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Enantioselective Approach for Expanding the Three‐Dimensional Space of Tetrahydroquinoline to Develop BET Bromodomain Inhibitors **
Author(s) -
Lespinasse MarieAnge,
Wei Kaiyao,
Perrin Justine,
Winkler Matthias,
Hamaidia Sieme,
Leroy Alexis,
Macek Jilkova Zuzana,
Philouze Christian,
Marche Patrice N.,
Petosa Carlo,
Govin Jérôme,
Emadali Anouk,
Wong YungSing
Publication year - 2022
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.202202293
Subject(s) - enantioselective synthesis , bromodomain , nucleophile , combinatorial chemistry , electrophile , chemistry , catalysis , mannich reaction , nanotechnology , organic chemistry , acetylation , materials science , biochemistry , gene
The pharmaceutical industry has a pervasive need for chiral specific molecules with optimal affinity for their biological targets. However, the mass production of such compounds is currently limited by conventional chemical routes, that are costly and have an environmental impact. Here, we propose an easy access to obtain new tetrahydroquinolines, a motif found in many bioactive compounds, that is rapid and cost effective. Starting from simple raw materials, the procedure uses a proline‐catalyzed Mannich reaction followed by the addition of BF 3 ⋅ OEt 2 , which generates a highly electrophilic aza‐ ortho ‐quinone methide intermediate capable of reacting with different nucleophiles to form the diversely functionalized tetrahydroquinoline. Moreover, this enantioselective one‐pot process provides access for the first time to tetrahydroquinolines with a cis ‐2,3 and trans ‐3,4 configuration. As proof of concept, we demonstrate that a three‐step reaction sequence, from simple and inexpensive starting compounds and catalysts, can generate a BD2‐selective BET bromodomain inhibitor with anti‐inflammatory effect.