Transition metal- and lipase-catalyzed reactions: Dynamic resolutions, hydrogen transfer and enzyme engineering
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
This thesis mainly focuses on chemoenzymatic processes and can be divided into three parts: The first part of the thesis, chapters 2-4, is devoted to the development of combined ruthenium- and enzyme-catalyzed dynamic processes. In these processes the metal catalyst racemizes (epimerizes) the alcohol substrate via hydrogen transfer and the enzyme transforms the substrate into enantiomerically enriched product. Chapter 2 focuses on bicyclic diols, where a process was developed to provide the enantiomerically pure product diacetates in high yield. The diacetates were then hydrolyzed using various protocols to yield the corresponding enantio- and diastereoenriched diols. Two of the substrates were mono-oxidized to yield the enantioenriched hydroxyketones in high yield. One of the hydroxyketones was subsequently employed in the formal synthesis of Sertraline in a highly enantioselective manner. Chapter 3 deals with the application of dynamic kinetic resolution in the synthesis of a pesticide derivative, which is obtained in high yield and high enantiomeric excess. Chapter 4 describes the use of dynamic kinetic resolution to set the configuration of a non-activated stereocenter in primary alcohols by taking advantage of the intermediate aldehydes intrinsic enolization behavior. A wide range of primary alcohols with a stereogenic center in β-position were dynamically resolved using this approach.
The second part, chapters 5-6, deals with different types of enzyme engineering. In chapter 5, a lipase from Pseudomonas aeruginosa was mutated using directed evolution to increase the enantioselectivity of the lipase towards an allenic substrate. In chapter 6, a racemization catalyst was anchored to the active site of both cutinase and Candida Antarctica lipase.
In the last part, chapter 7, an immobilized transition metal catalyst was used in transfer hydrogenation, a process which is closely related to the racemization of alcohols. The catalyst was used to reduce carbonyl compounds to the corresponding alcohols and was applicable to a wide range of substrates.
Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2009. , 58 p.
Dynamic kinetic resolution, dynamic kinetic asymmetric transformation, hydrogen transfer, directed evolution, enzyme engineering
Research subject Organic Chemistry
IdentifiersURN: urn:nbn:se:su:diva-31386ISBN: 978-91-7155-955-5OAI: oai:DiVA.org:su-31386DiVA: diva2:276803
2009-12-15, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
de Vries, Johannes G., Professor
Bäckvall, Jan-Erling, Professor
At the time of the doctoral defense, the following papers were unpublished and had a status as follows:
Paper 1: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.2009-11-262009-11-112011-02-25Bibliographically approved
List of papers