A radial setup helps automated synthesis branch out

Some chemists have moved beyond round-bottom flasks and started developing automated synthesis systems that use flow chemistry to make molecules. These systems usually synthesize compounds in a linear fashion, where all of the steps are happening simultaneously, like an assembly line, explains Kerry Gilmore of the Max Planck Institute of Colloids and Interfaces. “Each time we choose a new target we have to reconfigure the entire system to accommodate that new process.” Although such reconfigurations can be automated with robots, Gilmore says that doesn’t address the fundamental problem.

Now, along with Sourav Chatterjee, Mara Guidi, and Peter H. Seeberger, Gilmore developed a new, radial, automated synthesis setup that can build multiple types of small molecules without having to reconfigure the setup for each compound or when changing reaction conditions. The approach relies on a central switching station that moves reagents to and from satellite reactors (Nature 2020, DOI: 10.1038/s41586-020-2083-5). The design could help speed the development of processes for making medicines and make multitudes of small molecules under standardized conditions.

Gilmore found inspiration to solve the problem of linear setups in touch-screen soda fountains, like the Coca-Cola Freestyle or Pepsi Spire, that make custom mixes of flavors into a single beverage. “It really got me thinking about how you can have one platform and whatever kind of, presumably disgusting, soda combination that you want,” he says. “I started thinking about how we can do that for chemistry.”

The radial setup provides access to many types of reaction conditions on demand. His team used it to prepare the anticonvulsant drug rufinamide via multiple routes and also to make a small library of rufinamide derivatives. What’s more, Gilmore says, “It really opens up the idea of remote accessibility for chemistry because it’s fully automated.” Chemists don’t need to be in the lab to swap in and out different reactors, like in a linear system. “I can log in from anywhere in the world and run my chemistry,” he says. That feature has become particularly relevant as Gilmore shuts down his lab during the COVID-19 pandemic.

“This approach to automated synthesis will be at the core of many platforms in the future,” says Aaron Beeler, an expert in flow chemistry at Boston University. The Max Planck team, he says, “identified many of the limitations that are inherent in traditional linear automated platforms—issues that have plagued automated synthesis for decades,” and then used flow chemistry to develop “a platform that can be truly modular with minimal reconfiguration.”