Title

Studies Directed Toward the Enantioselective Synthesis of Cymbalta?

Authors

Colin McKinlay

Document Type

Article

Publication Date

2011

Abstract

Progress on the synthesis of duloxetine, marketed as Cymbalta?, will be presented. Cymbalta?, a potent antidepressant, targets neural serotonin-norepinephrine channels, successfully treating 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. The resulting enantiopure cyanohydrin is then coupled to vinyl thiophene via a Grubbs-catalyzed cross metathesis. This step establishes the requisite carbon backbone of Cymbalta?. A substitutive palladium-catalyzed 1,3-chiral shift appends the α-naphthol moiety to the desired position with complete enantiofidelity . Synthetic challenges and experimental details will be reported.

Advisor

Don Deardorff

Department

chemistry

Support

Howard Hughes Medical Institute Undergraduate Science Education Grant

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