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High-Throughput Enzymatic Method for Enantiomeric Excess Determination of O-Acetylated Cyanohydrins
KTH, School of Biotechnology (BIO), Biochemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.ORCID iD: 0000-0002-1743-7650
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2006 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 7, 2234-2235 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 128, no 7, 2234-2235 p.
Keyword [en]
acetic acid derivative; cyanohydrin; enzyme; acetylation; article; catalyst; chemical modification; enantiomer; enzyme activity; high throughput screening; Acetylation; Animals; Benzaldehydes; Esterases; Hydrolysis; Lipase; Liver; NAD; Nitriles; Stereoisomerism; Swine
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-6920DOI: 10.1021/ja058474rISI: 000235562900040Scopus ID: 2-s2.0-33644501771OAI: oai:DiVA.org:kth-6920DiVA: diva2:11767
Note
QC20100809Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Efficient Synthesis and Analysis of Chiral Cyanohydrins
Open this publication in new window or tab >>Efficient Synthesis and Analysis of Chiral Cyanohydrins
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

This thesis deals with the development of new methods for efficient synthesis and analysis in asymmetric catalysis. It focuses on the preparation of chiral cyanohydrins by enantioselective addition of cyanide to prochiral aldehydes.

The initial part of the thesis describes the development of a dual Lewis acid– Lewis base activation system for efficient synthesis of chiral O-acylated and Ocarbonylated cyanohydrins. This system was used for the preparation of a variety of cyanohydrins in high isolated yields and with up to 96% ee. Activation of the cyanide by nucleophilic attack of the Lewis base at the carbonyl carbon atom was supported experimentally.

Secondly, convenient procedures for the synthesis of polymer-bound chiral YbCl3-pybox and Ti-salen complexes are described. The polymeric complexes were employed in cyanation of benzaldehyde.

A T-shaped microreactor was used for screening of reaction conditions for the enantioselective cyanation of benzaldehyde using trimethylsilyl cyanide and acetyl cyanide as cyanide sources. A microreactor charged with the polymeric Tisalen complex was used for enantioselective cyanation of benzaldehyde.

Finally, an enzymatic method for high throughput analysis of ee and conversion of products from chiral Lewis acid–Lewis base-catalysed additions of α- ketonitriles to prochiral aldehydes was developed. The method could be used for the analysis of a variety of O-acylated cyanohydrins. Microreactor technology was successfully combined with high throughput analysis for efficient catalyst optimisation.

Place, publisher, year, edition, pages
Stockholm: KTH, 2007. 54 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2007:11
Keyword
asymmetric catalysis, cyanohydrins, microreactor, polymersupported catalyst, ketonitriles, titanium, lanthanide, Lewis acid, Lewis base
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-4315 (URN)978-91-7178-599-2 (ISBN)
Public defence
2007-04-13, Sal F3, KTH, Lindstedtsvägen 26, Stockholm, 10:15 (English)
Opponent
Supervisors
Note
QC 20100809Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2010-08-09Bibliographically approved
2. Serine Hydrolase Selectivity: Kinetics and applications in organic and analytical chemistry
Open this publication in new window or tab >>Serine Hydrolase Selectivity: Kinetics and applications in organic and analytical chemistry
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The substrate selectivities for different serine hydrolases were utilized in various applications, presented in papers I-VI. The articles are discussed in the thesis in view of the kinetics of the enzyme catalysis involved.

In paper I the enantioselectivities towards a range of secondary alcohols were reversed for Candida antarctica lipase B by site directed mutagenesis. The thermodynamic components of the enantioselectivity were determined for the mutated variant of the lipase.

In papers II-III Candida antarctica lipase B was engineered for selective monoacylation using two different approaches. A variant of the lipase created for substrate assisted catalysis (paper II) and three different variants with mutations which decreased the volume of the active site (paper III) were evaluated. Enzyme kinetics for the different variants were measured and translated into activation energies for comparison of the approaches.

In papers IV and V three different enzymes were used for rapid analysis of enantiomeric excess and conversion of O-acylated cyanohydrins synthesized by a defined protocol. Horse liver alcohol dehydrogenase, Candida antarctica lipase B and pig liver esterase were sequentially added to a solution containing the O-acylated cyanohydrin. Each enzyme caused a drop in absorbance from oxidation of NADH to NAD+. The product yield and enantiomeric excess was calculated from the relative differences in absorbance.

In paper VI a method for C-terminal peptide sequencing was developed based on conventional Carboxypeptidase Y digestion combined with matrix assisted laser desorption/ionization mass spectrometry. An alternative nucleophile was used to obtain a stable peptide ladder and improve sequence coverage.

Place, publisher, year, edition, pages
Stockholm: KTH, 2010. viii, 62 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2010:12
Keyword
Candida antarctica lipase B, monoacylation of diols, kinetic resolution, thermodynamics in enzyme catalysis, enzyme engineering
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-12831 (URN)978-91-7415-663-8 (ISBN)
Public defence
2010-06-04, FD5, AlbaNova University Center, Roslagstullsbacken 21, Stockholm, 15:42 (English)
Opponent
Supervisors
Note
QC20100629Available from: 2010-05-24 Created: 2010-05-12 Last updated: 2010-06-29Bibliographically approved
3. Enzyme selectivity as a tool in analytical chemistry
Open this publication in new window or tab >>Enzyme selectivity as a tool in analytical chemistry
2007 (English)Licentiate thesis, comprehensive summary (Other scientific)
Abstract [en]

Enzymes are useful tools as specific analytical reagents. Two different analysis methods were developed for use in the separate fields of protein science and organic synthesis. Both methods rely on the substrate specificity of enzymes. Enzyme catalysis and substrate specificity is described and put in context with each of the two developed methods.

In paper I a method for C-terminal peptide sequencing was developed based on conventional Carboxypeptidase Y digestion combined with matrix assisted laser desorption/ionization mass spectrometry. An alternative nucleophile was used to obtain a stable peptide ladder and improve sequence coverage.

In paper II and III, three different enzymes were used for rapid analysis of enantiomeric excess and conversion of O-acylated cyanohydrins synthesized by a defined protocol. Horse liver alcohol dehydrogenase, Candida antarctica lipase B and pig liver esterase were sequentially added to a solution containing the O-acylated cyanohydrin. Each enzyme caused a drop in absorbance from oxidation of NADH to NAD+. The conversion and enantiomeric excess of the sample could be calculated from the relative differences in absorbance.

Place, publisher, year, edition, pages
Stockholm: KTH, 2007. viii, 35 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2007:5
Keyword
substrate specificity, competing substrates, enantiomeric excess analysis, library screening, ladder sequencing, carboxypeptidase Y, 2-pyridylmethylamine, MALDI, Candia antarctica lipase B, pig liver esterase, horse liver alcohol dehydrogenase, acylated cyanohydrins
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-4377 (URN)978-91-7178-674-6 (ISBN)
Presentation
2007-06-01, FB54, AlbaNova, Roslagstullsbacken 21, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20101108Available from: 2007-05-15 Created: 2007-05-15 Last updated: 2010-11-08Bibliographically approved

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