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Phosphine Organocatalysis and Dealkenylative C(sp3)–C(sp2) Bond Functionalization

  • Author(s): Smaligo, Andrew James
  • Advisor(s): Kwon, Ohyun
  • et al.

This dissertation features several projects involving catalyst design and reaction development in the areas of organocatalysis and dealkenylative C(sp3)–C(sp2) bond functionalizations. The underlying theme throughout all of this work is the introduction of robust and modular transformations aimed at the synthesis of pharmaceutically-relevant scaffolds. Chemical reactions with these attributes are of utmost importance with regards to the synthesis and modification of biologically-active small-molecules, so these works seek to contribute to this goal.

Chapter One focuses on the design and synthesis of a new family of carvone-derived phosphine organocatalysts and their implementation in enantioselective allene–imine [3 + 2] annulations to give functionalized nitrogen heterocycles. A background of nucleophilic phosphine organocatalysis is presented to give context in this area. During these studies, a new fragmentation reaction was developed which was exploited in later work. The introduction of this catalyst family also enabled the enantioselective synthesis of a biologically-active small-molecule, efsevin.

Chapter Two discusses the development of the aforementioned C(sp3)–C(sp2) bond fragmentation reaction, hydrodealkenylation, in which an alkene C(sp3)–C(sp2) bond is converted to a C(sp3)–H bond. A history of ferrous-mediated fragmentations of organoperoxides is provided to show the extensive, yet unrealized potential of this type of transformation. This robust transformation was applicable in the syntheses of many desirable chiral scaffolds from abundant feedstock reagents. It was also shown that this transformation can be applied in the formal syntheses of five complex natural product scaffolds.

Chapter Three describes further development of the alkene C(sp3)–C(sp2) bond fragmentation in a new variation, dealkenylative thiylation, in which an alkene C(sp3)–C(sp2) bond is converted to a C(sp3)–S bond. Carbon–heteroatom bonds are commonly found in both natural products and pharmaceutical leads. Therefore, the development of reactions that forge these bonds are important. Contrary to known methods of synthesis, this dealkenylative radical approach enables the synthesis of complex chiral scaffolds containing aryl-sulfide motifs under relatively mild reaction conditions. These products were then subjected to various transformations to highlight the synthetic utility of the products.

Chapter Four highlights the development of a one-pot procedure, referred to as oxodealkenylation, in which an alkene C(sp3)–C(sp2) bond is converted to a C=O bond. Carbonyls are among the most versatile functional group handles, therefore conversion of the alkenes commonly found in abundant chiral pool feedstock into carbonyls would be highly desirable. This process was demonstrated on a variety of chiral pool-derived materials, providing novel building blocks in a facile fashion. Synthetic transformations of the products and mechanistic investigations are also provided in this work.

Chapter Five focuses on the synthesis of chiral pool-derived sulfinate salts and their applications in synthesis. Sulfinate salts are versatile and robust radical precursors. However, the synthesis of chiral sulfinates is seldom reported. Here, we utilized our previously developed dealkenylative thiylation to enable streamlined access to these types of sulfinates. Examples are also provided that demonstrate how these products can be used in the diversification of pharmaceutically-relevant scaffolds to give C(sp3)- and stereochemically-rich heterocyclic derivatives.

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