Enantioselective Flow Synthesis of a Tetrahydroquinoline SERM Enabled by Immobilized Chiral Phosphoric Acid Catalysis and Diboronic Acid Mediated Selective Nitro Reduction

Abstract

AbstractAn asymmetric enantioselective flow process is reported for the formal synthesis of a 1,2,3,4‐tetrahydroquinoline selective estrogen receptor modulator. Starting from an easily available 2‐nitrochalcone, the first part of the process comprised a telescoped nitro reduction/intramolecular cyclocondensation sequence using diboronic acid as a simple reductant. Subsequent enantioselective transfer hydrogenation in the presence of an immobilized phosphoric acid organocatalyst followed by telescoped N‐alkylation furnished the targeted chiral intermediate. The approach ensures flexibility regarding the scale of the synthesis, whilst minimizing the need for intermediate purifications and ensuring environmentally benign metal‐free conditions.