Chiral imidazolidinone organocatalysts (developed by Professor David MacMillan in 2000) are small, bench-stable, and environmentally friendly organic molecules designed to be highly effective at enantiofacial discrimination (in lieu of big enzymes and metal catalysts) under a facile aerobic atmosphere.

Excellent yields were reported by MacMillan et al. with a benzyl-substituted imidazolidinone catalyst in a first ever enantioselective Diels-Alder reaction. Upon condensation of the imidazolidinone and an α,β-unsaturated aldehyde, an iminium ion intermediate with a lowered energy of the Lowest Unoccupied Molecular Orbital (LUMO) was formed that enhanced reactivity towards a Diels-Alder diene compared to the uncatalyzed reaction.  This LUMO lowering strategy has also been applied in 1,3-dipolar cycloadditions,[1] Friedel-Crafts reactions,[2] Michael additions,[3] domino reactions,[4] and other transformations. [5]

Twenty-one years later, MacMillan[6] and Benjamin List[7] were awarded with the 2021 Nobel Prize in Chemistry for their independent discovery of iminium and enamine ion-mediated organocatalysis (respectively).

• Reagents: Benzyl-Substituted Imidazolidinone Catalyst [(5S)-2,2,3-Trimethyl-5-Phenylmethyl-4-Imidazolidinone Monohydrochloride], Methanol, Water
• Reactant: Diene (e.g. Cyclopentadiene), α,β-Unsaturated Aldehyde (e.g. Cinnamaldehyde)
• Product: Exo 93% ee
• Type of Reaction: (Chiral Amine-Catalyzed) Diels-Alder
• Bond Formation: C-C bond

Original Paper

• Ahrendt, K. A., Borths, C. J., MacMillan, D. W. C. New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction. Am. Chem. Soc. 2000, 122(17), 4243-4244.

 Top Citations

• The Advent and Development of Organocatalysis. Nature2008, 455, 304–308.

• Enantioselective Organocatalytic Cyclopropanations. The Identification of a New Class of Iminium Catalyst Based Upon Directed Electrostatic Activation. Am. Chem. Soc. 2005, 127(10), 3240-3241.

• A Click Strategy for the Immobilization of MacMillan Organocatalysts onto Polymers and Magnetic Nanoparticles. Lett. 2012, 14(14), 3668-3671.

Related Reactions

• 1,3-Dipolar Cycloaddition
• Friedel-Crafts Alkylation
• Michael Addition
• α-Fluorination
• Domino Reaction

 Related Compounds

• Methanol
• α,β-Unsaturated Aldehydes

[1] Jen, W. S., Wiener, J. J. M., MacMillan, D. W. C. New Strategies for Organic Catalysis: The First Enantioselective Organocatalytic 1,3-Dipolar Cycloaddition. J. Am. Chem. Soc. 2000, 122 (40): 9874-9875.

[2] Paras, N. A., MacMillan, D. W. C. New Strategies in Organic Catalysis: The First Enantioselective Organocatalytic Friedel−Crafts Alkylation. J. Am. Chem. Soc. 2001, 123 (18): 4370-4371.

[3] Paras, N. A., MacMillan, D. W. C. The Enantioselective Organocatalytic 1,4-Addition of Electron-Rich Benzenes to α,β-Unsaturated Aldehydes. J. Am. Chem. Soc. 2002, 124 (27): 7894-7895.

[4] Brown, S. P., Goodwin, N. C., MacMillan, D. W. C. The First Enantioselective Organocatalytic Mukaiyama−Michael Reaction: A Direct Method for the Synthesis of Enantioenriched γButenolide Architecture. J. Am. Chem. Soc. 2003, 125 (5): 1192-1194.

[5] Lelais, G., MacMillan, D. W. C. Modern Strategies in Organic Catalysis: The Advent and Development of Iminium Activation. Aldrichim. Acta 2006, 39: 79-87.

[6] Ahrendt, K. A., Borths, C. J., MacMillan, D. W. C. New strategies for organic catalysis: The first highly enantioselective organocatalytic Diels-Alder reaction. J. Am. Chem. Soc. 2000, 122 (17): 4243-4244.

[7] List, B., Lerner, R. A., Barbas, C. F. Proline-catalyzed direct asymmetric aldol reactions. J. Am. Chem. Soc. 2000, 122 (10): 2395-2396.