Convergence of multiple synthetic paradigms in a universally programmable chemical synthesis machine

• Published in: Nature chemistry Vol. 13; no. 1; pp. 63 - 69
• Main Authors: Angelone, Davide, Hammer, Alexander J. S., Rohrbach, Simon, Krambeck, Stefanie, Granda, Jarosław M., Wolf, Jakob, Zalesskiy, Sergey, Chisholm, Greig, Cronin, Leroy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2021; Nature Publishing Group
• Subjects: 639/638/403/933; 639/638/549/973; 639/638/898; 639/638/905; Analytical Chemistry; Automation; Biochemistry; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Convergence; Coupling (molecular); Cross coupling; Hardware; Inorganic Chemistry; Organic Chemistry; Peptide synthesis; Peptides; Physical Chemistry; Solid phases
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/s41557-020-00596-9

Although the automatic synthesis of molecules has been established, each reaction class uses bespoke hardware. This means that the connection of multi-step syntheses in a single machine to run many different protocols and reactions is not possible, as manual intervention is required. Here we show how the Chemputer synthesis robot can be programmed to perform many different reactions, including solid-phase peptide synthesis, iterative cross-coupling and accessing reactive, unstable diazirines in a single, unified system with high yields and purity. Developing universal and modular hardware that can be automated using one software system makes a wide variety of batch chemistry accessible. This is shown by our system, which performed around 8,500 operations while reusing only 22 distinct steps in 10 unique modules, with the code able to access 17 different reactions. We also demonstrate a complex convergent robotic synthesis of a peptide reacted with a diazirine—a process requiring 12 synthetic steps.
Automated synthesis technologies are often highly specialized, focusing only on a narrow set of reaction classes. Now, solid-phase peptide synthesis, iterative Suzuki–Miyaura cross-coupling and diazirine chemistry have all been automated using the same universal platform architecture. A convergent 12-step synthesis demonstrates the utility of the reported Chemputer system.