Unveiling the Hidden Performance of Whole Cells in the Asymmetric Bioreduction of Aryl‐containing Ketones in Aqueous Deep Eutectic Solvents

Abstract

In this contribution, we report the first successful baker's yeast reduction of arylpropanones using deep eutectic solvents (DESs) as biodegradable and non-hazardous co-solvents. The nature of DES [e.g. choline chloride/glycerol (2:1)] and the percentage of water in the mixture proved to be critical for both the reversal of selectivity and to achieve high enantioselectivity on going from pure water (up to 98:2 er in favour of the Senantiomer) to DES/aqueous mixtures (up to 98:2 er in favour of the R-enantiomer). As a result, both enantiomers of valuable chiral alcohols of pharmaceutical interest were prepared from the same biocatalyst by simply switching the solvent. The possible inhibition of some (S)-oxidoreductases making part of the genome of such a wild-type whole cell biocatalyst when DESs are used as cosolvents may pave the way for an anti-Prelog reduction. The scope and limitations of this kind of biotransformations for a range of aryl-containing ketones are also discussed.

Whole-Cell Biocatalyst for Chemoenzymatic Total Synthesis of Rivastigmine

“…On the other hand, the employment of a ChCl/Gly eutectic mixture with increasing percentages of water provided 3 with yields up to 32% and an ee >98%, however, still in favor of the S-enantiomer (Table 1, entries 11,12). Thus, an inversion of stereopreference promoted by baker's yeast was not observed compared to the bioreduction carried out in pure water (Table 1, entry 4) [25]. As for ketone 2, by running its bioreduction in pure water, the expected alcohol 4 could be isolated in only 12% yield after 24 h incubation, although enantiomerically enriched (ee >98%) in favor of the S-enantiomer (Table 1, entry 13), whereas an erosion of its ee (95%) was detected after 120 h of incubation in a ChCl/Gly-based eutectic mixture with 20 w% of water (Table 1, entry 14).…”

“…Deep eutectic solvents ChCl/Gly (1:2 mol/mol), ChCl/D-fructose (3:2 w/w), and L-(+)-lactic acid/ChCl (2:1 mol/mol) were prepared by gently heating under stirring at 60-80 • C for 5 min the corresponding individual components until a clear solution was obtained [25]. All the chemicals and solvents were of commercial grade, further purified by distillation or crystallization prior to use.…”

Stereoselective Chemoenzymatic Synthesis of Optically Active Aryl-Substituted Oxygen-Containing Heterocycles

“…All optically active halohydrins 2a-j and oxygen-containing heterocycles 3a-j obtained by bioreductions of halo-ketones had analytical and spectroscopic data identical to those previously reported or to the commercially available compounds. Racemic mixtures (for HPLC references) were synthesized by NaBH 4 reduction in EtOH with 87%-96% yields according to the reported procedures [32][33][34][35].…”

“…Our group recently focused on the development of new bio-catalyzed whole-cell biotransformations for the enantioselective preparation of chiral secondary alcohols, which are valuable precursor compounds for active pharmaceutic ingredients (APIs) [32][33][34][35].…”

“…To date, different yeasts have proven to be effective for the synthesis of functionalized styrene oxides with high stereoselectivity [39], whereas whole-cell biocatalysts with different stereo-preferences (e.g., Kluyveromyces marxianus, Lactobacillus reuteri) have been successfully employed for the preparation of enantio-enriched secondary alcohols [32][33][34][35]. With the aim of identifying the best whole-cell biocatalyst able to reduce different chloroketones with high enantioselectivity, we started our study by screening various biocatalysts for the stereoselective reduction of 3-chloro-1-arylpropanones (Table 1).…”