Citation: Dingding Xia, Chundong Huang, Zhimin Hu, Zhiyong Leng, Miaomiao Zhuo, Shoubhik Das, Shaofei Ni, Yu Zhang, Weidong Zhang. Tandem N–H insertion/C–H functionalization-S_N1 reaction to access unnatural amino esters and the concise synthesis of Streptindole and Arsindoline B[J]. Chinese Chemical Letters, ;2026, 37(10): 112224. doi: 10.1016/j.cclet.2025.112224 shu

Tandem N–H insertion/C–H functionalization-S_N1 reaction to access unnatural amino esters and the concise synthesis of Streptindole and Arsindoline B

Dingding Xia ^{a, b, c, 1} ,
Chundong Huang ^{d, e, 1} ,
Zhimin Hu ^{f, 1} ,
Zhiyong Leng ^{b, 1} ,
Miaomiao Zhuo ^b ,
Shoubhik Das ^g ,
Shaofei Ni ^{d, e, *,} ,
Yu Zhang ^{b, c, *,} ,
Weidong Zhang ^{c, f, *,}

a.
School of Pharmacy, Xinxiang University, Xinxiang 453003, China
b.
Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
c.
State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, NMPA Key Laboratory for Research and Evaluation of Innovative Drug, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
d.
College of Chemistry & Chemical Engineering, Shantou University, Shantou 515063, China
e.
Chemistry and Chemical Engineering Guangdong Laboratory, Shantou 515063, China
f.
School of Pharmacy, Second Military Medical University, Shanghai 200433, China
g.
Department of Chemistry, University of Bayreuth, Bayreuth 95447, Germany

sfni@stu.edu.cn

yzhang@shutcm.edu.cn

wdzhangy@hotmail.com

Received Date: 24 August 2025
Revised Date: 26 November 2025
Accepted Date: 5 December 2025
Available Online: 6 December 2025

Figures(5)

