title: Mechanistic investigations into the enantioselective Conia-ene reaction catalyzed by cinchona-derived amino urea pre-catalysts and Cu(I).
abstract: The enantioselective Conia-ene cyclization of alkyne-tethered β-ketoesters is efficiently catalyzed by the combination of cinchona-derived amino-urea pre-catalysts and copper(I) salts. The reaction scope is broad and a series of substrates can be efficiently cyclized with high yields and enantioselectivities. Herein, we present a detailed mechanistic study based on experimental considerations and quantum mechanical calculations. Several variables, such as the nature of the organic pre-catalyst and the metal-ion source, have been thoroughly investigated. Kinetic studies, as well as kinetic isotope effects and deuterium labeling experiments have been used to gain further insights into the mechanism and prove the cooperative nature of the catalytic system. Our studies suggest that the rate-limiting step for the reaction involves the β-ketoester deprotonation and that the active species responsible for the enantiodeterming step is monomeric in amino-urea pre-catalyst. Computational studies provide a quantitative understanding of the observed stereoinduction and identify hydrogen bonding from the urea group as a crucial factor in determining the observed enantioselectivity.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.).
authors.forename: Filippo
authors.initials: F
authors.lastname: Sladojevich
authors.forename: Ángel L
authors.initials: ÁL
authors.lastname: Fuentes de Arriba
authors.forename: Irene
authors.initials: I
authors.lastname: Ortín
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ferrali
authors.forename: Robert S
authors.initials: RS
authors.lastname: Paton
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Dixon
mesh_terms: D002384:Catalysis; D002929:Cinchona / Q000737:chemistry*; D002930:Cinchona Alkaloids / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D003500:Cyclization; D015394:Molecular Structure; D011789:Quantum Theory; D013237:Stereoisomerism; D014508:Urea / Q000737:chemistry*
chemical_list: D002930:Cinchona Alkaloids; D003300:Copper; D014508:Urea
keywords: Conia-ene reaction; asymmetric catalysis; cinchona alkaloids; quantum mechanical calculations; reaction mechanism