Biocatalytic reduction of beta,delta-diketo esters: a highly stereoselective approach to all four stereoisomers of a chlorinated beta,delta-dihydroxy hexanoate.
A stereoselective chemoenzymatic synthesis of all four stereoisomers of tert-butyl 6-chloro-3,5-dihydroxy-hexanoate (6a) is presented. The key step of the sequence is a highly regio- and enantioselective single-site reduction of tert-butyl 6-chloro-3,5-dioxohexanoate (1a) by two enantiocomplementary biocatalysts. Alcohol dehydrogenase from Lactobacillus brevis (recLBADH) afforded a 72% yield of enantiopure tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate [(S)-2a]. The enantiomer (R)-2a was prepared with 90-94% ee by Baker's yeast reduction in a biphasic system (50% yield). Both biotransformations were performed on a gram scale. The beta-keto group of the enantiomeric delta-hydroxy-beta-keto esters 2a thus obtained was reduced by syn- and anti-selective borohydride reductions. Permutation of the reduction methods yielded all four stereoisomers of the crystalline target compound 6a (> or = 99.3% ee, dr > or = 205:1), which is a versatile 1,3-diol building block. recLBADH accepts a variety of beta,delta-diketo esters as was determined in a photometric assay. tert-Butyl 3,5-dioxo-hexanoate (1b) and tert-butyl 3,5-dioxo-heptanoate (1c) were reduced on a preparative scale as well to afford the corresponding delta-hydroxy-beta-keto esters (R)-2b and (R)-2c with 99.4% ee and 98.1% ee, respectively.
Wolberg
M
M
Institut für Biotechnologie 2, Forschungszentrum Jülich GmbH, Germany.
Hummel
W
W
Müller
M
M
D001419:Bacteria / Q000378:metabolism; D002208:Caproates / Q000737:chemistry*; D002384:Catalysis; D004952:Esters / Q000737:chemistry* / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D015003:Yeasts / Q000378:metabolism
D002208:Caproates; D004952:Esters; D006843:Hydrocarbons, Chlorinated