An Enantioselective Synthesis of CymbaltaTM Colin McKinlay and Vincent van Rixel

A complete synthesis of Duloxetine, marketed as Cymbalta?, is achieved using an enantiomerically conserved route. Cymbalta? is a potent antidepressant which targets neural serotonin channels, making it successful at treating patients with major depressive disorder, generalized anxiety disorder, diabetic neuropathy, and fibromyalgia. However, Cymbalta? is a chiral molecule, in which the (S) enantiomer acts as the serotonin reuptake inhibitor, while the (R) enantiomer has little biological activity. Consequently, discovering an enantioselective synthesis of this drug is highly pharmaceutically relevant in treating the aforementioned disorders. The proposed synthetic route utilizes oxynitrilase, an enzyme extracted from raw almonds to establish a chiral center on the substrate crotonaldehyde, affording an (R)-cyanohydrin. This chiral center is maintained through subsequent reactions which add various organic moieties to the molecule. In addition to the cyanohydrins, the two most synthetically critical reactions in this synthesis are a Grubbs metathesis which adds a vinyl thiophene to the substrate, and a substituted palladium catalyzed 1,3-chiral shift. These three reactions have been performed with high yields, establishing our synthetic route as a viable path leading to the final production of Cymbalta?