Building Complex Scaffolds Using Strained Aryne Intermediates and Chemoenzymatic Synthesis
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Building Complex Scaffolds Using Strained Aryne Intermediates and Chemoenzymatic Synthesis

  • Author(s): Anthony, Sarah
  • Advisor(s): Garg, Neil K
  • et al.
Abstract

This dissertation describes research pertaining to the synthesis of natural products and reaction methodology development. The synthesis of complex molecules remains a worthwhile pursuit as natural products and their derivatives are frequently a source of inspiration for new drugs. Additionally, the synthesis of complex molecules provides an avenue to test methodologies and develop novel strategies towards them. Reaction development enables the discovery of new reactivity and new disconnections to access complex small molecules more efficiently. Both total synthesis and reaction development continues to push the boundaries of synthetic organic chemistry. Chapter one offers a current perspective on the field of strained cyclic alkynes and allenes. Despite being validated over fifty years ago, strained cyclic alkynes and allenes have only recently been used to access complex small molecules. This chapter highlights recent methodologies and syntheses using strained arynes, allenes, and alkynes to generate complex products bearing stereodefined quaternary centers or generate products with multiple fused rings in high enantioenrichment. Chapter two describes the development of a methodology using strained cyclic alkynes and strained arynes to generate products bearing stereodefined quaternary stereocenters. Arynes and strained cyclic alkynes are highly electrophilic species and strategies to use these them in stereospecific reactions are limited. Accessing quaternary stereocenters remains a challenging, but important goal of synthetic chemistry. Specifically, the strategy pursued utilized enantioenriched enamines and arynes or cyclic alkynes to generate α-arylated or vinylated β-ketoesters in a stereospecific fashion. Chapter three describes the total synthesis of secologanin and strictosidine. Strictosidine is the last common biosynthetic precursor to all monoterpene indole alkaloids, which is a class of natural products with over three thousand compounds isolated to date. Presented here is a new strategy to access strictosidine enabled by a blend of both synthetic chemistry and biocatalysis. This strategy was then used to access aryne derivatives of strictosidine and a related natural product, strictosamide. The in situ generated arynes were trapped with dienes to access derivatives of these natural products. Chapter four describes the discovery of two homologous groups of pericyclase enzymes, which are enzymes that catalyze pericyclic reactions. Specifically, one group catalyzes a stereoselective hetero-Diels–Alder reaction and the other catalyzes an Alder-ene reaction, which was previously unknown in biology. A chemoenzymatic synthesis was utilized to access the substrate of the Diels–Alder reaction and Alder-ene reaction.

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