Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The aim of this work is the convergence of distinct automated synthesis approaches into a single programmable and unified technology.
Fig. 2: Mapping of a specific synthesis to a generalized automated laboratory hardware assembly.
Fig. 3: Automated synthesespresented in this work.
Fig. 4: Summary of the available hardware modules.
Fig. 5: Implementation and topology of the synthesis platform.

Data availability

All the data are available in the supplementary volume. This includes full experimental details to build the Chemputer as well as compound characterization.

Code availability

The code to run the hardware for the automated platforms and the scripts to run the reactions are available in the supplementary volume and in the open-source repository (https://github.com/croningp/ChemputerConvergence).

References

  1. 1.

    Peplow, M. Organic synthesis: the robo-chemist. Nature 512, 20–22 (2014).

    CAS  Article  Google Scholar 

  2. 2.

    Davies, I. W. The digitization of organic synthesis. Nature 570, 175–181 (2019).

    CAS  Article  Google Scholar 

  3. 3.

    Merrifield, R. B. Automated synthesis of peptides. Science 150, 178–185 (1965).

    CAS  Article  Google Scholar 

  4. 4.

    Alvarado-Urbina, G. et al. Automated synthesis of gene fragments. Science 214, 270–274 (1981).

    CAS  Article  Google Scholar 

  5. 5.

    Plante, O. J., Palmacci, E. R. & Seeberger, P. H. Automated solid-phase synthesis of oligosaccharides. Science 291, 1523–1527 (2001).

    CAS  Article  Google Scholar 

  6. 6.

    Li, J. et al. Synthesis of many different types of organic small molecules using one automated process. Science 347, 1221–1226 (2015).

    CAS  Article  Google Scholar 

  7. 7.

    Coley, C. W. et al. A robotic platform for flow synthesis of organic compounds informed by AI planning. Science 365, eaax1566 (2019).

    CAS  Article  Google Scholar 

  8. 8.

    Adamo, A. et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 352, 61–67 (2016).

    CAS  Article  Google Scholar 

  9. 9.

    Chatterjee, S., Guidi, M., Seeberger, P. H. & Gilmore, K. Automated radial synthesis of organic molecules. Nature 579, 379–384 (2020).

    CAS  Article  Google Scholar 

  10. 10.

    Steiner, S. et al. Organic synthesis in a modular robotic system driven by a chemical programming language. Science 363, eaav2211 (2019).

    CAS  Article  Google Scholar 

  11. 11.

    Merrifield, R. B., Stewart, J. M. & Jernberg, N. Instrument for automated synthesis of peptides. Anal. Chem. 38, 1905–1914 (1966).

    CAS  Article  Google Scholar 

  12. 12.

    Kates, S. A., Daniels, S. B. & Albericio, F. Automated allyl cleavage for continuous-flow synthesis of cyclic and branched peptides. Anal. Biochem. 212, 303–310 (1993).

    CAS  Article  Google Scholar 

  13. 13.

    Jensen, K. J., Shelton, P. T. & Pedersen, S. L. Peptide Synthesis and Applications (Humana Press, 2013).

  14. 14.

    Zheng, H. et al. An automated Teflon microfluidic peptide synthesizer. Lab Chip 13, 3347 (2013).

    CAS  Article  Google Scholar 

  15. 15.

    Iyer, L. K., Moorthy, B. S. & Topp, E. M. Photolytic cross-linking to probe protein–protein and protein–matrix interactions in lyophilized powders. Mol. Pharm. 12, 3237–3249 (2015).

    CAS  Article  Google Scholar 

  16. 16.

    Cheng, X. et al. Light-triggered assembly of gold nanoparticles for photothermal therapy and photoacoustic imaging of tumors in vivo. Adv. Mater. 29, 1604894 (2017).

    Article  Google Scholar 

  17. 17.

    Matsuguma, H. J. & Audrieth, L. F. The stability of aqueous solutions of hydroxylamine-O-sulphonic acid. J. Inorg. Nucl. Chem. 12, 186–192 (1959).

    CAS  Article  Google Scholar 

  18. 18.

    Mehr, S. H. M., Craven, M., Leonov, A. I., Keenan, G. & Cronin, L. A universal system for digitization and automatic execution of the chemical synthesis literature. Science 370, 101–108 (2020).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank BUCHI for supplying us with an R-300 rotary evaporator and an API to interface it with the Chemputer software package, D. Castro for help with the NHS-diazirine peptide synthesis and purity assessment, H. Mehr for Python advice on the conductivity sensor development and A. Jones for suggesting the diazirine synthesis challenge. We also thank M. Symes, P. Kitson and N. Bell for comments on the manuscript as well as N. A. B. Johnson for her artistic depiction of the Chemputer platform in the TOC graphic. We thank the following funders: EPSRC (Grant Nos. EP/H024107/1, EP/J00135X/1, EP/J015156/1, EP/K021966/1, EP/K023004/1, EP/L023652/1), ERC (project 670467 SMART-POM). This research was developed with funding from the Defense Advanced Research Projects Agency (DARPA). The views, opinions and/or findings expressed are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the US Government.

Author information

Affiliations

Authors

Contributions

L.C. conceived the concept, the selection of the chemistry, the architecture, outline module design, and the programming approach. D.A., A.J.S.H., S.R., S.K., J.M.G. and J.W. helped configure the robots, run the synthetic protocols and characterize the products. The new modules were designed and built by D.A., A.J.S.H., S.R. and S.Z., and the construction manuals were compiled by G.C. L.C. wrote the paper together with D.A., A.J.S.H. and S.R. with help from all the authors.

Corresponding author

Correspondence to Leroy Cronin.

Ethics declarations

Competing interests

L.C. is the founder of DeepMatter Group PLC and Chemify Ltd., which aims to commercialize various aspects of the digitization of chemistry, including discovery and synthesis using universal robotic platforms.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–152, Tables 1–33, building instructions, methods, module test results and discussions.

Supplementary Data

Raw and processed NMR data.

Supplementary Data

STL files for all 3D printed parts.

Supplementary Data

DXF files for all laser cut parts.

Supplementary Data

Circuit schematics and firmware for all custom-made PCBs.

Supplementary Data

Various schematics for different Chemputer modules.

Supplementary Software

Python modules and scripts used to execute the automated syntheses.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Angelone, D., Hammer, A.J.S., Rohrbach, S. et al. Convergence of multiple synthetic paradigms in a universally programmable chemical synthesis machine. Nat. Chem. 13, 63–69 (2021). https://doi.org/10.1038/s41557-020-00596-9

Download citation

Further reading

Search

Quick links