Abstract
Automated iterative small-molecule synthesis has the potential to advance and democratize the discovery of new medicines, materials and many other classes of functional chemical matter. To date, however, this approach has been limited because each carbon–carbon bond-forming step takes about a day. Here we report a next-generation small-molecule synthesizer that operates an order of magnitude faster than previous systems through improvements in both chemistry and engineering. Key advances include the discovery that rapid Suzuki–Miyaura cross-couplings under homogeneous conditions, although not tolerated by N-methyliminodiacetic acid boronates, are fully compatible with their more stable tetramethyl-N-methyliminodiacetic acid boronate counterparts, and the development of optimized cartridges for rapid catch-and-release purification. These findings move the field of small-molecule synthesis a step closer to democratizing its core discovery engine.
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Data availability
The data and methods that support the findings of this study are available in the Supplementary Information, which describes the manual and automated synthesis methods, kinetic studies and control experiments.
Change history
11 June 2024
A Correction to this paper has been published: https://doi.org/10.1038/s44160-024-00601-w
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Acknowledgements
This work was supported by the Molecule Maker Lab Institute, an AI Research Institutes programme supported by the US National Science Foundation under grant number 2019897 (M.D.B.). N.H.A. was supported by the Department of Defense (DoD) through the National Defense Science and Engineering Graduate (NDSEG) Fellowship Program. Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect those of the NSF. The authors gratefully acknowledge S. Denmark, V. Kassel and M. Bock for advice regarding TMSOK-promoted couplings. D.J.B. thanks the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children’s Research Hospital for support.
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M.D.B., W.W., N.H.A. and D.J.B. conceived this project. W.W., N.H.A., D.J.B., T.T.-E., W.H.K., K.N.S.M., A.J.L., J.M.B. and M.D.B. designed and executed the experiments. W.W., N.H.A., D.J.B. and M.D.B. wrote the paper.
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The University of Illinois has filed patent applications related to MIDA and TIDA boronates with M.D.B., W.W., N.H.A., D.J.B. and T.T.-E. as inventors. The other authors declare no competing interests.
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Experimental details, Supplementary Sections 1–4, Figs. 1–34 and Tables 1–7.
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Wang, W., Angello, N.H., Blair, D.J. et al. Rapid automated iterative small-molecule synthesis. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00558-w
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DOI: https://doi.org/10.1038/s44160-024-00558-w
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