Application of Michael/Aldol Cascade Cyclization Reactions in Natural Product Synthesis

doi:10.6023/A25070247

Acta Chimica Sinica ›› 2025, Vol. 83 ›› Issue (11): 1397-1413.DOI: 10.6023/A25070247 Previous Articles Next Articles

Review

Michael/aldol串联环化反应在天然产物合成中的应用

赵雅宸^a, 俞飚^a^,^b^,^*()

^a 国科大杭州高等研究院化学与材料科学学院杭州 310024
^b 中国科学院上海有机化学研究所生命过程小分子调控全国重点实验室上海 200032

投稿日期:2025-07-05 发布日期:2025-08-20
通讯作者: 俞飚

作者简介:

赵雅宸, 国科大杭州高等研究院博士后, 2018年硕士毕业于郑州大学, 2023年博士毕业于中国科学院上海有机化学研究所(导师: 俞飚研究员), 2023年9月加入国科大杭州高等研究院俞飚工作室进行博士后工作, 从事天然产物全合成研究.

俞飚, 1989年本科毕业于北京大学技术物理系, 1995年于中科院上海有机化学研究所获博士学位, 1996年于纽约大学完成博士后. 历任中科院上海有机化学研究所助理研究员、副研究员、研究员(1999). 主要从事聚糖和糖缀合物的化学合成、合成方法学和化学生物学研究.

基金资助:
项目受上海市科技计划(22YS1401000)

Application of Michael/Aldol Cascade Cyclization Reactions in Natural Product Synthesis

Zhao Yachen^a, Yu Biao^a^,^b^,^*()

^a School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024
^b State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032

Received:2025-07-05 Published:2025-08-20
Contact: Yu Biao
Supported by:
Shanghai Science and Technology Plan Project(22YS1401000)

In modern natural product synthesis, chemists are often able to execute two or even multiple chemical reactions to occur in one pot by designing substrate structures and screening reaction conditions, thus to synthesize target molecules in a concise and efficient manner. Such a reaction sequence is termed a cascade reaction. Michael addition and aldol reaction are the two most applied classic reactions in organic synthesis. By regulating the reaction conditions and designing the substrates, they can occur successively in the same system to form complex cyclic systems. This cascade reaction is termed Michael/aldol cascade cyclization reaction, which can effectively improve the atomic and step economy of a synthesis. This review comprises more than 40 reported studies on natural product synthesis as examples to summarize nine common types of Michael/aldol cascade cyclization reactions, to demonstrate their applications as key steps in complex natural product synthesis, and to outlook on the direction of further developments of this methodology.

Key words: Michael addition, aldol reaction, cascade reaction, cyclization reaction, natural product synthesis

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Zhao Yachen, Yu Biao. Application of Michael/Aldol Cascade Cyclization Reactions in Natural Product Synthesis[J]. Acta Chimica Sinica, 2025, 83(11): 1397-1413.

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Fig. & Tab. 47

Scheme 1. Two types of Michael/aldol cascade cyclization reactions

Scheme 2. Work from the Alonso group (2010)

Scheme 3. Work from the Yamamoto group (2007)

Scheme 4. Work from the Hong group (2012)

Scheme 5. Work from the McNulty group (2014)

Scheme 6. Work from the Han group (2019)

Scheme 7. Work from the Han group (2020)

Scheme 8. Work from the Yao group (2012)

Scheme 9. Work from the Soos group (2020)

Scheme 10. Work from the Han group (2025, aspidosperma)

Scheme 11. Work from the Baran group (2016)

Scheme 12. Work from the Kigoshi group (2022)

Scheme 13. Work from the Han group (2025, cryptoquinonemethide)

Scheme 14. Work from the Chen group (2025) and the Ding group (2023)

Scheme 15. Work from the Nagorny group (2016)

Scheme 16. Work from the Liu group (2012)

Scheme 17. Work from the Greaney group (2012)

