Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases

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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. (Figure presented.).

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Marx, L., Ríos-Lombardía, N., Farnberger, J. F., Kroutil, W., Benítez-Mateos, A. I., López-Gallego, F., … Berglund, P. (2018). Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases. Advanced Synthesis and Catalysis, 360(11), 2157–2165. https://doi.org/10.1002/adsc.201701485

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