Chemists in Switzerland have developed a standardized console for the automated synthesis of complex organic molecules.1 This instrument uses prepackaged capsules and requires minimal user involvement. At the push of a button, drug-like compounds are established and cleaned.
The automation of chemical synthesis has long been a goal in the scientific community, and with increasing technological capabilities, the field has made tremendous advances in recent years. Traditionally, automated reaction systems perform simple iterative reactions to produce chain-like molecules such as peptides, DNA, and oligomers. With the expansion of the possibilities for automated synthesis, many scientists have turned their attention to the production of more specialized target molecules. Humans usually make these molecules in the laboratory, which requires time, technical expertise, and a variety of scientific equipment, among other things. While automated systems invariably save time, most current methods still require significant manual input (programming, setup, and cleaning) and non-standard equipment (glassware, stir plates, and heaters).
To master these challenges, Jeffrey Bode’s team at the Swiss Federal Institute of Technology at ETH Zurich and the industrial employees at Synple Chem AG have developed a capsule-based system with a standardized structure. The instrument has simple glass or Teflon containers, rotary valves, syringe pumps, stirring and heating elements, an RFID scanner and a touch screen, all of which are neatly packaged in the console. Reactants and cleaning media are pre-packaged in polyethylene capsules that can be easily loaded onto the console. Then, on the instruction of a short script, the instrument controls the flow of the reaction medium to carry out a series of chemical manipulations in each of the cartridges. The net result is a safe and reproducible response system that requires limited technical knowledge and input from the user. ‘[It’s] like a coffee machine on a capsule basis – only for chemical reactions, ”says Bode. “Of course we can make coffee with a stove, kettle, filter, filter paper, etc., but it is easier and more reproducible to use prepackaged capsules that only require us to press a button.”
In 2013, Bode’s group invented the Stannylamine Protocol (SnAP).2 SnAP chemistry uses a copper catalyst to make saturated N.-Heterocycles from stannylamine and aldehyde precursors. The methodology has since been adopted industrially, but has some drawbacks that inspired the group to automate chemistry. ‘[The] The reaction was labor intensive and there were some problems with the delivery of the copper reagents. We wanted to make our chemistry simple and completely reproducible, ”says Bode. Here they translated the SnAP protocol into their capsule-based setup, where the user only has to select an aldehyde feedstock and weigh it – the instrument then does the rest of the work. It loads the aldehyde onto a functionalized resin in the first capsule to create the reactive SnAP precursor. Next, it is fed into a cartridge in which a copper catalyst completes the cyclization reaction; The active copper catalyst complex is generated in situ at this stage, which overcomes previous problems with the copper reagents. Finally, the third and fourth prepackaged cartridges perform processing and purification steps to deliver the desired heterocycle with high purity. The group also performed a number of widely used reductive amination reactions using a slightly modified set-up.
With just a few simple steps, the researchers carried out sequential cyclization and amination reactions and demonstrated the potential of their new system for the production of complex organic molecules. “This is a nice piece of work that simplifies the handling of some materials for an automated basic chemistry,” says Lee Cronin of the University of Glasgow, UK, an expert in automated chemical synthesis. ‘Although the system itself does not seem modular yet, it is easy to imagine that multiple systems could be linked together to expand the architecture. Likewise, [it has] a true synthesis standard using a code-to-chemistry generator, [which] enables the reaction to be mapped onto the reactor architecture. This should be the next big step. ‘
Bode realizes that the new instrument “cannot do everything … but can do a few things well and completely freehand”. The group is actively developing the console to expand the type of response it can perform. Ultimately, they believe the tool will accelerate the synthesis of compound libraries for drug discovery. ‘We posit that a handful of good assembly reactions and a few hundred common building blocks can be put together into millions of molecules. [which] will play a major role in the full automation and democratization of drug discovery. ‘