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Transition metal- and lipase-catalyzed reactions: Dynamic resolutions, hydrogen transfer and enzyme engineering
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. (Jan-Erling Bäckvall)
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Organic Chemistry, Stockholm University , 2009. , s. 58
Nyckelord [en]
Dynamic kinetic resolution, dynamic kinetic asymmetric transformation, hydrogen transfer, directed evolution, enzyme engineering
Nationell ämneskategori
Organisk kemi
Forskningsämne
organisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-31386ISBN: 978-91-7155-955-5 (tryckt)OAI: oai:DiVA.org:su-31386DiVA, id: diva2:276803
Disputation
2009-12-15, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning
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.Tillgänglig från: 2009-11-26 Skapad: 2009-11-11 Senast uppdaterad: 2011-02-25Bibliografiskt granskad
Delarbeten
1. Asymmetric synthesis of bicyclic diol derivatives through metal and enzyme catalysis: Application to the formal synthesis of sertraline
Öppna denna publikation i ny flik eller fönster >>Asymmetric synthesis of bicyclic diol derivatives through metal and enzyme catalysis: Application to the formal synthesis of sertraline
2010 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 16, nr 13, s. 4031-4036Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Enzyme- and ruthenium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of bicyclic diols to their diacetates was highly enantio- and diastereoselective to give the corresponding diacetates in high yield with high enantioselectivity (99.9 % ee). The enantiomerically pure diols are accessible by simple hydrolysis (NaOH, MeOH), but an alternative enzyme-catalyzed ester cleavage was also used to give the trans-diol (R,R)-1 b in extremely high diastereomeric purity (trans/cis=99.9:0.1, >99.9 % ee). It was demonstrated that the diols can be selectively oxidized to the ketoalcohols in a ruthenium-catalyzed Oppenauer-type reaction. A formal enantioselective synthesis of sertraline from a simple racemic cis/trans diol 1 b was demonstrated.

Ort, förlag, år, upplaga, sidor
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2010
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:su:diva-47342 (URN)10.1002/chem.200903114 (DOI)000276735900020 ()
Forskningsfinansiär
Vetenskapsrådet
Anmärkning
authorCount :3Tillgänglig från: 2010-12-01 Skapad: 2010-12-01 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
2. Synthesis of a neonicotinoide pesticide derivative via chemoenzymatic dynamic kinetic resolution
Öppna denna publikation i ny flik eller fönster >>Synthesis of a neonicotinoide pesticide derivative via chemoenzymatic dynamic kinetic resolution
2009 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 74, nr 19, s. 7407-7410Artikel i tidskrift (Refereegranskat) Published
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:su:diva-30231 (URN)10.1021/jo9014276 (DOI)000270039300025 ()
Tillgänglig från: 2009-10-07 Skapad: 2009-10-07 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
3. Dynamic kinetic resolution of primary alcohols with an unfunctionalized stereogenic center in the beta-position
Öppna denna publikation i ny flik eller fönster >>Dynamic kinetic resolution of primary alcohols with an unfunctionalized stereogenic center in the beta-position
2007 (Engelska)Ingår i: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 349, s. 1577-1581Artikel i tidskrift (Refereegranskat) Published
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:su:diva-22519 (URN)10.1002/adsc.200700222 (DOI)
Tillgänglig från: 2007-08-09 Skapad: 2007-08-09 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
4. Directed evolution and axial chirality: optimization of the enantioselectivity of Pseudomonas aeruginosa lipase towards the kinetic resolution of a racemic allene
Öppna denna publikation i ny flik eller fönster >>Directed evolution and axial chirality: optimization of the enantioselectivity of Pseudomonas aeruginosa lipase towards the kinetic resolution of a racemic allene
Visa övriga...
2007 (Engelska)Ingår i: Chemical Communications, ISSN 1359-7345, Vol. 20, s. 1913-1915Artikel i tidskrift (Refereegranskat) Published
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:su:diva-22367 (URN)10.1039/b700849j (DOI)000246723000010 ()
Tillgänglig från: 2007-06-20 Skapad: 2007-06-20 Senast uppdaterad: 2010-01-25Bibliografiskt granskad
5. Site-Specific Covalent Immobilization of a Racemization Catalyst onto Lipase-containing Beads
Öppna denna publikation i ny flik eller fönster >>Site-Specific Covalent Immobilization of a Racemization Catalyst onto Lipase-containing Beads
Visa övriga...
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

The synthesis and application of the novel heterogeneous bifunctional catalyst CALB-5 as a racemization and resolution catalyst for the dynamic kinetic resolution is described. The semisynthetic ruthenium lipase hybrid CALB-5 was obtained by inhibiting CALB beads with the novel ruthenium phosphonate complex 5 possessing a lipase active site-directed phosphonate group. By partially inhibiting the lipase beads with 5, a bifunctional catalytic system was obtained. Racemization, by the Ru-catalytic site, gave 0% ee after 24 h, and the kinetic resolution, enzymatic acylation by the uninhibited CALB sites, gave 28% conversion of 1-phenylethanol after 3 h with >99% ee of the acetylated product. A dynamic kinetic resolution experiment of (S)-1-phenylethanol with CALB-5 gave the acylated (R)-product in 18% yield and with >99% ee.

Nationell ämneskategori
Organisk kemi
Forskningsämne
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-31311 (URN)
Tillgänglig från: 2009-11-10 Skapad: 2009-11-10 Senast uppdaterad: 2010-01-25Bibliografiskt granskad
6. Hydrogenized Wilkinson´s Catalyst for Transfer Hydrogenation of Carbonyl Compounds
Öppna denna publikation i ny flik eller fönster >>Hydrogenized Wilkinson´s Catalyst for Transfer Hydrogenation of Carbonyl Compounds
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Combining the advantages of homogeneous and heterogeneous catalysis is possible by heterogenization of homogeneous transition metal complexes based on a grafting/anchoring technique. Wilkinson’s catalyst ((RhCl(PPh3)3) immobilized on common silica showed high activity and selectivity in transfer hydrogenation reactions of different carbonyl compounds in isopropanol. Reactions conducted at reflux in isopropanol afforded the corresponding carbinols in high yields in short reaction times. The heterogeneous feature of the catalyst allows easy recovery and efficient reuse in the same reaction up to 5 times without loss of catalytic activity.

Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:su:diva-31385 (URN)
Tillgänglig från: 2009-11-11 Skapad: 2009-11-11 Senast uppdaterad: 2010-01-25Bibliografiskt granskad

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