Scheme 18. Work from the Chiu group (1998~2001)

Scheme 19. Work from the Constantino group (2008)

Scheme 20. Work from the White group (2011)

Scheme 21. Work from the Stoltz group (2011)

Scheme 22. Work from the Frontier group (2014)

Scheme 23. Work from the Trauner group (2018)

Scheme 24. Work from the Lu group (2024)

Scheme 25. Work from the Evans group (2013)

Scheme 26. Work from the Bräse group (2003, 2005)

Scheme 27. Work from the Nicolaou and Chen group (2008)

Scheme 28. Work from the Lei group (2019)

Scheme 29. Work from the Kuwahara group (2019)

Scheme 30. Work from the Gao group (2020)

Scheme 31. N-Michael-aldol cascade reaction and its competitive reactions

Scheme 32. Work from the Chavan group (2008)

Scheme 33. Work from the Tomioka group (2001)

Scheme 34. Work from the Zhao group (2016)

Scheme 35. Work from the Lee group (2021)

Scheme 36. Work from the Buda group (2019, 2020)

Scheme 37. Work from the Porco group (2011)

Scheme 38. Work from the Greaney group (2012)

Scheme 39. Work from the Frontier group (2013)

Scheme 40. Work from the Woggon group (2008, 2009)

Scheme 41. Work from the Bräse group (2009)

Scheme 42. Work from the Frontier group (2013)

Scheme 43. Work from the Ding group (2015)

Scheme 44. Work from the Yang group (2022)

Scheme 45. Work from the Jia group (2024)

Scheme 46. Work from the Bräse group (2011)

Scheme 47. Work from the Trauner group (2018)

