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High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones: Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine

Authors

  • Elina Buitrago,

    1. Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, SE-10691 Stockholm (Sweden), Fax: (+46) 8-154908
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  • Helena Lundberg,

    1. Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, SE-10691 Stockholm (Sweden), Fax: (+46) 8-154908
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  • Hans Andersson,

    1. Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, SE-10691 Stockholm (Sweden), Fax: (+46) 8-154908
    2. Current address: Medivir AB, PO Box 1086, SE-14122 Huddinge (Sweden)
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  • Per Ryberg,

    1. AstraZeneca R&D, SE-15185 Södertälje (Sweden)
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  • Hans Adolfsson

    Corresponding author
    1. Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, SE-10691 Stockholm (Sweden), Fax: (+46) 8-154908
    • Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, SE-10691 Stockholm (Sweden), Fax: (+46) 8-154908
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Abstract

A total of 21 amino acid based ligands including hydroxy amide, thioamide, and hydroxamic acid functionalities, respectively, were combined with [Ru(p-cymene)Cl2]2 and [RhCp*Cl2]2, and used as catalysts for the asymmetric transfer hydrogenation of four different heteroaromatic ketones in 2-propanol. The reactions were performed on a Chemspeed automated high-throughput screening robotic platform. Optimal catalysts were identified for the individual heterocyclic substrate classes. Based on these results, the formal syntheses of the antidepressant drugs (R)-fluoxetine and (S)-duloxetine were conducted by using the found catalysts in the key reaction step, which results in high isolated yields (94 %) and excellent product enantioselectivities (>99 % ee) of the formed 1,3-amino alcohols.

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