Highly enantioselective bioreduction of N-methyl-3-oxo-3-(thiophen-2-yl) propanamide for the production of (S)-duloxetine

Abstract

Whole cells of Rhodotorula glutinis reduced N-methyl-3-oxo-3-(thiophen-2-yl) propanamide at 30 g/l to (S)-N-methyl-3-hydroxy-3-(2-thienyl) propionamide, an intermediate in the production of (S)-duloxetine, a blockbuster antidepressant drug, in 48 h. The reaction had excellent enantioselectivity (single enantiomer, [99.5% enantiomeric excess [ee]) with a[95% conversion.

Bioreductive production of enantiopure (S)-duloxetine intermediates catalyzed with ketoreductase ChKRED15

“…8). The reaction afforded much higher substrate tolerance than previously reported bioreduction of duloxetine precursors [16,21,37,38]. For the same substrate, previous study used high concentration of whole cells of R. glutinis (42 g CDW/l), which yielded compromised stereoselectivity when substrate concentration exceeded 30 g/l [16].…”

“…Only the (S)-enantiomer is pharmaceutically active for the treatment of anxiety, diabetes-related pain, fibromyalgia and chronic musculoskeletal pain, including lower back pain and osteoarthritis [13][14][15]. According to the retrosynthetic strategy, several chiral alcohol precursors act as the key intermediate for (S)-duloxetine [16], which could be achieved by direct asymmetric reduction of the corresponding ketones (Fig. 1).…”

“…It has been reported that intermediates (S)-2b and (S)-6b can be achieved with >99% ee using the whole cells of Candida tropicalis [20] and Rhodotorula glutinis [16], respectively, and (S)-3b and (S)-5b with 98% ee using isolated ketoreductases from Exiguobacterium sp. [21] and Thermoanaerobacter sp.…”

Characterization of a robust anti-Prelog short-chain dehydrogenase/reductase ChKRED20 from Chryseobacterium sp. CA49

“…Despite the extensive development of transitional metal-catalyzed asymmetric reduction of ketones as the main approach to obtain chiral alcohols, the biocatalytic reduction has risen very rapidly, which often provides excellent activity, stereoselectivity and economic advantage under environment-friendly reaction conditions without the risk of metal contamination [1][2][3][4][5][6][7]. Both cell-free enzymes and whole microorganisms have been applied to the asymmetric reduction processes.…”

Enhancement of asymmetric bioreduction of N,N-dimethyl-3-keto-3-(2-thienyl)-1-propanamine to corresponding (S)-enantiomer by fusion of carbonyl reductase and glucose dehydrogenase

“…1) (Ren et al 2015;Tang et al 2011;Wada et al 2004;Zhang et al 2015). Immobilized cells of Saccharomyces cerevisiae have been applied to produce (S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol with the optical purity of 99% enantiomeric excess (e.e.)…”