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Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction
Author(s) -
Guney Tezcan,
Wenderski Todd A.,
Boudreau Matthew W.,
Tan Derek S.
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201802880
Subject(s) - aryl , chemistry , ring (chemistry) , moiety , combinatorial chemistry , drug discovery , tandem , cascade reaction , stereochemistry , ketone , oxidative phosphorylation , organic chemistry , catalysis , biochemistry , materials science , composite material , alkyl
Medium‐ring natural products exhibit diverse biological activities but such scaffolds are underrepresented in probe and drug discovery efforts due to the limitations of classical macrocyclization reactions. We report herein a tandem oxidative dearomatization‐ring‐expanding rearomatization (ODRE) reaction that generates benzannulated medium‐ring lactams directly from simple bicyclic substrates. The reaction accommodates diverse aryl substrates (haloarenes, aryl ethers, aryl amides, heterocycles) and strategic incorporation of a bridgehead alcohol generates a versatile ketone moiety in the products amenable to downstream modifications. Cheminformatic analysis indicates that these medium rings access regions of chemical space that overlap with related natural products and are distinct from synthetic drugs, setting the stage for their use in discovery screening against novel biological targets.