Citation: Yan Zong, Qiuchen Huang, Xiaomei Zou, Qifan Zhou, Yuanmei Wen, Dong Li, Yongzhi Chen, Xuefeng Tan, Gen-Qiang Chen, Xumu Zhang. Enantioselective total synthesis of 3-deoxy-epothilone B enabled by efficient asymmetric catalysis[J]. Chinese Chemical Letters, ;2026, 37(8): 112162. doi: 10.1016/j.cclet.2025.112162 shu

Enantioselective total synthesis of 3-deoxy-epothilone B enabled by efficient asymmetric catalysis

Yan Zong ^{a, b} ,
Qiuchen Huang ^a ,
Xiaomei Zou ^e ,
Qifan Zhou ^a ,
Yuanmei Wen ^a ,
Dong Li ^c ,
Yongzhi Chen ^a ,
Xuefeng Tan ^d ,
Gen-Qiang Chen ^{a, *,} ,
Xumu Zhang ^{a, c, *,}

a.
Department of Chemistry, Shenzhen Grubbs Institute, Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, and Medi-Pingshan, Southern University of Science and Technology, Shenzhen 518000, China
b.
Department of Natural Products Chemistry, Key Lab of Chemical Biology, School of Pharmaceutical Sciences, Shandong University, Ji’nan 250012, China
c.
Chemistry and Chemical Engineering Guangdong Laboratory, Shantou 515031, China
d.
Department of Chemistry, City University of Hong Kong, Hong Kong 999077, China
e.
Medical School, Shandong Xiehe University, Ji’nan 250109, China

chengq@sustech.edu.cn

zhangxm@sustech.edu.cn

Received Date: 3 July 2025
Revised Date: 12 November 2025
Accepted Date: 23 November 2025
Available Online: 24 November 2025

Figures(4)

