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Sulfur fluoride exchange

Nature Reviews Methods Primers volume 3, Article number: 58 (2023) Cite this article

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Abstract

Click chemistry is a conceptual strategy to rapidly synthesize and discover functional molecules. Sulfur fluoride exchange (SuFEx) is a click reaction that has revolutionized multiple research fields. In this Primer, we delve into the essential elements of SuFEx operation, catalysis and SuFExable connective hubs. We also explore the cutting-edge applications of SuFEx in drug development, polymer science and biochemistry. Additionally, we examine the potential limitations and promising prospects for this versatile click reaction.

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Fig. 1: SuFEx.
Fig. 2: Investigation into the sulfur fluoride exchange mechanism.
Fig. 3: Enhancing SuFEx reactivity and practicability.
Fig. 4: SuFEx-based medicinal chemistry.
Fig. 5: Unique applications of SuFEx towards function discovery.
Fig. 6: Advances in SuFEx-based polymerizations.
Fig. 7: Biocompatible SuFEx methods.

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Acknowledgements

J.E.M. is financially supported by the NCI Cancer Center Support Grant 5P30CA045508, The F. M. Kirby Foundation, Sunshine Foundation, S. J. Edwards, The Starr Foundation and The Wasily Family Foundation. J.D. is thankful for the financial support from Ministry of Science and Technology of China, Major State Basic Research Development Program of China (2021YFF0701704) and Shanghai Pilot Program for Basic Research, Shanghai Jiao Tong University. H.Z. is supported by the National Science Foundation of China (Grants 21871208 and 22011530163, both to H.Z.), Tianjin University and Wageningen University (both H.Z. and N.K.). K.B.S. is supported by the National Institutes of Health (R01GM117145). Q.Z. is the Connie and Bob Lurie Fellow of the Damon Runyon Cancer Research Foundation (DRG-2434-21). B.M.K. was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) and funded by the Ministry of Science and ICT (No. NRF-2017M3A9F6029755).

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Author notes

  1. Qinheng Zheng

    Present address: Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA

Authors and Affiliations

  1. Cancer Center, Cold Spring Harbor Laboratory, New York, NY, USA

    Joshua A. Homer & John E. Moses

  2. Institute of Translational Medicine, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China

    Long Xu & Jiajia Dong

  3. School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Long Xu & Jiajia Dong

  4. Laboratory of Organic Chemistry, Wageningen University, Wageningen, Netherlands

    Namitharan Kayambu & Han Zuilhof

  5. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    Qinheng Zheng & K. Barry Sharpless

  6. Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, South Korea

    Eun Joung Choi & Byeong Moon Kim

  7. School of Pharmaceutical Science and Technology, Tianjin University, Nankai District, Tianjin, China

    Han Zuilhof

  8. Shanghai Artificial Intelligence Laboratory, Shanghai, China

    Jiajia Dong

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Contributions

Introduction (J.A.H. and J.E.M.); Experimentation (J.A.H., L.X., N.K., H.Z., J.D. and J.E.M.), Applications (J.A.H., N.K., Q.Z., E.J.C., B.M.K., K.B.S., H.Z. and J.E.M.); Reproducibility and data deposition (J.A.H. and J.E.M.); Limitations and optimizations (J.A.H. and J.E.M.); Outlook (J.A.H. and J.E.M.); Overview of the Primer (J.A.H. and J.E.M.). J.A.H. and J.E.M. coordinated the compilation of the manuscript.

Corresponding author

Correspondence to John E. Moses.

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Competing interests

Details of patents covering material related to the content of this Primer can be found in the Supplementary information. The other authors declare no competing interests.

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Nature Reviews Methods Primers thanks Nicholas Ball, Tae Kyo Park and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Dispersity

A measure of the heterogeneity of a polymer sample.

Organosuperbase

Strong organic base with a basicity greater than that of proton sponge (pKBH+ 18.6 in MeCN).

Orthogonality

The selective reactivity of functional groups only when exposed to specific reaction conditions, while remaining untouched in all other instances.

SuFExability

The propensity of an S–F-containing functional group to undergo catalyst-mediated exchange.

SuFExable

Functional groups containing sulfur-fluoride bonds that are compatible electrophiles in the sulfur fluoride exchange (SuFEx) reaction (such as sulfonyl fluorides, fluorosulfates and iminosulfur oxydifluorides).

SuFExed

The incorporation of a sulfur fluoride exchangeable (SuFExable) group to the native structure of a molecule (such as ligand and drug).

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Homer, J.A., Xu, L., Kayambu, N. et al. Sulfur fluoride exchange. Nat Rev Methods Primers 3, 58 (2023). https://doi.org/10.1038/s43586-023-00241-y

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