The development of unnatural α-amino esters as key building blocks for peptide drug discovery remains a significant challenge due to the inherent limitations of natural amino acids and scarcity of unnatural amino acids. By leveraging the dual reactivity of α-diazo sulfonium salts, this study reports the efficient synthesis of unnatural α-amino esters via a rhodium-catalyzed three-component tandem strategy. This method undergoes the sequential N–H insertion and nucleophilic substitution (S_N1) reactions, avoiding the tedious and complex reaction operations. In addition, tandem C–H functionalization-S_N1 processes for the facile construction of 1,1-di(hetero)aryl compounds were also achieved. The utility of this methodology was demonstrated by its application in the concise synthesis of the bioactive natural products Streptindole and Arsindoline B, as well as its successful scalability to gram-scale quantities. Furthermore, the mechanistic insights obtained from DFT (density functional theory) calculations provide a rational explanation of the reaction pathway, highlighting the pivotal role of rhodium-carbynoid intermediates.
- Unnatural α-amino esters,
- α-Diazo sulfonium salts,
- Three-component tandem strategy,
- N–H insertion/C–H functionalization,
- Natural products' synthesis
1. [1]
  I. Rady, I.A. Siddiqui, M. Rady, et al., Canc. Lett. 402 (2017) 16–31. doi: 10.1016/j.canlet.2017.05.010
2. [2]
  A. Tilborg, B. Norberg, J. Wouters, Eur. J. Med. Chem. 74 (2014) 411–426. doi: 10.1016/j.ejmech.2013.11.045
3. [3]
  X. Xu, R. Lai, Chem. Rev. 115 (2015) 1760–1846. doi: 10.1021/cr4006704
4. [4]
  K.K. Sharma, K. Sharma, K. Rao, et al., J. Med. Chem. 67 (2024) 19932–19965. doi: 10.1021/acs.jmedchem.4c00110
5. [5]
  N. Krall, F.P. da Cruz, O. Boutureira, et al., J. Med. Chem. 58 (2015) 7719–7733. doi: 10.1021/acs.jmedchem.5b00612
6. [6]
  T.A. Hill, N.E. Shepherd, F. Diness, et al., Angew. Chem. Int. Ed. 53 (2014) 13020–13041. doi: 10.1002/anie.201401058
7. [7]
  M.A.T. Blaskovich, J. Med. Chem. 59 (2016) 10807–10836. doi: 10.1021/acs.jmedchem.6b00319
8. [8]
  C. Cabrele, T.A. Martinek, O. Reiser, et al., J. Med. Chem. 57 (2014) 9718–9739. doi: 10.1021/jm5010896
9. [9]
  Z. Li, B. Yu, Chem. Eur. J. 25 (2019) 16528–16532. doi: 10.1002/chem.201904395
10. [10]
  D. Gillingham, N. Fei, Chem. Soc. Rev. 42 (2013) 4918–4931. doi: 10.1039/c3cs35496b
11. [11]
  K. Tishinov, N. Fei, D. Gillingham, Chem. Sci. 4 (2013) 4401–4406. doi: 10.1039/c3sc51363g
12. [12]
  N.A. Tamayo, Y. Bo, V. Gore, et al., J. Med. Chem. 55 (2012) 1593–1611. doi: 10.1021/jm2013634
13. [13]
  X. Li, S. Chen, W.D. Zhang, et al., Chem. Rev. 120 (2020) 10079–10144. doi: 10.1021/acs.chemrev.0c00532
14. [14]
  Y. Wu, D. Lu, Y. Jiang, et al., J. Med. Chem. 64 (2021) 5802–5815. doi: 10.1021/acs.jmedchem.0c02237
15. [15]
  X. Li, C. Liao, Y. Xu, et al., J. Am. Chem. Soc. 145 (2023) 322–333. doi: 10.1021/jacs.2c09990
16. [16]
  Y. Zhang, J. Vanderghinste, J. Wang, et al., Nat. Comm. 15 (2024) 1474–1482. doi: 10.1038/s41467-024-45790-2
17. [17]
  D.S. Dhanoa, S.W. Bagley, R.S.L. Chang, et al., J. Med. Chem. 36 (1993) 4239–4249. doi: 10.1021/jm00078a014
18. [18]
  M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 120 (1998) 4901–4902. doi: 10.1021/ja980139y
19. [19]
  C. Zhu, T. Akiyama, Tetrahedron Lett. 53 (2012) 416–418. doi: 10.1016/j.tetlet.2011.11.061
20. [20]
  E.P. Jones, P. Jones, A.G.M. Barrett, Org. Lett. 13 (2011) 1012–1015. doi: 10.1021/ol1030469
21. [21]
