Mechanistic Investigations into the Enantioselective Conia-Ene Reaction Catalyzed by Cinchona-Derived Amino Urea Pre-Catalysts and CuI
Dr. Filippo Sladojevich
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)
Search for more papers by this authorÁngel L. Fuentes de Arriba
Organic Chemistry Department, University of Salamanca, Plaza de los Caídos 1-5, Salamanca, 37008 (Spain.)
Search for more papers by this authorDr. Irene Ortín
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)
Search for more papers by this authorDr. Ting Yang
GlaxoSmithKline (China) R&D, Building No. 3, 898 Halei Road Zhangjiang Hi-tech Park, Pudong Shanghai 201203 (China.)
Search for more papers by this authorDr. Alessandro Ferrali
Enantia S.L. C/Baldiri Reixac, 1008028 Barcelona (Spain.)
Search for more papers by this authorCorresponding Author
Dr. Robert S. Paton
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)Search for more papers by this authorCorresponding Author
Prof. Darren J. Dixon
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)Search for more papers by this authorDr. Filippo Sladojevich
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)
Search for more papers by this authorÁngel L. Fuentes de Arriba
Organic Chemistry Department, University of Salamanca, Plaza de los Caídos 1-5, Salamanca, 37008 (Spain.)
Search for more papers by this authorDr. Irene Ortín
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)
Search for more papers by this authorDr. Ting Yang
GlaxoSmithKline (China) R&D, Building No. 3, 898 Halei Road Zhangjiang Hi-tech Park, Pudong Shanghai 201203 (China.)
Search for more papers by this authorDr. Alessandro Ferrali
Enantia S.L. C/Baldiri Reixac, 1008028 Barcelona (Spain.)
Search for more papers by this authorCorresponding Author
Dr. Robert S. Paton
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)Search for more papers by this authorCorresponding Author
Prof. Darren J. Dixon
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.)Search for more papers by this authorGraphical Abstract
Cooperation is key! A detailed mechanistic study on the enantioselective Conia-ene reaction catalyzed by cinchona-derived amino urea pre-catalysts and CuI is reported (see scheme; Tf=trifluoromethanesulfonate). A combination of experimental considerations and quantum mechanical calculations has been carried out to prove the cooperative nature of the system and propose a plausible catalytic cycle.
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.
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