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Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights.

  • Wanner B Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich , 8093 Zürich, Switzerland.
  • Kreituss I Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich , 8093 Zürich, Switzerland.
  • Gutierrez O Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
  • Kozlowski MC Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
  • Bode JW Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich , 8093 Zürich, Switzerland.
  • 2015-08-27
Published in:
  • Journal of the American Chemical Society. - 2015
Acylation
Amines
Catalysis
Heterocyclic Compounds
Hydroxamic Acids
Kinetics
Methane
Models, Molecular
Molecular Conformation
Stereoisomerism
English The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes and chiral hydroxamic acids has emerged as a promising method to obtain enantio-enriched amines with high selectivity factors. In this report, we describe the catalytic kinetic resolution of disubstituted piperdines with practical selectivity factors (s, up to 52) in which we uncovered an unexpected and pronounced conformational effect resulting in disparate reactivity and selectivity between the cis- and trans-substituted piperidine isomers. Detailed experimental and computational studies of the kinetic resolution of various disubstituted piperidines revealed a strong preference for the acylation of conformers in which the α-substituent occupies the axial position. This work provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution.
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  • English
Open access status
green
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https://sonar.ch/global/documents/24297
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