Biocatalytic synthesis towards both antipodes of 3-hydroxy-3-phenylpropanitrile a precursor to fluoxetine, atomoxetine and nisoxetine

  • Hammond R
  • Poston B
  • Ghiviriga I
 et al. 
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Abstract

The bakers' yeast reduction of 3-oxo-3-phenylpropanenitrile (1) has been difficult to achieve due to a dominant alkylating mechanism. A library of 20 bakers' yeast reductases, that are overexpressed in Escherichia coli, were screened against (1). Four enzymes were found to reduce this substrate and by varying the enzyme both enantiomers of 3-hydroxy-3-phenylpropanitrile (2) could be prepared with a high enantiomeric excess. In addition, the Escherichia coli whole-cell system can be optimized to nearly eliminate the competing alkylating mechanism. By using this system, a formal biocatalytic synthesis of both antipodes of fluoxetine, atomoxetine and nisoxetine has been demonstrated. © 2006 Elsevier Ltd. All rights reserved.

Author-supplied keywords

  • Atomoxetine
  • Bakers' yeast
  • Fluoxetine
  • Nisoxetine
  • ProzacTM
  • Reductase
  • StraterraTM

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Authors

  • Richard J. Hammond

  • Benjamin W. Poston

  • Ion Ghiviriga

  • Brent D. Feske

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