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Towards Automated Organic Synthesis Chemistry


Figure 1: New automated synthesizer builds complex molecules from modular building blocks. Example of molecule, with a secodaphnane core structure, assembled from three components (purple, red and blue).

A team from the University of Illinois has made a great breakthrough in synthetic chemistry by developing an automated machine (Figure 1) that can synthesize a range of small organic molecules only with the push of a button. Simple building blocks are assembled to form up to 14 classes of molecules, including some complicated ones with multiple rings.

The chemist Martin D. Burke of the University of Illinois and coworkers describe the synthetic method and the new machine in an article published in Science (DOI: 10.1126/science.aaa5414). The biotech company Revolution Medicines, 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. This new tool could speed up the research for new medications, probes and electronic device components.

“The synthesis and purification of small organic molecules are still 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” comments synthetic chemist Kenichiro Itami of Nagoya University.

Last year, Burke and his team developed a modular way to make most of the polyene motifs found in natural products (DOI: 10.1038/nchem.1947). The chemists deconstructed polyenes into component parts. They derivatized each component with methyliminodiacetic acid (MIDA) boronate and used cycles of Suzuki-Miyaura cross-coupling, a palladium-catalyzed C–C bond-forming reaction, to add each part to a synthetic intermediate. During each cycle, they deprotected the growing synthetic intermediate by removing the MIDA group from the boronate, activating it for coupling. They 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 led them to develop a “catch and release” system, in which intermediates are immobilized on silica gel after each coupling, excess reagents and by-products are washed away, and the intermediate is then released for the next step.

The researchers also designed and built a synthesizer to automate the three basic steps (Figure 2) 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.

Figure 2: Each automated synthesis cycle involves deprotection (D), coupling (C), and purification (P) and couples a modular building block—a reagent (red rectangle) derivatized with a halogen (X) and MIDA boronate (line structure)—to a synthetic intermediate or an initial building block (blue rectangle).

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.”