Citation: Chuangchuang Liu, Yilian Song, Wenjie Ju, Xin Liu, Min Liang, Yingsheng Zhao. A highly efficient approach to Z-monofluoroolefin-dehydroamino acid derivatives from gem-difluoroalkenes[J]. Chinese Chemical Letters, ;2026, 37(4): 111167. doi: 10.1016/j.cclet.2025.111167 shu

A highly efficient approach to Z-monofluoroolefin-dehydroamino acid derivatives from gem-difluoroalkenes

Chuangchuang Liu ^{a, 1} ,
Yilian Song ^{a, 1} ,
Wenjie Ju ^{a, 1} ,
Xin Liu ^a ,
Min Liang ^a ,
Yingsheng Zhao ^{a, b, *,}

a.
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical, Engineering and Materials Science, Soochow University, Suzhou 215123, China
b.
School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453000, China

yszhao@suda.edu.cn

Received Date: 28 December 2024
Revised Date: 18 March 2025
Accepted Date: 1 April 2025
Available Online: 2 April 2025

Figures(8)

Amino acids are the building blocks of proteins and various bioactive molecules. Fluorination is a key strategy in medicinal chemistry, making the development of new and efficient methods for fluorinating amino acids highly desirable. While many fluorination reagents have been developed, their application on amino acid frameworks remains limited. In this study, we demonstrate that ethyl 3-bromo-2-((diphenylmethylene)amino)-3,3-difluoropropanoate is an effective gem-difluoroalkenes precursor for constructing a library of monofluoroolefin amino acids via a Pd-catalyzed cross-coupling reaction.
- Fluorinated amino acids,
- Novel gem-difluoroalkenes precursor,
- Suzuki coupling,
- Heck reaction,
- Late-stage functionalization
1. [1]
  M. Hird, Chem. Soc. Rev. 36 (2007) 2070–2095. doi: 10.1039/b610738a
2. [2]
  K. Müller, C. Faeh, F. Diederich, Science 317 (2017) 1881–1886.
3. [3]
  S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008) 320–330. doi: 10.1039/B610213C
4. [4]
  R. Smits, C.D. Cadicamo, K. Burger, B. Koksch, Chem. Soc. Rev. 37 (2008) 1727–1739. doi: 10.1039/b800310f
5. [5]
  Y. Yu, A. Liu, G. Dhawan, et al., Chin. Chem. Lett. 32 (2021) 42–52.
6. [6]
  A. Papapetropoulos, S. Topouzis, S. Alexander, et al., British J. Pharma. 181 (2024) 1553–1575. doi: 10.1111/bph.16337
7. [7]
  M. Drouin, J. Paquin, Beilstein J. Org. Chem. 13 (2017) 2637–2658. doi: 10.3762/bjoc.13.262
8. [8]
  W. Dai, H. Shi, X. Zhao, S. Cao, Org. Lett. 18 (2016) 4284–4287. doi: 10.1021/acs.orglett.6b02026
9. [9]
  Y. Wang, X. Qi, Q. Ma, P. Liu, G.C. Tsui, ACS Catal. 11 (2021) 4799–4809. doi: 10.1021/acscatal.0c05141
10. [10]
  J.Q. Wu, S.S. Zhang, H. Gao, et al., J. Am. Chem. Soc. 139 (2017) 3537–3542. doi: 10.1021/jacs.7b00118
11. [11]
  Z. Zhu, L. Lin, J. Xiao, Z. Shi, Angew. Chem. Int. Ed. 61 (2022) e202113209. doi: 10.1002/anie.202113209
12. [12]
  R. Kojima, K. Kubota, H. Ito, Chem. Commun. 53 (2017) 10688–10691. doi: 10.1039/C7CC05225A
13. [13]
  J. Hu, X. Han, Y. Yuan, Z. Shi, Angew. Chem. Int. Ed. 56 (2017) 13342–13346. doi: 10.1002/anie.201708224
14. [14]
  Q. Ma, C. Liu, G.C. Tsui, Org. Lett. 22 (2020) 5193–5197. doi: 10.1021/acs.orglett.0c01813
15. [15]
  Q. Ma, Y. Wang, G.C. Tsui, Angew. Chem. Int. Ed. 59 (2020) 11293–11297. doi: 10.1002/anie.202002219
16. [16]
  H. Sakaguchi, Y. Uetake, M. Ohashi, et al., J. Am. Chem. Soc. 139 (2017) 12855–12862. doi: 10.1021/jacs.7b08343
17. [17]
  H. Ito, T. Seo, R. Kojima, K. Kubota, Chem. Lett. 47 (2018) 1330–1332. doi: 10.1246/cl.180656
18. [18]
  H. Sakaguchi, M. Ohashi, S. Ogoshi, Angew. Chem. Int. Ed. 57 (2018) 328–332. doi: 10.1002/anie.201710866
19. [19]
  G. Coates, H.Y. Tan, C. Kalff, A.J.P. White, M.R. Crimmin, Angew. Chem. Int. Ed. 58 (2019) 12514–12518. doi: 10.1002/anie.201906825
20. [20]
  H. Zhang, E. Wang, S. Geng, et al., Angew. Chem. Int. Ed. 60 (2021) 10211–10218. doi: 10.1002/anie.202100049
21. [21]
  S.S. Yan, D.S. Wu, J.H. Ye, et al., ACS Catal. 9 (2019) 6987–6992. doi: 10.1021/acscatal.9b02351
22. [22]
