Chemoenzymatic synthesis of the chiral side-chain of statins: application of an alcohol dehydrogenase catalysed ketone reduction on a large scale.
The chemoenzymatic synthesis of the tert-butyl (S)-6-chloro-5-hydroxy-3-ketohexanoate is described. Our approach relies on a highly regio- and enantioselective reduction of a beta,delta-diketohexanoate ester catalysed by NADP(H)-dependent alcohol dehydrogenase of Lactobacillus brevis (LBADH). A detailed description of the scale-up of the enzymatic synthesis of the hydroxyketo ester is given which includes a scale-up of the substrate synthesis as well, i.e. the preparation of diketo ester on a 100 g scale. Furthermore, studies directed towards improving the co-catalyst [NADP(H)] consumption of the enzymatic key step by kinetic studies and application of a biphasic reaction medium were performed.
Wolberg
Michael
M
Institute of Biotechnology 2, Research Center Jülich, 52425 Jülich, Germany.
Filho
Murillo Villela
MV
Bode
Silke
S
Geilenkirchen
Petra
P
Feldmann
Ralf
R
Liese
Andreas
A
Hummel
Werner
W
Müller
Michael
M
D000426:Alcohol Dehydrogenase / Q000737:chemistry*; D019149:Bioreactors; D001709:Biotechnology / Q000295:instrumentation / Q000379:methods*; D002384:Catalysis; D004867:Equipment Design; D004952:Esters; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007659:Ketones; D007700:Kinetics; D052196:Levilactobacillus brevis / Q000201:enzymology; D008956:Models, Chemical; D009249:NADP; D013237:Stereoisomerism
D004952:Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007659:Ketones; D009249:NADP; D006903:Hydroxymethylglutaryl CoA Reductases; D000426:Alcohol Dehydrogenase