UCLA UCLA Electronic Theses and Dissertations Title Computational Studies on the Reactivity, Selectivity and Molecular Dynamics of Cycloaddition Reactions Permalink https://escholarship.org/uc/item/1jk894mq Author Yu, Peiyuan Publication Date 2017 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA Los Angeles Computational Studies on the Reactivity, Selectivity and Molecular Dynamics of Cycloaddition Reactions A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Peiyuan Yu 2017 © Copyright by Peiyuan Yu 2017 ABSTRACT OF THE DISSERTATION Computational Studies on the Reactivity, Selectivity and Molecular Dynamics of Cycloaddition Reactions by Peiyuan Yu Doctor of Philosophy in Chemistry University of California, Los Angeles, 2017 Professor Kendall N. Houk, Chair 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 ii 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 with dienes have also been explored. The usually observed 1,3-dipolar cycloaddition was not observed because of strong tether distortion in the (3+2) TS. iii The dissertation of Peiyuan Yu is approved. Neil Kamal Garg Jennifer M. Murphy Kendall N. Houk, Committee Chair University of California, Los Angeles 2017 iv DEDICATION To my parents, to whom I owe most, for their unconditional love and support… v TABLE OF CONTENTS List of Schemes...............................................................................................................................x List of Figures.................................................................................................................................vi List of Tables................................................................................................................................xv Acknowledgement.......................................................................................................................xvi Vita.............................................................................................................................................xviii Chapter 1. Transannular [6+4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A................................................................................................................................1 1.1 Abstract................................................................................................................................1 1.2 Introduction..........................................................................................................................1 1.3 Computational Methods.......................................................................................................3 1.4 Results and Discussion........................................................................................................4 1.4.1 Model reaction, transition structure, and free energy diagram...................................5 1.4.2 Effects of tethers on the barrier of reaction and relative stability of the [6+4] and [4+2] cycloadducts......................................................................................................9 1.4.3 Effects of methyl substituents on the relative stability of the [6+4] and [4+2] cycloadducts..............................................................................................................12 1.5 Conclusion.........................................................................................................................13 1.6 References..........................................................................................................................14 Chapter 2. How Water and Enzyme SpnF Catalyze the Transannular Diels–Alder Reaction: A Study of Medium Effects on Dynamic Mechanisms............................................18 2.1 Abstract..............................................................................................................................18 2.2 Introduction........................................................................................................................18 2.3 Computational Methods.....................................................................................................22 2.4 Results and Discussion......................................................................................................23 2.4.1 Conformational ensembles for reactant, ambimodal TS-A and Diels–Alder TS- B................................................................................................................................23 2.4.2 Computed free energies of activation.......................................................................25 vi 2.4.3 Reaction dynamics simulations.................................................................................28 2.5 Conclusion.........................................................................................................................35 2.6 References..........................................................................................................................36 Chapter 3. Mechanisms and Origins of Periselectivity of the Ambimodal [6+4] Cycloadditions of Tropone to Dimethylfulvene........................................................................39 3.1 Abstract..............................................................................................................................39 3.2 Introduction........................................................................................................................39 3.3 Computational Methods.....................................................................................................44 3.4 Results and Discussion......................................................................................................45 3.4.1 Possible [6+4] and [4+2] cycloadducts.....................................................................45 3.4.2 Transition states and free energies of activation.......................................................47 3.4.3 Molecular dynamics simulations..............................................................................51 3.4.4 Frontier molecular orbital (FMO) analysis...............................................................53 3.4.5 [1,5] Hydrogen shift and second [6+4] cycloaddition of tropone.............................54 3.5 Conclusion.........................................................................................................................56 3.6 References..........................................................................................................................58 Chapter 4. Biochemical Characterization of a Eukaryotic Decalin-Forming Diels– Alderase........................................................................................................................................61