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Accelerating the discovery of multicatalytic cooperativity

Nature volume 648, pages 333–340 (2025)Cite this article

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Abstract

Cooperative catalysis, in which multiple catalytic units operate synergistically, underpins a variety of synthetically and mechanistically important organic reactions1,2,3,4. Despite its potential utility in new reactivity contexts, approaches to the discovery of cooperative catalysts have been limited, typically relying on serendipity or on previous knowledge of single-catalyst reactivity1,5. Systematic searches for unanticipated types of catalyst cooperativity must contend with vast combinatorial complexity and are therefore not undertaken6,7,8,9,10. Here we describe a pooling–deconvolution algorithm, inspired by group testing11, which identifies cooperative catalyst behaviours with low experimental cost while accommodating potential inhibitory effects between catalyst candidates. The workflow was validated first on simulated cooperativity data and then by experimentally identifying previously documented cooperativity between organocatalysts in an enantioselective oxetane-opening reaction. The workflow was then applied in a discovery context to a Pd-catalysed decarbonylative cross-coupling reaction, enabling the identification of several ligand pairs that promote the target transformation at substantially lower catalyst loading and temperature than previously reported with single-ligand systems.

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Fig. 1: Challenges and opportunities for the empirical discovery of catalytic cooperativity.
Fig. 2: Development and simulation-based testing of pooling–deconvolution algorithm.
Fig. 3: Validation of pooling–deconvolution workflow on a catalytic enantioselective oxetane opening.
Fig. 4: Deploying the pooling–deconvolution workflow to discover ligand cooperativity in a Pd-catalysed decarbonylative Suzuki–Miyaura coupling.

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Data availability

All data are available in the main text, in the SI, and on Zenodo (https://doi.org/10.5281/zenodo.17316238). Illustrations of “automated plating” and “high-throughput UPLC” in Fig. 4b were created in Adobe Illustrator.

Code availability

All code is available on Zenodo (https://doi.org/10.5281/zenodo.17316238). In addition to a persistent version on Zenodo, the Python library developed for simulation and execution is maintained on GitHub under the GPL 3.0 license (https://github.com/msh-yi/multicat-data).

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Acknowledgements

This work was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, the National Science Foundation through grant no. CHE-2247494, and the National Institutes of Health through grant no. GM149244. We thank D. Strassfeld for documenting and investigating cooperativity in the TMSBr oxetane opening reaction and for their discussions. We thank G. Lovinger for early exploration of cooperativity in the TMSCl oxetane opening reaction and for early conceptual discussions. We thank S. Li for early exploration of Cu-based ligand cooperativity. We thank T. Adrianov, M. Brenner, D. X. Chen, D. Diaz, W. Goh, S. Gopalakrishnan, D. Gordon, A. LaPorte, S. Nistanaki, E. R. Raguram and C. Wagen for helpful discussions. We thank C. Yeung, N. Sciammetta, E. Edelstein, A. Neel, R. Ruck, S. Grosser, the Catalysis and Capabilities Network, Discovery Process Chemistry, and Data-Rich Experimentation at Merck & Co., Inc., Rahway, NJ, USA for generous experimental resources. We thank S. Miller for a generous donation of catalyst 1k. We thank an anonymous referee for proposing an operational, well-behaved definition of Q.

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Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Marcus H. Sak, Richard Y. Liu & Eric N. Jacobsen

  2. Process Research and Development, Merck & Co., Inc., Boston, MA, USA

    Eugene E. Kwan

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  2. Richard Y. Liu
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Contributions

M.H.S., E.E.K. and E.N.J. conceptualized the study. M.H.S. conducted the formal analysis. E.N.J. and E.E.K. helped with funding acquisition. M.H.S. conducted the investigation. M.H.S., E.N.J., E.E.K. and R.Y.L. devised the methodology. E.N.J. administered the project. E.E.K., E.N.J. and R.Y.L. provided the resources. M.H.S. wrote the software. E.N.J., E.E.K. and R.Y.L. supervised the project. M.H.S. validated the study, performed data visualization and wrote the original draft. M.H.S., E.N.J., E.E.K. and R.Y.L. reviewed and edited the paper.

Corresponding authors

Correspondence to Richard Y. Liu, Eugene E. Kwan or Eric N. Jacobsen.

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Sak, M.H., Liu, R.Y., Kwan, E.E. et al. Accelerating the discovery of multicatalytic cooperativity. Nature 648, 333–340 (2025). https://doi.org/10.1038/s41586-025-09813-2

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