Understanding Chiral Proton Catalysis Using Cinchonium Derivatives in aza-Michael Additions, Auria-Luna, F.; Marqués-López, E.; Gimeno, M. C.; Alegre-Requena, J. V.; Herrera, R. P.; Adv. Synth. Catal. 2025, e202401458, early view. DOI: 10.1002/adsc.202401458.
Abstract. This work presents a detailed mechanistic study of a quininium-catalyzed aza-Michael reaction, providing essential information for advancing chiral proton catalysis (CPC). The use of cinchona derivatives as chiral proton catalysts demonstrates their potential beyond their conventional roles as base-promoted and phase-transfer catalysts. Competitive reaction pathways are explored using density functional theory (DFT), wavefunction theory, and microkinetic simulations. Theoretical analyses are complemented with experimental titration and kinetic techniques to verify the intrinsic details of the reaction. This study reveals an intricate hydrogen bond network formed in the rate- and selectivity-determining step, involving four noncovalently attached components that favor a stronger substrate⋅⋅⋅catalyst interaction in the R transition state. Significantly, this research emphasizes the pivotal role of carboxylate anions as nucleophile-activating bases impacting reaction yield and enantioselectivity. Therefore, this work introduces cinchonium derivatives as new options for CPC and provides a thorough mechanistic analysis significant in expanding this underdeveloped catalytic domain.
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C bond formation reactions. These DESs serve as both organocatalysts and reaction media in the aldol reaction, reducing the need for additional toxic or hazardous chemicals. By employing these DESs, we were able to activate the desired reaction through the condensation of ketones and L-proline via enamine activation. This approach eliminates the requirement for traditional, often environmentally harmful, organic solvents. Notably, diethylene glycol played a crucial role in modulating the reaction performance, including conversion and enantioselectivity. Diethylene glycol is a relatively safer alternative compared to other commonly used solvents or additives with potential environmental and health risks. Moreover, reducing the L-proline content in the DESs led to a slight increase in the enantiomeric excess of the predominant diastereomeric product. This finding suggests the possibility of minimizing the use of L-proline, which can be advantageous from both cost and environmental perspectives.
Herrera-OrganoCatalisis Asimétrica Group 