Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Enzyme- and Transition Metal-Catalyzed Asymmetric Transformations: Application of Enzymatic (D)KR in Enantioselective Synthesis
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dynamic kinetic resolution (DKR) is a powerful method for obtaining compounds with high optical purity. The process relies on the combination of a kinetic resolution with an in situ racemization. In this thesis, a combination of an immobilized hydrolase and a transition metal-based racemization catalyst was employed in DKR to transform racemic alcohols and amines into enantioenriched esters and amides, respectively.

In the first part the DKR of 1,2-amino alcohols with different rings sizes and N-protecting groups is described. We showed that the immobilization method used to support the lipase strongly influenced the stereoselectivity of the reaction.

The second part deals with the DKR of C3-functionalized cyclic allylic alcohols affording the corresponding allylic esters in high yields and high ee’s. The protocol was also extended to include carbohydrate derivatives, leading to inversion of a hydroxyl substituted chiral center on the carbohydrate.

The third part focuses on an improved method for obtaining benzylic primary amines. By using a novel, recyclable catalyst composed of Pd nanoparticles on amino-functionalized mesocellular foam, DKR could be performed at 50 °C. Moreover, Lipase PS was for the first time employed in the DKR of amines.

In the fourth part DKR was applied in the total synthesis of Duloxetine, a compound used in the treatment of major depressive disorder. By performing a six-step synthesis, utilizing DKR in the enantiodetermining step, Duloxetine could be isolated in an overall yield of 37% and an ee >96%.

In the final part we investigated how the enantioselectivty of reactions catalyzed by Candida Antarctica lipase B for δ-substituted alkan-2-ols are influenced by water. The results showed that the enzyme displays much higher enantioselectivity in water than in anhydrous toluene. The effect was rationalized by the creation of a water mediated hydrogen bond in the active site that helps the enzyme form enantiodiscriminating binding modes.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2014. , 78 p.
Keyword [en]
Dynamic Kinetic Resolution, Kinetic Resolution, Enzyme Catalysis, Asymmetric Synthesis
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-108351ISBN: 978-91-7649-008-2 (print)OAI: oai:DiVA.org:su-108351DiVA: diva2:757670
Public defence
2014-11-27, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2014-11-05 Created: 2014-10-22 Last updated: 2016-04-11Bibliographically approved
List of papers
1. An Efficient Dynamic Kinetic Resolution of N-Heterocyclic 1,2-Amino Alcohols
Open this publication in new window or tab >>An Efficient Dynamic Kinetic Resolution of N-Heterocyclic 1,2-Amino Alcohols
2011 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 353, no 13, 2321-2327 p.Article in journal (Refereed) Published
Abstract [en]

A chemoenzymatic dynamic kinetic resolution (DKR) of N-heterocyclic amino alcohols is described. Various lipases were studied as biocatalysts for the kinetic resolution of N-heterocyclic 1,2-amino alcohols. The influence of the support of the enzymes on the enantioselectivity in the resolution of different substrates is highlighted. Various 3-acetoxypyrrolidines and -piperidines were obtained in high yield and high enantiomeric excess in efficient DKR reactions.

Keyword
amino alcohols, biocatalysis, dynamic kinetic resolution, enzymatic catalysis, lipase
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-67265 (URN)10.1002/adsc.201100466 (DOI)000295230900008 ()
Note
authorCount :3Available from: 2011-12-30 Created: 2011-12-27 Last updated: 2017-12-08Bibliographically approved
2. Enzyme- and Ruthenium-Catalyzed Dynamic Kinetic Resolution of Functionalized Cyclic Allylic Alcohols
Open this publication in new window or tab >>Enzyme- and Ruthenium-Catalyzed Dynamic Kinetic Resolution of Functionalized Cyclic Allylic Alcohols
2013 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, no 23, 12114-12120 p.Article in journal (Refereed) Published
Abstract [en]

Enantioselective synthesis of functionalized cyclic allylic alcohols via dynamic kinetic resolution has been developed. Cyclopentadienylruthenium catalysts were used for the racemization, and lipase PS-IM or CALB was employed for the resolution. By optimization of the reaction conditions the formation of the enone byproduct was minimized, making it possible to prepare a range of optically active functionalized allylic alcohols in good yields and high ee's.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-98273 (URN)10.1021/jo402086z (DOI)000328231600050 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:3;

Available from: 2014-01-09 Created: 2014-01-03 Last updated: 2017-12-06Bibliographically approved
3. Epimerization of Glycal Derivatives by a Cyclopentadienylruthenium Catalyst: Application to Metalloenzymatic DYKAT
Open this publication in new window or tab >>Epimerization of Glycal Derivatives by a Cyclopentadienylruthenium Catalyst: Application to Metalloenzymatic DYKAT
2014 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 45, 14756-14762 p.Article in journal (Refereed) Published
Abstract [en]

