Optimization and Applications of the Catalytic Enantioselective Borylative Migration of Functionalized Piperidines

• Author / Creator

  Kim, You-Ri

• The catalytic enantioselective borylative migration developed in 2009 by our laboratory is a convenient, single-step method that provides enantiomerically enriched heterocyclic allylboronates. However, this chemistry occasionally provided lower yields and enantioselectivity when used with piperidinyl precursor. Because piperidine derivatives are of great importance in the pharmaceutical industry due to their prevalence in biologically active molecules, we focused on the re-optimization of the reaction conditions for the catalytic enantioselective borylative migration, to identify an economical, industry-friendly procedure that could provide piperidine derivatives in a multi-gram scale. The following parameters were examined: the nature of the alkenylsulfonate and the N-protecting group of the substrate, the source and stoichiometry of palladium and diphosphine ligand, solvent, reaction concentration, temperature, and time. With a more robust and industry-friendly procedure in hand, applications of this chemistry were explored to functionalize piperidine derivatives further. First, aldehyde allylboration was re-optimized and subsequently exploited in the intramolecular Heck reaction to furnish tricyclic α-hydroxyalkyl dehydropiperidine. Suzuki-Miyaura cross-coupling conditions to yield [3,4]-biaryl piperidine derivatives were also attempted. Finally, some mechanistic studies were conducted to validate the previously proposed mechanism for this chemistry. Another synthetic target of interest explored in this thesis was β-borono-nitroethylene, which could be used as a novel precursor for the synthesis of pharmaceutically relevant chiral β-amino alcohols. Due to the lack of literature precedents for the synthesis of β-borono-nitro-olefin derivatives, several established procedures for the formation of olefins or nitro-olefins were attempted: metal-mediated nitration of alkenyl boronates; cross-metathesis or transmetalation of nitro-olefin derivatives; nucleophilic addition of nitromethane to halogenated boronates; copper-catalyzed conjugate borylation of nitro-olefins; lanthanum-catalyzed asymmetric Michael addition; and Miyaura borylation of (2-bromo-2-nitrovinyl)benzene.

• Subjects / Keywords

  • Chiral piperidine
  • Piperidine
  • Allylboronate
  • Borylation
  • Allylboration

• Graduation date

  Fall 2016

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3J38KT8J

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.