Advances in Asymmetric Synthesis of Chiral Organofluorine Compounds via Hypervalent Iodine Catalysis

doi:10.6023/cjoc202606029

Abstract

Organofluorine compounds are widely applied in pharmaceuticals and agrochemicals, yet naturally occurring organic fluorides are extremely rare. Notably, the construction of carbon-fluorine bonds poses considerable challenges. Hypervalent iodine(III) catalysis offers a distinct approach to the asymmetric synthesis of chiral organofluorine compounds under mild conditions by reversing the polarity of inexpensive nucleophilic fluoride sources to generate electrophilic hypervalent iodine(III) fluoride species. This Review systematically summarizes the progress in hypervalent iodine(III)-catalyzed asymmetric synthesis of chiral organofluorine compounds from 2014 to the present, covering the construction of chiral monofluorinated, difluorinated, and polyfluorinated molecules. Representative transformations discussed include carbonyl α-fluorination, olefin fluorocyclization, fluorinative dearomatization of phenols, fluorination of allenes, 1,2-difluorination, gem-difluorination, 1,3-difluorination, and fluorination of CF₃-substituted alkenes. Key aspects of the reported systems, including catalyst design, enantioselectivity control and catalytic mechanisms, are discussed. Finally, current challenges and future directions are highlighted.

Key words: hypervalent iodine(III), asymmetric catalysis, nucleophilic fluorination, chiral organofluorine compounds, umpolung

Cite this article

Zhong Shengyu, Shi Lei. Advances in Asymmetric Synthesis of Chiral Organofluorine Compounds via Hypervalent Iodine Catalysis[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202606029.

