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Title: A short total synthesis of (±)-paroxetine and a formal asymmetric synthesis of (–)-paroxetine
Author: Despiau, Carole
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2013
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Paroxetine, a selective serotonin reuptake inhibitor, is a potent drug used for the treatment of depression for more than 20 years. Although numerous syntheses have been reported for this molecule, the manufacturing process still uses a resolution step, as it remains the shortest way to access paroxetine on a large scale. Our synthesis of paroxetine offers an alternative solution, delivering the final compound in only six steps from commercially available material. This has been possible thanks to the use of both organo- and organometallic catalysis to introduce the two chiral centres. Formaldehyde has been used in a direct proline-catalysed aldol reaction, allowing the selective introduction of a hydroxymethyl group with good atom economy. Optimisation of a cobalt-catalysed Kumada-type Csp3-Csp2 cross coupling reaction on a secondary bromide enabled us to introduce the aryl substituent in the 4-position. Furthermore, the generation of a configurationally labile cobalt intermediate in the cross coupling reaction has been successfully exploited to develop a diastereoselective arylation. The use of methanol for the introduction of a hydroxymethyl group via transfer hydrogenative coupling has also been briefly investigated for incorporation in an asymmetric synthesis of abacavir.
Supervisor: Linclau, Bruno Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry