Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters

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Abstract
Synthetic application of asymmetric catalysis relies on strategic alignment of bond construction to creation of chirality of a target molecule. Remote desymmetrization offers distinctive advantages of spatial decoupling of catalytic transformation and generation of a stereogenic element. However, such spatial separation presents substantial difficulties for the chiral catalyst to discriminate distant enantiotopic sites through a reaction three or more bonds away from a prochirality center. Here, we report a strategy that establishes acyclic quaternary carbon stereocenters through cross-coupling reactions at distal positions of aryl substituents. The new class of amino acid-derived ionic chiral catalysts enables desymmetrizing (enantiotopic-group-selective) Suzuki-Miyaura reaction, Sonogashira reaction, and Buchwald-Hartwig amination between diverse diarylmethane scaffolds and aryl, alkynyl, and amino coupling partners, providing rapid access to enantioenriched molecules that project substituents to widely spaced positions in the three-dimensional space. Experimental and computational investigations reveal electrostatic steering of substrates by the C-terminus of chiral ligands through ionic interactions. Cooperative ion-dipole interactions between the catalyst's amide group and potassium cation aid in the preorganization that transmits asymmetry to the product. This study demonstrates that it is practical to achieve precise long-range stereocontrol through engineering the spatial arrangements of the ionic catalysts' substrate-recognizing groups and metal centers.
Funding Information
  • Ministry of Education - Singapore (MOE2019-T2-2-139)
  • Universit? Paris-Saclay
  • Centre National de la Recherche Scientifique
  • National University of Singapore (A-0004522-00-00)

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