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Investigation into the Dyotropic Rearrangement of Arene-Allene Cycloadducts, Studies Toward the Synthesis of Isonitrile-Containing Diterpene Natural Products, and Synthesis of Indolines via Cobalt(III)-Carbene Radical Catalysis

  • Author(s): Karns, Alexander
  • Advisor(s): Vanderwal, Christopher D
  • et al.
Abstract

Described herein is a compilation of studies in both methodology development and total synthesis in organic chemistry. Chapter 1 describes in detail notable discoveries in the field of dyotropic rearrangements, highlighting computational investigations, methodological analyses, and application to the total synthesis of natural products. Chapter 2 summarizes the formal dyotropic rearrangement observed initially by Gerhard Himbert, and discusses the scope, limitations, and applications of this unique bicyclic rearrangement. Chapter 3 discusses our collaborative computational and experimental investigation into the formal dyotropic shift of arene-allene cycloadducts. Notable contributions include the discovery of Lewis acid-promoted dyotropic rearrangement conditions and isolation of a “trapped intermediate”, strongly supporting a proposed two-step polar mechanism.

Chapter 4 discusses in detail the isocyanoterpene natural products, including their proposed biogenesis, their observed bioactivity, and synthetic strategies by which they can be obtained in a laboratory setting. Chapter 5 elaborates specifically on the kalihinane family of natural products, highlighting their isolation, and summarizing total syntheses targeting their complex structures. Chapter 6 summarizes our progress toward the synthesis of kalihinanes that contain a tetrahydropyran ring. Notable contributions include a convergent sequence that procures an acyclic precursor to the kalihinane core and several methods by which this acyclic precursor can be cyclized to form the tetrahydropyran ring.

Chapter 7 describes in detail the isolation of (+)-7,20-diisocyanoadociane and summarizes the total synthesis efforts toward the completed natural product. Chapter 8 highlights our improvements to our previously published formal synthesis of DICA, which lowers the step count from 24 steps to 17 steps, increases the overall yield significantly, and targets an intermediate from which the natural product can be obtained with high diastereoselectivity.

Chapter 9 provides a short summary of the field of cobalt(III)-carbene radical catalysis, including both mechanistic studies and applications to small molecule synthesis. Chapter 10 details our application of this unique reactivity to a rapid and efficient synthesis of indolines. The discovery and optimization of this methodology is described in detail, accompanied by an investigation into both scope and mechanism.

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