Organic Process Research & Development
Article
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quantitative conversions, which emphasizes the high compat-
ibility of the chemical and enzymatic reaction steps (Scheme 4).
In summary, a chemoenzymatic process for the production of
key intermediate (R)-2b leading to the “blockbuster” drug
rosuvastatin (1) was developed, comprising a seven-step
reaction sequence without mandatory isolation steps. The
two consecutive biotransformations run on excellent substrate
concentrations of up to 4.0 and 2.0 M respectively, to afford the
desired chiral monoester (R)-14 with a final product
concentration of 220 g/L. Recently this process was transferred
to the industrial partner Sandoz for internal work on process
scale-up, and a patent application on the biocatalytic
enantioselective synthesis of 3-hydroxy-glutaric acid mono-
esters and their use was filed.6 The successful implementation
of two recyclable biocatalysts for the enantioselective synthesis
of the chiral monoester (R)-14 in combination with organic-
chemical derivatization under retention of the stereogenic
information underlines the great potential of biocatalysis in the
development of novel industrially applicable retrosynthetic
chemoenzymatic routes to active pharmaceutical ingredients.
(6) Konig, B.; Wetterich, F.; Groger, H.; Metzner, R. Process for
̈
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enantioselective synthesis of 3-hydroxy-glutaric acid monoesters and
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(8) For overviews of the industrial synthetic routes to rosuvastatin,
see: (a) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substances: Syntheses, Patents, Applications; Thieme:
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(9) For recent developments regarding an alternative route using a
formylated statin side chain, see: (a) Osl
Kopitar, G.; Mrak, P.; Casar, Z.; Marr, A. C. PLoS One 2013, 8,
̌
aj, M.; Cluzeau, J.; Orkic,
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D.;
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No. e62250. (b) Casar, Z.; Steinbucher, M.; Kosm
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rlj, J. J. Org. Chem.
̈
2010, 75, 6681−6684.
(10) Sterk, D.; Casar, Z.; Jukic,
2155−2160.
(11) Lin, W.; Zheng, H.; Liu, X. PCT Int. Appl. WO 2011/124050
A1, Oct 13, 2011.
̌
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M.; Kosm
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(12) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai, K.
ASSOCIATED CONTENT
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Bioorg. Med. Chem. 1997, 5, 437−444.
S
* Supporting Information
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(15) For more examples of enzyme separation via ultrafiltration, see:
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AUTHOR INFORMATION
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Corresponding Authors
Present Addresses
⊥R.M.: Asano Active Enzyme Molecule Project, ERATO, JST
Biotechnology Research Center, Toyama Prefectural Univer-
sity, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.
#W.H.: Faculty of Chemistry, Bielefeld University, Universi-
tatsstr. 25, 33615 Bielefeld, Germany.
̈
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Sandoz AG for financial and technical support and
student Susann Rath for experimental support.
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