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Enzymes as catalysts in synthesis of enantiomerically pure building blocks: secondary alcohols bearing two vicinal stereocenters
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2005 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Enzymes as tools in organic synthesis have provided enormous advantages. This thesis deals with the applications of enzymes in the kinetic resolutions of racemic compounds. The stereochemistry of chiral compounds and the kinetics of α/β hydrolase lipases are presented. From a practical point of view, the handling of a large number of parameters that influences the kinetic resolutions, especially enantioselectivity (E-value) are systematically described. A variety of approaches employed for raising the yields to over 50% are additionally discussed.

Methods for the preparation of synthetically useful chiral building blocks were developed in this thesis. Thus, resolution of secondary alcohols bearing two vicinal stereocentres are studied. These building blocks can serve as starting materials for the synthesis of various enantiomerically pure compounds for agrochemistry, pharmaceuticals, chemical industry, and particularly for the total synthesis of pheromones.

Racemic 3-substitued 2-hydroxybutane derivatives were produced in fairly high diastereomeric purities by a variety of chemical approaches, such as epimerization, metal-catalysed asymmetric addition etc. Kinetic resolution of these racemates was achieved by enzyme-catalysed reactions. Two lipases, Candida antarctica lipase B and Pseudomonas cepacia lipase were found to be useful in acylations as well as hydrolyses. In the biotransformations studied, the presence and nature of the second vicinal stereocentre in the chiral secondary alcohols investigated seemed to be important, e.g. in terms of the efficiencies of sequential kinetic resolutions, and altering the selectivities as well.

Place, publisher, year, edition, pages
Stockholm: KTH , 2005. , vi, 65 p.
Series
Trita-IOK, ISSN 1100-7974 ; 2005:96
Keyword [en]
enzyme, kinetic resolution, enantioselectivity, lipase, diastereoselectivity, epimerisation, metal-catalysed transformation, intramolecular alkylation.
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:kth:diva-424ISBN: 91-7178-129-3 (print)OAI: oai:DiVA.org:kth-424DiVA: diva2:11413
Public defence
2005-09-30, Sal K2, Teknikringen 28, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20101020Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2010-10-20Bibliographically approved
List of papers
1. Chemoenzymatic preparation of (2S,3S)- and (2R,3R)-2,3-butanediols and their esters from mixtures of d,l- and meso-diols
Open this publication in new window or tab >>Chemoenzymatic preparation of (2S,3S)- and (2R,3R)-2,3-butanediols and their esters from mixtures of d,l- and meso-diols
2001 (English)In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 12, no 5, 771-778 p.Article in journal (Refereed) Published
Abstract [en]

An efficient method of preparing the pure enantiomers of 2,3-butanediol front commercially available mixtures of the d,l- and meso-isomers was developed. It furnished (2S,3S)-2.3-butanediol with > 99% e.e. and a >9.5/0.5 diastereomeric ratio and (2R,3R)-2,3-butanediol in 95% e.e. and >9.5/<5 diastereomeric ratio.

Keyword
sequential kinetic resolution, 2 consecutive steps, computer-program, lipase, hydrolysis, transesterification, optimization, simulation, isomers
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-6643 (URN)10.1016/S0957-4166(01)00109-4 (DOI)000168596200015 ()
Note
QC 20101020Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2010-10-20Bibliographically approved
2. Preparation of the four stereoisomers of 3-bromo-2-butanol or their acetates via lipase-catalysed resolutions of the racemates derived from dl- or meso-2,3-butanediol.
Open this publication in new window or tab >>Preparation of the four stereoisomers of 3-bromo-2-butanol or their acetates via lipase-catalysed resolutions of the racemates derived from dl- or meso-2,3-butanediol.
2005 (English)In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 16, 2607-2611 p.Article in journal (Refereed) Published
Abstract [en]

The four stereoisomeric 3-bromo-2-butanols and/or their acetates were prepared via lipase-catalysed kinetic resolution by hydrolyses of the acetates of the (+/-)-syn- and (+/-)-anti-3-bromo-2-butanols, or via esterifications of the alc hols. The diastereomeric bromoacetates were obtained by syntheses from the dl- and meso-2,3-butanediols, respectively. On a preparative scale, the four stereoisomers, either as the free alcohols or as their acetates, were obtained in > 95% ee, and in 35-40% yield (based on the starting racemates).

