Investigations of Strained Cyclic Intermediates and Pericyclic Reactions for Complex Molecule Synthesis
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Investigations of Strained Cyclic Intermediates and Pericyclic Reactions for Complex Molecule Synthesis

  • Author(s): Ramirez, Melissa
  • Advisor(s): Houk, Kendall N.;
  • Garg, Neil K.
  • et al.

This dissertation describes experimental and computational efforts in the fields of strained cyclic intermediate chemistry and the application of pericyclic reactions for complex molecule synthesis. Strained cyclic intermediates have long fascinated the chemical community. Although once avoided in organic synthesis because of their high reactivity and fleeting nature, strained cyclic intermediates now have a wide array of applications, being employed in the synthesis of natural products, medicinally privileged scaffolds, ligands, agrochemicals, and organic materials. Herein, key mechanistic features of the Diels–Alder/retro-Diels–Alder (DA/r-DA) cascade of strained cyclic alkynes and arynes with oxadiazinones, which provide rapid access to diverse polycyclic aromatic hydrocarbons (PAHs), are investigated. The utility of the methodology in accessing the carbon frameworks of extended PAHs is demonstrated. Furthermore, the structure and reactivity of strained cyclic allenes, which have seen fewer applications than arynes and cyclic alkynes, in Diels–Alder cycloadditions are studied towards developing a predictive model for regioselectivity and enantiospecificity. Mechanistic studies on the (4+2) and (2+2) cycloadditions of keteniminium cations with 1,3-dienes and the Claisen cascades of aryl propargyl ethers are described. These studies better our understanding of the origins of product selectivity and demonstrate the synergism of experiments and computations in strategically incorporating pericyclic reactions in complex molecule synthesis.Chapter one involves a computational and experimental study of the reaction of oxadiazinones and strained alkynes to give PAHs. The reaction proceeds by way of a pericyclic reaction cascade and leads to the formation of four new carbon–carbon bonds. We interrogate several mechanistic aspects of the reaction using Density Functional Theory (DFT) calculations and perform experimental studies that enable the rapid synthesis of new PAHs, including tetracene and pentacene scaffolds. These studies provide fundamental insight regarding the aforementioned cycloaddition cascades and synthetic access to PAH scaffolds and are expected to enable the synthesis of new materials. Chapters two, three, and four describe the development of Diels–Alder reactions with cyclic allenes towards establishing a predictive model for regioselectivity and stereoselectivity based on allene substituent effects. More specifically, chapter two provides an experimental and computational study of azacyclic allenes featuring the syntheses of stable allene precursors, the mild generation and Diels–Alder trapping of the desired cyclic allenes, and explanations of the observed regio- and diastereoselectivities via computational analysis. Chapter three is concerned with the development of (4+2), (3+2), and (2+2) cycloadditions of the parent oxacyclic allene to provide an array of heterocycles. Furthermore, an enantioenriched oxacyclic allene is accessed via catalytic, decarboxylative asymmetric allylation of an α-silylated substrate and trapped in a Diels– Alder cycloaddition with complete transfer of stereochemical information. Chapter four outlines a computational investigation of the factors contributing to endo selectivity in Diels– Alder reactions with strained cyclic allenes, which is consistently observed in experiments with six-membered cyclic allenes. The contributions of a new type of secondary orbital interaction resulting from the twisted nature of the strained allene, and electrostatic effects, to endo selectivity are established. Overall, the studies provided in chapters two, three, and four are expected to prompt the further use of long-avoided strained cyclic allenes in chemical synthesis. Finally, chapters five and six are concerned with reaction mechanism and selectivity of pericyclic transformations that provide access to complex molecule scaffolds. Chapter five focuses on the selectivities of (4+2) and (2+2) cycloadditions of keteniminium cations, which serve as versatile electrophiles in organic synthesis, with 1,3-dienes. Cyclic dienes are fixed in the s-cis conformation and undergo selective (4+2) cycloaddition with the C=N bond of tetramethylketeniminium cation while acyclic dienes selectively react at the C=C bond of the keteniminium cation in stepwise (2+2) cycloadditions. Chapter six provides a computational study of the Claisen cascades of aryl propargyl ethers and substituent effects on product selectivity. The reaction mechanism involves a rate determining Claisen rearrangement as the first step. The study represents the first computational analysis of the mechanism of cyclization leading to fused cyclopropyl products and is also one of the few theoretical studies on Claisen rearrangement/electrocyclization cascades leading to benzopyran derivatives. It is anticipated that the report will enable further synthetic method development and expansion of these historically important reaction cascades in accessing architecturally complex natural products.

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