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
  • Graduation date
    Spring 2021
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • 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.