  C. Zhu, Y.F. Zhang, Z.Y. Liu, et al., Chem. Sci. 10 (2019) 6721–672.
23. [23]
  F.P. Wu, Y. Yuan, J. Liu, X.F. Wu, Angew. Chem. Int. Ed. 60 (2021) 8818–8822. doi: 10.1002/anie.202017365
24. [24]
  S. Xie, X. Gao, H. Wu, F. Zhou, J. Zhou, Org. Lett. 22 (2020) 8424–8429. doi: 10.1021/acs.orglett.0c03051
25. [25]
  J. Xie, J. Yu, M. Rudolph, F. Rominger, A.S.K. Hashmi, Angew. Chem. Int. Ed. 55 (2016) 9416–9421. doi: 10.1002/anie.201602347
26. [26]
  J. Li, Q. Lefebvre, H. Yang, Y. Zhao, H. Fu, Chem. Commun. 53 (2017) 10299–10302. doi: 10.1039/C7CC05758J
27. [27]
  H. Yang, C. Tian, D. Qiu, et al., Org. Chem. Front. 6 (2019) 2365–2370. doi: 10.1039/c9qo00495e
28. [28]
  J. Wang, B. Huang, C. Yang, W. Xia, Chem. Commun. 55 (2019) 11103–11106. doi: 10.1039/c9cc05293c
29. [29]
  C. Zhu, Y. Zhang, Z. Liu, et al., Chem. Sci. 10 (2019) 6721–6726. doi: 10.1039/c9sc01336a
30. [30]
  S. Xie, X. Gao, H. Wu, F. Zhou, J. Zhou, Org. Lett. 22 (2020) 8424–8429. doi: 10.1021/acs.orglett.0c03051
31. [31]
  X. Lu, Y. Wang, B. Zhang, et al., J. Am. Chem. Soc. 139 (2017) 12632–12637. doi: 10.1021/jacs.7b06469
32. [32]
  X. Qi, Q. Ma, P. Liu, G.C. Tsui, ACS Catal. 11 (2021) 4799–4809. doi: 10.1021/acscatal.0c05141
33. [33]
  Y. Wang, G.C. Tsui, Org. Lett. 25 (2023) 6217–6221. doi: 10.1021/acs.orglett.3c02452
34. [34]
  S. Porey, Y. Bairagi, S. Guin, X. Zhang, D. Maiti, ACS Catal. 13 (2023) 14000–14011. doi: 10.1021/acscatal.3c02975
35. [35]
  S.S. An, D.S. Wu, J.H. Ye, et al., ACS Catal. 9 (2019) 6987–6992. doi: 10.1021/acscatal.9b02351
36. [36]
  D.H. Tan, E. Lin, W.W. Ji, et al., Adv. Synth. Catal. 360 (2018) 1032–1037. doi: 10.1002/adsc.201701497
37. [37]
  J. Hu, X. Han, Y. Yuan, Z. Shi, Angew. Chem. Int. Ed. 56 (2017) 13342–13346. doi: 10.1002/anie.201708224
38. [38]
  W. Dai, H. Shi, X. Zhao, S. Cao, Org. Lett. 18 (2016) 4284–4287. doi: 10.1021/acs.orglett.6b02026
39. [39]
  T. Ma, Y. Chen, Y. Li, Y. Ping, W. Kong, ACS Catal. 9 (2019) 9127–9133. doi: 10.1021/acscatal.9b03172
40. [40]
  L. Kong, B. Liu, X. Zhou, F. Wang, X. Li, Chem. Commun. 53 (2017) 10326–10329. doi: 10.1039/C7CC06048C
41. [41]
  J.Q. Wu, S.S. Zhang, H. Gao, et al., J. Am. Chem. Soc. 139 (2017) 3537–3545. doi: 10.1021/jacs.7b00118
42. [42]
