Tetrodotoxin (TTX), a natural poison spewed by puffer fish and sea snails, has potential as a powerful painkiller, but it can be tricky to make in the lab. Myriad ways to synthesize TTX exist, but they tend to be long, dangerous, and difficult to scale up. Seeking a more concise method, Dirk Trauner of the University of Pennsylvania and an international team of chemists developed a new path to TTX that takes 22 steps and has an 11% overall yield—shorter and significantly more efficient than previous methods, which take 25–67 steps with overall yields of less than 1% (Science 2022, DOI: 10.1126/science.abn0571). Cutting down the synthesis time, and thus the potential exposure of chemists to the poison, makes the process easier and safer. TTX cannot be made biosynthetically in a lab, so having a concise synthesis is important, Trauner says. The researchers start with a commercially available glucose derivative and do several parts of the synthesis in a single reaction flask. Some of the chemistry needed for the transformation is “pretty sophisticated,” Trauner says, including oxidative hydroxy lactonization, a method the group invented that converts a hydroxy alkyne to a hydroxyl lactone using a ruthenium catalyst. The reactions are versatile and could allow chemists to make TTX derivatives that are less toxic but still act as painkillers.