Epimerization of a non-anomeric stereogenic center in carbohydrates is an important transformation in the synthesis of natural products. In this study an epimerization procedure of the allylic alcohols of glycals by cyclopentadienylruthenium catalyst 1 is presented. The epimerization of 4,6-O-benzylidene-D-glucal 4 in toluene is rapid, and an equlibrium with its D-allal epimer 5 is established within 5min at room temperature. Exchange rates for allal and glucal formation were determined by 1D H-1 EXSY NMR experiments to be 0.055s(-1) and 0.075s(-1), respectively. For 4-O-benzyl-L-rhamnal 8 the epimerization was less rapid and four days of epimerization was required to achieve equilibration of the epimers at room temperature. The epimerization methodology was subsequently combined with acylating enzymes in a dynamic kinetic asymmetric transformation (DYKAT), giving stereoselective acylation to the desired stereoisomers 12, 13, and 15. The net effect of this process is an inversion of a stereogenic center on the glycal, and yields ranging from 71% to 83% of the epimer were obtained.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2014
Keyword
carbohydrates, dynamic kinetic asymmetric transformation, enzyme catalysis, inversion, NMR spectroscopy
National Category
Chemical Sciences Organic Chemistry
Identifiers
urn:nbn:se:su:diva-110176 (URN)10.1002/chem.201403720 (DOI)000344358900029 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:4;

Available from: 2015-02-09 Created: 2014-12-08 Last updated: 2017-12-04Bibliographically approved
4. Chemoenzymatic Dynamic Kinetic Resolution of Primary Amines Using a Recyclable Palladium Nanoparticle Catalyst Together with Lipases
Open this publication in new window or tab >>Chemoenzymatic Dynamic Kinetic Resolution of Primary Amines Using a Recyclable Palladium Nanoparticle Catalyst Together with Lipases
Show others...
2014 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 9, 3747-3751 p.Article in journal (Refereed) Published
Abstract [en]

A catalyst consisting of palladium nanoparticles supported on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was used in chemoenzymatic dynamic kinetic resolution (DKR) to convert primary amines to amides in high yields and excellent ee's. The efficiency of the nanocatalyst at temperatures below 70 degrees C enables reaction conditions that are more suitable for enzymes. In the present study, this is exemplified by subjecting 1-phenylethylamine (1a) and analogous benzylic amines to DKR reactions using two commercially available lipases, Novozyme-435 (Candida antartica Lipase B) and Amano Lipase PS-C1 (lipase from Burkholderia cepacia) as biocatalysts. The latter enzyme has not previously been used in the DKR of amines because of its low stability at temperatures over 60 degrees C. The viability of the heterogeneous Pd-AmP-MCF was further demonstrated in a recycling study, which shows that the catalyst can be reused up to five times.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-104395 (URN)10.1021/jo500508p (DOI)000335490700002 ()
Funder
Berzelii Centre EXSELENTEU, European Research CouncilKnut and Alice Wallenberg FoundationSwedish Research Council
Note

AuthorCount:5;

Available from: 2014-06-12 Created: 2014-06-10 Last updated: 2017-12-05Bibliographically approved
5. 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: 2017-12-11Bibliographically approved
6. Investigation of the Impact of Water on the Enantioselectivity Displayed by CALB in the Kinetic Resolution of δ-Functionalized Alkan-2-ol Derivatives
Open this publication in new window or tab >>Investigation of the Impact of Water on the Enantioselectivity Displayed by CALB in the Kinetic Resolution of δ-Functionalized Alkan-2-ol Derivatives
2014 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 42, 13517-13521 p.Article in journal (Refereed) Published
Abstract [en]

It is shown that the low enantioselectivity of Candida antarctica lipase B (CALB)-catalyzed transesterification of a δ-functionalized alkan-2-ol to its acetate does not correlate at all with the high enantioselectivity of the CALB-catalyzed hydrolysis of the corresponding acetate in water. This lack of correlation is unusual and for unfunctionalized alkan-2-ol derivatives there is a very good correlation between the enantioselectivity of transesterification of the alcohol and hydrolysis of the corresponding acetate (E>200 in both cases). The results confirm previous predictions from molecular modeling. The water effect was mimicked by CALB variant Ala281Ser, which showed an enhanced enantioselectivity in transesterification of δ-functionalized alkan-2-ols compared to wild-type CALB.

Keyword
CALB, enantioselectivity, hydrolysis, lipase, transesterification
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-108352 (URN)10.1002/chem.201404233 (DOI)000342797500010 ()
Funder
Knut and Alice Wallenberg Foundation
Available from: 2014-10-22 Created: 2014-10-22 Last updated: 2017-04-18Bibliographically approved

Open Access in DiVA

fulltext(1677 kB)411 downloads
File information
File name FULLTEXT01.pdfFile size 1677 kBChecksum SHA-512
b721c58d7c69734bddb2cbdcafd7d8f5684f5b3ccba2c0d479b447e9cc10021bc5356d02b2171d8d42b52727a3cdc8e5559b3e51e135db1df815f56fe75f0d18
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Lihammar, Richard
By organisation
Department of Organic Chemistry
Organic Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 411 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

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 341 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf