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Enantioselective Approach for Expanding the Three‐Dimensional Space of Tetrahydroquinoline to Develop BET Bromodomain Inhibitors

Von Wiley-VCH zur Verfügung gestellt

Simple and selective. Assembling simple functional groups by proline organocatalysis coupled with the addition of BF3 ⋅ OEt2 in the same flask allows for the mild formation of aza-ortho-quinone methide species that undergo nucleophilic addition to give access to enantio-enriched tri-substituted tetrahydroquinolines with a novel configuration. This advanced three-dimensional structure, after only two additional steps, gave rise to a valuable enantiopure and selective anti-inflammatory compound.


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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