咔唑醌天然产物的合成研究进展

doi:10.6023/cjoc202412020

摘要/Abstract

咔唑醌天然产物因其良好的抗疟疾、抗肿瘤和抗病毒等生物活性受到了广泛关注, 成为药物化学领域的重要研究对象. 综述了近三十年来咔唑醌类化合物的合成策略, 主要包括过渡金属催化(钯、铜、钌等)、无过渡金属催化及氧化反应等方法, 这些策略实现了咔唑醌类化合物的高效简洁合成. 同时展望了未来的研究方向, 包括开发更高效的催化剂体系、拓展反应底物范围及发展绿色合成方法, 以进一步提升咔唑醌类化合物在药物研发领域的应用潜力. 最后深入探索其构效关系, 为基于咔唑醌母核的新药创制提供新的策略与思路.

关键词: 咔唑醌, 天然产物, 全合成, 生物活性

Carbazolequinone natural products have attracted extensive attention due to their good antimalarial, antitumor, and antiviral biological activities, making them a prominent research target in the field of medicinal chemistry. The synthesis strategies of carbazolequinone compounds are summarized in the past three decades, mainly including transition metal catalysis (palladium, copper, ruthenium, etc.), transition metal-free catalysis and oxidation reaction methods, which can be used to synthesize carbazolequinone compounds in a concise and efficient manner. Moreover, future research directions are envisioned, including the development of more efficient catalytic systems, expansion of substrate scope and advancement of green synthesis methods. These efforts aim to broaden the application prospects of carbazolequinone compounds in drug development. Finally, an in-depth exploration of their structure-activity relationships provides novel strategies and insights for the discovery and design of new drugs based on the carbazolequinone scaffold.

Key words: carbazolequinone, natural product, total synthesis, biological activity

引用此文

莫百川, 李婷婷, 王芳, 李晓杰, 巴达日夫. 咔唑醌天然产物的合成研究进展[J]. 有机化学, 2025, 45(8): 2746-2766.

Baichuan Mo, Tingting Li, Fang Wang, Xiaojie Li, Darifu Ba. Recent Progress in the Synthesis of Carbazolequinone Natural Products[J]. Chinese Journal of Organic Chemistry, 2025, 45(8): 2746-2766.

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图/表 52

图1. 代表性的咔唑醌天然产物

Figure 1. Representive carbazolequinone natural products

图式1. 钯催化氧化环化合成咔唑醌类化合物

Scheme 1. Synthesis of carbazolequinones by Pd-catalyzed oxidative cyclization

图式2. 钯催化5-芳胺基-2-苯硫基-1,4-苯醌的氧化偶联制备咔唑醌类化合物

Scheme 2. Pd-catalyzed oxidative coupling of 5-anilino-2-phenylthio-1,4-benzoquinones to prepare carbazolequinones

