Enantioselective Preparation of a cis-β-Boronyl Cyclobutylcarboxyester Scaffold and Its Highly Diastereoselective Nickel/Photoredox Dual-Catalyzed Cross-Coupling

• Author / Creator

  Nguyen, Kevin

• Chiral cyclobutanes are components of numerous bioactive natural products and
  consequently they have also gained significant attention in medicinal chemistry. Optically enriched
  cyclobutylboronates can serve as valuable synthetic intermediates for the synthesis of a broad variety of
  chiral cyclobutanes through exploiting the versatility of the boronyl functionality. Herein, by using a
  high-throughput ligand screening approach, the first method for the asymmetric conjugate borylation of
  a cyclobutene 1-carboxyester was optimized, leading to a highly enantioenriched cis-β-boronyl
  cyclobutylcarboxyester scaffold (99% ee, >20:1 dr). Of the 118 ligands screened, the Naud family of
  phosphine-oxazoline ligands was found to be the most effective. Computational modeling of the
  possible pre-insertion complexes shows a large preference for the π-bound Cu(I)–alkene complex where
  the substrate's large benzhydryl ester occupies a relatively unhindered quadrant of the chiral ligand in a
  spatially tight environment that is highly specific for the cyclobutenoate substrate and fails to
  accommodate larger ring substrates. The cis diastereoselectivity is proposed to arise from a sterically
  controlled, irreversible protodecupration step. A highly diastereoselective nickel/photoredox dualcatalyzed
  Csp3–Csp2 cross-coupling of the corresponding trifluoroborate salt with aryl/heteroaryl
  bromides and cycloalkenyl nonaflates was developed, providing access to a wide diversity of trans-β-
  aryl/heteroaryl and cycloalkenyl cyclobutylcarboxyesters with excellent diastereoselectivity and
  retention of optical purity (91–99% ee, >20:1 dr). Azaheterocyclic halides, which are notoriously
  challenging substrates in Pd-catalyzed cross-coupling, are successful with this Ni/photoredox manifold.
  A model based on steric control is proposed for the key carbon-carbon bond forming step leading to
  high diastereoselectivity. Despite the radical nature of the cross-coupling conditions, the flanking
  carboxyester proved to be a reliable chirality relay group to maintain the stereochemical integrity of the
  organoboron intermediate. Furthermore, mild oxidation of the carbon-boron bond and extension of the
  catalytic asymmetric conjugate borylation reaction to a three-component aldol reaction with an aldehyde
  affords valuable enantioenriched cyclobutane products.

• Subjects / Keywords

  • chiral ligands
  • conjugate borylation
  • cross-coupling
  • cyclobutanes
  • diastereoselectivity
  • enantioselective catalysis

• Graduation date

  Spring 2021

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-3rdz-w339

• 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.