While working one evening in a laboratory at Scripps Research in San Diego in 1999, Benjamin List was thinking about enzymes, those highly efficient, natural catalysts. Enzymes are more than just amino acids. Often groups of aminos and acids are located directly on their active site.

Amino... acid. What if a simple amino acid possessed catalytic properties comparable to those of a complex enzyme? List recalls a memorable detail from a lecture. In the 1970s, someone had successfully used proline as a catalyst. However, when List himself put this same miniscule natural amino acid into a glass flask, he was uncertain. Is this just a wild idea, or does it have the potential to become something great?

However, it was clear the next morning that it had worked! Together with the American David W. C. MacMillan, who discovered something similar at virtually the same time, List had established another type of catalysis known as organocatalysis. Today, such catalysis simplifies the synthesis of drugs and allows them to be produced in a more efficient and green manner, often making environmentally toxic and expensive metal catalysts no longer necessary. The jury in Stockholm found the work worthy of a Nobel Prize, which was awarded to both List and MacMillan.

What makes List tick as a person? And what is life like after winning a Nobel Prize? The 53-year-old director of the Max-Planck-Institut für Kohlenforschung located in Mülheim, Germany, spoke to Catarina Pietschmann from a high-speed Intercity Express (ICE) train while on his way home from a lecture. The scientist and journalist have known each other since their days together in the lab at Freie Universität Berlin at the beginning of the 1990s, which is why they address each other informally in German.

Ben, how did your life change after receiving the call from Stockholm?

It was quite intense. I had appointments every day until Christmas, mostly with the media. But I don’t want to complain. I like it and I enjoy promoting a little bit of chemistry, too.

Your list of awards is long and, with the Nobel Prize, it now includes the most prestigious award of all. Has this dampened your motivation?

My motivation does not come from the hope of winning awards, but rather from the fact that I love what I do! A few days before the call our team gathered for an international dinner. Everyone brought something from his or her native country. At some point during the evening, I experienced a moment of happiness and thought, “Wow! This is the peak of your professional career. I have the best doctoral candidates I have ever had. We have amazing projects, extremely stimulating collaborations, and exciting publications in the best journals. It has simply been a wonderful, productive period...  And then I was torn away for a while, and my actual work, which I love so much, was put on the back burner.

However, you have a point there. But it’s more about changing gears, not motivation. You ask yourself if you want to continue as before or start something new. All my dreams regarding organocatalysis have now largely come true. For some reactions, we are working with catalytic additives in the range of parts per million. The catalysts are now better than any enzyme or metal complex, and they are being used for technical applications.

Do you have any ideas about your next topic of research?

I am increasingly intrigued by areas that combine basic and applied research. One of the most important tasks facing humanity is reducing carbon dioxide emissions. It would be amazing to be able to remove it directly from the atmosphere. It would also be fascinating to be able to convert CO₂ directly into carbon and oxygen, a reaction that has not been done yet. This is what I am currently thinking about.

It all started with your chemistry studies at Freie Universität Berlin.

Yes, I wanted to be in Berlin. In 1988, the Internet was not yet accessible to everyone. So I called the local directory assistance and asked for the university’s number. The woman on the other end was confused and asked: Which university? And I said, “I have no idea. Just pick one, please.” And that’s how I ended up at Freie Universität, and I’ve never regretted it!

What are your memories of that time?

I loved studying in Dahlem! When I departed from the S-Bahn station in Berlin-Mitte during the gray morning hours and arrived at the Botanical Gardens (Botanischer Garten) station, it was like entering a green oasis. The weather always seemed better in Dahlem. The chemistry department was good. The professors were good, starting with Johann Mulzer, who was later our doctoral adviser. But there were also impressive scientists in the field of inorganic chemistry, for example, Konrad Seppelt, who worked in fluorine chemistry, and Wolf Peter Fehlhammer, who worked in organometallic chemistry.

In addition to now being a professor yourself and giving frequent lectures, you are also an honorary professor at the University of Cologne. What do you apply from your studies to your current work?

When I have a passionate interest in something, it emanates throughout the lecture hall. Johann Mulzer always did a good job of that. Step by step, he used colored chalk to draw reaction mechanisms and synthesis pathways of complex natural substances. Calmly and without hurrying. And he would casually ask questions that some wise guy then answered ...

You did your doctorate in 1997 on the synthesis of the vitamin B12 molecule. At that time, total synthesis was the pinnacle of organic chemistry. How do you see it today?

Of course, one can question whether a doctoral student should spend five years recreating a substance that occurs already in nature. But I still find it appealing because it is the ultimate discipline that demonstrates the greatness and signature of a researcher. The first synthesis of the macrolide antibiotic erythromycin took Robert B. Woodward’s team about 100 steps in 1981. By the time of E. J. Corey, it was only 30 to 40 steps, and over the years it has become fewer and fewer. This shows how much chemical synthesis has improved, and what effect this has had on the elegance, efficiency, and length of syntheses.

You now serve as a doctoral adviser to multiple Ph.D. students. You seem to be the prototype of the modern team leader: approachable, creative, and empathetic at the same time. What did you pick up from your doctoral adviser, and what do you do differently?