Here an enantioselective total synthesis of bioactive 3-deoxy-epothilone B is reported. Key features of this synthesis include Nelson’s alkaloid-catalyzed asymmetric ketene-aldehyde [2 + 2] cycloaddition to expeditiously construct the froward cis/trans configuration of C6−C8 position in a stereospecific manner and the subsequent allylic transposition nucleophilic addition to forge the C2−C4 unit. Other key steps involve an iridium-catalyzed asymmetric hydrogenation (AH) to introduce the C15 stereogenic center and a rhodium-catalyzed linear selective hydroformylation to install the C1 unit with our catalytic systems. In addition, the highly electrophilic enantioenriched β-lactone is regarded as a potential synthon for modular syntheses of a series of C1−C4 modified epothilones. Further biological activity evaluation indicated significant cytotoxicity of 3-deoxy-epothilone B against a panel of human tumor cell lines.
- Total synthesis,
- Asymmetric hydrogenation,
- [2+2] Cycloaddition,
- Allylic transposition,
- Antitumor agent
1. [1]
  K. Gerth, N. Bedorf, G. Hoefle, H. Irschik, H. Reichenbach, J. Antibiot. 49 (1996) 560–563. doi: 10.7164/antibiotics.49.560
2. [2]
  G. Höfle, N. Bedorf, H. Steinmetz, et al., Angew. Chem. Int. Ed. 35 (1996) 1567–1569. doi: 10.1002/anie.199615671
3. [3]
  I.H. Hardt, H. Steinmetz, K. Gerth, et al., J. Nat. Prod. 64 (2001) 847–856. doi: 10.1021/np000629f
4. [4]
  K.H. Altmann, B. Pfeiffer, S. Arseniyadis, B.A. Pratt, K.C. Nicolaou, ChemMedChem 2 (2007) 396–423. doi: 10.1002/cmdc.200600206
5. [5]
  K.H. Altmann, Preclinical pharmacology and structure-activity studies of epothilones, in: K.H. Altmann, G. Höfle, R. Müller, J. Mulzer, K. Prantz (Eds.), The Epothilones: An Outstanding Family of Anti-Tumor Agents: From Soil to the Clinic, Springer Vienna, Vienna, 2009, pp. 157–220.
6. [6]
  T.K. Allred, F. Manoni, P.G. Harran, Chem. Rev. 117 (2017) 11994–12051. doi: 10.1021/acs.chemrev.7b00126
7. [7]
  P. Zhang, M. Sun, R. Qiu, et al., Cancer Chemoth. Pharm. 68 (2011) 971–978. doi: 10.1007/s00280-011-1571-6
8. [8]
  P. Zhang, Z. Tong, F. Tian, et al., J. Hematol. Oncol. 9 (2016) 68. doi: 10.1080/02286203.2016.1188344
9. [9]
  P. Zhang, T. Sun, Q. Zhang, et al., Lancet Oncol. 18 (2017) 371–383. doi: 10.1016/S1470-2045(17)30088-8
10. [10]
  F. Li, T. Huang, Y. Tang, et al., Cell Death Dis. 12 (2021) 338. doi: 10.1038/s41419-021-03619-6
11. [11]
  R.M. Borzilleri, X. Zheng, R.J. Schmidt, et al., J. Am. Chem. Soc. 122 (2000) 8890–8897. doi: 10.1021/ja001899n
12. [12]
  W. Zhan, Y. Jiang, S. Sharma, et al., Chem. Eur. J. 17 (2011) 14792–14804. doi: 10.1002/chem.201102630
13. [13]
  R.E. Taylor, Y. Chen, A. Beatty, D.C. Myles, Y. Zhou, J. Am. Chem. Soc. 125 (2003) 26–27. doi: 10.1021/ja028196l
14. [14]
  K.C. Nicolaou, D. Rhoades, Y. Wang, et al., J. Am. Chem. Soc. 139 (2017) 7318–7334. doi: 10.1021/jacs.7b02655
15. [15]
  K.C. Nicolaou, D. Vourloumis, T. Li, et al., Angew. Chem. Int. Ed. 36 (1997) 2097–2103. doi: 10.1002/anie.199720971
16. [16]
  D.S. Su, A. Balog, D. Meng, et al., Angew. Chem. Int. Ed. 36 (1997) 2093–2096. doi: 10.1002/anie.199720931
