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Influence of Organic Solvents on Enzymatic Asymmetric Carboligations.

ABSTRACT: The asymmetric mixed carboligation of aldehydes with thiamine diphosphate (ThDP)-dependent enzymes is an excellent example where activity as well as changes in chemo- and stereoselectivity can be followed sensitively. To elucidate the influence of organic additives in enzymatic carboligation reactions of mixed 2-hydroxy ketones, we present a comparative study of six ThDP-dependent enzymes in 13 water-miscible organic solvents under equivalent reaction conditions. The influence of the additives on the stereoselectivity is most pronounced and follows a general trend. If the enzyme stereoselectivity in aqueous buffer is already >99.9% ee, none of the solvents reduces this high selectivity. In contrast, both stereoselectivity and chemoselectivity are strongly influenced if the enzyme is rather unselective in aqueous buffer. For the S-selective enzyme with the largest active site, we were able to prove a general correlation of the solvent-excluded volume of the additives with the effect on selectivity changes: the smaller the organic solvent molecule, the higher the impact of this additive. Further, a correlation to log P of the additives on selectivity was detected if two additives have almost the same solvent-excluded volume. The observed results are discussed in terms of structural, biochemical and energetic effects. This work demonstrates the potential of medium engineering as a powerful additional tool for varying enzyme selectivity and thus engineering the product range of biotransformations. It further demonstrates that the use of cosolvents should be carefully planned, as the solvents may compete with the substrate(s) for binding sites in the enzyme active site.

SUBMITTER: Gerhards T

PROVIDER: S-EPMC3549479 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Influence of Organic Solvents on Enzymatic Asymmetric Carboligations.

Gerhards Tina T Mackfeld Ursula U Bocola Marco M von Lieres Eric E Wiechert Wolfgang W Pohl Martina M Rother Dörte D

Advanced synthesis & catalysis 20121004 14-15

The asymmetric mixed carboligation of aldehydes with thiamine diphosphate (ThDP)-dependent enzymes is an excellent example where activity as well as changes in chemo- and stereoselectivity can be followed sensitively. To elucidate the influence of organic additives in enzymatic carboligation reactions of mixed 2-hydroxy ketones, we present a comparative study of six ThDP-dependent enzymes in 13 water-miscible organic solvents under equivalent reaction conditions. The influence of the additives o ...[more]

PMID: 23349644

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Project description:Recently, DNA has been evaluated as a chiral scaffold for metal complexes to construct so called 'DNA-based hybrid catalysts', a robust and inexpensive alternative to enzymes. The unique chiral structure of DNA allows the hybrid catalysts to catalyze various asymmetric synthesis reactions. However, most current studies used aqueous buffers as solvents for these asymmetric reactions, where substrates/products are typically suspended in the solutions. The mass transfer limitation usually requires a long reaction time. To overcome this hurdle and to advance DNA-based asymmetric catalysis, we evaluated a series of ionic liquids (ILs), inorganic salts, deep eutectic solvents (DES), glymes, glycols, acetonitrile and methanol as co-solvents/additives for the DNA-based asymmetric Michael addition. In general, these additives induce indistinguishable changes to the DNA B-form duplex conformation as suggested by circular dichroism (CD) spectroscopy, but impose a significant influence on the catalytic efficiency of the DNA-based hybrid catalyst. Conventional organic solvents (e.g. acetonitrile and methanol) led to poor product yields and/or low enantioselectivities. Most ILs and inorganic salts cause the deactivation of the hybrid catalyst except 0.2 M [BMIM][CF3COO] (95.4% ee and 93% yield) and 0.2 M [BMIM]Cl (93.7% ee and 89% yield). Several other additives have also been found to improve the catalytic efficiency of the DNA-based hybrid catalyst (control reaction without additive gives >99% ee and 87% yield): 0.4 M glycerol (>99% ee and 96% yield at 5 °C or 96.2% ee and 83% yield at room temperature), 0.2 M choline chloride/glycerol (1:2) (92.4% ee and 90% yield at 5 °C or 94.0% ee and 88% yield at room temperature), and 0.5 M dipropylene glycol dimethyl ether (>99% ee and 87% yield at room temperature). The use of some co-solvents/additives allows the Michael addition to be performed at a higher temperature (e.g. room temperature vs 5 °C) and a shorter reaction time (24 h vs 3 days). In addition, we found that a brief pre-sonication (5 min) of DNA in MOPS buffer prior to the reaction could improve the performance of the DNA-based hybrid catalyst. We have also shown that this DNA-based catalysis method is suitable for a variety of different substrates and relatively large-scale reactions. In conclusion, a judicious selection of benign co-solvents/additives could improve the catalytic efficiency of DNA-based hybrid catalyst.

Dataset Information

Influence of Organic Solvents on Enzymatic Asymmetric Carboligations.

Publications

Influence of Organic Solvents on Enzymatic Asymmetric Carboligations.

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