BioChem - DOS

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

Advanced synthesis & catalysis

Marx, Lisa; Rí os‐ Lombardí a, Nicolá s; Farnberger, Judith F.; Kroutil, Wolfgang; Bení tez‐ Mateos, Ana I.; Ló pez‐ Gallego, Fernando; Morí s, Francisco; Gonzá lez‐ Sabí n, Javier; Berglund, Per

<P><B>Abstract</B></P><P>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&#x2010;acetonaphthone yielded an enantiopure (<I>R</I>)&#x2010;amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (<I>S</I>)&#x2010;alcohol, which was easily converted into the previous (<I>R</I>)&#x2010;amine. In addition, the reduction was efficiently performed with the KRED and its cofactor co&#x2010;immobilized on the same porous surface. This self&#x2010;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&#x2010;based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.</P><P/>

2018

John Wiley and Sons Inc.

cc-by-nc

1615-4150

1615-4169

360

11

pp.2157-2165

10.1002/adsc.201701485

http://click.ndsl.kr/servlet/OpenAPIDetailView?keyValue=05787966&target=NART&cn=NART84802234

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/adsc.201701485