Origin of Stereoselectivity in Cooperative Asymmetric Catalysis Involving N-Heterocyclic Carbenes and Lewis Acids toward the Synthesis of Spirooxindole Lactone

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• 作者：Yernaidu Reddi ; Raghavan B. Sunoj
• 刊名：ACS Catalysis
• 出版年：2017
• 出版时间：January 6, 2017
• 年：2017
• 卷：7
• 期：1
• 页码：530-537
• 全文大小：571K
• ISSN：2155-5435

文摘

An increasing number of examples are now being reported that use chiral N-heterocyclic carbenes (NHCs) in conjunction with Lewis acids to enhance catalytic potential. Herein, we provide molecular insights into an NHC-catalyzed stereoselective annulation reaction between N-methylisatin and an enal leading to spirooxindole lactone in the presence of LiCl as the Lewis acid. Mechanistic features as well as the origin of enantio- and diastereoselectivities of the catalytic reaction have been unraveled using the density functional theory (B3LYP-D3) method. The key mechanistic steps of the reaction are identified to proceed through the formation of a Breslow intermediate between the chiral NHC catalyst and the enal, an enantioselective addition of the re face of this intermediate to the re face of the carbonyl group of N-methylisatin, and an intramolecular proton transfer and lactonization that eventually provide access to (2S,3R)-spirooxindole lactone as the final product. In the most preferred pathway, the Lewis acid is bound to the carbonyl group of the substrate in the form of LiCl(THF). We note that both DBU and LiCl(THF) employed in the reaction play crucial roles respectively in the formation of the initial Breslow intermediate (between the enal and NHC) and in the stereocontrolling C–C bond formation as well as in an ensuing intramolecular proton transfer. The explicit participation of LiCl(THF) is found to lower the activation barriers by 6.4 and 8 kcal/mol, respectively, for the stereoselective C–C bond formation and an ensuing intramolecular proton transfer, in comparison to the pathway devoid of the Lewis acid. The predicted enantio- and diastereoselectivities using the LiCl(THF)-bound transition state models have been in good agreement with the experimental observations. A number of weak interactions such as C–H···O, C–H···π, Cl···π, and lone pair···π have been identified as playing a vital role in offering additional stabilization to the transition state that corresponds to the major stereoisomer of the spirocyclic product.