Enantioselective and practical syntheses of R- and S-fluoxetines

doi:10.1016/S0040-4039(01)93743-8

Tetrahedron Letters

Volume 30, Issue 39, 1989, Pages 5207-5210

https://doi.org/10.1016/S0040-4039(01)93743-8 Get rights and content

Abstract

An efficient synthetic route to either R- or S-fluoxetine is described which depends on the use of a chiral, enzyme-like catalyst (chemzyme) to establish the stereocenter and which makes these important therapeutic agents readily available in enantiomerically pure form.

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Although reduction of aromatic β-ketonitriles can be obtained by chemical chiral catalysts,13,14 biocatalysis has proved to be an efficient and green alternative; biocatalytic reduction is mostly performed with isolated enzymes,15–18 since the use of whole cells is often limited by the occurrence of a—competitive ethylation, resulting from non-enzymatic aldol condensation between aromatic β-ketonitriles and acetaldehyde (formed by the whole cells in the presence of glucose or ethanol), followed by reduction of the activated CC by enoate reductases.19–23 Optically pure aromatic halohydrins are versatile synthons that have been used for the synthesis of many pharmaceuticals, including drugs for psychiatric disorders, such as (R)-Fluoxetine,24–27 (R)-Duloxetine,27,28 or (R)-Ibutilide, an antiarrhythmic agent.29 Preparation of aromatic halohydrins by enzymatic reduction of the corresponding aromatic α-haloketones is also a valid option.
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Enantioselective and practical syntheses of R- and S-fluoxetines

Abstract

Tetrahedron Letters

J. Clin. Psychiatry

J. Med. Chem.

J. Med. Chem.