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Development of Stereospecific Nickel-Catalyzed Cross-Coupling Reactions

  • Author(s): Tollefson, Emily Jean
  • Advisor(s): Jarvo, Elizabeth R
  • et al.

The development of asymmetric transition-metal-catalyzed reactions has emerged as an important area of research in the past decade. Advances in the field are transforming the way chemists approach the construction of target compounds. This dissertation focuses on the expansion of stereospecific nickel-catalyzed reactions to synthesize small unnatural polyketide analogs, chiral long chain carboxylic acids, and highly substituted cyclopropanes. In the presence of an achiral nickel catalyst, a bidentate phosphine ligand, and a Grignard reagent, aryl-substituted tetrahydropyrans and tetrahydrofurans undergo a stereospecific ring-opening to afford acyclic polyketide analogs with complex stereoarrays and promising anti-cancer activity. Reactions proceed with inversion of stereochemistry at the benzylic position and are substrate controlled. Similarly, enantioenriched aryl-substituted lactones undergo a Negishi-type cross-coupling with dimethylzinc to afford enantioenriched carboxylic acids. The utility of this reaction was demonstrated in a two-step synthesis of an anti-dyslipidemia agent.

The nickel catalyst system was employed to develop the first stereospecific reductive cross-coupling reaction. 2-Aryl-4-chlorotetrahydropyrans undergo an intramolecular ring contraction to afford highly substituted cyclopropanes. The reactions proceed with retention at the benzylic center and inversion at the alkyl halide position. Vinyl-substituted tetrahydropyrans are also amenable substrates for this transformation and afford vinylcyclopropane products with excellent control of stereochemistry. This is the first reported reductive coupling between alkyl ethers and alkyl halides and provides a new, mild synthetic route to both aryl- and vinyl-substituted cyclopropanes.

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