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Nobel Prize

Pioneers of asymmetric organocatalysis win 2021 Nobel Prize in Chemistry

Benjamin List and David W. C. MacMillan take home the prize for revolutionizing chiral organic synthesis with small-molecule catalysts

by Leigh Krietsch Boerner
October 6, 2021


Reaction scheme for L-proline-catalyzed intermolecular aldol reaction
Credit: © Frank Vinken (List); Princeton University, Department of Chemistry, © Todd Reichart (MacMillan)
Benjamin List and David W. C. MacMillan won the 2021 Nobel Prize in Chemistry for pioneering organocatalysis.

The 2021 Nobel Prize in Chemistry has gone to Benjamin List of the Max Planck Institute for Kohlenforschung, and David W. C. MacMillan of Princeton University for the discovery of asymmetric organocatalysis. Asymmetric organocatalysis uses small organic molecules as catalysts instead of traditional catalysts such as enzymes or metals. These molecules are able to catalyze reactions to selectively form one enantiomer of a particular compound—meaning one version of two mirror-image molecules.

Reaction scheme for L-proline-catalyzed intermolecular aldol reaction
In 2000, List and coworkers used L-proline to catalyze an intermolecular aldol reaction.
Reaction scheme for a Diels-Alter reaction catalyzed by a chiral imidazolidinone.
Also in 2000, MacMillan and coworkers showed that showed that a chiral imidazolidinone can catalyze the Diels-Alder reaction between α,β-unsaturated aldehydes and dienes.

Asymmetric organocatalysis is a widely used technique and especially important to the drug discovery process. Biologically active molecules are often chiral, and organocatalysts provide a way to make candidate drug compounds quickly and efficiently.

Using small organic molecules as catalysts is akin to mimicking enzymes, says David Nicewicz, an organocatalytic chemist at the University of North Carolina, Chapel Hill, who worked with MacMillan as a post-doctoral researcher over a decade ago. In this way, the work “really tapped into some of the basic chemistry that could be found in nature,” he says.

"I think [the Nobel committee’s selection] is an excellent choice because in chemistry, as we know, we value the ability to come up with new solutions and new ways of synthesis,” American Chemical Society president H. N. Cheng told C&EN. “Organocatalysis is a great advance and this is a fitting recognition of their contributions."

Credit: C&EN/Darren Weaver/ACS Productions
Hear more about how the winning science has impacted drug development in this special episode of C&EN’s podcast, Stereo Chemistry.

MacMillan’s work in this area started with making amines into iminium ions and using the iminium ions to catalyze a large number of organic reactions, including the initial Diels-Alder reaction. List worked early on with the chiral compound L-proline, and used it to catalyze an intermolecular aldol reaction. Later work included using Brønsted acids as catalysts.

“Dave and Ben were really critical people in bringing this recognition and making breakthroughs that show people the things that could be possible with this area of research,” says Vy M. Dong, an organic chemist at the University of California, Irvine, who completed her PhD with MacMillan at the California Institute of Technology.

Speaking at the Nobel conference Wednesday, List noted that chirality is present throughout nature. He said that by using chiral organic molecules as catalysts, “handedness is transferred in the catalytic reaction onto the substrates so that you get more of these kind of molecules.”

“When we think about medicine, and how your medicines will interact with enzymes and proteins, that fit also involves a sharing of chiral information,” Dong says. “As a result of that, we need access to medicines that are also single enantiomers.”

The 2001 Nobel prize in chemistry was awarded to William S. Knowles, Ryoji Noyori, and K. Barry Sharpless for asymmetric catalysis, which offers enantiomerically selective catalysis using metal catalysts. List’s and MacMillan’s contributions substitute organic molecules for the metal catalysts, making the synthesis cleaner and more environmentally friendly; metal catalysts can be toxic to people or the environment. This advantage is especially important in making medicines, Dong says, because any traces of metals need to be removed from the final drug and the metal-removal process is both expensive and time consuming. “The organic catalysts really provide a way to do that chemistry in a more green, sustainable fashion,” she says.


This story was updated on Oct. 6, 2021, to include comments from List during the Nobel announcement, additional comments from Vy Dong, and more context on List's work.


This story was updated on Oct. 7, 2021, to correct the description of Vy M. Dong. She is an organic chemist, not an organocatalytic chemist.


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