Studies on an Enantioselective Synthesis of Cymbalta

Authors:

Christopher Discolo, Colin McKinlay, Michael Patton, Jayson Yuter

Mentor:

Donald Deardorff, Professor of Chemistry, Occidental College

A synthetic strategy for duloxetine, marketed as Cymbalta™, will be presented. Cymbalta™, a potent antidepressant, targets neural serotonin-norepinephrine channels, successfully treats patients with major depressive disorder, generalized anxiety disorder, diabetic neuropathy, and fibromyalgia. The (S)-enantiomer of duloxetine acts as a serotonin reuptake inhibitor while the (R)-enantiomer exhibits little biological activity. Consequently, we have developed an enantiosynthetic strategy for the preparation of the (S)-enantiomer. The first step in our proposed synthetic route utilizes the almond enzyme oxynitrilase to induce asymmetry in the achiral substrate crotonaldehyde with yields of 94% and an enantiomeric excess of greater than 99%. The resulting enantiopure cyanohydrin then undergoes an ethyl esterification to afford the crotonyl α-hydroxy ethyl ester with yields of 82% and enantiomeric excess of 99%. The ester is then coupled to 2-vinyl thiophene via a Grubbs-catalyzed cross metathesis with yields of 50% and enantiomeric excess of 95%. This step establishes the requisite carbon backbone of Cymbalta™. An ethoxy carbonylation is then performed to convert the hydroxyl group into a carbonate leaving group to prepare the allylic system for the palladium transposition. The ethoxy carbonylation is performed with yields of 75% and enantiomeric excess of 92%. A substitutive palladium-catalyzed α, γ-chiral transposition appends the α-naphthol moiety to the desired position with enantiofidelity. Subsequent reactions append functionality to this skeleton. Recent work has been done to characterize the major product of the palladium transposition through Nuclear Magnetic Resonance Spectroscopy (NMR) and Infrared Spectroscopy (IR). The 1H NMR spectra shows a singlet at 6.3ppm indicative of a phenolic proton demonstrating that the thiophene aryl ether is not the major product in the palladium transposition. Reactions have been performed to synthesize chemical analogues to the thiophene aryl ether in attempt to determine what product is created in the palladium transposition.


Presented by:

Christopher Discolo

Date:

Saturday, November 23, 2013

Poster:

36

Room:

Poster Session 1 - Villalobos Hall

Presentation Type:

Poster Presentation

Discipline:

Chemistry