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Mechanistic Investigations into the Enantioselective Conia‐Ene Reaction Catalyzed by Cinchona‐Derived Amino Urea Pre‐Catalysts and CuI
Authors:Dr Filippo Sladojevich  Ángel L Fuentes de Arriba  Dr Irene Ortín  Dr Ting Yang  Dr Alessandro Ferrali  Dr Robert S Paton  Prof Darren J Dixon
Institution:1. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.);2. Organic Chemistry Department, University of Salamanca, Plaza de los Caídos 1‐5, Salamanca, 37008 (Spain.);3. GlaxoSmithKline (China) R&D, Building No. 3, 898 Halei Road Zhangjiang Hi‐tech Park, Pudong Shanghai 201203 (China.);4. Enantia S.L. C/Baldiri Reixac, 1008028 Barcelona (Spain.)
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.
Keywords:asymmetric catalysis  cinchona alkaloids  Conia‐ene reaction  quantum mechanical calculations  reaction mechanism
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