  P. Tian, C. Feng, T.P. Loh, Nat. Commun. 6 (2015) 7472–7479. doi: 10.1038/ncomms8472
43. [43]
  L. Kong, X. Zhou, X. Li, Org. Lett. 18 (2016) 6320–6323. doi: 10.1021/acs.orglett.6b03203
44. [44]
  D. Zell, U. Dhawa, V. Müller, et al., ACS Catal. 7 (2017) 4209–4213. doi: 10.1021/acscatal.7b01208
45. [45]
  N. Li, J. Chang, L. Kong, X. Li, Org. Chem. Front. 5 (2018) 1978–1982. doi: 10.1039/c8qo00297e
46. [46]
  R.T. Thornbury, F.D. Toste, Angew. Chem. Int. Ed. 55 (2016) 11629–11632. doi: 10.1002/anie.201605651
47. [47]
  L. Yang, W.W. Ji, E. Lin, et al., Org. Lett. 20 (2018) 1924–1927. doi: 10.1021/acs.orglett.8b00471
48. [48]
  Y. Wang, G.C. Tsui, Org. Lett. 26 (2024) 5822–5826. doi: 10.1021/acs.orglett.4c02112
49. [49]
  H. Zhou, W.A. van der Donk, Org. Lett. 3 (2001) 593–596. doi: 10.1021/ol006997s
50. [50]
  M.K. Wang, Y.C. Luo, H.Y. Zhao, et al., ACS Catal. 13 (2023) 14090–14102. doi: 10.1021/acscatal.3c03578
51. [51]
  C. Xu, R. Cheng, Y.C. Luo, M.K. Wang, X.G. Zhang, Angew. Chem. Int. Ed. 59 (2020) 18741–18747. doi: 10.1002/anie.202008498
52. [52]
  C. Xu, Z.F. Yang, L. An, X.G. Zhang, ACS Catal. 9 (2019) 8224–8229. doi: 10.1021/acscatal.9b02488
53. [53]
  L.C. Yu, J.W. Gu, S. Zhang, X.G. Zhang, J. Org. Chem. 82 (2017) 3943–3949. doi: 10.1021/acs.joc.7b00111
54. [54]
  S. Chen, B.B. Yuan, Y.L. Wang, L. Ackermann, Angew. Chem. Int. Ed. 62 (2023) e202301168. doi: 10.1002/anie.202301168
55. [55]
  S.N. Han, S.D. Liu, L. Liu, L. Ackermann, J. Li, Org. Lett. 21 (2019) 5387–5391. doi: 10.1021/acs.orglett.9b01400
56. [56]
  Z.X. Ruan, S.K. Zhang, C.J. Zhu, et al., Angew. Chem. Int. Ed. 56 (2017) 2045–2049. doi: 10.1002/anie.201611595
57. [57]
  X.P. Jiang, Y.Q.Q. Jiang, Q.Q. Liu, et al., J. Org. Chem. 87 (2022) 3546–3554. doi: 10.1021/acs.joc.1c03095
58. [58]
  W.T. Fan, Y.T. Li, D.J. Wang, S.J. Ji, Y.S. Zhao, J. Am. Chem. Soc. 14 (2020) 20524–20530. doi: 10.1021/jacs.0c09545
59. [59]
  X. Xu, N. Tao, W.T. Fan, et al., J. Org. Chem. 85 (2020) 13868–13876. doi: 10.1021/acs.joc.0c01909
60. [60]
  G.L. Tu, D.J. Wang, C.C. Yuan, J.Y. Zhang, Y.S. Zhao, J. Org. Chem. 85 (2020) 10740–10749. doi: 10.1021/acs.joc.0c01257
61. [61]
  G.L. Tu, C.C. Yuan, Y.T. Li, J.Y. Zhang, Y.S. Zhao, Angew. Chem. Int. Ed. 57 (2019) 15597–15601.
