Use of Chiral HPLC-MS for Rapid Evaluation of the Yeast-Mediated Enantioselective Bioreduction of a Diaryl Ketone

Welch, Christopher J.; Grau, Brendan; Moore, Jeff; Mathre, David J.

doi:10.1021/jo015966n

Cited by 52 publications

(30 citation statements)

References 3 publications

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“…[36] Preliminary results have shown that selected strains from Hansenula nonfermentans, santamariae, ernobii, Rhodosporidium toruloides, Candida bombi, and C. sorbophila reduced diaryl ketones with high selectivity, producing the alcohol product with > 95% ee, but the substrate was not specified and the conversion was less than 12%. [37] Debaryomyces marama enantioselectively reduced p-chlorobenzophenone to give a 48% yield of the S-alcohol with 34% of ketone being recovered. [38] Recently, the reductions of a series of diaryl ketones were tested with commercially available ketoreductases, and high enantioselectivity was obtained in some cases.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Reduction of Diaryl Ketones Catalyzed by a Carbonyl Reductase from Sporobolomyces salmonicolor and its Mutant Enzymes

Zhu

Ling³

et al. 2009

Adv Synth Catal

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Abstract:The carbonyl reductase from red yeast Sporobolomyces salmonicolor AKU4429 (SSCR) and its mutant enzymes effectively catalyzed the enantioselective reduction of diaryl ketones to give the corresponding chiral alcohols. Both conversion and enantioselectivity were dependent on the co-solvent in the reaction medium. Diaryl ketones with a para-substituent on one of the phenyl groups were reduced with high enantioselectivity (up to 99% ee), which is difficult to achieve using chemical methods such as chiral borane reduction, asymmetric hydrogenation or hydrosilylation. Mutation of SSCR at Q245 resulted in a higher amount of (S)-enantiomer in the products, and in the case of mutant Q245P with para-substituted diaryl ketones as substrate, this effect was so remarkable that the reduction enantiopreference was switched from (R) to (S). The present study provides valuable information about the catalytic properties of the carbonyl reductase SSCR toward the reduction of diaryl ketones, serving as basis for further engineering of this enzyme to develop efficient biocatalysts for highly enantiospecific reduction of diaryl ketones without high electronic dissymmetry or an ortho-substituent on one of the aryl groups.

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Section: Introductionmentioning

confidence: 99%

Enantioselective Reduction of Diaryl Ketones Catalyzed by a Carbonyl Reductase from Sporobolomyces salmonicolor and its Mutant Enzymes

Zhu

Ling³

et al. 2009

Adv Synth Catal

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“…Mass spectrometry detection can sometimes be used to deconvolute overlapping peaks of differing mass, an approach which we have previously found useful in high throughput analysis to support enzyme screening. 33 A drawback of this approach can be the problem of ion suppression/ion enhancement, wherein the overlapping substance either decreases or increases the propensity of the target compound to become ionized in the electrospray process, thereby leading to errors in quantitation. In the present case, SFC-MS can be used to deconvolute the overlapping peaks, as shown in Figure 4.…”

Section: Sfc Analysismentioning

confidence: 99%

Fast methods of enantiopurity determination for the Soai reaction: Towards a general enantioenrichment detector?

Welch¹,

Biba²,

Sajonz³

2006

Chirality

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The Soai reaction system possesses a remarkable combination of characteristics (enantioselective autocatalysis, strong positive nonlinearity leading to asymmetric amplification, ability to be triggered by wide variety of exogenous enantioenriched materials) that make it a potential starting point for a generalized detector for enantioenrichment. In this study we apply standard approaches used in pharmaceutical process research to the problem of developing a rapid method for analysis of the enantiopurity of the Soai reaction product. Several methods for rapid analysis (<1 min per sample) are described, including an approach using chiral supercritical fluid chromatography (SFC) and an approach using achiral chromatography with circular dichroism (CD) detection. Some thoughts on incorporation into a device for generalized enantioenrichment detection are presented.

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“…[3,4] Currently, parallel chromatographic methods are mostly employed for that purpose. [5][6][7][8][9] The development of optical spectroscopic assays (e.g. absorption or fluorescence) should ease the instrumentation dependence and increase the speed of high-throughput assays.…”

Section: Introductionmentioning

confidence: 99%

Two Methods for the Determination of Enantiomeric Excess and Concentration of a Chiral Sample with a Single Spectroscopic Measurement

Zhu

Shabbir

Anslyn

2006

Chemistry A European J

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The previously established enantioselective indicator–displacement assays (eIDAs) for the determination of concentration and enantiomeric excess (ee) require two spectroscopic measurements for each chiral sample. To further simplify the operation of eIDAs, we now introduce two innovative analytical methods, both of which utilize a dual‐chamber quartz cuvette, which reduces the number of spectroscopic measurements from two to one. An attractive feature of this cuvette is that the concentration‐ and ee‐dependent absorption data can be collected at the isosbestic points or transparent regions of the spectra recorded in each individual chamber, thereby reflecting optical changes that occur in the other chamber. Therefore, two independent equations, which are needed to solve the values of the two independent variables—concentration and ee—can be established with only a single spectroscopic measurement. The first method takes advantage of this feature in conjunction with a judicious choice of indicator/host combinations to generate concentration‐ and ee‐dependent calibration curves. Our second method removes the requirement to measure equilibrium constants and molar absorptivities altogether through the use of artificial neural networks (ANNs). The most frequently used three‐layer feed‐forward network is generated, which relates the absorption data to concentration and ee of the samples by training with a back propagation procedure. Here, the data collection is not limited to the isosbestic points or transparent regions. Both approaches enabled accurate and rapid determination of concentration and ee of chiral samples. The technology removes the relative difficulty, which is the need for two separate measurements for concentration and ee respectively, of analyzing chiral samples compared to achiral samples. When implemented in a high‐throughput format, this technology should greatly facilitate the discovery of asymmetric catalysts in the same way as conventional high‐throughput screening assays.

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Use of Chiral HPLC-MS for Rapid Evaluation of the Yeast-Mediated Enantioselective Bioreduction of a Diaryl Ketone

Cited by 52 publications

References 3 publications

Enantioselective Reduction of Diaryl Ketones Catalyzed by a Carbonyl Reductase from Sporobolomyces salmonicolor and its Mutant Enzymes

Enantioselective Reduction of Diaryl Ketones Catalyzed by a Carbonyl Reductase from Sporobolomyces salmonicolor and its Mutant Enzymes

Fast methods of enantiopurity determination for the Soai reaction: Towards a general enantioenrichment detector?

Two Methods for the Determination of Enantiomeric Excess and Concentration of a Chiral Sample with a Single Spectroscopic Measurement

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