A Practical Synthesis of the Antidepressant (S)-Duloxetine

Serotonin and norepinephrine neurotransmitters are intimately involved in a number of neurochemical and physiological processes, such as depression and pain disorders. Selective serotonin or norepinephrine reuptake inhibitors are the important class of antidepressants, such as fluoxetine, niso-xetine, tomoxetine, and duloxetine featuring the structural similarity of 1-ary-3-aminopropanol.1 Among them, duloxe-tine belongs to a class of antidepressant drugs that simultane-ously inhibit the reuptake of serotonin as well as norepine-phrine. Even though duloxetine was originally marketed as a racemic mixture, (S)-enantiomeric form is now available since it has substantially beneficial biological effects com-pared with its antipode.2 This also could draw much atten-tion for the preparation of enantiomerically pure duloxetine. Currently, (S)-duloxetine is prescribed for the treatment of major depressive disorder and stress-related urinary in-continence under the name of Cymbalta. Recently, numerous avenues to provide an enantiomeri-cally pure duloxetine have been elaborated using various precursors, in which Friedel-Crafts reaction of thiophene with glyoxylate, aldol reaction of thiophene-2-carboxaldehyde with thioamide or malonic acid half thioester, and dynamic kinetic resolution of 2-hydroxy-2-(2-thienyl)acetonitrile have been reported.3 Nonetheless, asymmetric reduction of β-substituted ketones is perhaps among the most attractive and straightforward strategies to meet practical demands, in fact enantiomerically enriched γ-chloro or-dimethylamino alcohols are most frequently employed for the preparation of (S)-duloxetine. The initial synthesis of (S)-duloxetine has been reported based on a chirally-modified LAH reductio