Science http://doi.org/3cc (2015)

The idea of automating the synthesis of small complex molecules, while appealing, is certainly a massive task, but it is one that can be made significantly easier with a building-block-based iterative synthesis strategy. In previous research, Martin Burke and co-workers, from the University of Illinois at Urbana–Champaign, developed such a synthesis strategy using N-methyliminodiacetic acid (MIDA)-protected boronic acids. They showed that a molecule featuring a halogen and a MIDA-protected boronate could be used in a Suzuki reaction, with no fear of the protected boronate reacting. Then, a simple hydrolysis could deprotect the product, opening up a new reactive boronic acid site for the next Suzuki reaction.

Burke and co-workers have now used this chemistry to form the basis of an automated synthesis machine. The key to this was to address the issue of intermediate purification. They realized that MIDA-containing compounds showed a high affinity for silica gel with typical polar solvents (for example methanol or ether), but eluted rapidly when tetrahydrofuran (THF) was used. This allowed the purification procedure to be automated — undesired compounds can be washed away before isolating the MIDA-containing product simply by switching the chromatography solvent. The MIDA boronate thus acts as a purification tag and, importantly, because it is also the reactive handle no additional functional group is necessary to automate the purification.

With these results in hand, the group built a machine that could automate the deprotection–coupling–purification sequence and repeat it as many times as needed. It uses computer-controlled syringe pumps to transfer solutions of the required reactants to modules that carry out different tasks. The first deprotects a MIDA-protected boronate with base. This solution is then added to a solution of the next building block in the coupling reaction module. Once the reaction is complete, the mixture is loaded onto a module containing silica gel to remove by-products and excess reagents before the purified product is washed-off with THF, priming it for the next iteration in the synthesis. Multiple natural products and related molecules were made with the machine, including complex macrocyclic and polycyclic molecules.