Johann Mulzer never coached us too much. I have adopted a bit of his hands-off approach. But I’m always available, and my door is always open. I walk around the laboratory a lot and talk to people. I am aware that there’s a reason it’s called “doctoral father” (Doktorvater) in German. It’s a connection you maintain for life. It is a bit like with relatives. You can get angry with them and not want to talk anymore, but, ultimately, they are still there.

It’s important to me that my students don’t become mere catalysis researchers, but full-fledged chemical synthesis experts. I see to this by doing brainteasers every Wednesday during the seminar, something I learned from Johann Mulzer. I even use the same format as before. Someone partially sketches the synthesis of a natural substance that was recently published, and then the team has to figure out the missing steps. Only I don’t pick out someone to “solve” it. Today, we do things more collaboratively, as team players.

At some point in every doctoral thesis, progress falters. How do you manage to motivate your advisees?

Difficulties are actually something valuable. In the end, everyone learns and improves from them. I’m more worried when someone comes and after fourteen days has already completely thought through their project. They sometimes demotivate themselves. When things get really stuck, we have long talks and I show them different prospects. What will you have achieved if you stay the course? Maybe it will turn into a great paper in Science? You’ve discovered something cool, so maybe you’ll be able to patent it. It’ll be your ticket! Take advantage of the time, and work at full throttle. But in all seriousness, it’s better to work enthusiastically and passionately at the beginning. That’s my motto. Not necessarily this work-life balance that the younger generation has adopted.

It sounds like our parents talking.

Yes! But it’s true. You first have to build something before you can enjoy life. I think it’s smarter to do that early on and become as independent as possible. Otherwise, you’ll have a boss for the rest of your life.

When do you get your best ideas?

It used to be while jogging, which is so boring that you automatically start thinking. However, I’ve never had a problem generating ideas. When I’m not disturbed and don’t have any appointments, which unfortunately rarely happens these days, I sit at my desk on the ninth floor and look out over the Ruhr region through the wide window. There is always a stack of paper next to me and my favorite pencil, which I then use to sketch something. Or I read a publication and think about how it could be done even better, or more elegantly, or in a more revolutionary way.

Research in many areas came to a halt during the Covid-19 pandemic. How did you deal with this at the Max-Planck-Institut für Kohlenforschung?

Since vents in our lab provide good air circulation, we were able to continue working. Of course, in shifts and remotely. We soon started thinking about what we could contribute. We are, after all, trained chemists on the cutting edge of research, which is how we would like to think of ourselves. Like other academic institutions, we produced hand disinfectant using isopropanol, hydrogen peroxide, and a little fragrance, and donated 10,000 liters of it to the city of Mülheim.

But then we remembered that chemistry is capable of so much more. We may often be perceived as environmental polluters who dump plastic in the ocean, but the worst viral pandemic to date, HIV, was banished using small drug molecules. In other words, with the help of chemistry and catalysis.

Today, proline is used as a catalyst in the large-scale production of the HIV drug Darunavir.

Exactly, and using our method! I was inspired by the history of HIV and thought constantly about how important it would be to develop medications against Covid-19 as well. At the time, Remdesivir, which was actually developed by Gilead against Ebola, was very promising. It was approved and could have been a big hit, but the synthesis, which comprises twelve steps, is highly complicated. Gilead estimated that it would take at least a year to produce it in large quantities.

And that’s when the idea hit you...

I thought let’s try to find a quicker way and do something new. Everyone set their work aside and the whole lab worked together. We formed two teams that competed to develop synthesis ideas and discussed them intensively via video conference. Ultimately, they came up with a synthesis pathway that looks great on paper and comprises just three steps. It’s quite powerful, contains only carbon–carbon bond-forming steps, and has no detours via protecting groups and redox reaction. Just the way I like it.

Did it also work in the lab?

It became complicated. Starting with the fact that the sugar ribose, which is a basic material, was sold out everywhere. Apparently, everyone in the world wanted to make Remdesivir. Finally, I bought ribose “for bodybuilders” on Amazon.

Over time, quite a few employees jumped ship and went back to their original research. But a core group stayed the course and figured out the first key step. However, by the time we were actually finished a year later, there were already concerns about the low efficacy of Remdesivir against Covid-19. Then it wasn’t such a hot topic anymore, and the momentum was gone. It was no longer sufficient for publication in Science or Nature. But we still have the best synthesis for it! It’s now published, patented, and we’re in talks with Gilead.

Recent studies show that Remdesivir, if given early enough, can save high-risk patients from having to undergo invasive ventilation.

That would be cool. At any rate, this work has lit a little fire under me to solve real-world problems. I think it’s almost arrogant today to say, “Sorry, climate change, the pandemic, or whatever, isn’t our job. I’d rather work on selenium–phosphorus compounds because they’ve never been done before.” We as chemists can really help solve important problems.

---

The interview was conducted by Catarina Pietschmann. It was originally published in German on February 26, 2022, in the Tagesspiegel newspaper supplement published by Freie Universität Berlin.