图式3. 芳胺与2-甲基-1,4-苯醌的选择性加成反应

Scheme 3. Regioselective addition of arylamines to 2-methyl-1,4-benzoquinone

图式4. 连续两个钯催化合成murrayaquinone A

Scheme 4. Two sequential Pd-catalyzed synthesis of murrayaquinone A

图式5. 钯催化微波辅助合成咔唑醌类化合物

Scheme 5. Pd-catalyzed microwave-assisted synthesis of carbazolequinones

图式6. Kusurkar课题组合成calothrixin B的路线

Scheme 6. Kusurkar’s group synthetic route to calothrixin B

图式7. Ishikura课题组合成calothrixins A和calothrixin B的路线

Scheme 7. Ishikura’s group synthetic route to calothrixin A and calothrixin B

图式8. Nagarajan课题组合成calothrixin A和calothrixin B的路线

Scheme 8. Nagarajan’s group synthetic route to calothrixin A and calothrixin B

图式9. Sieveking课题组制备咔唑醌类化合物

Scheme 9. Sieveking’s group prepared carbazoloquinones

图式10. Kaliyaperumal课题组合成calothrixin B路线

Scheme 10. Kaliyaperumal’s group synthetic route to calothrixin B

图式11. Kaliyaperumal课题组合成murrayaquinone A的路线

Scheme 11. Kaliyaperumal’s group synthetic route to murrayaquinone A

图式12. Hibino课题组合成咔唑醌类化合物的路线

Scheme 12. Hibino’s group synthetic route to carbazolequinones

图式13. 邻羰基咔唑醌类化合物的合成路线

Scheme 13. Synthetic route for the preparation of o-carbocar- bazolequinones

图式14. 钯催化合成咔唑醌衍生物的方法

Scheme 14. Strategies for Pd-catalyzed synthesis of carbazoquinones

图式15. Pd催化C—H芳基化的可能反应机理

Scheme 15. Plausible mechanism for Pd-catalyzed C—H arylation

图式16. Clift课题组合成calothrixin B和A的路线

Scheme 16. Clift’s group synthetic route to calothrixin B and calothrixin A

图式17. 刘晟课题组合成calothrixin B的路线

Scheme 17. Liu’s group synthetic route to calothrixin B

图式18. Calothrixin A和calothrixin B的合成

Scheme 18. Synthesis of calothrixin A and calothrixin B

图式19. Murrayaquionne A的合成路线

Scheme 19. Synthetic route toward murrayaquionne A

图式20. 钯催化双芳基化合成咔唑醌类化合物

Scheme 20. Synthesis of carbazolequinones by Pd-catalyzed double arylation

图式21. 钯催化分子内环化合成咔唑醌类化合物

Scheme 21. Pd-catalyzed intramolecular cyclization for synthesis of carbazoloquinones

图式22. 钯催化合成咔唑醌类化合物

Scheme 22. Pd-catalyzed coupling synthesis of carbazoloquinones

图式23. Pd催化合成各种取代基团的咔唑醌

Scheme 23. Pd catalyzed synthesis of various substituted carbazolequinones

图式24. 可见光诱导Pd催化合成咔唑醌类化合物

Scheme 24. Visible-light-induced Pd-catalyzed synthesis of carbazolequinones

图式25. 光引发钯催化C—H胺化反应可能的机理

Scheme 25. Proposed mechanism for visible-light-promoted Pd-catalyzed C—H

图式26. CuCl2催化合成murrayaquinone A

Scheme 26. CuCl2-catalyzed synthesis of murrayaquinone A

图式27. 铜催化氨基萘醌分子内环化合成咔唑醌类化合物

Scheme 27. Copper-catalyzed intramolecular cyclization of aminonaphthoquinone for the synthesis of carbazolequinones

图式28. 通过Sonogashira偶联和铜催化氧化环化反应合成calothrixin B

Scheme 28. Total synthesis of calothrixin B via Sonogashira coupling/copper-catalyzed oxidative cyclization

图式29. 通过Suzuki交叉偶联和铜催化合成calothrixin B

Scheme 29. Total synthesis of calothrixin B via Suzuki cross-coupling and copper-catalyzed reaction

图式30. 串联关环复分解和脱氢反应合成murrayaquinone A

Scheme 30. Synthesis of murrayaquinone A via tandem ring-closing metathesis and dehydrogenation reaction

图式31. 串联关环复分解和脱氢反应合成咔唑醌类化合物

Scheme 31. Synthesis of carbazolequinones via tandem ring-closing metathesis and dehydrogenation reaction

图式32. Ellipticine quinones化合物的合成路线

Scheme 32. Synthesis route of ellipticine quinones

图式33. 使用FeCl3介导的多米诺反应合成咔唑醌类化合物

Scheme 33. Synthesis of carbazolequinones using FeCl3-mediated domino reaction protocol

图式34. Calothrixin A和calothrixin B的全合成

Scheme 34. Total synthesis of calothrixin A and calothrixin B

图式35. 铱催化咔唑转化为咔唑醌

Scheme 35. Iridium-catalyzed conversion of carbazole to carbazolequinone

图式36. Rh(III)催化的醌与芳烃交叉偶联反应制备咔唑醌

Scheme 36. Rh(III)-catalyzed cross-coupling of quinones with arenes to prepare carbazolequinones

图式37. 金催化末端二炔氧化环化生成咔唑醌类化合物

Scheme 37. Gold catalyzed oxidative cyclization of terminal diynes to carbazolequinones

图式38. 碱促进呋喃吲哚酮与芳炔合成咔唑醌类化合物

Scheme 38. Base-promoted synthesis of carbazolequinones from furoindolones and aryne