  Y. Li, Y.X. Su, Y.T. Zhao, et al., ACS Catal. 12 (2022) 13143–13148. doi: 10.1021/acscatal.2c03937
22. [22]
  M.L. Li, H. Yu, Y.H. Li, et al., Science 66 (2019) 990–994. doi: 10.1126/science.aaw9939
23. [23]
  S. Li, X. Yang, Y. Wang, et al., Adv. Synth. Catal. 360 (2018) 4452–4456. doi: 10.1002/adsc.201801018
24. [24]
  H. Tian, W. Xu, Y. Liu, et al., Org. Lett. 22 (2020) 5005–5008. doi: 10.1021/acs.orglett.0c01574
25. [25]
  B. Liu, S.F. Zhu, W. Zhang, et al., J. Am. Chem. Soc. 129 (2007) 5834–5835. doi: 10.1021/ja0711765
26. [26]
  I.K. Mangion, I.K. Nwamba, M. Shevlin, et al., Org. Lett. 11 (2009) 3566–3569. doi: 10.1021/ol901298p
27. [27]
  Y. Matsumoto, J. Sawamura, Y. Murata, et al., J. Am. Chem. Soc. 142 (2020) 8498–8505. doi: 10.1021/jacs.0c02707
28. [28]
  M. Wang, C. Wang, Y. Huo, et al., Nat. Commun. 12 (2021) 6873–6881. doi: 10.1038/s41467-021-27086-x
29. [29]
  C. Huo, Y. Yuan, M. Wu, et al., Angew. Chem. Int. Ed. 53 (2014) 13544–13547. doi: 10.1002/anie.201406905
30. [30]
  M. Salman, Z.Q. Zhu, Z.Z. Huang, Org. Lett. 18 (2016) 1526–1529. doi: 10.1021/acs.orglett.6b00162
31. [31]
  K. Li, G. Tan, J. Huang, et al., Angew. Chem. Int. Ed. 52 (2013) 12942–12945. doi: 10.1002/anie.201306181
32. [32]
  T.A. Trinh, J.M. Schomaker, Nat. Synth. 2 (2023) 600–601. doi: 10.1038/s44160-023-00278-7
33. [33]
  C.J. Moody, Angew. Chem. Int. Ed. 46 (2007) 9148–9150. doi: 10.1002/anie.200703016
34. [34]
  S. Biswas, C. Bolm, Org. Lett. 26 (2024) 1511–1516. doi: 10.1021/acs.orglett.4c00216
35. [35]
  I.D. Jurberg, H.M.L. Davies, Chem. Sci. 9 (2018) 5112–5118. doi: 10.1039/c8sc01165f
36. [36]
  S. Hu, J. Wu, Z. Lu, et al., J. Org. Chem. 86 (2021) 3223–3231. doi: 10.1021/acs.joc.0c02588
37. [37]
  J. Aziz, J.D. Brion, A. Hamze, et al., Adv. Synth. Catal. 355 (2013) 2417–2429. doi: 10.1002/adsc.201300466
38. [38]
  S.S. So, A.E. Mattson, J. Am. Chem. Soc. 134 (2012) 8798–8801. doi: 10.1021/ja3031054
39. [39]
  D. Xia, R. Wu, J. Wang, et al., ACS Catal. 13 (2023) 9806–9816. doi: 10.1021/acscatal.3c02350
40. [40]
  Y. Zhang, Y. Li, S.F. Ni, et al., Chem. Sci. 14 (2023) 10411–10419. doi: 10.1039/d3sc04188c
41. [41]
  Q. Li, D. Wang, J. Wang, et al., Sci. China Chem. 68 (2025) 1937–1944. doi: 10.1007/s11426-024-2380-4
42. [42]
  Y. Zhang, X. Han, P. Wang, et al., ACS Central Sci. 11 (2025) 742–752. doi: 10.1021/acscentsci.5c00099
43. [43]
  X. Han, P. Wang, L. Zhang, et al., J. Nat. Prod. 88 (2025) 1663–1670. doi: 10.1021/acs.jnatprod.5c00420
44. [44]
  Y. Zhang, X. Li, D. Li, et al., Green Chem. 6 (2024) 4600–4608. doi: 10.1039/d3gc04431a
45. [45]
  R. Weiss, J. Seubert, F. Hampel, Angew. Chem. Int. Ed. 33 (1994) 1952-1593. doi: 10.1002/anie.199419521
46. [46]
  S. Timmann, M. Alcarazo, Chem. Commun. 59 (2023) 8032–8042. doi: 10.1039/d3cc01620j
47. [47]
  B. Xu, S.F. Zhu, Z.C. Zhang, et al., Chem. Sci. 5 (2014) 1442–1448. doi: 10.1039/c3sc52807c
48. [48]
  Y. Liang, H. Zhou, Z.X. Yu, J. Am. Chem. Soc. 131 (2009) 17783–17785. doi: 10.1021/ja9086566
49. [49]
  E. Palomo, A.K. Sharma, Z. Wang, et al., J. Am. Chem. Soc. 145 (2023) 4975–4981. doi: 10.1021/jacs.3c00012
50. [50]
  L. Jiang, Z. Wang, M. Armstrong, et al., Angew. Chem. Int. Ed. 60 (2021) 6177–6184. doi: 10.1002/anie.202015077
51. [51]
  Z. Wang, A.G. Herraiz, A.M. del Hoyo, et al., Nature 554 (2018) 86–91. doi: 10.1038/nature25185
52. [52]
  S. Timmann, T.H. Wu, C. Golz, et al., Chem. Sci. 15 (2024) 5938–5943. doi: 10.1039/d4sc01138d
53. [53]
  X. Li, C. Golz, M. Alcarazo, Angew. Chem. Int. Ed. 60 (2021) 6943–6948. doi: 10.1002/anie.202014775
