Asymmetric Total Synthesis and Biological Evaluation of the Natural PDE4 Inhibitor Toddacoumalone

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of...

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Bibliographic Details
Published inOrganic letters Vol. 22; no. 2; pp. 584 - 588
Main Authors Hou, Ke-Qiang, Chen, Xue-Ping, Huang, Yiyou, Chan, Albert S. C, Luo, Hai-Bin, Xiong, Xiao-Feng
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 17.01.2020
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
CATALYSIS
DESIGN
DIENES
DIELS-ALDER REACTIONS
4+2 CYCLOADDITION
ALKYLATION
COUMARINS
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Summary:We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyrano­quinolinones and 3-methyl­crotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a′ with the best PDE4 inhibitory activity (IC50 = 0.18 μM).
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ISSN:1523-7060
1523-7052
DOI:10.1021/acs.orglett.9b04355