Change search
ReferencesLink to record
Permanent link

Direct link
Asymmetric transformation of ß- and γ-functionalized alcohols: Study of combined ruthenium-catalyzed racemization and enzymatic resolution
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Jan-Erling Bäckvall)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The major part of this thesis describes the asymmetric synthesis of β- and γ-amino alcohols through the combination of ruthenium catalyzed racemization and enzymatic kinetic resolution.

The dynamic kinetic resolution, DKR, protocol for chlorohydrins was improved by employing Bäckvall’s catalyst, which is a base activated racemization catalyst, in combination with Burkholderia cepacia lipase. These optimized conditions broadened the substrate scope and improved the yields and ee’s of the obtained chlorohydrin acetates. The utility of the method was demonstrated in the synthesis of (S)-salbutamol.

In the second part of the thesis, DKR was utilized in the enantio-determining step of the total synthesis of (R)-duloxetine. Optimized DKR conditions, combining Bäckvall’s catalyst together with Candida antarctica lipase B, afforded a β-cyano acetate in high yield and ee. (R)-Duloxetine was accessible through synthetic alterations of the enantioenriched β-cyano acetate in high overall yield.

A dynamic kinetic asymmetric transformation, DYKAT, protocol to obtain enantio- and diastereomerically pure γ-amino alcohols was developed. In a first step N-Boc-aminoketones were obtained in high enantiomeric purity through a proline-catalyzed Mannich reaction. Subsequent in situ reduction coupled with a highly efficient DYKAT yielded γ-amino acetates in high dr and ee. The γ-amino alcohols were available through simple hydrolysis/deprotection with retained stereochemistry.

In the final part of the thesis a heterogeneous bifunctional catalytic system is reported, which combines the catalytic properties of transition metal-catalyzed racemization with enzymatic acylation. A novel ruthenium-phosphonate complex was synthesized and then covalently anchored to the active site of solid supported Candida antarctica lipase B. The partially inhibited beads proved to be catalytically active both in racemization as well as enzymatic acylation.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2011. , 91 p.
Keyword [en]
Kinetic resolution, dynamic kinetic resolution, kinetic asymmetric transformation, dynamic kinetic asymmetric transformation, enzyme catalysis, racemization, asymmetric synthesis, chlorohydrin, cyano acetate, amino alcohol, metalloenzyme, bifunctional catalytic system
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-56947ISBN: 978-91-7447-307-0OAI: oai:DiVA.org:su-56947DiVA: diva2:414208
Public defence
2011-06-10, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: Epub ahead of print.Available from: 2011-05-13 Created: 2011-05-02 Last updated: 2011-06-15Bibliographically approved
List of papers
1. Highly efficient route for enantioselctive preparation of chlorohydrins via dynamic kinetic resolution
Open this publication in new window or tab >>Highly efficient route for enantioselctive preparation of chlorohydrins via dynamic kinetic resolution
2008 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 10, no 21, 4807-4810 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic kinetic resolution (DKR) of various aromatic chlorohydrins with the use of Pseudomonas cepacia lipase (PS-C “Amano” II) and ruthenium catalyst 1 afforded chlorohydrin acetates in high yields and high enantiomeric excesses. These optically pure chlorohydrin acetates are useful synthetic intermediates and can be transformed to a range of important chiral compounds.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-15314 (URN)10.1021/ol801749z (DOI)000260534500025 ()
Available from: 2009-01-05 Created: 2009-01-05 Last updated: 2013-04-18Bibliographically approved
2. Chemoenzymatic dynamic kinetic resolution as a key step in the enantioselective synthesis of (S)-salbutamol
Open this publication in new window or tab >>Chemoenzymatic dynamic kinetic resolution as a key step in the enantioselective synthesis of (S)-salbutamol
2011 (English)In: Collection of Czechoslovak Chemical Communications, ISSN 0010-0765, Vol. 76, no 7, 919-927 p.Article in journal (Refereed) Published
Abstract [en]

