Stereoselective Synthesis and Biological Evaluation of ent‐Asperolide C and its Analogues

A stereoselective synthesis of ent‐asperolide C and its analogues is described. A chiral‐pool approach was used with a linear sequence of 10 steps, starting from readily available and inexpensive andrographolide. The approach features the construction of a five‐membered lactone skeleton with suitabl...

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Bibliographic Details
Published in:European journal of organic chemistry 2018-01, Vol.2018 (4), p.477-484
Main Authors: Xin, Zhengyuan, Song, Yunlong Lu, Zhiqiang, He, Yuchen, Li, Jiabin, Lin, Kejiang, Xue, Xiaowen
Format: Article
Language:English
Subjects:
Biological activity
Biotechnology
Chiral pool
Crystallography
Epoxidation
Natural products
Ring opening
Stereochemistry
Synthesis
Synthesis design
Total synthesis
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Summary:A stereoselective synthesis of ent‐asperolide C and its analogues is described. A chiral‐pool approach was used with a linear sequence of 10 steps, starting from readily available and inexpensive andrographolide. The approach features the construction of a five‐membered lactone skeleton with suitable chiral centres from andrographolide through diastereoselective epoxidation of the exocyclic double bond, and tandem oxidative cleavage of the C‐14=C‐15 double bond and subsequent epoxide ring opening. The stereochemistry of 8 was established by X‐ray crystallographic analysis. Four analogues of ent‐asperolide C were synthesized, and their biological activities were evaluated against A539 and HeLa cell lines. Compound 12 was found to show a weak to moderate antiproliferation effect against both cell lines. The first synthesis of ent‐asperolide C and its analogues is described, along with an evaluation of their cytotoxicity. ent‐Asperolide C was synthesized in 10 steps from the naturally occurring diterpenoid andrographolide, with asymmetric epoxidation of the exocyclic double bond, and tandem oxidative cleavage of the C‐14=C‐15 double bond and subsequent epoxide ring opening as the key steps.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201701292