 + 4] cycloaddition proposed as a step in the biosynthesis of heronamide A has been modeled using density functional theory. The proposed cycloaddition is highly stereoselective, affording a single product. The reaction proceeds through an ambimodal transition state that directly leads to a [4 + 2] adduct in addition to the observed [6 + 4] adduct. Interconversion of these adducts is possible via a facile Cope rearrangement. The [6 + 4] adduct is thermodynamically more stable than the [4 + 2] adduct by 5.2 kcal mol(-1) due to a combination of the ring and steric strain in the [4 + 2] product. The results strongly support the plausibility of the proposed transannular [6 + 4] cycloaddition in the biogenesis of heronamide A and may provide insights to designing substrates that selectively undergo [6 + 4] cycloaddition to form unbridged 10-membered rings.

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Section: Solvation Only Has a Minor Effect On The Barriers Of Reactmentioning

confidence: 99%

Transannular [6 + 4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A

Patel

Houk

2015

J. Am. Chem. Soc.

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“…In our trajectory study of a diradical-mediated fourfold degen- erate rearrangement (30) reported experimentally by Baldwin and Keliher (31), we found that the product ratio is related in a simple way to the momentum distribution at the TS and that the distribution of structures is also important. A closely related issue is post-TS product selectivity, often on a bifurcating PES (32,33) or involving chemical activation of an intermediate from high energy reactants (34,35). The sampling procedure in the present study uses harmonic frequencies and normal modes at the TS to generate a set of coordinates and momenta that approximate a quantum mechanical Boltzmann distribution of vibrational levels on the TS dividing surface.…”

mentioning

confidence: 99%

Dynamics, transition states, and timing of bond formation in Diels–Alder reactions

Black

Liu

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

197

203

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The time-resolved mechanisms for eight Diels-Alder reactions have been studied by quasiclassical trajectories at 298 K, with energies and derivatives computed by UB3LYP/6-31G(d). Three of these reactions were also simulated at high temperature to compare with experimental results. The reaction trajectories require 50-150 fs on average to transverse the region near the saddle point where bonding changes occur. Even with symmetrical reactants, the trajectories invariably involve unequal bond formation in the transition state. Nevertheless, the time gap between formation of the two new bonds is shorter than a C─C vibrational period. At 298 K, most Diels-Alder reactions are concerted and stereospecific, but at high temperatures (approximately 1,000 K) a small fraction of trajectories lead to diradicals. The simulations illustrate and affirm the bottleneck property of the transition state and the close connection between dynamics and the conventional analysis based on saddle point structure.molecular dynamics | density functional theory | transition state theory | cycloadditions | concerted reaction T he Diels-Alder reaction is one of the most important reactions used in organic synthesis (1, 2), and its discovery was recognized by the Nobel Prize in Chemistry in 1950. The reaction is a paradigm for methods that efficiently increase structural complexity, because two single bonds, a six-membered ring, and up to four stereocenters are formed in a single step.Mechanisms of Diels-Alder reactions have been the subject of intensive scrutiny by experimental and theoretical methods (3-6). The timing of bond formation has been the focus of attention. Many experimental studies show that the Diels-Alder reaction is stereospecific with respect to both reactants (7), a result that is compatible with a concerted mechanism, traditionally defined as a reaction path involving no intermediates. DFT and ab initio calculations based on transition state theory predict that a concerted, one-step mechanism is the lowest energy pathway on the ground-state potential energy surface (PES) (8). However, at the time-resolved level, the two new carbon-carbon bonds may not form simultaneously along a dynamical trajectory. The time gap between formation of the two bonds is strongly connected to the expected degree of stereospecificity observed in the reaction, but the details of this relationship are uncertain due to several recent reports: (i) In studies of retro-Diels-Alder (retro-DA) dynamics at femtosecond time resolution of reaction R2 in Scheme 1, Zewail and coworkers found two sets of transients, one identified with concerted asynchronous trajectories, the other with diradicaloid stepwise trajectories (9, 10). Because reactants are photochemically activated, a full understanding of the experiments must include the role of conical intersections between ground and excited states (11). (ii) In thermal shock tube studies of the retro-DA reactions R1, R2, and R3 in Scheme 1, Lewis, Baldwin, and coworkers found that the retro-DA reaction of cis-4...

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“…We also found that the bornyl cation represented a bifurcation point on the PES. [18][19][20] Bifurcation points result in the breakdown of standard TST and have been observed in numerous nonbiological systems. [18][19][20] Such a bifurcation point presents an intriguing feature in biocatalysis, as initially observed in computational gas-phase studies of terpenes by Hong and Tantillo, [22] and a key question is how enzymes tackle such challenges.…”

Section: Reaction Dynamics In a Terpene Cyclasementioning

confidence: 99%

“…[11,17] A clear case in which TST is not directly applicable is for reactions on bifurcating potential or free energy surfaces. [18][19][20][21] In such cases, usual statistical rate theories are not applicable, and TST fails to predict the product branching ratios. Such nonstatistical dynamics have been observed in terpene cyclases (see below).…”

Section: Introductionmentioning

confidence: 99%

Multiscale Quantum‐Classical Simulations of Enzymes

Doron¹,

Weitman²,

Vardi-Kilshtain³

et al. 2014

Israel Journal of Chemistry

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Enzymes are remarkably efficient catalysts evolved to perform well‐defined and highly specific chemical transformations. Studying the nature of enzymatic rate enhancements is highly important from several aspects, including the rational design of synthetic catalysts and transition‐state inhibitors. Herein, we describe recent progress in our group in the development of multiscale simulation methods and their application to several enzyme systems. In particular, we describe the use of combined quantum mechanics/molecular mechanics (QM/MM) methods in classical and quantum simulations. The development of various novel path‐integral methods is reviewed. These methods are tailor‐made for enzyme systems, where only a few degrees of freedom involved in the chemistry need to be quantized. The application of the hybrid QM/MM quantum‐classical simulation approach to three case studies is presented. The first case involves proton transfer in nitroalkane oxidase, where the enzyme employs tunneling as a catalytic fine‐tuning tool. The second case presented involves orotidine 5′‐monophosphate decarboxylase, where multidimensional free energy simulations together with kinetic isotope effects are combined in the study of the reaction mechanism. Finally, we discuss the monoterpene cyclase bornyl diphosphate synthase, where non‐statistical dynamics is a key component in enzyme function.

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Control Elements in Dynamically Determined Selectivity on a Bifurcating Surface

Cited by 155 publications

References 100 publications

Transannular [6 + 4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A

Transannular [6 + 4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A

Dynamics, transition states, and timing of bond formation in Diels–Alder reactions

Multiscale Quantum‐Classical Simulations of Enzymes

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