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References

[1] (a) O′Hagan, D. Chem. Soc. Rev.2008, 37, 308.
(b) Liu Q.; Ni C.; Hu, J. Natl. Sci. Rev. 2017, 4, 303.
(c) Aufiero M.; Gilmour, R. Acc. Chem. Res. 2018, 51,1701.
(d) Meyer, S.; Häfliger, J.; Gilmour, R.Chem. Sci. 2021, 12, 10686.
(e) Poole, W. G.; Peron, F.; Fox, S. J.; Wells, N.; Skylaris, C.-K.; Essex, J. W.; Kuprov, I.; Linclau, B. J. Org. Chem. 2024, 89, 8789.
[2] (a) Müller K.; Faeh C.; Diederich F. Science2007, 317, 1881.
(b) Purser S.; Moore P. R.; Swallow S.; Gouverneur, V. Chem. Soc. Rev.2008, 37, 320.
(c) Gillis, E.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315.
[3] (a) Wang J.; Sánchez-Roselló M.; Aceña J. L.; del Pozo C.; Sorochinsky A. E.; Fustero S.; Soloshonok V. A.; Liu H. Chem. Rev.2014, 114, 2432.
(b) Zhou Y.; Wang J.; Gu Z.; Wang S.; Zhu W.; Aceña J. L.; Soloshonok V. A.; Izawa K.; Liu H. Chem. Rev.2016, 116, 422.
(c) Meanwell, N. A. J. Med. Chem. 2018, 61, 5822.
(d) Inoue, M.; Sumii, Y.; Shibata, N. ACS Omega 2020, 5, 10633.
(e) Grygorenko, O. O.; Melnykov, K. P.; Holovach, S.; Demchuk, O. ChemMedChem 2022, 17, e202200365.
(f) Du, Y.; Bian, Y.; Baecker, D.; Dhawan, G.; Semghouli, A.; Kiss, L.; Zhang, W.; Sorochinsky, A. E.; Soloshonok, V. A.; Han, J. Chem. Eur. J. 2025, 31, e202500662.
[4] (a) Fujiwara T.; O′Hagan, D. J. Fluorine Chem.2014, 167, 16.
(b) Ogawa Y., Tokunaga E., Kobayashi O., Hirai K., Shibata N. iScience2020, 23, 101467.
(c) Wang, Q., Song, H., and Wang, Q. Chin. Chem. Lett. 2022, 33, 626.
[5] (a) Preshlock S.; Tredwell M.; Gouverneur V. Chem. Rev.2016, 116, 719.
(b) Rong J.; Haider A.; Jeppesen T. E.; Josephson L.; Liang, S. H. Nat. Commun.2023, 14, 3257.
[6] (a) O′Hagan D.; Harper, D. B. J. Fluorine Chem.1999, 100, 127.
(b) Walker M. C.; Chang, M. C. Y. Chem. Soc. Rev.2014, 43, 6527.
(c) Reichel, M.; Karaghiosoff, K. Angew. Chem., Int. Ed. 2020, 59, 12268.
[7] O′Hagan D.; Deng H. Chem. Rev.2015, 115, 634.
[8] (a) Butler A.; Sandy M. Nature2009, 460, 848.
(b) Petkowski J. J.; Seager S.; Bains W. Sci. Rep.2024, 14, 15575.
[9] Wei L.; Huang C.; Luo Y.Sci. China: Life Sci. 2025, 55, 2124.
[10] (a) Lal G. S.; Pez G. P.; Syvret, R. G. Chem. Rev.1996, 96, 1737.
(b) Ma J.-A.; Cahard D. Chem. Rev.2004, 104, 6119.
(c) Brunet, V. A.; O′Hagan, D. Angew. Chem., Int. Ed. 2008, 47, 1179.
(d) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(e) Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.; Soloshonok, V. A.; Coelho, J. A. S.; Toste, F. D. Chem. Rev. 2018, 118, 3887.
(f) Li, M.; Xue, X.-S.; Cheng, J.-P. Acc. Chem. Res. 2020, 53, 182.
(g) Kalita, S. J.; Qi, J.; Xiao, L.; Saha, D.; Huang, Y.-Y.; Shibata, N. Chem. Rev. 2025, 125, 8477.
[11] (a) Meyer D.; Jangra H.; Walther F.; Zipse H.; Renaud P. Nat. Commun.2018, 9, 4888.
(b) Bui T. T.; Hong W. P.; Kim, H.-K. J. Fluorine Chem.2021, 247, 109794.
(c) Zou, Z.; Zhang, W.; Wang, Y.; Pan, Y. Org. Chem. Front. 2021, 8, 2786.
(d) Wang, M.; Ruskin, J.; Marques, J.; Garrison, N.; Lectka, T. Chem. Rev. 2025, 125, 9382.
(e) Li, J.; Chiou, M.-F.; Bao, H. Org. Chem. Front. 2026, 13, 10.1039/D6QO00260A.
