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Computational synthesis design for controlled degradation and revalorization

Nature Synthesis (2024)Cite this article

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Abstract

Degradation of larger and undesired or harmful molecules into smaller and, ideally, value-added products is one of the most important facets of circular chemistry. However, this task may be cumbersome for chemists who are accustomed to planning syntheses using bond-forming, rather than bond-breaking, methodologies. This work describes a forward-synthesis algorithm that can guide such degradation-oriented analyses. This algorithm uses a broad knowledge-base of degradative and related reactions and applies them to arbitrary small-molecule feeds to generate large synthetic networks within which it then traces degradative pathways that are chemically sound and lead to value-added products. Predictions of the algorithm are validated by proof-of-concept experiments entailing degradation and revalorization of two biomass feeds, d-glucose and quinine.

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Fig. 1: Degradative reaction networks.
Fig. 2: Scoring of degradative pathways according to process criteria.
Fig. 3: Examples of computer-designed degradation pathways starting from different feeds.
Fig. 4: Degradation of d-glucose into value-added 1,4-diaminobutane, 5.
Fig. 5: Degradation of quinine into smaller but value-added chemicals.

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Data availability

The User Manual and login details are available in Supplementary Information, section 1. The use of Allchemy’s degradation module is further illustrated in Supplementary Video 1. All degradation pathways described in this work and experimental validation data supporting this study are available in Supplementary Information, sections 2 and 3.

Code availability

The interactive Allchemy web application is freely available for academic users at https://degradation.allchemy.net (due to server capacity, access is limited to five concurrent academic users on a rolling basis and to two-week slots). To obtain access, please send an email (from your academic address) to admin@allchemy.net. Reaction rules are proprietary but their coding is explained in Supplementary Information, section 1.4. The code for the forward-expand reaction networks is provided at https://zenodo.org/records/10034684 or via a DOI search engine under https://doi.org/10.5281/zenodo.10034684.

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Acknowledgements

Development of the Degradation module within the Allchemy platform (by K.M., S.S., M.M., R.R. and B.A.G.) has been supported by internal funds of Allchemy. Calculations, analysis of pathways, and laboratory experiments (by A.Ż.-D. and O.O.K.) were supported by the National Science Centre, Poland (award 2020/39/D/ST4/01890 to A.Ż.-D.). Analysis of results and writing of the paper by B.A.G. was supported by the Institute for Basic Science, Korea (project code IBS-R020-D1 to B.A.G.). We thank the Mcule team for providing access to their catalogue and standardizing the price information therein to per-gramme.

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Authors and Affiliations

  1. Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland

    Anna Żądło-Dobrowolska, Karol Molga, Olga O. Kolodiazhna, Sara Szymkuć, Rafał Roszak & Bartosz A. Grzybowski

  2. Allchemy, Highland, IN, USA

    Karol Molga, Sara Szymkuć, Martyna Moskal & Rafał Roszak

  3. IBS Center for Algorithmic and Robotized Synthesis (CARS), Ulsan, South Korea

    Bartosz A. Grzybowski

  4. Department of Chemistry, UNIST, Ulsan, South Korea

    Bartosz A. Grzybowski

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  1. Anna Żądło-Dobrowolska
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Contributions

K.M., S.S., M.M., R.R. and B.A.G. designed and developed the Allchemy platform. A.Ż.-D. performed the analyses and computational calculations described in the paper, most syntheses described in Fig. 4 (d-glucose–1–2–3–4) and all the syntheses described in Fig. 5. O.O.K performed syntheses 3–5 described in Fig. 4. B.A.G. conceived and supervised the research and wrote the paper with help from A.Ż.-D.

Corresponding authors

Correspondence to Anna Żądło-Dobrowolska or Bartosz A. Grzybowski.

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Competing interests

K.M., S.S., M.M. and B.A.G. are consultants and/or stakeholders of Allchemy. Allchemy software is the property of Allchemy. The other authors declare no competing interests.

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Nature Synthesis thanks Calvin Chen, Fabrice Gallou 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

Experimental details, Supplementary Sections 1–4 (basic information, analysis of results, experimental validation, supplementary references), Figs. 1–81 and Tables 1–7.

Supplementary Video 1

Illustration of the use of Allchemy’s degradation module.

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Żądło-Dobrowolska, A., Molga, K., Kolodiazhna, O.O. et al. Computational synthesis design for controlled degradation and revalorization. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00497-6

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