10.1002/anie.202003219
Angewandte Chemie International Edition
COMMUNICATION
[17] K. B. Sharpless, R. Manetsch, Expert Opin. Drug Discov. 2006, 1, 525–
538.
synthesize a focused library of lead-like compounds: i) the
application of the recently introduced connective SuFEx hub
concept, and ii) the availability of a range of click-cycloaddition
transformations. We have further reported a new class of versatile
2-substituted-alkynyl-1-sulfonyl fluoride (SASF) SuFEx hubs (22
examples), that undergo an array of stereoselective click-
cycloaddition reactions to generate a structurally diverse library of
173 unprecedented sulfonyl fluoride containing heterocycles as
lead structures, which themselves can be further diversified
through late-stage SuFEx modification with an array of aryl silyl
ethers. In total, we have qualified the syntheses of 300 novel
compounds, including SASFs, aromatic heterocyclic sulfonyl
fluorides and sulfonates. The functionality of the library was
demonstrated through screening against MRSA, leading to the
identification of 16 hit compounds (11%).
[18] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew.
Chem. Int. Ed. 2002, 41, 2596–2599.
[19] C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057–
3064.
[20] X. Jiang, X. Hao, L. Jing, G. Wu, D. Kang, X. Liu, P. Zhan, Expert
Opin. Drug Discov. 2019, 14, 779–789.
[21] L. Li, Z. Zhang, Molecules 2016, 21, 1393.
[22] S. Neumann, M. Biewend, S. Rana, W. H. Binder, Macromol. Rapid
Commun. 2020, 41, 1900359.
[23] For the original report on the azide-strained alkyne reaction, see G. Wittig,
A. Krebs, Chem. Ber. 1961, 94, 3260–3275.
[24] N. J. Agard, J. A. Prescher, C. R. Bertozzi, J. Am. Chem. Soc. 2004, 126,
15046–15047.
[25] M. J. Kade, D. J. Burke, C. J. Hawker, J. Polym. Sci. A: Polym. Chem.
2010, 48, 743–750.
DOC is a powerful discovery method that takes full
advantage of the wider family of click reactions to generate
structurally diverse connections. Given the simplicity, reliability
and selectivity of the DOC approach, we believe it will find wide
application in lead-discovery endeavors.
[26] C. E. Hoyle, C. N. Bowman, Angew. Chem. Int. Ed. 2010, 49, 1540-1573.
[27] J. Dong, L. Krasnova, M. G. Finn, K. B. Sharpless, Angew. Chem. Int.
Ed. 2014, 53, 9430–9448.
[28] A. S. Barrow, C. J. Smedley, Q. Zheng, S. Li, J. Dong, J. E. Moses, Chem.
Soc. Rev. 2019, 48, 4731–4758.
[29] B. R. Baker, J. A. Hurlbut, J. Med. Chem. 1968, 11, 241–245.
[30] A. Narayanan, L. H. Jones, Chem. Sci. 2015, 6, 2650–2659.
[31] C. J. Smedley, M.-C. Giel, A. Molino, A. S. Barrow, D. J. D. Wilson, J. E.
Moses, Chem. Commun. 2018, 54, 6020–6023.
[32] C. J. Smedley, Q. Zheng, B. Gao, S. Li, A. Molino, H. M. Duivenvoorden,
B. S. Parker, D. J. D. Wilson, K. B. Sharpless, J. E. Moses, Angew. Chem.
Int. Ed. 2019, 58, 4552–4556.
Acknowledgements
We thank the ARC (J.E.M) (Future Fellowship; FT170100156),
and the NIH (K.B.S) (P50 GM103368, R01 GM117145) for
financial support. We thank the National Mass Spectrometry
Facility at Swansea University. We thank Jie Sun and the State
Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, CAS, for performing X-ray crystallography.
[33] C. J. Smedley, A. S. Barrow, C. Spiteri, M.-C. Giel, P. Sharma, J. E.
Moses, Chem. Eur. J. 2017, 23, 9990–9995.
[34] P. K. Chinthakindi, P. I. Arvidsson, Eur. J. Org. Chem. 2018, 3648–3666.
[35] J. J. Krutak, R. D. Burpitt, W. H. Moore, J. A. Hyatt, J. Org. Chem. 1979,
44, 3847–3858.
[36] R. M. Hedrick, US Patent 2653973, 1953.
[37] M.-C. Giel, C. J. Smedley, E. R. R. Mackie, T. Guo, J. Dong, T. P. Soares
da Costa, J. E. Moses, Angew. Chem. Int. Ed. 2020, 59, 1181–1186.
[38] Z. Liu, J. Li, S. Li, G. Li, K. B. Sharpless, P. Wu, J. Am. Chem. Soc. 2018,
140, 2919–2925.