[12] (a) Champagne P. A.; Desroches J.; Hamel J.-D.; Vandamme M.; Paquin J.-F. Chem. Rev.2015, 115, 9073.
(b) Caron, S. Org. Process Res. Dev.2020, 24, 470.
(c) Leibler, I. N.-M.; Gandhi, S. S.; Tekle-Smith, M. A.; Doyle, A. G. J. Am. Chem. Soc. 2023, 145, 9928.
[13] (a) Li X.; Chen P.; Liu, G. Beilstein J. Org. Chem.2018, 14, 1813.
(b) Bauer A.; Maulide N. Chem. Sci.2021, 12, 853.
(c) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2024, 124, 11108.
[14] Okuyama T.; Takino T.; Sueda T.; Ochiai, M. J. Am. Chem. Soc.1995, 117, 3360.
[15] Weinland R. F.; Stille, W. Ber. Dtsch. Chem. Ges.1901, 34, 2631.
[16] Stang P. J.; Zhdankin, V. V. Chem. Rev.1996, 96, 1123.
[17] (a) Zupan, M.; Pollak, A.J. Chem. Soc., Chem. Commun. 1975, 715.
(b) Hara S.; Nakahigashi J.; Ishi-I K.; Sawaguchi M.; Sakai H.; Fukuhara T.; Yoneda N. Synlett1998, 495.
(c) Sawaguchi, M.; Hara, S.; Yoneda, N.J. Fluor. Chem. 2000, 105, 313.
(d) Yoneda, N. J. Fluor. Chem. 2004, 125, 7.
[18] (a) Kitamura T.; Kuriki S.; Morshed M. H.; Hori Y. Org. Lett.2011, 13, 2392.
(b) Sarie J. C.; Thiehoff C.; Mudd R. J.; Daniliuc C. G.; Kehr G.; Gilmour, R. J. Org. Chem.2017, 82, 11792.
[19] Kong W.; Feige P.; de Haro T.; Nevado, C. Angew. Chem., Int. Ed.2013, 52, 2469.
[20] Roth H. G.; Romero N. A.; Nicewicz D. A. Synlett2016, 27, 714.
[21] (a) Dohi T.; Maruyama A.; Yoshimura M.; Morimoto K.; Tohma H.; Kita, Y. Angew. Chem., Int. Ed.2005, 44, 6193.
(b) Ochiai M.; Takeuchi Y.; Katayama T.; Sueda T.; Miyamoto, K. J. Am. Chem. Soc.2005, 127, 12244.
[22] (a) Cai Q.; Ma, H. Acta Chim. Sin.2019, 77, 213 (in Chinese)
(蔡倩, 马浩文, 化学学报, 2019, 77, 213).
(b) Parra, A. Chem. Rev. 2019, 119, 12033.
(c) Singh, F. V.; Shetgaonkar, S. E.; Krishnan, M.; Wirth, T. Chem. Soc. Rev. 2022, 51, 8102.
[23] Basdevant B.; Legault, C. Y. Org. Lett.2015, 17, 4918.
[24] Suzuki S.; Kamo T.; Fukushi K.; Hiramatsu T.; Tokunaga E.; Dohi T.; Kita Y.; Shibata N. Chem. Sci.2014, 5, 2754.
[25] Pluta R.; Krach P. E.; Cavallo L.; Falivene L.; Rueping M. ACS Catal.2018, 8, 2582.
[26] Wang Y.; Yuan H.; Lu H.; Zheng W.-H. Org. Lett.2018, 20, 2555.
[27] Zhou H.-J.; Yao Y.-P.; Zhang T.; Chen B.; Wu X.; Zhao H.; Zeng J.; Chen J.-A.; Xiao X.; Chen F.-E. Green Chem.2023, 25, 10447.
[28] Zhong S.; Yu Z.; Zhu Y.; Shi L. Org. Lett.2025, 27, 3452.
[29] (a) Scheidt F.; Neufeld J.; Schäfer M.; Thiehoff C.; Gilmour R. Org. Lett.2018, 20, 8073.
(b) Neufeld J.; Stünkel T.; Mück-Lichtenfeld C.; Daniliuc C. G.; Gilmour, R. Angew. Chem., Int. Ed.2021, 60, 13647.
(c) Wang, Q.; Biosca, M.; Himo, F.; Szabό, K. J. Angew. Chem., Int. Ed. 2021, 60, 26327.
(d) Longuet, M.; Vitse, K.; Martin-Mingot, A.; Michelet, B.; Guégan, F.; Thibaudeau, S. J. Am. Chem. Soc. 2024, 146, 12167.
(e) Sweeting, S. G.; Lennox, A. J. J. J. Am. Chem. Soc. 2025, 147, 19329.
[30] Woerly E. M.; Banik S. M.; Jacobsen, E. N. J. Am. Chem. Soc.2016, 138, 13858.
[31] Menie K. M.; Banik S. M.; Reichert E. C.; Jacobsen, E. N. J. Am. Chem. Soc.2018, 140, 4797.
[32] Sarie J.; Thiehoff C.; Neufeld J.; Daniliuc C. G.; Gilmour, R. Angew. Chem., Int. Ed.2020, 59, 15069.
[33] Häfliger J.; Sokolova O. O.; Lenz M.; Daniliuc C. G.; Gilmour, R. Angew. Chem., Int. Ed.2022, 61, e202205277.
