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A short total synthesis of (±)-paroxetine and a formal asymmetric synthesis of (–)-paroxetine

A short total synthesis of (±)-paroxetine and a formal asymmetric synthesis of (–)-paroxetine
A short total synthesis of (±)-paroxetine and a formal asymmetric synthesis of (–)-paroxetine
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.
Despiau, Carole
63dedec0-1553-4032-806d-f0938804b3c7
Despiau, Carole
63dedec0-1553-4032-806d-f0938804b3c7
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba

(2013) A short total synthesis of (±)-paroxetine and a formal asymmetric synthesis of (–)-paroxetine. University of Southampton, School of Chemistry, Doctoral Thesis, 232pp.

Record type: Thesis (Doctoral)

Abstract

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.

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Published date: 9 December 2013
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 360900
URI: http://eprints.soton.ac.uk/id/eprint/360900
PURE UUID: d8f83ec7-405b-470d-a854-40ea0ddac18f
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

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Date deposited: 10 Jan 2014 14:58
Last modified: 06 Jun 2018 12:52

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