Citation: Fengqing Wang, Changxing Qi, Chunmei Chen, Qin Li, Qingyi Tong, Weiguang Sun, Zhengxi Hu, Minyan Wang, Hucheng Zhu, Lianghu Gu, Yonghui Zhang. Discovery and enantioselective total synthesis of antitumor agent asperfilasin A via a regio- and diastereoselective Nazarov cyclization[J]. Chinese Chemical Letters, ;2025, 36(6): 110252. doi: 10.1016/j.cclet.2024.110252 shu

Discovery and enantioselective total synthesis of antitumor agent asperfilasin A via a regio- and diastereoselective Nazarov cyclization

Fengqing Wang ^{a, 1} ,
Changxing Qi ^{a, 1} ,
Chunmei Chen ^{a, 1} ,
Qin Li ^a ,
Qingyi Tong ^a ,
Weiguang Sun ^a ,
Zhengxi Hu ^a ,
Minyan Wang ^{b, *,} ,
Hucheng Zhu ^{a, *,} ,
Lianghu Gu ^{a, *,} ,
Yonghui Zhang ^{a, *,}

a.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
b.
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China

wangmy@nju.edu.cn

zhuhucheng@hust.edu.cn

gulianghu@hust.edu.cn

zhangyh@mails.tjmu.edu.cn

Received Date: 15 May 2024
Revised Date: 9 July 2024
Accepted Date: 15 July 2024
Available Online: 15 July 2024

Figures(5)

Asperfilasin A (1), featuring a unique 5/5 cyclopenta[c]pyrrol-one bicyclic core, represents a newly discovered skeletal cytochalasan isolated from Aspergillus flavipes. The enantioselective total synthesis was efficiently accomplished from the key intermediate (S)-6 with three contiguous stereocenters in 5 steps and the synthetic 1 induced G2/M-phase cell cycle arrest of HT29 cells and apoptosis of HL60 and NB4 cells by activation of caspase-3 and degradation of PARP. (S)-6, bearing three contiguous chiral centers, was efficiently constructed by a novel Nazarov cyclization reaction containing basic nitrogen, which was less developed, primarily due to the incompatibility of basic nitrogen under acidic reaction conditions. This reaction allows a wide range of pentadienone substrates containing basic nitrogen to undergo Nazarov cyclization in a single regioselective and diastereoselective manner and is capable of generating three stereocenters simultaneously. Furthermore, the mechanism of the Nazarov cyclization and the origin of the regio- and diastereoselectivity were elucidated by DFT calculations and deuteration experiments, providing valuable insights into the reaction and serving as a guide for future applications involving substrates containing basic nitrogen.
- Cytochalasan,
- Antitumor activity,
- Nazarov cyclization,
- Basic nitrogen,
- Contiguous stereocenters,
- DFT calculations
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