Peiyuan Yu

Catalytic Asymmetric [4+2] Annulation Initiated by an Aza‐Rauhut–Currier Reaction: Facile Entry to Highly Functionalized Tetrahydropyridines

Under control: The first example of chiral amino phosphine catalysts for the title reaction between vinyl ketones and N-sulfonyl-1-aza-1,3-dienes has been developed. Under ambient conditions, this protocol provides straightforward access to densely functionalized, enantioenriched tetrahydropyridines with high levels of sterecontrol in good to excellent yields.

Distortion-Controlled Reactivity and Molecular Dynamics of Dehydro-Diels–Alder Reactions

We report density functional theory (M06-2X) studies of a series of dehydro-Diels-Alder (DDA) reactions. For these and the parent reaction, the stepwise mechanisms have similar barriers, whereas the barriers of the concerted mechanisms differ significantly. The reactivity of DDA reactions is controlled by distortion energy. The concerted and stepwise mechanisms of the hexadehydro-Diels-Alder (HDDA) reaction are competitive with activation barriers of ∼36 kcal/mol. This is because a large distortion energy (∼43 kcal/mol) is required to achieve the concerted transition state geometry. MD simulations reveal that productive concerted trajectories display a strong angle bending oscillation (∼25° oscillation amplitude), while the stepwise trajectories show only a chaotic pattern and less pronounced bending vibrations.

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

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.

Why Alkynyl Substituents Dramatically Accelerate Hexadehydro-Diels–Alder (HDDA) Reactions: Stepwise Mechanisms of HDDA Cycloadditions

The hexadehydro-Diels-Alder (HDDA) reactions between suitably substituted 1,3-diynes and alkynes produce highly reactive benzynes under thermal conditions without catalysts. DFT calculations and distortion/interaction analyses show that, for the activated substrates, the stepwise diradical pathway is more favorable than the concerted [4 + 2] process. One manifestation of this mechanism is that alkynyl substituents dramatically accelerate HDDA reactions, mainly by decreasing the distortion energy required to achieve the diradical transition state.

Molecular Dynamics of Dimethyldioxirane C-H Oxidation.

We report molecular dynamics simulations of the reaction of dimethyldioxirane (DMDO) with isobutane. The reaction involves hydrogen atom abstraction in the transition state, and trajectories branch to the oxygen rebound pathway, which gives tert-butanol and acetone, or a separated radical pair. In the gas phase, only 10% of the reactive trajectories undergo the oxygen rebound pathway, but this increases to 90% in simulations in an implicit acetone solvent (SMD) because the oxygen rebound becomes barrierless in solution. Short-lived diradical species were observed in the oxygen rebound trajectories. The time gap between C-H bond-breaking and C-O bond formation ranges from 30 to 150 fs, close to the <200 fs lifetime of radical pairs from DMDO hydroxylation of trans-1-phenyl-2-ethylcyclopropane measured by Newcomb.

Diazo Esters as Dienophiles in Intramolecular (4 + 2) Cycloadditions: Computational Explorations of Mechanism

The first experimental examples of Diels-Alder (DA) reactions of diazo compounds as heterodienophiles with dienes have been studied with density functional theory (DFT) using the M06-2X functional. For comparison, the reactivities of diazo esters as dienophiles or 1,3-dipoles with 1,3-dienes in intermolecular model systems have been analyzed by the distortion/interaction model. The 1,3-dipolar cycloaddition is strongly favored for the intermolecular system. The intramolecular example is unique because the tether strongly favors the (4 + 2) cycloaddition.

