Enantioselective approach for expanding the three‐dimensional space of tetrahydroquinoline to develop bet bromodomain inhibitors - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Chemistry - A European Journal Année : 2022

Enantioselective approach for expanding the three‐dimensional space of tetrahydroquinoline to develop bet bromodomain inhibitors

Justine Perrin
  • Fonction : Auteur
Matthias Winkler
  • Fonction : Auteur
Carlo Petosa

Résumé

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 BF3.OEt2, 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.
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Dates et versions

hal-03806738 , version 1 (08-10-2022)

Identifiants

Citer

Marie‐ange Lespinasse, Kaiyao Wei, Justine Perrin, Matthias Winkler, Sieme Hamaidia, et al.. Enantioselective approach for expanding the three‐dimensional space of tetrahydroquinoline to develop bet bromodomain inhibitors. Chemistry - A European Journal, 2022, 2022, pp.e202202293. ⟨10.1002/chem.202202293⟩. ⟨hal-03806738⟩
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