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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 1â€acetonaphthone yielded an enantiopure (R)â€amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)â€alcohol, which was easily converted into the previous (R)â€amine. In addition, the reduction was efficiently performed with the KRED and its cofactor coâ€immobilized on the same porous surface. This selfâ€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 TAâ€based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.
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| 3. |
- 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 (>99 % ee) and diastereomeric ratio (99:1) at 29 % conversion (the maximum theoretical yield is 50 %) 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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