图式39. Mal课题组合成calothrixin B的路线

Scheme 39. Mal’s group synthetic route for calothrixin B

图式40. 呋喃并吲哚酮通过Hauser环化反应合成咔唑醌

Scheme 40. Synthesis of carbazolequinone by Hauser annulation of furoindolones

图式41. 芳炔和2-氨基菲啶二酮的[3＋2]环加成合成咔唑醌类化合物

Scheme 41. Synthesis of carbazolequinones via formal [3＋2] cycloaddition of arynes and 2-aminophenanthridinedione

图式42. 芳炔和2-氨基醌的[3＋2]环加成合成咔唑醌类物质

Scheme 42. Synthesis of carbazolequinones by formal [3＋2] cycloaddition of arynes and 2-aminoquinones

图式43. 双三氟乙酰氧基碘苯氧化制备carbazomycin G

Scheme 43. Preparation of carbazomycin G by oxidation of [bis(trifluoroacetoxy)iodo]benzene

图式44. Murrayaquinone A的合成路线

Scheme 44. Route for the synthesis of murrayaquinone A

图式45. Carbazomycin G的全合成

Scheme 45. Total synthesis of carbazomycin G

图式46. Dethe课题组合成calothrixin B的路线

Scheme 46. Dethe’s group synthetic route to calothrixin B

图式47. Nagarajan课题组合成calothrixin B的路线

Scheme 47. Nagarajan’s group synthetic route to calothrixin B

图式48. Cheon课题组合成calothrixin B的路线

Scheme 48. Cheon’s group synthetic route to calothrixin B

图式49. Pabbaraja课题组合成calothrixin B的路线

Scheme 49. Pabbaraja’s group synthetic route to calothrixin B

图式50. 碘氧化溴代Fischer-Borsche环为咔唑醌类化合物

Scheme 50. Iodine oxidation of brominated Fischer-Borsche rings to carbazolequinones

图式51. 碘/高碘酸氧化Fischer-Borsche环为咔唑醌类物质

Scheme 51. Iodine/periodic acid oxidation of Fischer-Borsche rings to carbazolequinones

