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Harnessing the Reactivity of Strained Intermediates and Biosynthetic Machinery

  • Author(s): Barber, Joyann
  • Advisor(s): Garg, Neil K
  • et al.
Abstract

This dissertation describes efforts in strained allene and alkyne methodology, as well as collaborative efforts at the interface of organic synthesis and bioengineering to construct complex molecules. Strained intermediates, though once only an intellectual curiosity, have proven to be useful synthetic building blocks in organic synthesis. This dissertation describes the expansion of cyclic allene chemistry to include (3+2) cycloadditions, as well as a greater understanding of the reactivities of nitrogen-containing analogs. Additionally, the use of strained alkyne intermediates to construct compounds relevant to materials chemistry is explained. Moreover, the synthesis of a key biosynthetic precursor for monoterpene indole alkaloids, as well as the combination of bioengineering and synthetic chemistry to access complex natural products, is described.

Chapter one describes the first 1,3-dipolar cycloadditions of 1,2-cyclohexadiene, an synthetically underutilized strained intermediate. Our approach relies on the slow generation of 1,2-cyclohexadiene from its silyl triflate precursor and trapping using nitrone partners, allowing access to isoxazolidine products. Computational studies provide mechanistic insight into this reaction and explain the observed regio- and diastereoselectivity trends. Moreover, the manipulation of the isoxazolidine products demonstrates the utility of strained allene intermediates as synthetic building blocks.

Chapter two details an experimental and computational study of azacyclic allenes. This includes the synthesis of precursors to several substituted allenes, the trapping of the allenes in various cycloadditions, and explanations of the observed selectivities. Additionally, we demonstrate that stereochemical information can be transferred via an enantioenriched allene, and when taken in combination with the selectivities, highlights that azacyclic allenes can be harnessed as valuable synthetic building blocks for complex molecule synthesis.

Chapter three describes a modular approach towards polycyclic aromatic hydrocarbon (PAH) scaffolds. More specifically, we rely on strained alkyne and aryne intermediates to construct these PAH motifs. This study demonstrates underscore the importance of heterocyclic strained intermediates to prepare new organic materials.

Chapters four and five depict the synergy between chemical synthesis and bioengineering. More specifically, chapter four describes the discovery of an enzyme that can promote hydroalkoxylation reactions. Chapter five details the engineering of yeast enzymes to access an important monoterpene indole alkaloid building block, strictosidine, from its biosynthetic precursor, 8-hydroxygeraniol. Additionally, analysis and characterization of the shunt pathways present in this transformation are described.

Chapter six describes the development of a simple procedure to access 8-hydroxygeraniol. Our approach allows for large-scale production of this central biosynthetic precursor that should help enable biosynthetic studies to thousands of essential monoterpene indole alkaloids.

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