title: Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights.
abstract: 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.
authors: Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich , 8093 Zürich, Switzerland.
authors: Benedikt
authors: B
authors: Wanner
authors: Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich , 8093 Zürich, Switzerland.
authors: Imants
authors: I
authors: Kreituss
authors: Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors: Osvaldo
authors: O
authors: Gutierrez
authors: Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors: Marisa C
authors: MC
authors: Kozlowski
authors: Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich , 8093 Zürich, Switzerland.
authors: Jeffrey W
authors: JW
authors: Bode
mesh_terms: D000215:Acylation; D000588:Amines / Q000737:chemistry*; D002384:Catalysis; D006571:Heterocyclic Compounds / Q000737:chemistry; D006877:Hydroxamic Acids / Q000737:chemistry; D007700:Kinetics; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
chemical_list: D000588:Amines; D006571:Heterocyclic Compounds; D006877:Hydroxamic Acids; C030011:carbene; D008697:Methane