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Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases
KTH, School of Biotechnology (BIO), Industrial Biotechnology.
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2018 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 360, no 11, p. 2157-2165Article in journal (Refereed) Published
Abstract [en]

Abstract Several chemoenzymatic routes have been explored for the preparation of cinacalcet, a calcimimetic agent. Transaminases (TAs) and ketoreductases (KREDs) turned out to be useful biocatalysts for the preparation of key optically active precursors. Thus, the asymmetric amination of 1‐acetonaphthone yielded an enantiopure (R)‐amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)‐alcohol, which was easily converted into the previous (R)‐amine. In addition, the reduction was efficiently performed with the KRED and its cofactor co‐immobilized on the same porous surface. This self‐sufficient heterogeneous biocatalyst presented an accumulated total turnover number (TTN) for the cofactor of 675 after 5 consecutive operational cycles. Finally, in a preparative scale synthesis the TA‐based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018. Vol. 360, no 11, p. 2157-2165
Keywords [en]
Cinacalcet, Transaminases, Ketoreductases, Asymmetric synthesis, Biocatalysis
National Category
Biocatalysis and Enzyme Technology
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-224455DOI: 10.1002/adsc.201701485ISI: 000434349400014Scopus ID: 2-s2.0-85042563096OAI: oai:DiVA.org:kth-224455DiVA, id: diva2:1191332
Projects
Biocascades
Funder
EU, Horizon 2020, 634200
Note

QC 20180326

Available from: 2018-03-18 Created: 2018-03-18 Last updated: 2018-06-27Bibliographically approved

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Publisher's full textScopushttps://onlinelibrary.wiley.com/doi/abs/10.1002/adsc.201701485

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