Chemists, Meet the Synthia Tool

In graduate school, I designed and synthesized over 30 new organic compounds designed to be metal ion chelators. Some of them really worked. The synthesis part of the project was always very interesting since I did not know if the reactions would work. One part of my Ph.D. preliminary exam involved proposing synthetic routes to several particular target compounds. This was really fun for me.

However, I’ve not kept up with the numerous advances in reactions for synthetic organic chemistry. About a month ago, I saw an advertisement for Synthia, a computer-enabled tool for retroplanning of organic synthesis routes. Just enter the desired structure, including stereochemistry, and the tool takes over and connects the dots between the desired product and common starting materials using a library of 65,000 (and growing) organic reactions, which are called “rules” in addition to 10 million known molecules and 350,000 commercially available building blocks to design a synthetic route.

Synthia is the new name that MilliporeSigma calls the business tool it acquired from Grzybowski Scientific Inventions (GSI), which called the program “Chematica.” The tool’s performance is demonstrated in eight examples of high-value compounds.1 In all cases, the retrosynthetic program either reduced steps and bench time while improving yield or enabled the first published synthesis. Synthia runs on a 64-core machine. Good results are available in about 20 minutes.

The press release2 claims: “Virtual synthesis significantly reduces the time between chemical target conception and route evaluation by using a lab’s preferences to filter millions of data points. The tool quickly and efficiently provides optimized routes, providing significant benefit to all researchers, especially those working in medicinal chemistry and drug discovery.”

Clearly, the major value-add for the Synthia tool is helping medicinal chemists synthesize drug targets, including libraries, for populating studies of structure–activity relationships. For these, reducing synthesis time by 50% or so is a major improvement in productivity. However, preparation of analytical standards is another need. For example, forensic chemists need samples of possible drug analogs of fentanyl and cannabis. Proteomics labs might like help in making stable isotope-labeled proteins and peptides. Chemists studying natural products may find it useful to design synthetic routes to compounds proposed from their spectra alone.

Case study 8 is just such a case.1 The problem was to synthesize engelheptanoxide, a natural product isolated from the stems of Englehardia roxburghiana. Its structure has not been confirmed by synthesis. The Synthia tool helped plan a synthetic route using reaction chemistries suitable for the proposed product, which included enantioselective alkylation of a primary alcohol using the Krische protocol, which gave a 65% yield with 93% enatiomeric excess (ee). Similar enatiomeric reactions yielded further synthesis of the remaining two asymmetric centers. Depending on conditions, the overall yield was 30˗45%, with an ee between 72% and 88%, respectively.

Another potential application is synthesizing radiolabeled analytes. Reducing the synthesis time could be very beneficial if the half-life is short.

Interested in meeting the Synthia tool? The program is available as a license. In addition, MiliporeSigma can provide full service staff under contract to run your molecules for you.

References

  1. Klucznik, T.; Mikulak-Klucznik, B. et al. Efficient syntheses of diverse, medically relevant targets planned by computer and executed in the laboratory. Chem Mar 8, 2018, 4, 522–32.
  2. https://www.prnewswire.com/news-releases/milliporesigma-acquires-grzybowski-scientific-inventions-to-expand-chemical-synthesis-offering-300453639.html

Robert L. Stevenson, Ph.D., is Editor Emeritus, American Laboratory/Labcompare; e-mail: [email protected]

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