Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 16;14(4):521-529.
doi: 10.1021/acsmedchemlett.2c00538. eCollection 2023 Apr 13.

ChemBeads-Enabled Photoredox High-Throughput Experimentation Platform to Improve C(sp2)-C(sp3) Decarboxylative Couplings

Nathan J Gesmundo  1 , Noah P Tu  1 , Kathy A Sarris  1 , Ying Wang  1
Affiliations

ChemBeads-Enabled Photoredox High-Throughput Experimentation Platform to Improve C(sp2)-C(sp3) Decarboxylative Couplings

Nathan J Gesmundo et al. ACS Med Chem Lett. .

Abstract

Enthusiasm surrounding nickel/photoredox C(sp2)-C(sp3) cross-couplings is very high; however, these methods are sometimes challenged by complex drug-like substrates in discovery chemistry. In our hands this has been especially true of the decarboxylative coupling, which has lagged behind other photoredox couplings in internal adoption and success. Herein, the development of a photoredox high-throughput experimentation platform to optimize challenging C(sp2)-C(sp3) decarboxylative couplings is described. Chemical-coated glass beads (ChemBeads) and a novel parallel bead dispenser are used to expedite the high-throughput experimentation process and identify improved coupling conditions. In this report, photoredox high-throughput experimentation is utilized to dramatically improve low-yielding decarboxylative C(sp2)-C(sp3) couplings, and libraries, using conditions not previously identified in the literature.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Summary of nickel/photoredox C(sp2)–C(sp3) cross-couplings from our method comparison study along with decarboxylative coupling examples.
Figure 2
Figure 2
Preparation of ChemBeads.
Figure 3
Figure 3
Picture and schematics of the parallel bead dispenser.
Figure 4
Figure 4
Decarboxylative coupling HTE. Plate design, workflow validation, and use examples. Histograms and heatmap visualizations generated using UVPdt/UVIS data after min-max normalization. Additional head-to-head protocol comparisons for 6 and 7 are available in the Supporting Information.
Figure 5
Figure 5
Comparative study of initial coupling conditions versus HTE coupling conditions using parallel library synthesis. Boc-Pro-OH was present in duplicate. Acids are presented in the following order: primary then secondary then tertiary acids.
Figure 6
Figure 6
Comparative study breakdown and summary.
See this image and copyright information in PMC

References

    1. Shevlin M. Practical High-Throughput Experimentation for Chemists. ACS Med. Chem. Lett. 2017, 8 (6), 601–607. 10.1021/acsmedchemlett.7b00165. - DOI - PMC - PubMed
    1. Krska S. W.; DiRocco D. A.; Dreher S. D.; Shevlin M. The Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical Synthesis. Acc. Chem. Res. 2017, 50 (12), 2976–2985. 10.1021/acs.accounts.7b00428. - DOI - PubMed
    1. Cernak T.; Gesmundo N. J.; Dykstra K.; Yu Y.; Wu Z.; Shi Z.-C.; Vachal P.; Sperbeck D.; He S.; Murphy B. A.; Sonatore L.; Williams S.; Madeira M.; Verras A.; Reiter M.; Lee C. H.; Cuff J.; Sherer E. C.; Kuethe J.; Goble S.; Perrotto N.; Pinto S.; Shen D.-M.; Nargund R.; Balkovec J.; DeVita R. J.; Dreher S. D. Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)Pyridinyl-1H-Benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors. J. Med. Chem. 2017, 60 (9), 3594–3605. 10.1021/acs.jmedchem.6b01543. - DOI - PubMed
    1. Santanilla A. B.; Regalado E. L.; Pereira T.; Shevlin M.; Bateman K.; Campeau L.-C.; Schneeweis J.; Berritt S.; Shi Z.-C.; Nantermet P.; Liu Y.; Helmy R.; Welch C. J.; Vachal P.; Davies I. W.; Cernak T.; Dreher S. D. Nanomole-Scale High-Throughput Chemistry for the Synthesis of Complex Molecules. Science 2015, 347 (6217), 49–53. 10.1126/science.1259203. - DOI - PubMed
    1. Perera D.; Tucker J. W.; Brahmbhatt S.; Helal C. J.; Chong A.; Farrell W.; Richardson P.; Sach N. W. A Platform for Automated Nanomole-Scale Reaction Screening and Micromole-Scale Synthesis in Flow. Science 2018, 359 (6374), 429–434. 10.1126/science.aap9112. - DOI - PubMed