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High Throughput Synthesis and Analysis of Acylated 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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2007 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 13, no 15, 4334-4341 p.Article in journal (Refereed) Published
Abstract [en]

The yields and optical purities of products obtained from chiral Lewis acid/Lewis base-catalysed additions of alpha-ketonitriles to prochiral aldehydes could be accurately determined by an enzymatic method. The amount of remaining aldehyde was determined after its reduction to an alcohol, whilst the two product enantiomers were analysed after subsequent hydrolysis first by the (S)-selective Candida antarctica lipase B and then by the unselective pig liver esterase. The method could be used for analysis of products obtained from a number of aromatic aldehydes and aliphatic ketonitriles. Microreactor technology was successfully combined with high-throughput analysis for efficient catalyst optimization.

Place, publisher, year, edition, pages
2007. Vol. 13, no 15, 4334-4341 p.
Keyword [en]
asymmetric synthesis; cyanohydrins; enantioselectivity; enzymes; high-throughput screening; microreactors
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-7108DOI: 10.1002/chem.200601638ISI: 000246879100022Scopus ID: 2-s2.0-34250318478OAI: oai:DiVA.org:kth-7108DiVA: diva2:12021
Note
QC 20100809Available from: 2007-05-15 Created: 2007-05-15 Last updated: 2017-12-14Bibliographically approved
In thesis
1. 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
2. New Methods for Chiral Cyanohydrin Synthesis
Open this publication in new window or tab >>New Methods for Chiral Cyanohydrin Synthesis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with method development in asymmetric catalysis and specifically syntheses of enantioenriched O-functionalized cyanohydrins.

The first part describes the development of a method for the synthesis of O‑alkoxycarbonylated and O-acylated cyanohydrins. Ethyl cyanoformate and acyl cyanides were added to aldehydes in a reaction catalyzed by a chiral dimeric Ti-salen complex together with a tertiary amine. High yields and enantioselectivities were in most cases obtained. Mechanistic studies were performed and a reaction mechanism was proposed. ­

The second part describes a method in which the undesired minor enantiomer in a Lewis acid–Lewis base-catalyzed acylcyanation is continuously recycled into prochiral starting material. Close to enantiopure O‑acylated cyanohydrins were obtained in high yields.

The third part deals with asymmetric acylcyanations of ketones. Acetyl cyanide was found to add to α‑ketoesters in a reaction catalyzed by a chiral Lewis base. Yields up to 77% and 82% ee were obtained.

The final part describes an enzymatic method for high-throughput analysis of O‑acylated cyanohydrins. The enantiomeric excess and conversion were determined for products obtained from a number of aromatic and aliphatic aldehydes.

Place, publisher, year, edition, pages
Stockholm: KTH, 2009. 54 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2009:12
Keyword
acyl cyanides, asymmetric synthesis, biocatalysis, cyanide, cyanohydrins, dual activation, enzymes, high-throughput screening, Lewis acid, Lewis base, metal catalysis, minor enantiomer recycling, salen, titanium
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-10205 (URN)978-91-7415-263-0 (ISBN)
Public defence
2009-05-08, F3, Lindstedtsvägen 26, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100818Available from: 2009-05-07 Created: 2009-04-06 Last updated: 2010-09-22Bibliographically approved
3. 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
4. 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

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