参考文献 58

[1]	Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
[2]	Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Chem. Rev. 2012, 112, 3193. doi: 10.1021/cr200447s pmid: 22480243
[3]	Takeya, K.; Itoigawa, M.; Furukawa, H. Eur. J. Pharmacol. 1989, 169, 137. pmid: 2599008
[4]	Wu, T.-S.; Huang, S.-C.; Wu, P.-L.; Lee, K.-H. Bioorg. Med. Chem. Lett. 1994, 4, 2395.
[5]	Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; De Chazal, N, M.; Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron 1999, 55, 13513.
[6]	Xu, S.; Nijampatnam, B.; Dutta, S.; Velu, S. E. Mar. Drugs 2016, 14, 17.
[7]	Parvatkar, P. T. Curr. Org. Chem. 2016, 20, 839.
[8]	Bernardo, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Smith, G. D.; Waring, P.; Wilkes, B. A. J. Med. Chem. 2004, 47, 4958. pmid: 15369400
[9]	Norman, A. R.; Norcott, P.; McErlean, C. S. P. Tetrahedron Lett. 2016, 57, 4001.
[10]	Knölker, H.-J.; Fröhner, W. J. Chem. Soc., Perkin Trans. 1 1998, 173.
[11]	Bittner, S.; Krief, P.; Massil, T. Synthesis 1991, 1991, 215.
[12]	Knölker, H.-J.; Reddy, K. R. Heterocycles 2003, 60, 1049.
[13]	Scott, T. L.; Söerberg, B. C. G. Tetrahedron 2003, 59, 6323.
[14]	Sridharan, V.; Martín, M. A.; Menéndez, J. C. Eur. J. Org. Chem. 2009, 2009, 4614.
[15]	Bhosale, S. M.; Gawade, R. L.; Puranik, V. G.; Kusurkar, R. S. Tetrahedron Lett. 2012, 53, 2894.
[16]	Abe, T.; Ikeda, T.; Choshi, T.; Hibino, S.; Hatae, N.; Toyata, E.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem. 2012, 2012, 5018.
[17]	Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2013, 78, 2802. doi: 10.1021/jo302821v pmid: 23421392
[18]	Sieveking, I.; Thomas, P.; Estévez, J. C.; Quiñones, N.; Cuéllar, M. A.; Villena, J.; Espinosa-Bustos, C.; Fierro, A.; Tapia, R. A.; Maya, J. D.; López-Muñoz, R.; Cassels, B. K.; Estévez, R. J.; Salas, C. O. Bioorg. Med. Chem. 2014, 22, 4609.
[19]	Kaliyaperumal, S. A.; Banerjee, S. Org. Biomol. Chem. 2014, 12, 6105. doi: 10.1039/c4ob00493k pmid: 24881674
[20]	Fujii, M.; Nishiyama, T.; Choshi., T.; Satsuki., N.; Fujiwaki, T.; Abe, T.; Ishikura, M.; Hibino, S. Tetrahedron 2014, 70, 1805.
[21]	Martínez-Cifuentes, M.; Clavijo-Allancan, G.; Zuñga-Hormazabal, P.; Aranda, B.; Barriga, A.; Weiss-López, B.; Araya-Maturana, R. Int. J. Mol. Sci. 2016, 17, 1071.
[22]	Mandal, A.; Mondal, S. K.; Jana, A.; Manna, S. K.; Ali, S. A.; Samanta, S. J. Heterocycl. Chem. 2017, 54, 2529.
[23]	Mori-Quiroz, L. M.; Dekarske, M. M.; Prinkki, A. B.; Clift, M. D. J. Org. Chem. 2017, 82, 12257. doi: 10.1021/acs.joc.7b02101 pmid: 29086565
[24]	Lin, K.; Jian, Y.; Zhao, P.; Zhao, C.; Pan. W.; Liu, S. Org. Chem. Front. 2018, 5, 590.
[25]	Zhao, Z. M.; He, Y. Highlights Sciencepap. Oline 2018, 11, 1086 (in Chinese).
	(赵子萌, 贺耘, 中国科技论文在线精品论文, 2018, 11, 1086.)
[26]	Kun, Z.; Xu, H.; Liu, Z.; Song, C. Chin. J. Org. Chem. 2019, 39, 1142 (in Chinese).
	(张坤, 徐红进, 刘咨博, 宋传君, 有机化学, 2019, 39, 1142.) doi: 10.6023/cjoc201812005
[27]	Li, X.; Song, Z.; Chen, X.; Cai, Y.; Liu, Y.; Chen, C.; Peng, J. Chin. J. Org. Chem. 2020, 40, 950 (in Chinese).
	(李雪, 宋子锐, 陈鑫, 蔡轶超, 刘雅婕, 陈春霞, 彭进松, 有机化学, 2020, 40, 950.) doi: 10.6023/cjoc201909040
[28]	Suematsu, N.; Ninomiya, M.; Sugiyama, H.; Udagawa, T.; Tanaka, K.; Koketsu, M. Bioorg. Med. Chem. Lett. 2019, 29, 2243. doi: S0960-894X(19)30418-4 pmid: 31253531
