In:
ChemBioChem, Wiley, Vol. 23, No. 5 ( 2022-03-04)
Abstract:
( S )‐3‐Cyclopentyl‐3‐hydroxypropanenitrile is the key precursor for the synthesis of ruxolitinib. The bioreduction of 3‐cyclopentyl‐3‐ketopropanenitrile ( 1 a ) offers an attractive method to access this important compound. A carbonyl reductase (PhADH) from Paraburkholderia hospita catalyzed the reduction of 1 a giving the ( S )‐alcohol ( 1 b ) with 85 % ee. Rational engineering of PhADH resulted in a double mutant H93C/A139L, which enhanced the enantioselectivity from 85 % to 〉 98 %, as well as a 6.3‐fold improvement in the specific activity. The bioreduction of 1 a was performed at 200 g/L (1.5 M) substrate concentration, leading to isolation of ( S )‐ 1 b in 91 % yield. Similarly, using this mutant enzyme, 3‐cyclohexyl‐3‐ketopropanenitrile ( 2 a ) and 3‐phenyl‐3‐ketopropanenitrile ( 3 a ) were reduced at high concentration affording the corresponding alcohols in 〉 99 % ee, and 90 % and 92 % yield, respectively. The results showed that the variant H93C/A139L was a powerful biocatalyst for reduction of β‐substituted‐β‐ketonitriles.
Type of Medium:
Online Resource
ISSN:
1439-4227
,
1439-7633
DOI:
10.1002/cbic.202100589
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2019276-9
detail.hit.zdb_id:
2020469-3
SSG:
12