[34] Wang Q.; Lübcke M.; Biosca M.; Hedberg M.; Eriksson L.; Himo F.; Szabό, K. J. J. Am. Chem. Soc.2020, 142, 20048.
[35] Zhu W.; Zhen X.; Wu J.; Cheng Y.; An J.; Ma X.; Liu J.; Qin Y.; Zhu H.; Xue J.; Jiang X. Nat. Commun.2021, 12, 3957.
[36] Chen J.; Li J.; Li X. Org. Lett.2025, 27, 13827.
[37] Stünkel T.; Siebold K.; Okumatsu D.; Murata K.; Ruyet L.; Daniliuc C. G.; Gilmour R. Chem. Sci.2023, 14, 13574.
[38] Wang Z.-X.; Xu Y.; Gilmour R. Nat. Commun.2024, 15, 5770.
[39] Banik S. M.; Medley J. W.; Jacobsen, E. N. J. Am. Chem. Soc.2016, 138, 5000.
[40] Molnár I. G.; Gilmour, R. J. Am. Chem. Soc.2016, 138, 5004.
[41] Scheidt F.; Schäfer M.; Sarie J. C.; Daniliuc C. G.; Molloy J. J.; Gilmour, R. Angew. Chem., Int. Ed.2018, 57, 16431.
[42] Haj M. K.; Banik S. M.; Jacobsen, E. N. Org. Lett.2019, 21, 4919.
[43] Banik S. M.; Medley J. W.; Jacobsen E. N. Science2016, 353, 51.
[44] Zhou B.; Haj M. K.; Jacobsen E. N.; Houk K. N.; Xue, X.-S. J. Am. Chem. Soc.2018, 140, 15206.
[45] Levin M. D.; Ovian J. M.; Read J. A.; Sigman M. S.; Jacobsen, E. N. J. Am. Chem. Soc.2020, 142, 14831.
[46] Häfliger J.; Livingstone K.; Daniliuc C. G.; Gilmour R. Chem. Sci.2021, 12, 6148.
[47] Tu F.-H.; Wang Y.; Li Z.; Yang S.; Li Y.; Tan D.-H.; Li Q.; Gao H.; Wang, H. Cell Rep. Phys. Sci.2022, 3, 101194.
[48] Ruyet L.; Roblick C.; Häfliger J.; Wang Z.-X.; Stoffels T. J.; Daniliuc C. G.; Gilmour, R. Angew. Chem., Int. Ed.2024, 63, e202403957.
[49] Banik S. M.; Mennie K. M.; Jacobsen, E. N. J. Am. Chem. Soc.2017, 139, 9152.
[50] Sharma H. A.; Mennie K. M.; Kwan E. E.; Jacobsen, E. N. J. Am. Chem. Soc.2020, 142, 16090.
[51] Zhong S.; Gan S.; Zhang X.; Song L.; Shi L. Adv. Sci.2025, 12, e06041.
[52] Kwon Y.-D.; Son J.; Chun J.-H. Org. Lett.2018, 20, 7902.
[53] Dean A. C.; Randle E. H.; Lacey A. J. D.; Giorio G. A. M.; Doobary S.; Cons B. D.; Lennox, A. J. J. Angew. Chem., Int. Ed.2024, 63, e202404666.
[54] Tu H.-F.; Lin S.; Tang Y.-J.; Liu L.-C.; Li Q.; Wang, H. Tetrahedron Chem.2023, 8, 100052.
[55] Meyer S.; Häfliger J.; Schäfer M.; Molloy J. J.; Daniliuc C. G.; Glimour, R. Angew. Chem., Int. Ed.2021, 60, 5430.
[56] Schäfer M.; Stünkel T.; Daniliuc C. G.; Gilmour, R. Angew. Chem., Int. Ed.2022, 61, e202205508.
[57] Yu Y.-J.; Häfliger J.; Wang Z.-X.; Daniliuc C. G.; Gilmour, R. Angew. Chem., Int. Ed.2023, 62, e202309789.
[58] (a) Winterson B.; Bhattacherjee D.; Wirth, T. Adv. Synth. Catal.2023, 365, 2676.
(b) Sokolovs, I.; Suna, E.; Francke, R.Acc. Chem. Res. 2026, 59, 1949.
[59] Wang Q.; Biosca M.; Himo F.; Szabό, K. J. Angew. Chem., Int. Ed.2021, 60, 26327.
[60] Lv W.-X.; Li Y.; Cai Y.-H.; Tan D.-H.; Li Z.; Li J.-L.; Li Q.; Wang H. Chem. Sci.,2022, 13, 2981.
[61] (a) Ning, Y.; Sivaguru, P.; Zanoni, G.; Anderson, E. A.; Bi, X.Chem 2020, 6, 486.
(b) Liu, X.-B.; Feng, S.-X.; Lin, S.; Qin, Q.-H.; Wang, H.*; Li, Q.CCS Chem. 2026, 8, 271.
[62] Li Y.; Liu X.-B.; Sham V.; Logvinenko I.; Xue J.-H.; Wu J.-Y.; Fu J.-L.; Lin S.; Liu Y.; Li Q.; Mykhailiuk P. K.; Wang, H. Angew. Chem., Int. Ed.2025, 64, e202422899.

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