Chemists test computer-planned syntheses for the first time

Two synthetic routes to an ATR kinase inhibitor, one generated by humans and one by the computer program Chematica.

Planning efficient synthetic routes can seem like a dark art or feel like a Herculean labor of literature review. Chemists, for the first time, have tested a computer program’s ability to plan complete syntheses without human help, following the proposed routes in the lab (Chem 2018, DOI: 10.1016/j.chempr.2018.02.002).

The idea of a computer planning chemical syntheses isn’t new. Elias J. Corey of Harvard University developed the first version of such a program, called Logic and Heuristics Applied to Synthetic Analysis, in the 1970s, but it never lived up to its promise. Chematica is one of several new contenders that have popped up in the last couple of years. Bartosz Grzybowski at Ulsan National Institute of Science & Technology worked on the program for 15 years before selling it to MilliporeSigma in May 2017.

Grzybowski and his colleagues have programmed Chematica to follow about 50,000 rules of synthesis. On the basis of reactions published in the chemical literature, each rule tells the program what transformations are possible from any given molecule. Chematica’s algorithms navigate this network of options to generate synthetic routes to identified targets, looking for novel, efficient, and selective paths.

To demonstrate Chematica’s skill at synthesis planning, Grzybowski and his collaborators plugged eight targets into the program. MilliporeSigma had chosen six of the targets, all commercially viable molecules with pharmaceutical potential. Grzybowski’s group had picked the seventh, a molecule with several patented syntheses, and coauthor of the new paper Milan Mrksich of Northwestern University had chosen the eighth, a natural product without a published synthesis.

Chematica took about 15 to 20 minutes to plan each synthetic route. It suggested reaction conditions, which the chemists were allowed to adjust to optimize the syntheses. MilliporeSigma chemists carried out four of the syntheses. Graduate students and postdocs in Grzybowski’s and Mrksich’s labs performed the other four as part of a U.S. Department of Defense grant through the Defense Advanced Research Projects Agency to explore whether non-expert chemists could use programs like Chematica to synthesize chemicals.

The chemists successfully followed the program’s planned route to all eight targets. For the first seven targets, the Chematica route improved the yield or reduced the number of steps, total time, or cost compared with published routes. For the eighth, the chemists performed the first published synthesis of the natural product.

“These encouraging results should serve as a spark for another advancement in organic synthesis,” says K. C. Nicolaou, a synthetic chemist at Rice University, adding that Chematica could increase productivity in chemistry labs by eliminating the drudgery of planning syntheses of some molecules.

But other chemists question how much benefit Chematica could provide researchers. Several of the routes identified in the new paper represented only modest improvements in yield, or none at all. The group reports that the Chematica route to an ATR kinase inhibitor had a 22% yield, while the original paper reported 24% yield. The program was able to shorten the synthesis from seven steps to four and saved almost 20 hours compared with the published route.

John Maxwell, vice president of chemistry at Tango Therapeutics, says the paper’s comparisons don’t prove that Chematica plans better routes than human chemists. The chemists whose routes act as benchmarks, he points out, weren’t necessarily optimizing their syntheses for yield or length.

Some chemists wonder how Chematica and MilliporeSigma will handle intellectual property. Richmond Sarpong, a synthetic chemist at the University of California, Berkeley, says researchers may hesitate to use Chematica unless MilliporeSigma is clear about what access the company will have to the molecules that users input or who will own the intellectual property of the routes Chematica generates. Sarah Trice, head of commercial development for cheminformatics technologies at MilliporeSigma, says that molecule searches can be seen only by the user who performs them and that MilliporeSigma will not control the intellectual property on the synthetic paths Chematica proposes.

While Chematica may help chemists save time and money in synthesizing targets, Grzybowski says it won’t replace human ingenuity. “This doesn’t in any way take away from the discovery of new reactions,” he says.

MilliporeSigma has not announced when or how Chematica will become publicly available, but the company has been recruiting top synthetic chemists to test the program.


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