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Universal chemical programming language for robotic synthesis repeatability

Nature Synthesis volume 3, pages 488–496 (2024)Cite this article

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Abstract

The amount of chemical synthesis literature is growing quickly; however, it takes a long time to share and evaluate new processes among laboratories. Here we present an approach that uses a universal chemical programming language (χDL) to encode and execute synthesis procedures for a variety of chemical reactions, including reductive amination, ring formation, esterification, carbon–carbon bond formation and amide coupling on four different hardware systems in two laboratories. With around 50 lines of code per reaction, our approach uses abstraction to efficiently compress chemical protocols. Our different robotic platforms consistently produce the expected synthesis with yields up to 90% per step, allowing faster and more secure research workflows that can increase the throughput of a process by number-up instead of scale-up. Chemputer-type platforms at the University of Glasgow and the University of British Columbia Vancouver were used, as well as Opentrons robots and multi-axis cobotic robots to distribute and repeat experimental results. Protocols for three case studies involving seven reaction steps and three final compounds were validated and disseminated to be repeated in two international laboratories and on three independent robots.

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Fig. 1: Universality of χDL.
Fig. 2: Convergent synthesis of complex molecules with the ChemTorrent approach.
Fig. 3: Synthesis of H2IMes•HBF4 (4).
Fig. 4: Convergent synthesis workflow using the ChemTorrent approach.
Fig. 5: Comparison of spectral data for compound 8.
Fig. 6: Schematic representation of an advanced Chemputer setup.
Fig. 7: Carbonyl diimidazole assisted amide coupling.
Fig. 8: CDI-mediated amide coupling of 2-methoxybenzoic acid to 2-(2-chlorophenyl)ethylamine.

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Data availability

The experiment data that support the findings of this study are available in the manuscript files and from the corresponding author upon reasonable request. The source data underlying Supplementary Figs. 2 and 3 are provided in Supplementary Data 1.

Code availability

χDL files (.xdl) and Chemputer graph files (.json) can be opened and edited with the ChemIDE app on https://croningroup.gitlab.io/chemputer/xdlapp/. The χDL software standard is linked here: https://croningroup.gitlab.io/chemputer/xdl/standard/index.html. A complete docker image of the synthetic platforms and hardware can be made available by request.

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Acknowledgements

Financial support for this work was provided by the EPSRC (grants EP/L023652/1, EP/R01308X/1, EP/S019472/1 and EP/P00153X/1), Defence Advanced Research Projects Agency (DARPA) under the Accelerated Molecular Discovery Program (Cooperative Agreement HR00111920027, dated 1 August 2019). Additional support was provided by the Canada Foundation for Innovation (CFI) (CFI-35883) and the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2021-03168, Discovery Accelerator Supplement RGPAS-2021-00016). Student support was provided by the German Academic Scholarship Foundation (to R.R.) and an NSERC CGS-D scholarship (to M.G.). We thank D. Thomas, M. Siauciulis and E. Trushina from the Cronin Laboratory at the University of Glasgow and S. Rohrbach from Chemify Ltd for proofreading the manuscript and for support in the laboratory.

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Author notes

  1. These authors contributed equally: Robert Rauschen, Mason Guy.

Authors and Affiliations

  1. Advanced Research Centre, University of Glasgow, Glasgow, UK

    Robert Rauschen & Leroy Cronin

  2. Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada

    Mason Guy & Jason E. Hein

Authors
  1. Robert Rauschen
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  2. Mason Guy
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  3. Jason E. Hein
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  4. Leroy Cronin
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Contributions

L.C. and J.H. conceived the idea of utilizing χDL protocols between different laboratories and named the concept of this paper ‘ChemTorrent’. L.C. and J.H. together coordinated the research project and mentored R.R. and M.G. All experimental work was completed by R.R. and M.G. in equal contribution with help from the respective research groups in Glasgow and Vancouver. The body of this manuscript and the Supplementary Information were written by R.R. and M.G. with input from all the authors.

Corresponding authors

Correspondence to Jason E. Hein or Leroy Cronin.

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Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Linjiang Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Experimental details, Figs. 1–5 and Tables 1–3.

Supplementary Data 1

HPLC data for the traces of compounds 7, 8, 14 and 16 found in Supplementary Figs. 2 and 3.

Supplementary Code 1

χDL protocols and graph files for experiments detailed in the Supplementary Information.

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Rauschen, R., Guy, M., Hein, J.E. et al. Universal chemical programming language for robotic synthesis repeatability. Nat. Synth 3, 488–496 (2024). https://doi.org/10.1038/s44160-023-00473-6

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