Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling

doi:10.1126/science.adc8743

. 2022 Oct 28;378(6618):399-405.

doi: 10.1126/science.adc8743. Epub 2022 Oct 27.

Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling

Nicholas H Angello^#^{1

2}, Vandana Rathore^#^{1

2}, Wiktor Beker³, Agnieszka Wołos^{3

4}, Edward R Jira^{2

5}, Rafał Roszak^{3

4}, Tony C Wu^{6

7}, Charles M Schroeder^{1

2

5

8}, Alán Aspuru-Guzik^{6

7

9

10

11

12}, Bartosz A Grzybowski^{3

4

13

14}, Martin D Burke^{1

2

15

16

17}

Affiliations

¹ Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
² Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
³ Allchemy, Inc., Highland, IN, USA.
⁴ Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland.
⁵ Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁶ Department of Chemistry, University of Toronto, Toronto, ON, Canada.
⁷ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
⁸ Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁹ Vector Institute for Artificial Intelligence, Toronto, ON, Canada.
¹⁰ Canadian Institute for Advanced Research, Toronto, ON, Canada.
¹¹ Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada.
¹² Department of Materials Science and Engineering, University of Toronto, Toronto, ON, Canada.
¹³ Center for Soft and Living Matter, Institute for Basic Science, Ulsan, Republic of Korea.
¹⁴ Department of Chemistry, Ulsan Institute of Science and Technology, Ulsan, Republic of Korea.
¹⁵ Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
¹⁶ Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
¹⁷ Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

^# Contributed equally.

PMID: 36302014
DOI: 10.1126/science.adc8743

Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling

Nicholas H Angello et al. Science. 2022.

. 2022 Oct 28;378(6618):399-405.

doi: 10.1126/science.adc8743. Epub 2022 Oct 27.

Authors

Affiliations

¹ Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
² Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
³ Allchemy, Inc., Highland, IN, USA.
⁴ Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland.
⁵ Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁶ Department of Chemistry, University of Toronto, Toronto, ON, Canada.
⁷ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
⁸ Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁹ Vector Institute for Artificial Intelligence, Toronto, ON, Canada.
¹⁰ Canadian Institute for Advanced Research, Toronto, ON, Canada.
¹¹ Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada.
¹² Department of Materials Science and Engineering, University of Toronto, Toronto, ON, Canada.
¹³ Center for Soft and Living Matter, Institute for Basic Science, Ulsan, Republic of Korea.
¹⁴ Department of Chemistry, Ulsan Institute of Science and Technology, Ulsan, Republic of Korea.
¹⁵ Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
¹⁶ Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
¹⁷ Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

^# Contributed equally.

PMID: 36302014
DOI: 10.1126/science.adc8743

Abstract

General conditions for organic reactions are important but rare, and efforts to identify them usually consider only narrow regions of chemical space. Discovering more general reaction conditions requires considering vast regions of chemical space derived from a large matrix of substrates crossed with a high-dimensional matrix of reaction conditions, rendering exhaustive experimentation impractical. Here, we report a simple closed-loop workflow that leverages data-guided matrix down-selection, uncertainty-minimizing machine learning, and robotic experimentation to discover general reaction conditions. Application to the challenging and consequential problem of heteroaryl Suzuki-Miyaura cross-coupling identified conditions that double the average yield relative to a widely used benchmark that was previously developed using traditional approaches. This study provides a practical road map for solving multidimensional chemical optimization problems with large search spaces.

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Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling

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Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling

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