If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.



Automated synthesis system expands its molecular menu

Organic molecule maker can now churn out more complex compounds

by Leigh Krietsch Boerner
February 22, 2022


The automated system for building complex small organic molecules.
Credit: Martin Burke
The automated small molecule maker can churn out more complex compounds on the benchtop.

Flipping a switch to snap complex organic molecules together like legos sounds like the plot from science fiction, but may actually be in reach. Years ago, Martin Burke and coworkers at University of Illinois Urbana-Champaign built an automated molecule maker to make flat carbon-carbon bonds, and now they’ve upgraded their system to make 3D C-C single bonds. Through the strategic use of highly sterically hindered N-methyliminodiacetic acid boronates, Burke and team can direct their machine to make more complex molecules via two different known coupling reactions (Nature, 2022, DOI: 10.1038/s41586-022-04491-w). This system can potentially speed up the synthesis of small molecules for drug discovery and allow chemists without extensive organic synthesis expertise to make and use these essential compounds.

In the past, Burke and team built an automated molecule maker to synthesize flat C-C bonds by forming new C-C single bonds between two molecules that each contain C-C double bonds, which force a flat molecular shape. But the team wanted to link carbons between molecules with single C-C bonds because these molecules aren’t flat. “There are all kinds of interesting things that molecules can do when they become not flat, but rich in three-dimensional structure,” he says. In the last 10 years, chemistry researchers have made tremendous advances in ways to stick C-C bonds together, but that chemistry wasn’t compatible with the boronate compound Burke and team used as the backbone for their previous synthesis, methyliminodiacetic acid, so they needed to look for another approach.

Working with the cancer biotech company Revolution Medicines, which Burke co-founded, the group used the same building-block approach as in their previous work. The boronate group on the carbon fragment blocks unwanted polymerization of the small molecules, and tunes the reactivity through multiple coupling and deprotecting steps. The crucial difference in the new work was tweaking this boronate group to withstand the harsher conditions needed to make these new C-C bonds, but to still detach from the desired compound at the end of the synthesis. The team found what they were looking for in tetramethyl N-methyliminodiacetic acid (TIDA) boronates, hyper-stable variants of the backbone they used in their earlier automation.

The compound is compatible with multiple single bond C–C reactions, including commonly used 1,2-metallation rearrangement reactions and Suzuki-Miyaura coupling. This opens up the possibility of making a lot of different 3D molecules, Burke says.

Making C–C single bonds is a cornerstone of organic chemistry, and there are relatively few ways to automate this, says Jeffrey Bode, an organic chemist at Swiss Federal Institute of Technology in Zürich. “This work is a positive step to the iterative approach to constructing organic molecules,” he says.



This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.