62. [62]
  C.C. Yuan, L. Zhu, C.P. Chen, et al., Nat. Commun. 9 (2018) 1189–1199. doi: 10.1038/s41467-018-03341-6
63. [63]
  C.C. Yuan, L. Zhu, R.S. Zeng, Y. Lan, Y.S. Zhao, Angew. Chem. Int. Ed. 57 (2018) 1277–1281. doi: 10.1002/anie.201711221
64. [64]
  J. He, K. Yang, J. Zhao, S. Cao, Org. Lett. 21 (2019) 9714–9718. doi: 10.1021/acs.orglett.9b03815
65. [65]
  W.H. Chen, X.J. Pei, X.X. Li, Y.S. Feng, Synth. Commun. 50 (2020) 3212–3220. doi: 10.1080/00397911.2020.1797813
66. [66]
  T.L. Andersen, S.D. Friis, H. Audrain, et al., J. Am. Chem. Soc. 137 (2015) 1548–1555. doi: 10.1021/ja511441u
1. [1]
  Jing-Jing Zhang , Lujun Lou , Rui Lv , Jiahui Chen , Yinlong Li , Guangwei Wu , Lingchao Cai , Steven H. Liang , Zhen Chen . Recent advances in photochemistry for positron emission tomography imaging. Chinese Chemical Letters, 2024, 35(8): 109342-. doi: 10.1016/j.cclet.2023.109342
2. [2]
  Yue Sun , Liming Yang , Yaohang Cheng , Guanghui An , Guangming Li . Pd(I)-catalyzed ring-opening arylation of cyclopropyl-α-aminoamides: Access to α-ketoamide peptidomimetics. Chinese Chemical Letters, 2024, 35(6): 109250-. doi: 10.1016/j.cclet.2023.109250
3. [3]
  Shehla Khalid , Muhammad Bilal , Nasir Rasool , Muhammad Imran . Photochemical reactions as synthetic tool for pharmaceutical industries. Chinese Chemical Letters, 2024, 35(9): 109498-. doi: 10.1016/j.cclet.2024.109498
4. [4]
  Jiyang Liu , Xiangzhang Tao , Zhenlei Zou , Jia Xu , Hui Shu , Yi Pan , Weigang Zhang , Shengyang Ni , Yi Wang . Modular and practical synthesis of gem-difluoroalkenes via consecutive Ni-catalyzed reductive cross-coupling. Chinese Chemical Letters, 2025, 36(7): 110461-. doi: 10.1016/j.cclet.2024.110461
5. [5]
  Shulei Hu , Yu Zhang , Xiong Xie , Luhan Li , Kaixian Chen , Hong Liu , Jiang Wang . Rh(Ⅲ)-catalyzed late-stage C-H alkenylation and macrolactamization for the synthesis of cyclic peptides with unique Trp(C7)-alkene crosslinks. Chinese Chemical Letters, 2024, 35(8): 109408-. doi: 10.1016/j.cclet.2023.109408
6. [6]
  Quan Xu , Ye-Qing Du , Pan-Pan Chen , Yili Sun , Ze-Nan Yang , Hui Zhang , Bencan Tang , Hong Wang , Jia Li , Yue-Wei Guo , Xu-Wen Li . Computation assisted chemical study of photo-induced late-stage skeleton transformation of marine natural products towards new scaffolds with biological functions. Chinese Chemical Letters, 2025, 36(5): 110141-. doi: 10.1016/j.cclet.2024.110141
7. [7]
  Xuhui Fan , Fan Wang , Mengjiao Li , Faiza Meharban , Yaying Li , Yuanyuan Cui , Xiaopeng Li , Jingsan Xu , Qi Xiao , Wei Luo . Visible light excitation on CuPd/TiN with enhanced chemisorption for catalyzing Heck reaction. Chinese Chemical Letters, 2025, 36(1): 110299-. doi: 10.1016/j.cclet.2024.110299
8. [8]
  Junhua Li , Yu Fu , Yian Shi . A rapid access to fused polycyclic indolo[2,1-a]isoquinolins via Pd-catalyzed sequential Heck/C-H activation/amination reaction with diaziridinone. Chinese Chemical Letters, 2026, 37(3): 111376-. doi: 10.1016/j.cclet.2025.111376
9. [9]
  Chuan-Zhi Ni , Ruo-Ming Li , Fang-Qi Zhang , Qu-Ao-Wei Li , Yuan-Yuan Zhu , Jie Zeng , Shuang-Xi Gu . A chiral fluorescent probe for molecular recognition of basic amino acids in solutions and cells. Chinese Chemical Letters, 2024, 35(10): 109862-. doi: 10.1016/j.cclet.2024.109862
10. [10]