Keywords: Diversity Oriented Clicking • SuFEx Click Chemistry
• Sulfonyl Fluorides • Heterocycles • Cycloadditions
[39] Q. Zheng, J. L. Woehl, S. Kitamura, D. Santos-Martins, C. J. Smedley,
G. Li, S. Forli, J. E. Moses, D. W. Wolan, K. Barry Sharpless, Proc. Natl.
Acad. Sci. U.S.A. 2019, 116, 18808–18814.
[1]
[2]
The term click chemistry (CC) was first coined by K. Barry Sharpless in
1998 and was later published as a concept in 2001 see ref: [2].
H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2001, 40,
2004–2021.
[40] G. Meng, T. Guo, T. Ma, J. Zhang, Y. Shen, K. B. Sharpless, J. Dong,
Nature 2019, 574, 86–89.
[41] M. A. Tasdelen, Polym. Chem. 2011, 2, 2133–2145.
[42] H. Mayr, A. R. Ofial, Angew. Chem. Int. Ed. 2006, 45, 1844–1854.
[43] Diversity Oriented Clicking (DOC) falls under the wider umbrella of
Diversity Oriented Synthesis (DOS). However, DOC is a purely click-
chemistry oriented approach, while DOS (first described by S. L.
Schreiber) is a broader strategy for the efficient, simultaneous synthesis
of structurally diverse compounds, see: S. L. Schreiber, Science 2000,
287, 1964–1969. For selected references relating to the topic of DOS,
see: a) S. L. Kidd, T. J. Osberger, N. Mateu, H. F. Sore, D. R. Spring,
Front. Chem. 2018, 6, 460; b) K. T. Mortensen, T. J. Osberger, T. A. King,
H. F. Sore, D. R. Spring, Chem. Rev. 2019, 119, 10288–10317; c) I.
Pavlinov, E. M. Gerlach, L. N. Aldrich, Org. Biomol. Chem. 2019, 17,
1608–1623; d) G. Muncipinto, Cycloaddition reactions in Diversity‐
Oriented Synthesis. In Diversity‐Oriented Synthesis, A. Trabocchi (Ed.),
2013; e) Y. Wang, A. Ø. Madsen, F. Diness, M. Meldal, Chem. Eur. J.
2017, 23, 13869-13874.
[3]
[4]
J. E. Moses, A. D. Moorhouse, Chem. Soc. Rev. 2007, 36, 1249–1262.
W. Xi, T. F. Scott, C. J. Kloxin, C. N. Bowman, Adv. Funct. Mater. 2014,
24, 2572–2590.
[5]
[6]
M. D. Best, Biochemistry 2009, 48, 6571–6584.
P. Thirumurugan, D. Matosiuk, K. Jozwiak, Chem. Rev. 2013, 113,
4905–4979.
[7]
[8]
A. D. Moorhouse, J. E. Moses, ChemMedChem 2008, 3, 715–723.
S. Martens, J. O. Holloway, F. E. Du Prez, Macromol. Rapid Commun.
2017, 38, 1700469.
[9]
The aspirational criteria of a click reaction provide a template to help
guide the discovery of perfect reactions.
[10] For the original report on the azide–alkyne reaction, see: A. Michael, J.
Prakt. Chem. 1893, 48, 94–95.
[11] R. Huisgen, Angew. Chem. Int. Ed. 1963, 2, 565–598.
[12] R. Huisgen, Angew. Chem. Int. Ed. 1963, 2, 633–645.
[13] W. G. Lewis, L. G. Green, F. Grynszpan, Z. Radić, P. R. Carlier, P. Taylor,
M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 1053–1057.
[14] R. Manetsch, A. Krasiński, Z. Radić, J. Raushel, P. Taylor, K. B.
Sharpless, H. C. Kolb, J. Am. Chem. Soc. 2004, 126, 12809–12818.
[15] S. W. Millward, H. D. Agnew, B. Lai, S. S. Lee, J. Lim, A. Nag, S. Pitram,
R. Rohde, J. R. Heath, Integr. Biol. 2013, 5, 87–95.
[44] John E. Lesch. The First Miracle Drugs: How the Sulfa Drugs
Transformed Medicine. New York: Oxford University Press, 2006.
[45] One synthesis of a related 2-chloroethyne-1-sulfonyl fluoride has been
reported, see: B. M. Gladshtein, L. Z. Soborovskii, Zh. Org. Khim. 1960,
30, 1574–1577.
[16] S. K. Mamidyala, M. G. Finn, Chem. Soc. Rev. 2010, 39, 1252–1261.
This article is protected by copyright. All rights reserved.