54. [54]
  X. Ma, A. Sun, K.K. Wang, New J. Chem. 46 (2022) 6856–6859. doi: 10.1039/d2nj01186g
55. [55]
  L. Liu, Y. Zhang, Org. Lett. 25 (2023) 592–596. doi: 10.1021/acs.orglett.2c04114
56. [56]
  J.Y. Dong, H. Wang, S. Mao, et al., Adv. Synth. Catal. 363 (2021) 2133–2139. doi: 10.1002/adsc.202001436
57. [57]
  J. Li, X.C. Lu, Y. Xu, et al., Org. Lett. 22 (2020) 9621–9626. doi: 10.1021/acs.orglett.0c03663
58. [58]
  X.C. Xu, Y. Sang, M. Yang, et al., Org. Chem. Front. 11 (2024) 5502–5510. doi: 10.1039/d4qo00652f
59. [59]
  W.W. Zhao, M.Y. Tian, Y.L. Zhou, et al., Angew. Chem. Int. Ed. 63 (2024) e202318887. doi: 10.1002/anie.202318887
60. [60]
  Z. Wang, L. Jiang, P. Sarró, et al., J. Am. Chem. Soc. 141 (2019) 15509–15514. doi: 10.1021/jacs.9b08632
61. [61]
  L. Jiang, P. Sarró, W. Teo, et al., Chem. Sci. 13 (2022) 4327–4333. doi: 10.1039/d2sc00968d
62. [62]
  X. Wang, W.Y. Tong, B. Huang, J. Am. Chem. Soc. 144 (2022) 4952–4965. doi: 10.1021/jacs.1c12874
63. [63]
  J. Luo, M. Zhang, G. Liu, et al., Org. Chem. Front. 11 (2024) 3596–3601. doi: 10.1039/d4qo00401a
64. [64]
  H.F. Tu, A. Jeandin, M.G. Suero, J. Am. Chem. Soc. 144 (2022) 16737–16743. doi: 10.1021/jacs.2c07769
65. [65]
  Y. Qian, J. Tang, X. Zhou, et al., J. Am. Chem. Soc. 145 (2023) 26403–26411. doi: 10.1021/jacs.3c10460
66. [66]
  X. Yang, X. Zhou, W. Hu, et al., Nat. Commun. 16 (2025) 1434-1412. doi: 10.1038/s41467-025-56446-0
67. [67]
  Y. Wang, X. Wei, Y. Chen, et al., Org. Chem. Front. 12 (2025) 3653–3664.
68. [68]
  J.D. Pizarro, I.L. Schmidtke, A. Nova, et al., ACS Catal. 12 (2022) 6851–6856. doi: 10.1021/acscatal.2c01713
69. [69]
  X.S. Liu, Z. Tang, Z.Y. Si, et al., Angew. Chem. Int. Ed. 61 (2022) e202208874. doi: 10.1002/anie.202208874
70. [70]
  S. Jia, D. Xing, D. Zhang, et al., Angew. Chem., Int. Ed. 53 (2014) 13098–13101. doi: 10.1002/anie.201406492
71. [71]
  B. Ma, Z. Chu, B. Huang, et al., Angew. Chem. Int. Ed. 56 (2017) 2749–2753. doi: 10.1002/anie.201611809
72. [72]
  B. Xu, M.L. Li, X.D. Zuo, et al., J. Am. Chem. Soc. 137 (2015) 8700–8703. doi: 10.1021/jacs.5b05086
73. [73]
  Z. Yu, B. Ma, M. Chen, et al., J. Am. Chem. Soc. 136 (2014) 6904–6907. doi: 10.1021/ja503163k
74. [74]
  L.P. Zhao, P.J. Li, L. Wang, et al., Angew. Chem. Int. Ed. 61 (2022) e202207360. doi: 10.1002/anie.202207360
75. [75]
  L.P. Zhao, S.Y. Zhang, H.K. Liu, et al., J. Am. Chem. Soc. 145 (2023) 15553–15564. doi: 10.1021/jacs.3c04989
76. [76]
  H. Li, Q. Li, Z. Lu, et al., J. Am. Chem. Soc. 138 (2016) 15555–15558. doi: 10.1021/jacs.6b10880
77. [77]
  Z. Lu, H. Li, M. Bian, et al., J. Am. Chem. Soc. 137 (2015) 13764–13767. doi: 10.1021/jacs.5b09198
78. [78]
  Y. Zhang, X. Yang, H. Zhou, et al., Org. Chem. Front. 5 (2018) 2120–2125. doi: 10.1039/c8qo00341f
79. [79]
  T. Abe, S. Nakamura, R. Yanada, et al., Org. Lett. 15 (2013) 3622–3625. doi: 10.1021/ol401486s
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19. [19]
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20. [20]
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通讯作者: 陈斌, bchen63@163.com

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沈阳化工大学材料科学与工程学院沈阳 110142

Tandem N–H insertion/C–H functionalization-SN1 reaction to access unnatural amino esters and the concise synthesis of Streptindole and Arsindoline B

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通讯作者: 陈斌, bchen63@163.com

Tandem N–H insertion/C–H functionalization-S_N1 reaction to access unnatural amino esters and the concise synthesis of Streptindole and Arsindoline B