Microbial synthesis of a useful optically active (+)-isomer of lactone with bicyclo[4.3.0]nonane structure

Filip Boratyński,Teresa Olejniczak,Agata Janik-Polanowicz,Ewa Szczepańska

doi:10.1038/s41598-017-18876-9

Filip Boratyński, Teresa Olejniczak + Show 2 more

Open Access

https://doi.org/10.1038/s41598-017-18876-9

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Abstract

Lactone 2a of a bicyclo[4.3.0]nonane structure is a good starting material for synthesis of many attractive compounds. Enantiomerically enriched (−)-(3aR,7aS)-lactone 2a is produced by whole cells of bacteria. In order to examine the impact of the absolute configuration on biological activity we evaluated the process affording the opposite isomer. To this purpose Candida pelliculosa ZP22 characterized by high dehydrogenase activity was used. The goal of presented work was to perform bioreactor scale microbial one-pot oxidation of diol with selected yeast strain C. pelliculosa ZP22 to obtain chiral (+)-(3aS,7aR)-lactone 2a. The idea was to influence on alcohol dehydrogenase activity by increasing the activity of pro-(+)-ADH and simultanously diminishing the activity of pro-(−)-ADH. The optimization of biotransformation conditions involved the manipulation of the nutritional and physical parameters. Selection of the optimal medium in order to improve yield and process enantioselectivity was based on a two-level factorial design methodology. We have also studied the relationship between microbial growth and biosynthesis of lactone 2a. Preparative oxidation of diol 3a (400 mg/L, 2.9 mM) catalyzed by C. pelliculosa ZP22 in an optimized conditions afforded enantiomerically enriched (+)-(3aS,7aR)-isomer of lactone 2a with the isolated yield (30%).

Highlights

Asymmetric transformations catalyzed by whole cells of microorganisms or isolated enzymes have become an attractive alternative for traditional methods leading to optically pure compounds, which derive from either natural sources or by organic synthesis[1,2,3,4]
We are interested in the development of a stereoselective biooxidation, which will be significant in the multi-step synthesis of optically active lactones of a bicyclo[4.3.0]nonane structure
Biological properties of chiral compounds are many a time related to absolute configuration

Summary

Introduction

Asymmetric transformations catalyzed by whole cells of microorganisms or isolated enzymes have become an attractive alternative for traditional methods leading to optically pure compounds, which derive from either natural sources or by organic synthesis[1,2,3,4]. It is important in the synthesis of biologically active compounds in which biological activity usually depends on the absolute configuration in a molecule[5,6]. We are interested in the development of a stereoselective biooxidation, which will be significant in the multi-step synthesis of optically active lactones of a bicyclo[4.3.0]nonane structure Compounds of such structure represent a large group of natural phtalide derivatives[17]. Employing wild-type yeast strains as whole-cell biocatalysts imputes some limitations one of which is the presence of a large number of different dehydrogenases, which quite often overlap in substrate specificity

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