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Investigation of the Impact of Water on the Enantioselectivity Displayed by CALB in the Kinetic Resolution of δ-Functionalized Alkan-2-ol Derivatives
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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.

Place, publisher, year, edition, pages
2014. Vol. 20, no 42, 13517-13521 p.
Keyword [en]
CALB, enantioselectivity, hydrolysis, lipase, transesterification
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-108352DOI: 10.1002/chem.201404233ISI: 000342797500010OAI: oai:DiVA.org:su-108352DiVA: diva2:757366
Funder
Knut and Alice Wallenberg Foundation
Available from: 2014-10-22 Created: 2014-10-22 Last updated: 2017-04-18Bibliographically approved
In thesis
1. Enzyme- and Transition Metal-Catalyzed Asymmetric Transformations: Application of Enzymatic (D)KR in Enantioselective Synthesis
Open this publication in new window or tab >>Enzyme- and Transition Metal-Catalyzed Asymmetric Transformations: Application of Enzymatic (D)KR in Enantioselective Synthesis
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
Dynamic Kinetic Resolution, Kinetic Resolution, Enzyme Catalysis, Asymmetric Synthesis
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-108351 (URN)978-91-7649-008-2 (ISBN)
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
2. Catalytic Stereoselective Formation of C–O, C–C and C–B Bonds: A Voyage from Asymmetric Reactions Enabled by Lipases to Stereoselective Palladium-Catalyzed Oxidative Transformations of Enallenes
Open this publication in new window or tab >>Catalytic Stereoselective Formation of C–O, C–C and C–B Bonds: A Voyage from Asymmetric Reactions Enabled by Lipases to Stereoselective Palladium-Catalyzed Oxidative Transformations of Enallenes
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis has been focused on enzymatic kinetic resolutions and stereoselective oxidative transformations of enallenes catalyzed by PdII.

In the first part of the thesis, a detailed discussion on Candida antarctica lipase B (CALB)-catalyzed kinetic resolution (KR) of δ-functionalized alkan-2-acetates is shown. We gained a deeper insight into the mechanism of enzyme-substrate recognition. Changing from an anhydrous solvent to water or a water-containing organic solvent enhanced the enantioselectivity. The effect of –OH was also confirmed by a lipase mutant suggesting that the water molecule mentioned above can be partly mimicked.

In the second part of the thesis, we developed an efficient KR for allenic alcohols. On this basis, a novel synthesis of optically pure 2-substituted 2,3-dihydrofurans from allenic alcohols via a Ru-catalyzed cycloisomerization was reported. The developed protocol enabled us to assemble an optically pure precursor for total synthesis with three chiral centers from readily available allenol in 2 days.

In the third part, we reported a class of reactions involving C–H cleavage under mild conditions: PdII-catalyzed oxidative transformations of enallenes. These reactions are particularly attractive since a number of meticulous structures have been achieved from readily accessible starting materials. The directing effect of an unsaturated hydrocarbon was found to be key for these transformations.

In the final part, we developed the carbonylative insertion reaction discussed in the third part of the thesis into an asymmetric version. By using this methodology, a number of cyclopentenone compounds were obtained in good to excellent enantioselectivity.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2017. 76 p.
Keyword
Synthesis, Enzymatic kinetic resolution, Palladium, Allenes, Oxidative Transformations, Ruthenium
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-141519 (URN)978-91-7649-823-1 (ISBN)978-91-7649-824-8 (ISBN)
Public defence
2017-05-17, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2017-04-24 Created: 2017-04-05 Last updated: 2017-05-23Bibliographically approved

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