In the morning on October 6, I was still asleep when I received an email from Greg Scholes, Chair of Department of Chemistry at Princeton: David MacMillan wins Nobel Prize. My first reaction was to shout out: “Holy jeez!” and I jumped out of bed immediately. I’ve been in Princeton for 3+ years, and it was the first time that I was so proud of this university. What a joyful surprise, that a Nobel Prize laureate works just at end of the corridor of my own office…!

At the same moment, Dave Macmillan reluctantly woke up: He received messages from Sweden, and thought they were a prank by his students, and went back to sleep. Scholes had to call him continuously! Dave didn’t believe that he won the Nobel Prize until he saw his photo on the New York Times. Event at this moment of extreme excitement, he didn’t lose his mischievous character. He emailed his students: “Despite recent news events I still think it would be fun to keep subgroup at 9am today.”

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I learned Dave MacMillan’s work when I was still an undergrad at National University of Singapore. As soon as I understood it, I believed that it was something worthy of a Nobel Prize. My mom asked: So why hasn’t he got one? I said: Probably because he is still young! Now that Dave won the Nobel Prize, I think that it’s not because I was a “prophet” of some kind :), but because it’s just evident to every chemist that Dave is important.

The work that won Dave this Nobel Prize is called “nonsymmetric organocatalysis”. It has the feature of all the great scientific discovery: That less is more. In fact, it is so simple, that latecomers even don’t realize its existence, because its idea is already a subconscious part of us. Today, chemists live in a “post-MacMillan paradigm”, and a large part of the pharmaceutical industry is based on Dave’s concept of organocatalysis. We can hardly imagine how organic chemistry looked like before.

Once upon a time, “catalysis” and “asymmetric synthesis” were two concepts with very little overlap. A “catalyst” is a substance that accelerates chemical reactions: it allows reactants to form products quickly, but it is not consumed itself. A catalyst participates in the reaction, but exits in its original form. As we say in a Chinese poem: “Passing through the thousands of flowers but not being bothered by a leaf”. Previously, when we talked about catalysis, one thinks of the iron in the synthesis of ammonia, or the platinum that turns wine into vinegar, or strong acids and bases in typical carbonyl reactions. Of course, these catalysis accelerate reactions as expected, but they are messy: They often catalyze the desired reaction as well as undesirable side reactions. We say that they lack “specificity”.

On the other hand, “asymmetric synthesis” is analogous to cooking a delicate cuisine. Many organic molecules have two twin configurations: one that looks like a left hand, and one that looks like a right hand. The “twins” have the same properties in crude experiments, such as measurements of boiling point, melting point, acidity and redox reactivity. But when they enter the biological environment, they have very different “personalities”. The left-hand molecule could be an important drug, but its right-hand twin is a poison. And the reason is simple: just as humans have their hearts on the left-hand side, the microstructure of the biological world is “chiral”, i.e. it distinguishes left from right. Therefore, one of the greatest challenges in the pharmaceutical industry is to fabricate, in laboratory settings, only left-hand molecules (drug) and not right-hand molecules (poison). A very apparent strategy is to learn from the biological world: Want to make left-handed molecules? Just extract left-hand-like reactants from animals and plants!

 

But doing so has an obvious shortcoming: It consumes Nature too much. In the reactions above, if we want a kilogram of the product, we need about half a kilogram of chiral reactants. If the chiral reactant is rare, and the product is highly valued, then many animals and plants will be hurt!

Dave’s idea is simple: He combined “asymmetric synthesis” and “catalysis”. He noticed that catalysis is not just about accelerating reactions. The equally important character of a catalyst is that it enters and exits reactions without consuming itself. Dave thought that it would be great if we used chiral molecules not as reactants, but as catalysts, so that they could just “guide” reactants into their desired positions (left or right), and exit cleanly afterwards. If this can be achieved, then to produce a kilogram of a chiral product, we would theoretically need only a drop of the chiral catalyst, and the reactants (that must be massively consumed) can be simply some achiral oil products. In addition, Dave thought that such magic catalysts can be achieved by the most ordinary elements. The usual catalysts use metals, and especially heavy metals like platinum and palladium. This is because metals have many oxidation states and therefore flexible redox reactions. But if metals have many oxidations states, doesn’t carbon have them too? Organic chemistry is known for its diversity, so why not just use simple organic molecules to achieve the flexible redox needed for catalysis? If everyday elements like carbon, hydrogen, oxygen and nitrogen can achieve asymmetric catalysis, who needs heavy metals? If this can be realized, then still many more animals and plants can be saved!

With the powerful idea of organocatalysis, putting it into practice is straightforward. In the reaction below, Dave’s organocatalysts (“MacMillan’s catalyst”) is nothing unusual, being just a next-door neighbor of phenylalanine in our bodies, but it is extremely versatile, capable of catalyzing many enantioselective (i.e. selecting “left” instead of “right” molecules) reactions from aldol condensation to Diels-Alder.

 

The physicist C. N. Yang describes Paul Dirac in these words: “An agile spirit that generates everything, a unique style that surpasses the ordinary”. I would use the same words to describe Dave’s work in organocatalysis.

The beginning of organic chemistry is when Wohler synthesized urea from ammonium salts, showing that “animal force” is not needed to prepare organic molecules. But peculiarly, 200 years later, people are still obsessed with some kind of “animal force”: we subconsciously believed that only living organisms can effectively synthesize chiral molecules. (To be sure, the cells in our bodies are experts in asymmetric organocatalysis: The ATP synthase in every living cell is a protein that catalyzes.) But Dave showed that we don’t need living things to do asymmetric synthesis. We don’t even need proteins. Sometimes just an amino acid is enough. “Asymmetric organocatalysis” endows industrial reactions (on the scale of kilograms) with a biological precision. Who could have thought of this before?

***

Dave has a confident and exuberant character, and has been a strong leader of the Department of Chemistry. Before Covid, he would invite the whole department to his house for his birthday party. His house is as big as a hotel, and there is a gym, a bar and a billiard table in the basement. (When I went to his house, I thought to myself: “Wow he’s so rich!”) At the same time, Dave is humble and generous. He said that his students are who deserve the Nobel Prize most, and he himself is only their representative to pick up the prize. He would take his students to ski and hiking trips, and he would use his resources to generate more resources for the University and for science. When asked what was the impact for his Nobel Prize, he said: Firstly, my students will work harder. Secondly, the chemistry department will receive more money.

I’m extremely glad to be a colleague of Dave (though in a lab not quite related to his work). I look forward to more achievements of his group!