[29]	Chen, X.-L.; Dong, Y.; He, S.; Zhang, R.; Zhang, H.; Tang, L.; Zhang, X.-M.; Wang, J.-Y. Synlett 2019, 30, 615.
[30]	Sisodiya, S.; Paul, S.; Chaudhary, H.; Grewal, P.; Kumar, G.; Daniel, D. P.; Das, B.; Nayak, D.; Guchhait, S. K.; Kundu, C. N.; Banerjee, U. C. Bioorg. Med. Chem. Lett. 2021, 49, 128274.
[31]	Han, Y.; Jiang, W.; Zhang, J.; Peng, J.; Chen, C. Chin. J. Org. Chem. 2022, 42, 266 (in Chinese).
	(韩阳, 姜为超, 张靖, 彭进松, 陈春霞, 有机化学, 2022, 42, 266.) doi: 10.6023/cjoc202104037
[32]	Murphy, W. S.; Bertrand, M. J. Chem. Soc., Perkin Trans. 1 1998, 4115.
[33]	Inoue, A.; Nomura, Y.; Kuroki, N.; Konishi, K. J. Synth. Org. Chem. 1958, 16, 536.
[34]	Ramkumar, N.; Nagarajan, R. Org. Biomol. Chem. 2015, 13, 11046. doi: 10.1039/c5ob01766a pmid: 26395099
[35]	Ramkumar, N.; Nagarajan, R. RSC Adv. 2015, 5, 87838.
[36]	Nishiyama, T.; Choshi, T.; Kitano, K.; Hibino, S. Tetrahedron Lett. 2011, 52, 3876.
[37]	Nishiyama, T.; Hatae, N.; Yoshimura, T.; Takaki, S.; Abe, T.; Ishikura, M.; Hibino, S.; Choshi, T. Eur. J. Med. Chem. 2016, 121, 561. doi: S0223-5234(16)30473-1 pmid: 27318980
[38]	Nishiyama, T.; Hatae, N.; Mizutani, M.; Yoshimura, T.; Kitamura, T.; Miyano, M.; Fujii, M.; Satsuki, N.; Ishikura, M.; Hibino, S.; Choshi, T. Eur. J. Med. Chem. 2017, 136, 1. doi: S0223-5234(17)30345-8 pmid: 28477443
[39]	Ramalingam, B. M.; Saravanan, V.; Mohanakrishnan, A. K. Org. Lett. 2013, 15, 3726. doi: 10.1021/ol4015738 pmid: 23819770
[40]	Xu, S.; Nguyen, T.; Pomilio, I.; Vitale, M. C.; Velu, S. E. Tetrahedron 2014, 70, 5928.
[41]	Eastabrook, A. S.; Wang, C.; Davison, E. K.; Sperry, J. J. Org. Chem. 2015, 80, 1006. doi: 10.1021/jo502509s pmid: 25525818
[42]	Moon, Y.; Jeong, Y.; Kook, D.; Hong, S. Org. Biomol. Chem. 2015, 13, 3918.
[43]	Shu, C.; Shi, C.-Y.; Sun, Q.; Zhou, B.; Li, T.-Y.; He, Q.; Lu, X.; Liu, R.-S.; Ye, L.-W. ACS Catal. 2019, 9, 1019.
[44]	Mal, D.; Senapati, B. K.; Pahari, P. Tetrahedron 2007, 63, 3768.
[45]	Mal, D.; Roy, J.; Biradha, K. Org. Biomol. Chem. 2014, 12, 8196.
[46]	Roy, J.; Pal, R.; Mal, D. Tetrahedron Lett. 2015, 56, 6210.
[47]	Guo, J.; Kiran, I. N. C.; Gao, J.; Reddy, R. S.; He, Y. Tetrahedron Lett. 2016, 57, 3481.
[48]	Guo, J.; Kiran, I. N. C.; Reddy, R. S.; Gao, J.; Tang, M.; Liu, Y.; He, Y. Org. Lett. 2016, 18, 2499.
[49]	Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Tetrahedron 2000, 56, 5807.
[50]	Bhosale, S. M.; Momin, A. A.; Kusurkar, R. S. Tetrahedron 2012, 68, 6420.
[51]	Chakraborty, S.; Saha, C. Eur. J. Org. Chem. 2013, 2013, 5731.
[52]	Dethe, D. H.; Murhade, G. M. Eur. J. Org. Chem. 2014, 2014, 6953.
[53]	Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2014, 79, 736. doi: 10.1021/jo402593w pmid: 24372379
[54]	Lee, S.; Kim, K.-H.; Cheon, C.-H. Org. Lett. 2017, 19, 2785.
[55]	Singh, S.; Samineni, R.; Pabbaraja, S.; Mehta, G. Org. Lett. 2019, 21, 3372.
[56]	Humne, V. T.; Ghom, M. H.; Naykode, M. S.; Dangat, Y.; Vanka, K.; Lokhande, P. Org. Biomol. Chem. 2022, 20, 5726.
[57]	Naykode, M. S.; Lagad, P. M.; Ghom, M. H.; Lokhande, P. D.; Humne, V. T. Tetrahedron 2023, 138, 133413.
[58]	Angulo-Elizari, E.; Henriquez-Figuereo, A.; Morán-Serradilla, C.; Plano, D.; Sanmartín, C. Eur. J. Med. Chem. 2024, 268, 116249.