Asymmetric Total Synthesis and Biological Evaluation of the Natural PDE4 Inhibitor Toddacoumalone
Ke‐Qiang Hou, Xueping Chen, Yi‐You Huang, Albert S. C. Chan, Hai‐Bin Luo, Xiao‐Feng Xiong
Abstract
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).
Topics & Concepts
ChemistryTotal synthesisAmine gas treatingCycloadditionBiological activityCombinatorial chemistryCatalysisEnantioselective synthesisStereochemistryIC50Organic chemistryIn vitroBiochemistryPhosphodiesterase function and regulationCholinesterase and Neurodegenerative DiseasesChemical synthesis and alkaloids