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- Marx, Lisa, et al.
(författare)
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Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases
- 2018
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Ingår i: Advanced Synthesis and Catalysis. - : Wiley-VCH Verlagsgesellschaft. - 1615-4150 .- 1615-4169. ; 360:11, s. 2157-2165
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Tidskriftsartikel (refereegranskat)abstract
- 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 1âacetonaphthone yielded an enantiopure (R)âamine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)âalcohol, which was easily converted into the previous (R)âamine. In addition, the reduction was efficiently performed with the KRED and its cofactor coâimmobilized on the same porous surface. This selfâsufficient 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 TAâbased approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.
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- Marx, Lisa, et al.
(författare)
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Chemoenzymatic Synthesis of Sertraline
- 2020
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Ingår i: European Journal of Organic Chemistry. - : Wiley-VCH Verlagsgesellschaft. - 1434-193X .- 1099-0690. ; 2020:4, s. 510-513
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Tidskriftsartikel (refereegranskat)abstract
- A chemoenzymatic approach has been developed for the preparation of sertraline, an established anti-depressant drug. Ketoreductases (KREDs) were employed to yield a key chiral precursor. The bioreduction of the racemic tetralone exhibited excellent enantioselectivity (>99â% ee) and diastereomeric ratio (99:1) at 29â% conversion (the maximum theoretical yield is 50â%) after 7 hours. The resulting (S,S)-alcohol was efficiently oxidized to an enantiopure (S)-ketone, an immediate precursor of sertraline, by using sodium hypochlorite as oxidant and 2-azaadamantane N-oxyl (AZADO) as organocatalyst. Alternative routes aiming at the direct biocatalytic amination using imine reductases and transaminases were unsuccessful.
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