Creating Organic Compounds Using Both Low-Tech and High-Tech Methods

Participant Profile

Noritaka Chida

Noritaka Chida

Noritaka Chida (Professor, Department of Applied Chemistry)

Excluding bones and water, the human body is mostly composed of organic compounds. Life activities are also carried out through the interactions and reactions of organic compounds. Organic chemistry, the study of organic compounds, is a crucial and fundamental field for an essential understanding of humans and the planet, including life phenomena and environmental issues.

Familiar organic compounds that immediately come to mind include food, clothing, and plastics. When we catch a cold, we may also rely on "medicines" such as antipyretics and antibiotics. There are also dangerous organic compounds like aconite poison and pufferfish toxin. Compounds that exhibit medicinal or toxic effects are called "bioactive substances" and are candidates for "medicines." Many of them have complex chemical structures. Many of these compounds are obtained from natural sources (such as plants, animals, and microorganisms in soil and the sea), but often only in very small quantities. Therefore, to develop them as "medicines," it is necessary to synthesize them artificially (chemical synthesis), which includes obtaining derivatives with structures partially different from the natural compounds. The Molecular Organic Chemistry laboratory in the Department of Applied Chemistry is conducting research with one of its main themes being how to create bioactive substances that exhibit strong biological activity and have complex structures.

The chemical synthesis of bioactive substances proceeds with a seamless integration of "low-tech" and "high-tech" methods. First, we consider the pathway (synthetic route) to create the compound. This involves paper and pencil (or chalk and a blackboard), and molecular models. We contemplate what starting materials to use, what chemical reactions to employ, which carbon atoms to bond, and at what timing to introduce other elements (such as oxygen, nitrogen, sulfur, and halogens). We also have to consider the stereocontrol of asymmetric carbons. This intellectual work at the desk is a low-tech part that has remained completely unchanged for a long time. However, recently, it has become possible to search various databases and academic journals in the library from terminals in the lab, making literature searches dramatically more convenient in the last few years. This is thanks to high-tech. In any case, the ideas generated here are where a researcher's skill (and intellect) truly shines. It is important to refine these ideas through discussions with faculty and colleagues to devise an original and efficient synthetic route (Image 1).

Now, it's time to finally attempt the synthetic route I have envisioned. This manufacturing stage is low-tech. I assemble the reaction apparatus myself, put the starting materials and reagents into a flask, stir, and either heat or cool it (Image 2). I check the reaction with thin-layer chromatography (Image 3), and if the product is observed, I stop the reaction and perform a work-up using a separatory funnel... The reaction procedures for the Negishi coupling and the Suzuki coupling, which were awarded the Nobel Prize in 2010, are the same. Only the types of reagents used are different. The operations and work here have probably remained almost unchanged for over 50 years (Image 4). While automation of reactions is advancing in chemical plants that mass-produce the same compound, in a university laboratory, we attempt a wide variety of reactions under different conditions each time, so there is little merit in mechanization. Since the reaction process is not high-tech, the experimenter's skill and technique become more important here. To successfully advance the reaction, keen "observational skills" and skilled "craftsmanship" are required for things like color changes during the reaction, temperature control, the order of adding reagents, timing, and speed.

The stage of purifying the compound becomes a bit more high-tech. Using high-performance liquid chromatography, which combines a high-performance liquid delivery pump and a column with high separation capability, compounds can be purified in a short time (Image 5).

Now, does the resulting compound have the expected structure? This structure determination part is high-tech. There have been innovative advancements in the last 30 years or so. With a nuclear magnetic resonance spectrum of a very small sample (about 1 mg), we can understand the bonding of hydrogen and carbon atoms and the three-dimensional structure (Image 6). Also, by measuring the mass spectrum, we can determine the molecular weight of the compound. If the desired compound is successfully obtained, we use it as a starting material to attempt the next reaction. By performing this operation continuously over multiple steps (some compounds may require 50 or more steps), if all steps proceed well, the target compound can be synthesized. Of course, not all steps proceed as planned. In fact, cases where things do not go well (the reaction does not proceed, the compound decomposes, etc.) are more common, and in such cases, a re-examination of the synthetic route is necessary. Sometimes, a reaction different from what was expected may occur. However, you shouldn't be disappointed if the structure is different from the target compound! In a way, such times are an opportunity. You might be able to discover a new, unknown chemical reaction. We determine the structure of the obtained compound and consider why such a chemical reaction proceeded. Paper, pencil, and molecular models—the low-tech trio makes a comeback. Recently, we have been able to get help from high-tech methods like molecular orbital calculations and molecular mechanics calculations using computers (Image 7).

Figure 1 shows bioactive natural products recently chemically synthesized in our laboratory by making full use of these low-tech and high-tech processes, as well as brainpower and physical strength (?). All of these compounds are "lead compounds" that may become "medicines." The moment the final target compound is synthesized in your own flask according to your own ideas, you can experience a sense of accomplishment and satisfaction that only someone who has done organic synthesis can understand.

Now, does the synthesized compound have the expected biological activity? Let's conduct a biological activity test. You may have just created a compound with your own hands that could become a "medicine" to save human lives in the future.