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.
Subject(s)
Alcohol Dehydrogenase/chemistry , Biotechnology/methods , Ketones , Bioreactors , Biotechnology/instrumentation , Catalysis , Equipment Design , Esters , Hydroxymethylglutaryl CoA Reductases/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Kinetics , Levilactobacillus brevis/enzymology , Models, Chemical , NADP , StereoisomerismABSTRACT
[reaction: see text] A new method to facilitate the separation of diastereomeric syn- and anti-1,3-diols is described. The method relies on the different hydrolysis rates of the corresponding diastereomeric acetonides. Treatment of a dichloromethane solution of syn- and anti-1,3-diol-acetonide with a catalytic amount of diluted aqueous hydrochloric acid leads to the selective cleavage of the anti diastereomer. The resulting anti-1,3-diol can be easily separated from the unchanged syn-1,3-diol-acetonide.
