On the Mechanism of Bifunctional Squaramide‐Catalyzed Organocatalytic Michael Addition: A Protonated Catalyst as an Oxyanion Hole

Kótai, Bianka; Kardos, György; Hamza, Andrea; Farkas, Viktor; Pápai, Imre; Soós, Tibor

doi:10.1002/chem.201304553

Cited by 111 publications

(84 citation statements)

References 57 publications

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“…[38] As already described by Pµpai, [39] coordination of the b-ketoamide to the thiourea part of the Takemoto catalyst is energetically preferred, with a lower energy barrier for this CÀC bond formation of 18.2 kcal mol À1 (DG = 32.6 kcal mol À1 ). First, it should be noted that the CÀC bond-forming step is not thermodynamically favoured because the resulting intermediate lies higher in energy than the ternary complex deprotonated b-ketoamide-protonated catalyst-MVK (DDG = 3.9 kcal mol À1 ).…”

Section: Theoretical Studymentioning

confidence: 90%

Origin of the Enantioselectivity in Organocatalytic Michael Additions of β‐Ketoamides to α,β‐Unsaturated Carbonyls: A Combined Experimental, Spectroscopic and Theoretical Study

Quintard

Cheshmedzhieva

Duque

et al. 2014

Chemistry A European J

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The organocatalytic enantioselective conjugate addition of secondary β-ketoamides to α,β-unsaturated carbonyl compounds is reported. Use of bifunctional Takemoto's thiourea catalyst allows enantiocontrol of the reaction leading either to simple Michael adducts or spirocyclic aminals in up to 99 % ee. The origin of the enantioselectivity has been rationalised based on combined DFT calculations and kinetic analysis. This study provides a deeper understanding of the reaction mechanism, which involves a predominant role of the secondary amide proton, and clarifies the complex interactions occurring between substrates and the catalyst.

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Section: Theoretical Studymentioning

confidence: 90%

Origin of the Enantioselectivity in Organocatalytic Michael Additions of β‐Ketoamides to α,β‐Unsaturated Carbonyls: A Combined Experimental, Spectroscopic and Theoretical Study

Quintard

Cheshmedzhieva

Duque

et al. 2014

Chemistry A European J

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“…Enolization of acetylacetone promoted by the tertiary amine group of the bifunctional catalyst is followed by N-selective addition to nitrosobenzene under basic conditions.T he resulting ketimine is then transformed into the corresponding enoate,a nd the methyleneindolinone is activated by the same catalyst. [20] Subsequent intermolecular Michael addition and the final irreversible cyclization proceed smoothly to afford the enantioenriched product.…”

Section: Angewandte Zuschriftenmentioning

confidence: 99%

Squaramide‐Catalyzed Synthesis of Enantioenriched Spirocyclic Oxindoles via Ketimine Intermediates with Multiple Active Sites

