Stereoselective Reduction of Prochiral Cyclic 1,3-Diketones Using Different Biocatalysts

Abstract

We have developed biocatalytic methods for the stereoselective reduction of cyclic prochiral 1,3diketones for the production of optically active β-hydroxyketones and/or 1,3-diols. The recombinant ketoreductase KRED1-Pglu (formulated as purified catalyst) and whole cells of wild type E. coli DE3 Star were used as biocatalysts, displaying different and sometimes complementary stereoselectivity, thus allowing the preparation of stereochemically pure β-hydroxyketones (12-66% isolated yields, >99% e.e.) and 1,3-diols (40-60% isolated yields, > 99% e.e.).

Microbial alcohol dehydrogenases: recent developments and applications in asymmetric synthesis

“…Regio-and stereoselective reduction of ketones is remarkably attractive for the synthesis of steroids as testified by the huge steroid industry, which is mainly based on microbial biotransformations. 60 Recently, the biocatalytic reduction of ethyl secodione (20), a precursor for hormonal contraceptives, was screened with recombinant carbonyl reductase and yeast whole cells. 61 When recombinant carbonyl reductase (KRED1-Pglu) was used for reduction, the syn-product (13R,17S)-ethyl secol (21) was obtained with excellent enantioselectivity (>98% ee) and moderate yield (65%).…”

Extended Scope and Understanding of Zinc‐Dependent Alcohol Dehydrogenases for Reduction of Cyclic α‐Diketones

“…Due to high enantiospecificities and ‐selectivities, they are mainly used to generate chiral hydroxyl compounds [1a–c] . In this context, some ADHs also exhibit the ability to selectively reduce prochiral diketones to the corresponding hydroxyketones with only one defined chiral center [2a–d] . These compounds are intermediates of numerous active pharmaceutical ingredients [3a–j] and therefore valuable synthetic targets.…”

“…Only a few ADHs are capable to generate sterically demanding cyclic hydroxyketones with α‐ or β‐substitutions [2c,4a–f] . However, through a rational screening of metabolic pathways we succeeded in identifying a NADH‐dependent ADH of the medium chain dehydrogenase/reductase (MDR) superfamily that reduces 1,2‐cyclohexanedione to ( S )‐α‐hydroxycyclohexanone with outstanding activity [5a,b] .…”

Origin of the enantioselectivity of alcohol dehydrogenase

“…The desymmetrisation of substituted cyclopentane-1,3-dione was previously studied by chemical [1][2][3] and enzymatic catalysts. 4,5 Although high enantioselectivity was achieved by carbonyl reductase, 4,5 it is not known how the substrate would adapt itself in the catalytic pocket to give a certain stereoisomer product. Therefore, it is crucial to understand the preferred binding of the substrate in the enzyme in order to rationally engineer the enzyme to achieve stereodivergent products.…”