title: Chemoenzymatic synthesis of the chiral side-chain of statins: application of an alcohol dehydrogenase catalysed ketone reduction on a large scale.
abstract: 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.
authors.affiliation: Institute of Biotechnology 2, Research Center Jülich, 52425 Jülich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wolberg
authors.forename: Murillo Villela
authors.initials: MV
authors.lastname: Filho
authors.forename: Silke
authors.initials: S
authors.lastname: Bode
authors.forename: Petra
authors.initials: P
authors.lastname: Geilenkirchen
authors.forename: Ralf
authors.initials: R
authors.lastname: Feldmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Liese
authors.forename: Werner
authors.initials: W
authors.lastname: Hummel
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
mesh_terms: 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
chemical_list: D004952:Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007659:Ketones; D009249:NADP; D006903:Hydroxymethylglutaryl CoA Reductases; D000426:Alcohol Dehydrogenase