17. [17]
  S.J. Danishefsky, J. Org. Chem. 64 (1999) 8434–8456. doi: 10.1021/jo991006d
18. [18]
  M. Wang, X. Xia, Y. Kim, et al., Org. Lett. 1 (1999) 43–46. doi: 10.1021/ol990521v
19. [19]
  A. Regueiro-Ren, K. Leavitt, S.H. Kim, et al., Org. Lett. 4 (2002) 3815–3818. doi: 10.1021/ol026589j
20. [20]
  F. Cachoux, T. Isarno, M. Wartmann, K.H. Altmann, Angew. Chem. Int. Ed. 44 (2005) 7469–7473. doi: 10.1002/anie.200501760
21. [21]
  K.H. Altmann, Preparation of epothilone derivatives, WO2005090335 A1, 2005.
22. [22]
  R. Qiu, Production of epothilones derivatives in Myxococcus or Sorangium comprising PKS mutant gene, CN1521258A, 2004.
23. [23]
  K.C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, Z. Yang, Angew. Chem. Int. Ed. 35 (1996) 2399–2401. doi: 10.1002/anie.199623991
24. [24]
  K.C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, Angew. Chem. Int. Ed. 36 (1997) 525–527. doi: 10.1002/anie.199705251
25. [25]
  D. Schinzer, A. Limberg, A. Bauer, et al., Angew. Chem. Int. Ed. 37 (1998) 2675–2678. doi: 10.1002/(SICI)1521-3773(19981016)37:19<2675::AID-ANIE2675>3.0.CO;2-O
26. [26]
  C.R. Harris, S.D. Kuduk, A. Balog, et al., J. Am. Chem. Soc. 121 (1999) 7050–7062. doi: 10.1021/ja991189l
27. [27]
  J. Mulzer, A. Mantoulidis, E. Öhler, J. Org. Chem. 65 (2000) 7456–7467. doi: 10.1021/jo0007480
28. [28]
  C.B. Lee, Z. Wu, F. Zhang, et al., J. Am. Chem. Soc. 123 (2001) 5249–5259. doi: 10.1021/ja010039j
29. [29]
  J.D. White, R.G. Carter, K.F. Sundermann, M. Wartmann, J. Am. Chem. Soc. 123 (2001) 5407–5413. doi: 10.1021/ja010454b
30. [30]
  G. Koch, O. Loiseleur, D. Fuentes, A. Jantsch, K.H. Altmann, Org. Lett. 4 (2002) 3811–3814. doi: 10.1021/ol026480b
31. [31]
  D. Schinzer, Model Aldol Reactions, Wiley-VCH Verlag GmbH & Co. KGaA, 2004, pp. 311–328.
32. [32]
  J.D. Frein, R.E. Taylor, D.L. Sackett, Org. Lett. 11 (2009) 3186–3189. doi: 10.1021/ol900971r
33. [33]
  J. Wang, B.F. Sun, K. Cui, G.Q. Lin, Org. Lett. 14 (2012) 6354–6357. doi: 10.1021/ol303148g
34. [34]
  A.M. Haydl, B. Breit, Chem. Eur. J. 23 (2017) 541–545. doi: 10.1002/chem.201605011
35. [35]
  K.C. Nicolaou, S. Ninkovic, F. Sarabia, et al., J. Am. Chem. Soc. 119 (1997) 7974–7991. doi: 10.1021/ja971110h
36. [36]
  K.C. Nicolaou, N. Winssinger, J. Pastor, et al., Nature 387 (1997) 268–272. doi: 10.1038/387268a0
37. [37]
  D. Schinzer, A. Bauer, J. Schieber, Chem. Eur. J. 5 (1999) 2492–2500. doi: 10.1002/(SICI)1521-3765(19990903)5:9<2492::AID-CHEM2492>3.0.CO;2-R
38. [38]
  R.E. Taylor, Y. Chen, Org. Lett. 3 (2001) 2221–2224. doi: 10.1021/ol010094x
39. [39]
  T. Gaich, J. Mulzer, Org. Lett. 7 (2005) 1311–1313. doi: 10.1021/ol0500923
40. [40]
  A.W. Sun, S. Lackner, B.M. Stoltz, Trends Chem. 1 (2019) 630–643. doi: 10.1016/j.trechm.2019.05.008
41. [41]
  X. Shen, A.S. Wasmuth, J. Zhao, C. Zhu, S.G. Nelson, J. Am. Chem. Soc. 128 (2006) 7438–7439. doi: 10.1021/ja061938g
42. [42]
  C. Zhu, X. Shen, S.G. Nelson, J. Am. Chem. Soc. 126 (2004) 5352–5353. doi: 10.1021/ja0492900
43. [43]
  B. Chandra, D. Fu, S.G. Nelson, Angew. Chem. Int. Ed. 49 (2010) 2591–2594. doi: 10.1002/anie.200906245
44. [44]
