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Computational Studies on the Reactivity, Selectivity and Molecular Dynamics of Cycloaddition Reactions


The first part of this dissertation describes computational studies of higher-order cycloadditions with a focus on elucidating the origins of periselectivity. These reactions involve ambimodal transition states (TS) and bifurcations of potential energy surface.

Chapter 1 describes density functional theory (DFT) studies of a transannular [6+4] cycloaddition proposed in the biosynthesis of heronamide A, in which an unbridged 10-membered ring is formed. Ring and steric strains are found to be essential in controlling the product stability that makes this reaction feasible. Chapter 2 presents an Environment-Perturbed Transition State Sampling method to explore the mechanism of the enzyme SpnF-catalyzed Diels–Alder. A [6+4] cycloaddition is also involved and enzyme enhances the formation of [4+2] product, with respect to the counterparts in the gas phase and in water. Chapter 3 explores the mechanisms and selectivities of the cycloadditions of tropone to dimethylfulvene discovered in 1967 by Houk. The two proposed pathways by which a key intermediate are formed are united through the discovery of an ambimodal [6+4]/[4+6] TS using DFT calculations and molecular dynamics (MD) simulations.

The second part of this dissertation describes computational studies of Diels–Alder reactions and 1,3-dipolar cycloadditions using DFT calculations, with a focus on the mechanisms and the origins of regio- and stereoselectivities.

Chapter 4 reports the biochemical characterization of a Diels–Alderase found in the biosynthetic pathway of the cytotoxic myceliothermophin natural products. A theozyme model rationalizes both the substrate- and stereoselectivity of the enzyme. Chapter 5 discusses the concerted versus stepwise mechanisms of a series of dehydro-Diels–Alder (DDA) reactions. The reactivity of DDA reactions is controlled by the distortion energies required to achieve the TS geometries. Chapter 6 explores the mechanisms of Lewis acid-catalyzed Diels–Alder reactions of aryl allenes and acrylates. A stepwise mechanism involving short-lived zwitterion intermediates is established. The [2+2] cycloaddition is not observed experimentally because of the greater charge separation in the first step of the [2+2] cycloaddition. Chapter 7 focuses on the regioselectivity of 1,3-dipolar cycloadditions of benzo and mesitonitrile oxides with alkynyl pinacol and MIDA boronates. Calculated relative free energies of activation reproduce the experimentally observed product ratios. The electronic energies of activation are mainly controlled by distortion energies. Chapter 8 describes DFT studies of the first example of diazo esters as dienophiles in intramolecular Diels–Alder reactions with dienes. For comparison, the reactivities of diazo esters as 1,3-dipoles withdienes have also been explored. The usually observed 1,3-dipolar cycloaddition was not observed because of strong tether distortion in the (3+2) TS.

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