References 67

[19]	Varga S.; Angyal P.; Martin G.; Egyed O.; Holczbauer T.; Soos T. Angew. Chem., Int. Ed. 2020, 59, 13547.
[20]	Tan D.-X.; Zhou J.; Gu C.-Y.; Li Z.-Y.; Shen Y.-J.; Han F.-S. Che. 2025, 102440.
[21]	Martinez L. P.; Umemiya S.; Wengryniuk S. E.; Baran P. S. J. Am. Chem. Soc. 2016, 138, 7536.
[22]	Mitsugi K.; Takabayashi T.; Ohyoshi T.; Kigoshi H. Org. Lett. 2022, 24, 4635.
[23]	Zhang Y. H.; Deng L. H.; Tan D. X.; Han F. S. Angew. Chem., Int. Ed. 2025, 64, e202423944.
[24]	Yao W.; Liu Z.; Ling H.; Wang H.; Zheng H.; Wang S. H.; Zhu D. Y.; Zhang S. Y.; Chen X. J. Am. Chem. Soc. 2025, 147, 15963.
[25]	Sun D.; Chen R.; Tang D.; Xia Q.; Zhao Y.; Liu C. H.; Ding H. J. Am. Chem. Soc. 2023, 145, 11927.
[26]	Kaplan W.; Khatri H. R.; Nagorny P. J. Am. Chem. Soc. 2016, 138, 7194.
[27]	Huang X.; Song L.; Xu J.; Zhu G.; Liu B. Angew. Chem., Int. Ed. 2013, 52, 952.
[28]	Nazef N.; Davies R. D. M.; Greaney M. F. Org. Lett. 2012, 14, 3720.
[29]	Chiu P.; Chen B.; Cheng K. F. Tetrahedron Lett. 1998, 39, 9229.
[30]	Chiu P.; Szeto C.-P.; Geng Z.; Cheng K.-F. Org. Lett. 2001, 3, 1901.
[31]	Chiu P.; Szeto C. P.; Geng Z.; Cheng K. F. Tetrahedron Lett. 2001, 42, 4091.
[32]	Sass D. C.; Gomes Heleno V. C.; Callegari Lopes J. L.; Constantino M. G. Tetrahedron Lett. 2008, 49, 3877.
[33]	Sass D. C.; Heleno V. C.; Morais G. O.; Lopes J. L.; Lopes N. P.; Constantino M. G. Org. Biomol. Chem. 2011, 9, 6148.
[34]	Schwartz K. D.; White J. D. Org. Lett. 2011, 13, 248.
[1]	Tietze L. F.; Beifuss U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
[2]	Bai L.; Jiang X. Chem Catal. 2023, 3, 1.
[3]	Huang G.; Li X. Curr. Org. Synth. 2017, 14, 568.
[4]	Hagiwara H. Nat. Prod. Commun. 2021, 16, 1.
[5]	Zhang M.; Sha F.; Wu X. Chin. J. Org. Chem. 2025, 45, 1369 (in Chinese).
	(张明美, 沙风, 伍新燕, 有机化学, 2025, 45, 1369.)
[6]	Schetter B.; Mahrwald R. Angew. Chem., Int. Ed. 2006, 45, 7506.
[7]	Kalesse M.; Brodmann T.; Lorenz M.; Schäckel R.; Simsek S. Synlet. 2009, 2, 174.
[8]	Mandal S.; Mandal S.; Ghosh S. K.; Ghosh A.; Saha R.; Banerjee S.; Saha B. Synth. Commun. 2016, 46, 1327.
[9]	He Q.; Li J.; Yu S.; Wu D.; Ye J.; Huang P. Acta Chim. Sinic. 2023, 81, 1265 (in Chinese).
	(何倩, 李杰, 喻思佳, 吴东坪, 叶剑良, 黄培强, 化学学报, 2023, 81, 1265.)
[10]	Liu Z.-Q. Curr. Org. Chem. 2018, 22, 1347.
[35]	Mukherjee H.; McDougal N. T.; Virgil S. C.; Stoltz B. M. Org. Lett. 2011, 13, 825.
[36]	Carlsen P. N.; Mann T. J.; Hoveyda A. H.; Frontier A. J. Angew. Chem., Int. Ed. 2014, 53, 9334.
[37]	Hartrampf N.; Winter N.; Pupo G.; Stoltz B. M.; Trauner D. J. Am. Chem. Soc. 2018, 140, 8675.
[38]	Wang S.; Zhong C.; Huang Y.; Lu P. Angew. Chem., Int. Ed. 2024, 63, e202400515.
[39]	Catino A. J.; Sherlock A.; Shieh P.; Wzorek J. S.; Evans D. A. Org. Lett. 2013, 15, 3330.
[40]	Lesch B.; Brase S. Angew. Chem., Int. Ed. Engl. 2004, 43, 115.
[41]	Bräse S.; Lesch B.; Toräng J.; Nieger M. Synthesi. 2005, 11, 1888.
