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Total Synthesis of N-Methylwelwitindolinone B Isothiocyanate and Nickel-Catalyzed Reactions of Amide Derivatives

  • Author(s): Baker-Tripp, Emma Lee
  • Advisor(s): Garg, Neil K
  • et al.
Abstract

This dissertation describes our efforts toward the total synthesis of N-methyl welwitindolinone B isothioscyanate, as well as the development of reactions involving the nickel-catalyzed activation of amide C–N bonds. The welwitindolinones have been long-standing targets in total synthesis for over two decades due to their complex structures and interesting biological profiles. This dissertation describes the completed total synthesis of a particularly challenging family member, N-methylwelwitindolinone B isothiocyanate. Moreover, several nickel-catalyzed transformations of amides are described each showcasing the unique reactivity of this non-precious metal and highlighting the utility of amides, once considered inert substrates, as useful synthons in organic synthesis.

Chapter one describes our enantiospecific total synthesis of N-methylwelwitindolinone B isothiocyanate. Our approach to the natural product features an aryne cyclization to construct the bicyclo[4.3.1]decane core of the molecule, as well as a C–H nitrene insertion reaction to introduce the bridgehead nitrogen substituent. The key step involving a regio- and diastereoselective chlorinative oxabicycle opening is detailed, which enables the first total synthesis of N-methylwelwitindolinone B isothiocyanate.

Chapters two and three describe the development of nickel-catalyzed esterification reactions of amides. Chapter two showcases the first nickel-catalyzed activation of amides in an esterification of benzamides. This study suggests that amides could serve to be useful synthetic building blocks in a variety of cross-coupling reactions. Chapter three builds upon the previous study to expand the scope to include the activation of amides derived from aliphatic carboxylic acids.

Chapters four and five describe the development of nickel-catalyzed C–N bond-forming reactions of amides. More specifically, chapters four and five outline the transamidation reaction of aromatic and aliphatic amides, respectively. These methodologies utilize a two-step approach to enable the transamidation of secondary amides. These two methods address the long-standing challenge of secondary amide transamidation.

Chapter six describes the development of a nickel-catalyzed C–C bond-forming reaction of amides. The first nickel-catalyzed Suzuki–Miyaura coupling of aromatic amides is disclosed and provides a new and mild method for ketone synthesis. This study demonstrates that amides can now be utilized as synthons for use in C–C bond forming reactions through cleavage of the amide C–N bond.

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