Natural Product Chemistry: Confronting and Competing with Nature

"Natural products" are the various organic compounds that exist in nature. We select compounds with interesting chemical structures from this group and conduct research to synthesize them artificially. Furthermore, we extract natural products that cause interesting biological phenomena, determine their molecular structures, and investigate the mechanisms by which their functions are expressed. The natural world is full of mysterious phenomena and elaborate tricks beyond our imagination. By synthesizing compounds with complex, challenging structures with our own hands and minds, and by elucidating unexplained biological phenomena at the molecular level, we can discover new compounds, new properties of compounds, and new organic chemical reactions.

The natural product methyl sarcophytoate, obtained from coral, has a peculiar structure formed by the fusion of two cembranoids. In fact, the two precursor cembranoids are also extracted from the same coral. It appeared that they were combined via an organic chemical reaction known as the Diels-Alder reaction. When we tested this, we successfully obtained methyl sarcophytoate with the correct three-dimensional structure (the red part in the figure below), just as predicted. Of course, we also synthesized the two cembranoids from commercially available chemicals, leveraging our researchers' ingenuity. The mystery of the coral's biosynthesis was solved through chemistry just as our researchers had conceived, and this synthetic research also led to the discovery of a new organic chemical reaction.

The next complex natural product is another challenge from nature. Kendomycin is an ansa-type compound, fascinating not only for its chemical structure but also for its biological activity. Ansa-type compounds are molecules where a long carbon chain extends from an aromatic core (the red part in the figure below) and loops back to form a ring. The cyclization step is where a researcher's skill truly shines. This compound is produced by a species of actinomycete, which is thought to extend a carbon chain from the aromatic core and then form the ring at an opportune point. We decided to compete with the bacterium's synthetic route. We successfully synthesized kendomycin using a new method: by attaching an alkyne to one end of a long carbon chain and a carbene complex to the other, and then applying heat, we formed the aromatic core and simultaneously created the ring through a reaction known as the Dötz reaction. Although this artificial synthesis cannot match the bacterium in terms of time, cost, or the number of steps, it is a groundbreaking method because it enables the synthesis of a wide variety of ansa-type compounds that the bacterium cannot produce.

Now, let's discuss the elucidation of a biological phenomenon. It was long believed that hippopotamuses secrete a red sweat that protects their skin from ultraviolet rays and bacteria. Through painstaking effort, we extracted the red pigment from this sweat and became the first in the world to determine its molecular structure. We then demonstrated that this pigment possesses antibacterial properties and UV-absorbing capabilities, thereby chemically proving the function of the red sweat. The pigments consist of a red dicarboxylic acid and an orange monocarboxylic acid. In the course of our synthetic research, we discovered that oxidizing a single precursor produces both the red and orange pigments. The ratio of the two pigments produced depends on the oxidation conditions. The pigment ratio in a hippo's sweat changes when it is hot, startled, or angry. What governs this is not mere caprice, but rather a condition-dependent chemical reaction.

Finally, we discuss the elucidation of the toxic component of the deadly poisonous mushroom *Russula subnigricans*, which can be fatal even if only a few are consumed. Because many subspecies of this mushroom exist, it was unclear which was the true *Russula subnigricans*. We collected three candidate mushroom species and examined their components. With keen insight, a researcher noticed a mysterious component in one species that vanished when concentrated to dryness. This was the identity of the difficult-to-handle toxin: cyclopropene carboxylic acid, a volatile substance that polymerizes upon concentration. We also discovered that rhabdomyolysis, the characteristic symptom of poisoning by this mushroom, is caused by this low-molecular-weight carboxylic acid. This was the first step toward elucidating the mechanism of the poisoning.

As this shows, research aimed at synthesizing complex natural products with new methods or extracting the unknown compounds that govern mysterious biological phenomena involves great hardship. However, guided by our motto, "Research must be interesting," everyone in our lab is enthusiastically dedicated to their research day and night.