[42]	Nicolaou K. C.; Sun Y. P.; Peng X. S.; Polet D.; Chen D. Y. Angew. Chem., Int. Ed. 2008, 47, 7310.
[43]	Nicolaou K. C.; Peng X.-S.; Sun Y.-P.; Polet D.; Zou B.; Lim C. S.; Chen D. Y. K. J. Am. Chem. Soc. 2009, 131, 10587.
[11]	Heravi M. M.; Alipour B.; Zadsirjan V.; Malmir M. Asian J. Org. Chem. 2023, 12, 1.
[12]	Cagide‐Fagín F.; Alonso R. Eur. J. Org. Chem. 2010, 2010, 6741.
[13]	Li P.; Payette J. N.; Yamamoto H. J. Am. Chem. Soc. 2007, 129, 9534.
[14]	Hong B. C.; Hsu C. S.; Lee G. H. Chem. Commun. 2012, 48, 2385.
[15]	McNulty J.; Zepeda-Velazquez C. Angew. Chem., Int. Ed. 2014, 53, 8450.
[16]	Tan D. X.; Zhou J.; Liu C. Y.; Han F. S. Angew. Chem., Int. Ed. 2020, 59, 3834.
[17]	Zhou J.; Tan D. X.; Han F. S. Angew. Chem., Int. Ed. 2020, 59, 18731.
[18]	Ding X.-H.; Li X.; Liu D.; Cui W.-C.; Ju X.; Wang S.; Yao Z.-J. Tetrahedro. 2012, 68, 6240.
[44]	Yue Z.; Lam H. C.; Chen K.; Siridechakorn I.; Liu Y.; Pudhom K.; Lei X. Angew. Chem., Int. Ed. Engl. 2020, 59, 4115.
[45]	Kawamoto M.; Sato S.; Enomoto M.; Ogura Y.; Kuwahara S. Org. Lett. 2019, 21, 10099.
[46]	Que Y.; Shao H.; He H.; Gao S. Angew. Chem., Int. Ed. 2020, 59, 7444.
[47]	Qian H.; Zhao W.; Sung H. H.; Williams I. D.; Sun J. Chem. Commun. 2013, 49, 4361.
[48]	Chavan S.; Dhawane A.; Kalkote U. Synlet. 2008, 18, 2781.
[49]	Ono M.; Nishimura K.; Tsubouchi H.; Nagaoka Y.; Tomioka K. J. Org. Chem. 2001, 66, 8199.
[50]	Huang Y. M.; Liu Y.; Zheng C. W.; Jin Q. W.; Pan L.; Pan R. M.; Liu J.; Zhao G. Chem.-Eur. J. 2016, 22, 18339.
[51]	Jang D.; Choi M.; Chen J.; Lee C. Angew. Chem., Int. Ed. 2021, 60, 22735.
[52]	Banachowicz P.; Buda S. RSC Adv. 2019, 9, 12928.
[53]	Biduś N.; Banachowicz P.; Buda S. Tetrahedro. 2020, 76, 131397.
[54]	Dai Y.; Shen Y.; Gao S. Chin. J. Org. Chem. 2018, 38, 1608 (in Chinese).
	(代义华, 申艳芳, 高栓虎, 有机化学, 2018, 38, 1608.)
[55]	Sloman D. L.; Bacon J. W.; Porco J. A., Jr. J. Am. Chem. Soc. 2011, 133, 9952.
[56]	Ciesielski J.; Gandon V.; Frontier A. J. J. Org. Chem. 2013, 78, 9541.
[57]	Liu K.; Chougnet A.; Woggon W. D. Angew. Chem., Int. Ed. 2008, 47, 5827.
[58]	Liu K.; Woggon W. D. Eur. J. Org. Chem. 2010, 2010, 1033.
[59]	Bräse S.; Volz N.; Bröhmer M.; Nieger M. Synlet. 2009, 4, 550.
[60]	Pan S.; Xuan J.; Gao B.; Zhu A.; Ding H. Angew. Chem., Int. Ed. 2015, 54, 6905.
[61]	Wang Y.; Zhao R.; Yang M. J. Am. Chem. Soc. 2022, 144, 15033.
[62]	Chen L.; Chen P.; Zhang X.; Zhang Y.; Jia Y. Che. 2024, 10, 2473.
[63]	Bourcet E.; Brohmer M. C.; Nieger M.; Brase S. Org. Biomol. Chem. 2011, 9, 3136.
[64]	Grondal C.; Jeanty M.; Enders D. Nat. Chem. 2010, 2, 167.
[65]	Pellissier H. Curr. Org. Chem. 2021, 25, 1457.
[66]	Marques-Lopez E.; Herrera R. P.; Christmann M. Nat. Prod. Rep. 2010, 27, 1138.
[67]	Parella R.; Jakkampudi S.; Zhao J. C. G. ChemistrySelec. 2021, 6, 2252.

Michael/aldol串联环化反应在天然产物合成中的应用

Application of Michael/Aldol Cascade Cyclization Reactions in Natural Product Synthesis

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