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C−H Bond Activation for the Synthesis of Heterocyclic Atropisomers Yields Hedgehog Pathway Inhibitors
Author(s) -
Shan Gang,
Flegel Jana,
Li Houhua,
Merten Christian,
Ziegler Slava,
Antonchick Andrey P.,
Waldmann Herbert
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201809680
Subject(s) - atropisomer , chemistry , smoothened , annulation , enantioselective synthesis , stereochemistry , piperidine , ring (chemistry) , hedgehog signaling pathway , combinatorial chemistry , catalysis , organic chemistry , signal transduction , biochemistry
Axially chiral 4‐arylisoquinolones are endowed with pronounced bioactivity, and methods for their efficient synthesis have gained widespread attention. However, enantioselective synthesis of axially chiral 4‐arylisoquinolones by means of C−H activation has not been reported to date. Described here is a rhodium (III)‐catalyzed C−H bond activation and annulation for the atroposelective synthesis of axially chiral 4‐arylisoquinolones. The method employs chiral cyclopentadienyl ligands embodying a piperidine ring as backbone and yields the atropisomers with good to excellent yields and enantioselectivity. Biological relevance of the 4‐arylisoquinolones was demonstrated by their investigation in different cellular assays, leading to the discovery of novel non‐SMO (SMO= smoothened) binding Hedgehog pathway inhibitors.