Natural product chemistry: an amalgam of logical thinking and art

A “doctor” of people all over the world

My first memorable impressions of chemistry in my second year of high school were my first impressions of science more broadly. I was captivated by how we can logically think about what kind of reaction would happen or why a certain color change would happen. While this is true for physics and math, and I liked those as well, being able to observe actual compounds and changes made chemistry more fascinating to me. That said, at first, I wanted to enter the Faculty of Medicine, aiming to become a doctor. However, I took an organic chemistry class in my freshman year, and this encounter completely changed my mind. The professor explained each reaction methodically, why a certain reaction would occur at a specific position or region within a molecule or why it would not, and what would happen instead. I realized that chemistry could allow us to treat patients at the “micro” scale, without having to do invasive surgeries. I also considered that if I had become a doctor, then I could only help the person in front of me. But if I were to develop drugs, then in a sense, I could help a lot of people all over the world. So, I chose chemistry.

Chemistry as art

Organic chemistry is crucial for drug development, and natural products in particular holds promise for potential applications. Natural product chemistry is the process of isolating a certain compound found in a certain plant or animal and synthesize it with commercially available compounds. To do so, we first need to consider a feasible synthetic route to construct the natural products, and then we conduct experiments to confirm whether our hypothetical synthetic route is as good as we thought it would be. This is the overview of the total synthesis of a natural product. I was fascinated by the process because I felt it was not just academic work but rather a new form of art, and I chose it as my major. In high school science classes, it might seem like everything is already discovered, and there is no more space for creativity in science. But it could not be further from the truth, and natural product chemistry is the perfect example of this.

Faster, stronger, higher – in the lab

Artemisinin is a natural product that was discovered by Tu Youyou in 1972, earning her a Nobel Prize, and has been used to treat malaria since then. In our lab, biomimetic compound, a synthetic compund that mimics the properties and sturctures of a compound already existing naturally, called 6-aza-artemisinin was designed and synthesized, replacing a carbon atom by a nitrogen atom This compound shows promising biological activity against fibrosis and cancers. However, the synthetic route is not suitable for large-scale synthesis. Considering its potential for large-scale pharmaceutical use, further improvements to the current synthetic route are necessary.

Efficiency has a couple of components: yield, time, and amount of waste products. For example, if we start with 100 grams of compounds and manage to synthesize 50 grams of the target compound, that would be roughly a 50% yield. Time is also of importance: even a 100% yield might not be feasible for large-scale synthesis if it takes one week or one month. Making sure that we have as few waste products as possible is important in terms of environmental concerns, and it is also closely regulated by law.

The science and art of synthesis design

The first generation of the compound can be synthesized in four steps, which is relatively short, but the first two steps have low yields. So, my project was to develop a more efficient route. Rather than modifying the original one, I designed a completely new route. Every step of the design process requires logical thinking. First, we consider the three-dimensional structure of each molecule by building ball-and-stick models. Utilizing what we know in theory about how these three-dimensional structures and their positive and negative charges might interact with or hinder each other, we can predict quite well the kind of byproducts we might get. With the recent advances in computer technology, density functional theory (DFT) calculations, a method for computing the electronic density of compounds, have become practical even for experimental chemists, and consequently, we have been making increasing use of them. While this sounds very specific, there is a multitude of possible approaches, as there are various ways to cut and reconnect the bonds between atoms and molecules to get to the same end product. This is the art of synthesis. Moreover, in natural product synthesis, we are aiming to synthesize natural products that are often incredibly complex. So, when we do succeed, we get something beautiful.

Design, experiment, analyze, repeat

Although it all starts with a pen and paper, and we can roughly predict the waste products we might get, the yield and reaction time need empirical testing. So, once we have decided what reactions to try, we will set up the necessary reagents and solvents in the lab. Once the reaction is complete, which may take a couple of hours depending on the reaction, we isolate and purify the products and analyze the result using various techniques. For example, in the case of thin-layer chromatography (TLC), we can see the solvent moving away, revealing compound spots: a single spot means the compound is pure, while multiple sports mean that impurities are present. So, we can check with our own eyes whether the reaction indeed happened or not. Then, using, for example, NMR and mass spectroscopy. NMR spectroscopy gives us information about the protons in the compound, which helps us determine its structure. Mass spectroscopy helps us determine the molecular weight. Then, we integrate and discuss the data we gathered and set up the next plan. During this trial-and-error phase, we also generate new knowledge of organic chemistry, so that is an important aspect as well, in my opinion.

Challenges of the second-generation synthesis

I set out to rectify two problems by the second-generation synthesis of 6-aza-artemisinin. The first problem was the issue of diastereoselectivity. Molecules of the same composition, for example, a certain number of carbon and oxygen atoms, can have very different three-dimensional structures and thus effects. It means that it is not enough to synthesize a molecule of a certain composition. One has to synthesize one particular diastereomer from all the possible diastereomers, molecules that have the same composition, but their structures are neither mirror images nor superimposable. This problem I managed to overcome by imagining various patterns and testing them empirically.

The second problem I have yet to solve. It is the last step of the synthetic route, which means if I succeed in this reaction, my project is successful, and I can publish my results. Right now, I am trying to achieve a biomimetic reaction, a reaction that mimics a reaction already existing in nature. This is because when living organisms create complex compounds from simpler precursor molecules, they usually have high yields and the additional reagent is often air or water, so the likelihood of having environmentally friendly waste products is high. Of course, the challenge is that the reactions are usually very different from what we are used to doing in the lab. So, I am trying to achieve the best of both worlds.

Global Science Course

Photo taken from the laboratory at EPFL during my stay there as an exchange student ©Shogo Iwazaki

Even though I started my master’s degree here in Japan, I originally wanted to enroll in graduate school abroad. As preparation, I also enrolled in the Global Science Course as an undergraduate student. The program aims to facilitate international collaboration and communication, so all lectures are held in English. It has two branches: inbound and outbound students. Inbound students come to study at the University of Tokyo from overseas, while outbound students have to go abroad to gain international experience. Via the program, I got a chance to go to the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland as a visiting student. I joined the lab of Professor Jieping Zhu, one of the giants of natural product chemistry. I was really surprised to see the clear difference between working and not working in Switzerland. For example, researchers belonging to different research teams would often have discussions in groups about chemistry, perhaps about a problem or a paper. In my experience, people in Japan do research alone or only within the same group, and discussions between groups are rare. Another difference was in terms of work-life balance: Swiss researchers would only do research until the end of the official working day, though they would be very engaged throughout, often having discussions even during lunch breaks. Researchers in Japan, on the other hand, would work longer hours but would probably not keep up discussions even during lunch breaks.

Photo of the Matterhorn taken during a weekend trip ©Shogo Iwazaki

I love my research, so I want to combine the best of both worlds. I hope many future students will join the Global Science Course or another program at the School of Science to express their creativity and contribute their ideas to science.

※Year of Interview:2025
Photography:KAIZUKA Junichi
Text:Belta Emese
The interview was edited for brevity and clarity.

IWAZAKI Shogo

first-year master’s student in the Department of Chemistry

Iwazaki is currently a first-year master’s student in the Department of Chemistry, working on the second-generation synthesis of 6-aza-artemisinin. He has received the Takenaka Scholarship and the Faculty of Science Academic Encouragement Award. His hobbies include walking, soft tennis, badminton, and playing the guitar.