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Total Synthesis of Tubingensin B and Nickel-Catalyzed Methodologies Involving C–O or C–N Bond Activation

  • Author(s): Kim, Junyong
  • Advisor(s): Garg, Neil K
  • et al.
Abstract

This dissertation describes the total synthesis of tubingensin B and the development of two nickel-catalyzed methods. The two methodologies include the amination of aryl electrophiles in the green solvent 2-methyl-THF and the Suzuki–Miyaura coupling of aliphatic

amides via the activation of amide C–N bonds.

Chapter One highlights indole terpenoid natural products as the inspiration for the development of new synthetic methodologies and innovative strategies. This review showcases recent total syntheses of the natural products, penitrem D, emindole SB, paspaline, dixiamycin B, and tubingensins A and B.

Chapter Two pertains to the total synthesis of (–)-tubingensin B. Key steps of the synthesis involves a B-alkyl Suzuki–Miyaura reaction, a carbazolyne cyclization, and a radical cyclization to construct the core architecture of the molecule. Key to the synthesis of tubingensin B was the utilization of a heterocyclic aryne intermediate for the formation of a scaffold bearing vicinal quaternary centers. This synthesis illustrates the capability of aryne methodology in generating stereochemically complex structures.

Chapter Three describes the development of a green variant of a nickel-catalyzed amination reaction. As solvents comprise 85% of pharmaceutical waste, the use of a green solvent provides a considerable benefit for the potential application of the methodology to

industrial problems. We developed a method employing 2-Me-THF as a green solvent for the amination of aryl chlorides and sulfamates.

Chapter Four demonstrates the nickel-catalyzed Suzuki–Miyaura coupling of aliphatic amide derivatives. The methodology can be used to activate typically unreactive amide C–N bonds and, in turn, access an array of heterocyclic ketones.

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