The synthesis of (S)-salbutamol is described.  By utilizing DKR in the enantiodetermining step, employing Burkholderia cepacia lipase (PS-IM), (S)-acetate ((S)-6) was obtained in excellent enantiomeric excess (98%).  The subsequent transformations yielded the salt of (S)-salbutamol with retained stereochem.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-56944 (URN)10.1135/cccc2011029 (DOI)000292516100007 ()
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2012-01-20Bibliographically approved
3. A Chemoenzymatic Dynamic Kinetic Resolution Approach to Enantiomerically Pure (R)- and (S)-Duloxetine
Open this publication in new window or tab >>A Chemoenzymatic Dynamic Kinetic Resolution Approach to Enantiomerically Pure (R)- and (S)-Duloxetine
2011 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, no 10, 3917-3921 p.Article in journal (Refereed) Published
Abstract [en]

The synthesis of (R)-duloxetine is described. Dynamic kinetic resolution of β-hydroxynitrile rac-1 using Candida antarctica lipase B (CALB, N435) and ruthenium catalyst 6 afforded β-cyano acetate (R)-2 in high yield and in excellent enantioselectivity (98% ee). The subsequent synthetic steps were straightforward and (R)-duloxetine was isolated in 37% overall yield over 6 steps. The synthetic route also constitute a formal total synthesis of (S)-duloxetine.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-56948 (URN)10.1021/jo2003665 (DOI)000290465700034 ()
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2014-10-23Bibliographically approved
4. Enantioselective synthesis of syn- and anti-1,3-aminoalcohols via β-aminoketones and subsequent reduction/dynamic kinetic asymmetric transformation
Open this publication in new window or tab >>Enantioselective synthesis of syn- and anti-1,3-aminoalcohols via β-aminoketones and subsequent reduction/dynamic kinetic asymmetric transformation
2010 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 132, no 43, 15182-15184 p.Article in journal (Refereed) Published
Abstract [en]

β-Aminoketones obtained from imines in an organocatalytic Mannich reaction were transformed to enantio- and diastereomerically pure 1,3-aminoalcohols with two stereogenic centers via a combined reduction/dynamic kinetic asymmetric transformation. Both syn and anti diastereomers were obtained in high yield, dr, and ee.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-45969 (URN)10.1021/ja107857v (DOI)000283621700029 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2011-11-21Bibliographically approved
5. Covalent anchoring of a racemization catalyst to CALB-beads: towards dual immobilization of DKR catalysts
Open this publication in new window or tab >>Covalent anchoring of a racemization catalyst to CALB-beads: towards dual immobilization of DKR catalysts
Show others...
2011 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1873-3581, Vol. 52, no 14, 1601-1604 p.Article in journal (Refereed) Published
Abstract [en]

The preparation of a heterogeneous bifunctional catalytic system, combining the catalytic properties of an organometallic catalyst (racemization) with those of an enzyme (enantioselective acylation) is described. A novel ruthenium phosphonate inhibitor was synthesized and covalently anchored to a lipase immobilized on a solid support (CALB, Novozym® 435). The immobilized bifunctional catalytic system showed activity in both racemization of (S)-1-phenylethanol and selective acylation of 1-phenylethanol.

Keyword
Bifunctional catalytic system, Metalloenzyme, DKR, Lipases, Heterogeneous catalysis
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-56949 (URN)10.1016/j.tetlet.2011.01.106 (DOI)000288730900014 ()
Funder
Swedish Research Council
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2012-01-18Bibliographically approved

Open Access in DiVA

errata(67 kB)31 downloads
File information
File name ERRATA01.pdfFile size 67 kBChecksum SHA-512
fc5e4ee3d051394eba31832c5cc9e65d62746e4b1807777625013875db07871ef064e63cb3cdbdd70bf10c1f13f88b349cfc4088fc6604aaa88a956362fafa30
Type errataMimetype application/pdf
fulltext(1656 kB)792 downloads
File information
File name FULLTEXT01.pdfFile size 1656 kBChecksum SHA-512
fdde9a680ac9b74af0dec592f7e945c8d88d052b86a551b7fff70f8081ff105996bae5b3d2f86029c052898539a10a738307372cc9d3161e2199f27b1e3df068
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Träff, Annika
By organisation
Department of Organic Chemistry
Organic Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 792 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 221 hits
ReferencesLink to record
Permanent link

Direct link