title: Concerted amidation of activated esters: reaction path and origins of selectivity in the kinetic resolution of cyclic amines via N-heterocyclic carbenes and hydroxamic acid cocatalyzed acyl transfer.
abstract: The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity.
authors: Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors: Scott E
authors: SE
authors: Allen
authors: Sheng-Ying
authors: SY
authors: Hsieh
authors: Osvaldo
authors: O
authors: Gutierrez
authors: Jeffrey W
authors: JW
authors: Bode
authors: Marisa C
authors: MC
authors: Kozlowski
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry*; D002384:Catalysis; D004952:Esters / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000737:chemistry*; D007700:Kinetics; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D000577:Amides; D000588:Amines; D004952:Esters; D006571:Heterocyclic Compounds; D006877:Hydroxamic Acids; C030011:carbene; D008697:Methane