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

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.

Advances in deep eutectic solvents and water: applications in metal- and biocatalyzed processes, in the synthesis of APIs, and other biologically active compounds

“…By performing the above alkylation in toluene at 100 °C for 17 h, in a sealed reactor and under argon, (R)-19 was isolated in an overall yield of only 50%. 78 Amine alkylation with alco- View Article Online hols has also been achieved with good results by Williams and co-workers using 1 mol% [Cp*IrI 2 ] 2 in water, in the absence of base or other additives. 79 Vortioxetine ( 24) is a multi-modal acting drug with high affinity towards a range of serotoninergic targets, and is now on the market for the treatment of major depressive disorder.…”

Biocatalytic Ketone Reductions Using Biobeads

“…on a 2 mg scale. 22 Gratifyingly, we were able to achieve representative data using much smaller quantities at 0.036 mg of Kred (Table 3). While most entries preserved the % conversions and enantioselectivities, some entries afforded enhanced figures.…”

“…on a 2 mg scale. 22 Gratifyingly, we were able to achieve representative data using much smaller quantities at 0.036 mg of Kred ( Table 2. Performance of miniaturized BioBeads reaction Entry [a] Kred C(%) [b] ee(%) [b] Entry [a] Kred C(%) [b] ee(%) Entry [a] Kred C(%) [a] ee (%) [a] Entry [a] Kred C(%) [a] ee (%)…”

Application of Ketoreductase in Asymmetric Synthesis of Pharmaceuticals and Bioactive Molecules: An Update (2018–2020)

“…Berglund and co‐workers recently reported their efforts on the development of several chemo‐enzymatic routes to cinacalcet, the only approved drug acting as calcimimetic [29] . One of the two successful syntheses employed the ketoreductase‐catalzyed reduction of 1‐acetonaphthone ( 24 ) to ( S )‐1‐(1‐naphthyl)ethanol ( 25 ) as the key step (Scheme 17).…”