et al. 2015

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An ew method for the construction of five-membered spirocyclic oxindoles is based on aM ichael-Mannich cascade reaction of ak etimine intermediated catalyzedb y abifunctional quinine-derived squaramide.The desired products were obtained in excellent yields (up to 94 %) and stereoselectivities (up to > 20:1 d.r., > 99 %e e). As caled-up variant also proceeded smoothly showing that the one-pot reaction might find application in the synthesis of bioactivecompound libraries.The spirocyclic oxindole architecture is prevalent in both natural products and synthetic bioactive molecules (Figure 1). [1] In particular, enantiopure five-membered spirocyclic oxindoles have attracted tremendous attention owing to their diverse bioactivities and structural complexity.T he key challenge for the construction of such structures lies in the formation of multiple stereocenters,p articularly for those containing two adjacent quaternary centers.T herefore,n ew strategies for the synthesis of such spirocyclic oxindoles [2] with high levels of efficiency and selectivity from readily available starting materials are always in great demand.In the past few years,elegant advances have been made in the development of enantioselective syntheses of five-membered spirocyclic oxindoles.[3] In 2007, Tr ost [4] and co-workers disclosed ap alladium-catalyzed [3+ +2] cycloaddition for the assembly of such compounds.A side from transition-metal catalysis,o rganocatalytic cascade reactions provide an alternative powerful strategy for the preparation of spirocyclic oxindoles.A fter [3+ +2] cycloadditions catalyzed by chiral tertiary phosphines [5] or amines [6] had been reported, hydrogen bond donor catalyzed cascade reactions, [7] MichaelMichael reactions promoted by primary [8] or secondary amines, [9] NHC-catalyzed processes, [10] as well as alkylations mediated by phase transfer catalysts (PTCs) [11] were developed. More recently,s ynergistic catalysis [12] and CÀHb ond oxygenation [13] were also applied to the asymmetric construction of five-membered spirocyclico xindoles.Inspired by our ongoing interest in the development of reactions towards spirocyclico xindoles [14] and previous work on nitrosoarenes, [15] we hypothesized that the addition of b-dicarbonyl compounds to nitrosoarenes followed by aMichael-Mannich sequence in the presence of abifunctional catalyst would be an appropriate strategy to prepare enantioenriched spirocyclico xindoles (Scheme 1d). As an interesting electrophile,n itrosobenzene can react with ketones/ aldehydes to form either the a-aminooxylation [16] or the a-oxyamination products [17] (Scheme 1a). However,very few methods for the addition of b-dicarbonyl compounds [18] to nitrosoarenes to generate a-imino-b-dicarbonyl compounds have been reported thus far,a nd they all suffer from low yields (Scheme 1b). These products are very useful synthons that bear multiple nucleophilic and electrophilic sites.T othe best of our knowledge,t he application of these novel ketimines in asymmetric synthesis has not been repor...

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“…19 This finding may seem surprising, but it actually supports the view formulated recently in our previous work that the application of a single reactivity model might not always be sufficient to describe the mechanism of bifunctional noncovalent organocatalysis. 20 To test the two mechanistic scenarios against experimental data, calculations were carried out for analogous reactions with parasubstituted imines 4b and 4c as well. We find that both C-C bond formation mechanisms account qualitatively for the observed reactivity trend.…”

Section: Inhibition and Complexation Experimentsmentioning

confidence: 99%

Organocatalysts Fold To Generate an Active Site Pocket for the Mannich Reaction

et al. 2017

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Catalysts containing urea, thiourea, and tertiary amine groups fold into a three-dimensional organized structure in solution both in the absence as well as in the presence of substrates or substrate analogues, as indicated by solution NMR and computational studies. These foldamer catalysts promote Mannich reactions with both aliphatic and aromatic imines and malonate esters. Hammett plot and secondary kinetic isotope effects provide evidence for the C–C bond forming event as the turnover-limiting step of the Mannich reaction. Computational studies suggest two viable pathways for the C–C bond formation step, differing in the activation modes of the malonate and imine substrates. The results show that the foldamer catalysts may promote C–C bond formation with an aliphatic substrate bearing a cyclohexyl group by enhanced binding of the substrates by dispersion interactions, but these interactions are largely absent with a simpler catalyst. Additional control experiments demonstrate the ability of simple thiourea catalysts to promote competing side reactions with aliphatic substrates, such as reversible covalent binding of the thiourea sulfur to the imine which deactivates the catalyst, and imine to enamine isomerization reactions. In foldamer catalysts, the nucleophilicity of sulfur is reduced, which prevents catalyst deactivation. The results indicate that the improved catalytic performance of foldamer catalysts in Mannich reactions may not be due to cooperative effects of intramolecular hydrogen bonds but simply due to the presence of the folded structure that provides an active site pocket, accommodating the substrate and at the same time impeding undesirable side reactions.

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On the Mechanism of Bifunctional Squaramide‐Catalyzed Organocatalytic Michael Addition: A Protonated Catalyst as an Oxyanion Hole

Cited by 111 publications

References 57 publications

Origin of the Enantioselectivity in Organocatalytic Michael Additions of β‐Ketoamides to α,β‐Unsaturated Carbonyls: A Combined Experimental, Spectroscopic and Theoretical Study

Origin of the Enantioselectivity in Organocatalytic Michael Additions of β‐Ketoamides to α,β‐Unsaturated Carbonyls: A Combined Experimental, Spectroscopic and Theoretical Study

Squaramide‐Catalyzed Synthesis of Enantioenriched Spirocyclic Oxindoles via Ketimine Intermediates with Multiple Active Sites

Organocatalysts Fold To Generate an Active Site Pocket for the Mannich Reaction

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