  Z. Guo, R. Bao, Y. Li, et al., Angew. Chem. Int. Ed. 60 (2021) 14545–14553. doi: 10.1002/anie.202102614
45. [45]
  M. Mohammad, V. Chintalapudi, J.M. Carney, et al., Angew. Chem. Int. Ed. 58 (2019) 18177–18181. doi: 10.1002/anie.201908917
46. [46]
  S. Schulthoff, J.Y. Hamilton, M. Heinrich, et al., Angew. Chem. Int. Ed. 60 (2021) 446–454. doi: 10.1002/anie.202011472
47. [47]
  X. Wang, Z. Wang, X. Ma, et al., Angew. Chem. Int. Ed. 61 (2022) e202200258. doi: 10.1002/anie.202200258
48. [48]
  E. Yiannakas, M.I. Grimes, J.T. Whitelegge, A. Fürstner, A.N. Hulme, Angew. Chem. Int. Ed. 60 (2021) 18504–18508. doi: 10.1002/anie.202105732
49. [49]
  J. Egger, S. Fischer, P. Bretscher, et al., Org. Lett. 17 (2015) 4340–4343. doi: 10.1021/acs.orglett.5b02181
50. [50]
  C. Tan, W. Chen, X. Mu, et al., Org. Lett. 17 (2015) 2338–2341. doi: 10.1021/acs.orglett.5b00831
51. [51]
  S. Zhang, S. Zhang, Y. Fan, et al., Angew. Chem. Int. Ed. 62 (2023) e202313186. doi: 10.1002/anie.202313186
52. [52]
  J. Wang, B.F. Sun, K. Cui, G.Q. Lin, Org. Lett. 14 (2012) 6354–6357. doi: 10.1021/ol303148g
53. [53]
  H. Ece, Y. Tange, T. Yurino, T. Ohkuma, Synlett 32 (2021) 935–939. doi: 10.1055/a-1373-7017
54. [54]
  H. Zhang, G. Li, B. Su, et al., Sci. Rep. 7 (2017) 16916. doi: 10.1038/s41598-017-17015-8
55. [55]
  J. Yu, F. Huang, W. Fang, et al., Green Synth. Catal. 3 (2022) 175–178.
56. [56]
  C. Yin, Y.F. Jiang, F. Huang, et al., Nat. Commun. 14 (2023) 3718. doi: 10.1038/s41467-023-39375-8
57. [57]
  Y. Zong, X. Zou, J. Song, G.Q. Chen, X. Zhang, Org. Lett. 25 (2023) 6875–6880. doi: 10.1021/acs.orglett.3c02565
58. [58]
  Z. Meng, H. Yu, L. Li, et al., Nat. Commun. 6 (2015) 6096. doi: 10.1038/ncomms7096
59. [59]
  Y. Li, K. Dong, Z. Wang, K. Ding, Angew. Chem. Int. Ed. 52 (2013) 6748–6752. doi: 10.1002/anie.201302349
60. [60]
  G.Q. Chen, J.M. Huang, B.J. Lin, et al., CCS Chem. 2 (2020) 468–477. doi: 10.31635/ccschem.020.202000176
61. [61]
  X. Du, Y. Xiao, Y. Yang, et al., Angew. Chem. Int. Ed. 60 (2021) 11384–11390. doi: 10.1002/anie.202016705
62. [62]
  S.F. Zhu, Y.B. Yu, S. Li, L.X. Wang, Q.L. Zhou, Angew. Chem. Int. Ed. 51 (2012) 8872–8875. doi: 10.1002/anie.201204363
63. [63]
  Q. Wang, X. Liu, X. Liu, et al., Chem. Commun. 50 (2014) 978–980. doi: 10.1039/C3CC47727D
64. [64]
  M. Valluri, R.M. Hindupur, P. Bijoy, et al., Org. Lett. 3 (2001) 3607–3609. doi: 10.1021/ol016173q
65. [65]
  N. Martin, E.J. Thomas, Tetrahedron Lett. 42 (2001) 8373–8377. doi: 10.1016/S0040-4039(01)01795-6
66. [66]
  M. Yoshino, K. Eto, K. Takahashi, J. Ishihara, S. Hatakeyama, Org. Biomol. Chem. 10 (2012) 8164–8174. doi: 10.1039/c2ob26084k
67. [67]
  N.D. Bartolo, K.A. Woerpel, J. Org. Chem. 83 (2018) 10197–10206. doi: 10.1021/acs.joc.8b01430
68. [68]
  B. Tiwari, J. Zhang, Y.R. Chi, Angew. Chem. Int. Ed. 51 (2012) 1911–1914. doi: 10.1002/anie.201107473
69. [69]
  S.A. Shipilovskikh, A.E. Rubtsov, A.V. Malkov, Org. Lett. 19 (2017) 6760–6762. doi: 10.1021/acs.orglett.7b03512
70. [70]
  Y. Zong, R. Zhang, B. Ma, et al., Sci. Adv. 10 (2024) eado9607. doi: 10.1126/sciadv.ado9607
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