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

Nature Chemistry volume 13, pages 63–69 (2021)Cite this article

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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.

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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).

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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.

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Author notes

  1. These authors contributed equally: Davide Angelone, Alexander J. S. Hammer, Simon Rohrbach.

Authors and Affiliations

  1. School of Chemistry, University of Glasgow, University Avenue, Glasgow, UK

    Davide Angelone, Alexander J. S. Hammer, Simon Rohrbach, Stefanie Krambeck, Jarosław M. Granda, Jakob Wolf, Sergey Zalesskiy, Greig Chisholm & Leroy Cronin

Authors
  1. Davide Angelone
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  2. Alexander J. S. Hammer
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  7. Sergey Zalesskiy
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  8. Greig Chisholm
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  9. Leroy Cronin
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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.

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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.

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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.

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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

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