  Yanhui Zhong , Peisi Xie , Chengyi Xie , Lei Guo , Weiwei Chen , Shuyi Wang , Xiaoxiao Wang , Fuyue Wang , Zian Lin , Gongke Li , Zongwei Cai . Rigid urea-based structures drive analysis of chiral amino acids. Chinese Chemical Letters, 2026, 37(2): 112039-. doi: 10.1016/j.cclet.2025.112039
11. [11]
  Baokang Geng , Xiang Chu , Li Liu , Lingling Zhang , Shuaishuai Zhang , Xiao Wang , Shuyan Song , Hongjie Zhang . High-efficiency PdNi single-atom alloy catalyst toward cross-coupling reaction. Chinese Chemical Letters, 2024, 35(7): 108924-. doi: 10.1016/j.cclet.2023.108924
12. [12]
  Mengli Xu , Zhenmin Xu , Zhenfeng Bian . Achieving Ullmann coupling reaction via photothermal synergy with ultrafine Pd nanoclusters supported on mesoporous TiO2. Chinese Journal of Structural Chemistry, 2024, 43(7): 100305-100305. doi: 10.1016/j.cjsc.2024.100305
13. [13]
  Dong-Sheng Deng , Su-Qin Tang , Yong-Tu Yuan , Ding-Xiong Xie , Zhi-Yuan Zhu , Yue-Mei Huang , Yun-Lin Liu . C-F insertion reaction sheds new light on the construction of fluorinated compounds. Chinese Chemical Letters, 2024, 35(8): 109417-. doi: 10.1016/j.cclet.2023.109417
14. [14]
  Jiayu Xu , Meng Li , Baoxia Dong , Ligang Feng . Fully fluorinated hybrid zeolite imidazole/Prussian blue analogs with combined advantages for efficient oxygen evolution reaction. Chinese Chemical Letters, 2024, 35(6): 108798-. doi: 10.1016/j.cclet.2023.108798
15. [15]
  Zhen Dai , Linzhi Tan , Yeyu Su , Kerui Zhao , Yushun Tian , Yu Liu , Tao Liu . Site-specific incorporation of reduction-controlled guest amino acids into proteins for cucurbituril recognition. Chinese Chemical Letters, 2024, 35(5): 109121-. doi: 10.1016/j.cclet.2023.109121
16. [16]
  Xiang Huang , Dongzhen Xu , Yang Liu , Xia Huang , Yangfan Wu , Dongmei Fang , Bing Xia , Wei Jiao , Jian Liao , Min Wang . Asymmetric synthesis of difluorinated α-quaternary amino acids (DFAAs) via Cu-catalyzed difluorobenzylation of aldimine esters. Chinese Chemical Letters, 2024, 35(12): 109665-. doi: 10.1016/j.cclet.2024.109665
17. [17]
  Qian Ren , Xue Dai , Ran Cen , Yang Luo , Mingyang Li , Ziyun Zhang , Qinghong Bai , Zhu Tao , Xin Xiao . A cucurbit[8]uril-based supramolecular phosphorescent assembly: Cell imaging and sensing of amino acids in aqueous solution. Chinese Chemical Letters, 2024, 35(12): 110022-. doi: 10.1016/j.cclet.2024.110022
18. [18]
  Min-Hang Zhou , Jun Jiang , Wei-Min He . EDA-complexes-enabled photochemical synthesis of α-amino acids with imines and tetrabutylammonium oxalate. Chinese Chemical Letters, 2025, 36(1): 110446-. doi: 10.1016/j.cclet.2024.110446
19. [19]
  Yi-Xin Zhang , Fang-Qi Zhang , Ao-Pei Peng , Tao Jiang , Ya-Xi Meng , Yang Li , Shuang-Xi Gu , Yuan-Yuan Zhu . Enantioselective recognition of amino acids in water using emission-tunable chiral fluorescent probes. Chinese Chemical Letters, 2026, 37(1): 111500-. doi: 10.1016/j.cclet.2025.111500
20. [20]
  Xiao Tang , Erik V. Van der Eycken , Liangliang Song . Transition metal-catalyzed C-H activation/annulation for the construction of unnatural amino acids and peptides. Chinese Chemical Letters, 2026, 37(2): 111678-. doi: 10.1016/j.cclet.2025.111678

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(93)
HTML views(9)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142