Enantioselective Organocatalyzed Michael Addition of Isobutyraldehyde to Maleimides in Aqueous Media

Jae Ho Shim, Seok Hyun Cheun, Hyeon Soo Kim, Deok Chan Ha

Research output: Contribution to journalArticlepeer-review


Thiourea was introduced into (R,R)-1,2-diphenylethylenediamine as an organocatalyst to promote the reaction between isobutyraldehydes and maleimides. Enantioselective Michael addition reaction was carried out as an eco-friendly method using water as the solvent. As a result of the reaction between isobutyraldehyde and maleimide, ≥97% yield and 99% enantioselectivity were obtained at a low catalyst loading of 0.01 mol%. The solvent effect can be explained by theoretical calculations that indicate the participation of a transition state, in which the CF3 substituent of the catalyst is a hydrogen bond activated by the surrounding water molecules. This discovery enabled the use of low catalyst loading in the organic reactions of chiral substances for pharmaceutical applications. Furthermore, a solvent effect for Michael reaction of the organocatalysts was proposed, and the organic reaction mechanisms were determined through quantum calculations.

Original languageEnglish
Article number2759
Issue number9
Publication statusPublished - 2022 May 1

Bibliographical note

Funding Information:
Funding: This study was supported by the National Research Foundation (NRF) and funded by the Korean government (MSIT) (2021R1A6A3A01087948); by the Bio & Medical Technology Development Program of the NRF and funded by the Korean government (MSIT) (2021M3A9G1097744); and by a Korea University grant.

Publisher Copyright:
© 2022, MDPI. All rights reserved.


  • Aldehydes
  • Enantioselectivity
  • Michael addition
  • Organocatalyst
  • Spironolactone
  • Succinimides

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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