Mechanisms and Origins of Periselectivity of the Ambimodal [6 + 4] Cycloadditions of Tropone to Dimethylfulvene

The mechanisms and selectivities of the cycloadditions of tropone to dimethylfulvene have been investigated with M06-2X and B3LYP-D3 density functional theory (DFT) calculations and quasi-classical direct molecular dynamics simulations. The originally proposed reaction mechanism (Houk) involves a highly peri-, regio-, and stereoselective [6F + 4T] cycloaddition of tropone [4π] to dimethylfulvene [6π], followed by a [1,5] hydrogen shift, and, finally, a second [6 + 4] cycloaddition of tropone [6π] to the cyclopentadiene moiety [4π]. Paddon-Row and Warrener proposed an alternative mechanism: the initial cycloaddition involves a different [6T + 4F] cycloaddition in which fulvene acts as the 4π component, and a subsequent Cope rearrangement produces the formal [6F + 4T] adduct. Computations now demonstrate that the initial cycloaddition proceeds via an ambimodal transition state that can lead to both of the proposed [6 + 4] adducts. These adducts can interconvert through a [3,3] sigmatropic shift (Cope rearrangement). Molecular dynamics simulations reveal the initial distribution of products and provide insights into the time-resolved mechanism of this ambimodal cycloaddition. Competing [4 + 2] cycloadditions and various sigmatropic shifts are also explored.

Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase.

Phenalenones are polyketide natural products that display diverse structures and biological activities. The core of phenalenones is a peri-fused tricyclic ring system cyclized from a linear polyketide precursor via an unresolved mechanism. Toward understanding the unusual cyclization steps, the phn biosynthetic gene cluster responsible for herqueinone biosynthesis was identified from the genome of Penicillium herquei. A nonreducing polyketide synthase (NR-PKS) PhnA was shown to synthesize the heptaketide backbone and cyclize it into the angular, hemiketal-containing naphtho-γ-pyrone prephenalenone. The product template (PT) domain of PhnA catalyzes only the C4-C9 aldol condensation, which is unprecedented among known PT domains. The transformation of prephenalenone to phenalenone requires an FAD-dependent monooxygenase (FMO) PhnB, which catalyzes the C2 aromatic hydroxylation of prephenalenone and ring opening of the γ-pyrone ring simultaneously. Density functional theory calculations provide insights into why the hydroxylated intermediate undergoes an aldol-like phenoxide-ketone cyclization to yield the phenalenone core. This study therefore unveiled new routes and biocatalysts for polyketide cyclization.

Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition

Significance The investigation of time-resolved mechanisms of enzymatic reaction with accurate quantum-mechanics method is a holy grail of computational chemistry, and we now develop an efficient method, environment-perturbed transition-state sampling, to study single-molecule trajectories in enzymes and calculate activation barriers. In 2011, the Liu group published evidence for the first monofunctional Diels–Alderase, SpnF, in the biosynthetic pathway of Spinosyn A. We discovered later that the reaction bifurcates to the [4+2] and [6+4] adduct through a single ambimodal transition state. We now elucidate in detail the mechanism of the reaction and show how the SpnF enzyme dynamically controls product formation. Our method will find great application in the design of enzymes to control selectivity, particularly for reactions involving ambimodal transition states. SpnF is the first monofunctional Diels–Alder/[6+4]-ase that catalyzes a reaction leading to both Diels–Alder and [6+4] adducts through a single transition state. The environment-perturbed transition-state sampling method has been developed to calculate free energies, kinetic isotope effects, and quasi-classical reaction trajectories of enzyme-catalyzed reactions and the uncatalyzed reaction in water. Energetics calculated in this way reproduce the experiment and show that the normal Diels–Alder transition state is stabilized by H bonds with water molecules, while the ambimodal transition state is favored in the enzyme SpnF by both intramolecular hydrogen bonding and hydrophobic binding. Molecular dynamics simulations show that trajectories passing through the ambimodal transition state bifurcate to the [6+4] adduct and the Diels–Alder adduct with a ratio of 1:1 in the gas phase, 1:1.6 in water, and 1:11 in the enzyme. This example shows how an enzyme acts on a vibrational time scale to steer post-transition state trajectories toward the Diels–Alder adduct.

Origins of regioselectivity in 1,3-dipolar cycloadditions of nitrile oxides with alkynylboronates.

Density functional theory (M06-2X) studies of the regioselectivity of 1,3-dipolar cycloaddition reactions of benzo and mesitonitrile oxides with alkynyl pinacol and MIDA boronates are reported. Calculated relative free energies of activation reproduce the experimentally observed product ratios. The electronic energies of activation are found to be mainly controlled by distortion energies required to achieve the transition states. Both electronic and steric effects influence regioselectivities.