Keyword
kinetic resolution, halohydrins, epoxides
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:kth:diva-6644 (URN)10.1016/j.tetasy.2005.06.028 (DOI)000234625700013 ()
Note
Tidigare titel: Lipase-catalysed kinetic resolution furnishes the four stereoisomers of 3-bromo-2-butanol or its acetate from d,l- and meso-2,3-butanediol. QC 2010102Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2010-10-20Bibliographically approved
3. Chemoenzymatic preparation of isomerically pure 3-bromo-2-butyl ethyl malonate ester
Open this publication in new window or tab >>Chemoenzymatic preparation of isomerically pure 3-bromo-2-butyl ethyl malonate ester
(English)Manuscript (Other academic)
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-6645 (URN)
Note
QC 20101020Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2010-10-20Bibliographically approved
4. Enantiopure building blocks for the synthesis of 3-methyl-2-alkanols. Diastereoselective methylmetal addition to a chiral 2-methylaldehyde followed by lipase catalysed esterification
Open this publication in new window or tab >>Enantiopure building blocks for the synthesis of 3-methyl-2-alkanols. Diastereoselective methylmetal addition to a chiral 2-methylaldehyde followed by lipase catalysed esterification
2004 (English)In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 15, 2907-2915 p.Article in journal (Refereed) Published
Abstract [en]

The racemic synthetic building block (2R*,3R*)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R*,3R*)-2 was obtained in a high diastereomeric ratio [95:5, (2R*,3R*)/(2R*,3S*)-ratio] by Lewis acid catalysed dimethylzinc addition to racemic 2-methyl-3-(phenylsulfanyl)propanal (rac-1). Two consecutive acylations with vinyl acetate catalysed by Chirazyme L-2 (immobilised Candida antarctica lipase 13, CAL-B) led to preferential esterification of three of the four stereoisomers leaving (2S,3S)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2S,3S)-2 of 98:2 dr and 98% ee. The stereoisomerically impure acetate of (2R,3R)-3-methyl-4-(phenyisulfanyl)butan-2-ol (2R,3R)-2, obtained in the first CAL-B-catalysed acylation step, was hydrolysed and reesterified using CAL-A (immobilised Novozyme SP 525) as the catalyst, which left (2R,3R)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R,3R)-2 of 98:2 dr and 99% ee as the remaining substrate. The individual enantiomers of 2-methyl-3-(phenylsulfanyl)propanal 1 were prepared from readily available (S)- and (R)-3-hydroxy-2-methylpropanoic acid methyl ester and reacted with dimethylzinc to give both enantiomers of (2R*,3R*)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R, 3R)- or (2S,3S)-2 of both high dr and ee. These products were purified by lipase catalysed acylation to give the enantiomerically and diastereomerically highly pure enantiomers (>99.5:0.5 dr, >99.9% ee). Pure (2S,3S)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2S,3S)-2 was transformed into a potential pheromone precursor isolated from some pine sawflies of the genus Gilpinia, (2S,3R)-3-methylpentadecan-2-ol in 54% yield over eight steps.

Keyword
hypophosphite combination system, enantioselective total synthesis, candida-antarctica lipase, sex-pheromone, secondary alcohols, raney-nickel, reductive desulfurization, macrodiprion-nemoralis, microdiprion-pallipes, neodiprion-sertifer
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-6646 (URN)10.1016/j.tetasy.2004.07.049 (DOI)000224333100032 ()
Note
QC 20101020Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2010-10-26Bibliographically approved
5. Attempted intramolecular enolate alkylation of anti-3-bromo-2-butyl, ethyl malonate ester.
Open this publication in new window or tab >>Attempted intramolecular enolate alkylation of anti-3-bromo-2-butyl, ethyl malonate ester.
(English)Manuscript (Other academic)
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-6647 (URN)
Note
QC 20101020Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2010-10-20Bibliographically approved

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