Sladojevich Filippo, Fuentes de Arriba Ángel L, Ortín Irene, Yang Ting, Ferrali Alessandro, Paton Robert S, Dixon Darren J
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (U.K.).
Chemistry. 2013 Oct 11;19(42):14286-95. doi: 10.1002/chem.201200832. Epub 2013 Sep 5.
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.
金鸡纳碱衍生的氨基脲预催化剂与铜(I)盐的组合可有效催化炔烃连接的β-酮酯的对映选择性科尼亚-烯环化反应。该反应范围广泛,一系列底物能够以高产率和对映选择性高效环化。在此,我们基于实验考量和量子力学计算进行了详细的机理研究。对几个变量,如有机预催化剂的性质和金属离子源进行了深入研究。动力学研究以及动力学同位素效应和氘标记实验被用于进一步深入了解反应机理,并证明催化体系的协同性质。我们的研究表明,该反应的限速步骤涉及β-酮酯的去质子化,并且负责对映体决定步骤的活性物种在氨基脲预催化剂中是单体形式。计算研究提供了对所观察到的立体诱导的定量理解,并确定脲基团的氢键是决定所观察到的对映选择性的关键因素。