Machine Automates Assembly Of Small Molecules

A new automated machine can synthesize a range of small organic molecules with the push of a button. The synthesizer uses a chemical method that pieces together molecules from modular building blocks. With this technique, the machine synthesized 14 classes of molecules, including some complicated ones with multiple rings.

Organic chemist Martin D. Burke of the University of Illinois, Urbana-Champaign, and coworkers developed the synthetic method and the new machine (Science 2015, DOI: 10.1126/science.aaa5414). The biotech company Revolution Medicines, based in Redwood City, Calif., cofounded by Burke and the venture capital firm Third Rock Ventures, plans to use the technology in drug discovery and is designing a second-generation synthesizer. An automated synthesizer cranking out small molecules, the researchers say, could speed up the search for new medications, research probes, and electronic and solar device components, among other applications.

The work is “a tour de force in chemical synthesis,” comments synthetic chemist Kenichiro Itami of Nagoya University. “The synthesis and purification of small organic molecules has remained hard to automate. Almost all synthetic chemists, including myself, have been dreaming to achieve this because it will offer significant opportunities to rapidly identify functional small molecules.”

Last year, Burke and coworkers devised a modular way to make most of the polyene motifs found in natural products (Nat. Chem. 2014, DOI: 10.1038/nchem.1947; C&EN, May 19, 2014, page 7). The chemists conceptually deconstructed polyenes into component parts. They derivatized each component with methyliminodiacetic acid (MIDA) boronate and then used cycles of Suzuki-Miyaura cross-coupling, a palladium-catalyzed C–C bond-forming reaction, to add each part to a growing synthetic intermediate. During each cycle, they first deprotected the growing synthetic intermediate by removing the MIDA group from the boronate, activating it for coupling. The chemists showed they could synthesize more than 75% of polyene natural product motifs using just 12 building blocks.

In the new study, they discovered that MIDA boronates can also serve as purification tags. This allowed them to develop a “catch and release” system, in which intermediates are immobilized on silica gel after each coupling step, excess reagents and by-products are washed away, and the intermediate is then released for the next step.

They also designed and built a synthesizer to automate the three basic steps required for each synthetic cycle—deprotection, coupling, and purification. To run a synthesis, chemists place prepacked cartridges containing the necessary building blocks into the machine and then press a start button. Burke’s team demonstrated the approach by using it to produce milligram quantities of 14 classes of small molecules. This included complex large-ring and polycyclic compounds, which are made as linear precursors on the machine and then cyclized.

Synthetic chemist Cathleen M. Crudden of Queen’s University in Kingston, Ontario, points out that off-line reactions will still be needed to access some types of small molecules. “But being able to automate the synthesis of even the key cores of small molecules or their subunits is a huge step forward in organic chemistry.”