The 2021 Nobel Prize in Chemistry was awarded today to Benjamin List, director of the Max Planck Institut for Carbon Research, and David MacMillan, professor of chemistry at Princeton University, "for their development of asymmetric organocatalysis."
Two decades ago, List and MacMillan independently showed that small organic molecules could be used to catalyze many reactions, rather than the large enzymes or metal-containing compounds that had been used up to that point.
List showed that a single amino acid, proline, could substitute for the 350 amino acid enzyme aldolase in catalyzing aldol reactions. And MacMillan developed an organic molecule that could catalyze Diels-Alder reactions, which chemists use to build rings of carbon atoms. The catalyst lacked the metal atoms used in Diels-Alder catalysis previously, which were too unstable to use in industrial settings.
In a prepared statement, American Chemical Society president H.N. Cheng said that "In the big picture, the ability to create new compounds to address human problems is the strength of chemistry. Chemists are like magicians, and with asymmetric organocatalysis, we have a new magic wand for making important drugs."
The Nobel Committee's Peter Somfai did not invoke magic when describing the importance of the findings, but used a chess analogy instead.
Asymmetric organocatalysis, he told reporters, "is like adding a chess player that can move in different ways. It's completely changing the game."
A slightly stunned Benjamin List, who joined the announcement via telephone, told reporters that it was anything but obvious to him just how successful his endeavor would be.
Unaware of MacMillan's related attempts, "I literally felt like I was the only one working on this," he said. "And I thought, maybe it's a stupid idea, or maybe someone has tried it already."
The strength of organocatalysis is its ability to catalyze chirally specific reactions, which is important in biology and this, to the biopharma industry. Many chemical reactions produce mixes of molecules that are mirror images of each other, or, chemically, speaking, enantiomers.
Why chirality, or handedness, is so important remains a mystery. But its importance is obvious in Thalomid (thalidomide, Celgene). Thalomid was once approved for morning sickness – until it turned out that though one enantiomer of the drug does indeed treat morning sickness, the other is a potent teratogen, leading to thousands of children being born missing limbs. Women who take the drug for multiple myeloma must show two negative pregnancy tests and be willing to either use two forms of birth control or abstain from heterosexual sex for the duration of treatment.
Asymmetric organocatalysis is also more sustainable than its alternatives, because it reduces the use of metals, and allows many reactions to proceed in fewer steps and with less waste.
The influenza drug Tamiflu (oseltamivir), for example, can be produced in 5 instead of 12 steps using asymmetric organocatalysis. Strychnine, whose practical uses are limited to rat poisoners and mystery novelists, is a benchmark molecule to test out new synthesis methods because of its complexity. With asymmetric organocatalysis, that efficiency increased a whopping 7000-fold. While metal catalysts are toxic, List said that he had eaten proline, his first catalyst and an amino acid. "People use it as a food additive – I don't know why, because we make it in our own bodies," he said. "But it is completely nontoxic." He described the taste as "slightly sweet... like this discovery."
Somfai said during the press conference that an estimated 35% of global GDP involves chemical catalysis in one form or another, and so such increased efficiency adds up, and will continue to do so as the method is extended.
List predicted that asymmetric organocatalysis will continue to power breakthroughs. "The real revolution... of our discoveries," he said, "is only sort of surfacing now with these extremely reactive organocatalysts that can do stuff that you cannot do with enzymes or even with the most sophisticated metal complexes that people have developed."