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Design, Synthesis, Mechanistic Rationalization and Application of Asymmetric Transition-Metal Catalysts
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes mechanistic studies, rational ligand design, and synthesis of asymmetric transition metal catalysts. The topics addressed concerned [Papers I-VII]:

[I] The asymmetric addition of diethyl zinc to N-(diphenylphosphinoyl)benzalimine catalyzed by bicyclic 2-azanorbornyl-3-methanols was studied. An efficient route to both diastereomers of new bicyclic 2-azanorbornyl-3-methanols with an additional chiral center was developed, in the best case 97% ee was obtained with these ligands. The experimental results were rationalized by a computational DFT-study.

[II] An aza-Diels-Alder reaction of cyclopentadiene with chiral heterocyclic imines derived from (S)-1-phenylethylamine and different heteroaromatic aldehydes was developed. The cycloaddition proved to be highly diastereoselective and offers a very rapid access to possible biologically active compounds and interesting precursors for chiral (P,N)-ligands.

[III] A convenient and high-yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantio-enriched (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure.

[IV] The reaction mechanism of the iridium-phosphanooxazoline-catalyzed hydrogenation of unfunctionalized olefins has been studied by means of DFT-calculations (B3LYP) and kinetic experiments. The calculations suggest that the reaction involves an unexpected IrIII-IrV catalytic cycle facilitated by coordination of a second equivalent of dihydrogen. On the basis of the proposed catalytic cycle, calculations were performed on a full system with 88 atoms. These calculations were also used to explain the enantioselectivity displayed by the catalyst.

[V and VI] A new class of chiral (P,N)-ligands for the Ir-catalyzed asymmetric hydrogenation of aryl alkenes was developed. These new ligands proved to be highly efficient and tolerate a broad range of substrates. The enantiomeric excesses are, so far, the best reported and can be rationalized using the proposed selectivity model.

[VII] The complex formed between the quincorine-amine, containing both a primary and a quinuclidine amino function, and [Cp*RuCl]4 catalyzes the hydrogenation of aromatic and aliphatic ketones in up to 90% ee approx. 24-times faster than previously reported Ru-diamine complexes. The reason for the lower but opposite stereoselectivity seen with the quincoridine-amine, as compared to the quincorine-amine, was rationalized by a kinetic and computational study of the mechanism. The theoretical calculations also revealed a significantly lower activation barrier for the alcohol mediated split of dihydrogen, as compared to the non-alchol mediated process. A finding of importance also for the diphosphine/diamine mediated enantioselective hydrogenation of ketones.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 81
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 36
Keyword [en]
Organic chemistry, asymmetric catalysis, homogeneous hydrogenation, iridium, ruthenium, ligand design, mechanistic studies, kinetics, tolterodine
Keyword [sv]
Organisk kemi
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-5740ISBN: 91-554-6209-X (print)OAI: oai:DiVA.org:uu-5740DiVA, id: diva2:166193
Public defence
2005-04-28, B22, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Supervisors
Available from: 2005-04-07 Created: 2005-04-07Bibliographically approved
List of papers
1. A Theoretical and Experimental Study of the Asymmetric Addition of Dialkylzinc to N-(diphenylphosphinoyl)benzalimine
Open this publication in new window or tab >>A Theoretical and Experimental Study of the Asymmetric Addition of Dialkylzinc to N-(diphenylphosphinoyl)benzalimine
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1999 In: Chemistry-A European Journal, ISSN 0947-6539, Vol. 5, no 6, p. 1692-1699Article in journal (Refereed) Published
Abstract
Identifiers
urn:nbn:se:uu:diva-92875 (URN)
Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
2. Diels-Alder Reaction of Heterocyclic Imine Dienophiles
Open this publication in new window or tab >>Diels-Alder Reaction of Heterocyclic Imine Dienophiles
2000 In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 65, no 9, p. 2810-2812Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92876 (URN)
Available from: 2005-04-07 Created: 2005-04-07Bibliographically approved
3. Catalytic Asymmetric Total Synthesis of Muscarinic Receptor Antagonist (R)-Tolterodine
Open this publication in new window or tab >>Catalytic Asymmetric Total Synthesis of Muscarinic Receptor Antagonist (R)-Tolterodine
2005 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 347, no 5, p. 662-666Article in journal (Refereed) Published
Abstract [en]

A convenient and high yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantioenriched (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure. The configuration of the crucial stereocenter was preserved during the synthesis and the obtained product was identified by chiral HPLC to be the (R)-tolterodine enantiomer.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-92877 (URN)10.1002/adsc.200404234 (DOI)
Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2017-12-14Bibliographically approved
4. New Mechanistic Insights into the Iridium-Phosphanooxazoline Catalyzed Hydrogenation of Unfunctionalized Olefins: A DFT and Kinetic Study
Open this publication in new window or tab >>New Mechanistic Insights into the Iridium-Phosphanooxazoline Catalyzed Hydrogenation of Unfunctionalized Olefins: A DFT and Kinetic Study
2003 In: Chemistry-A European Journal, ISSN 0022-3263, Vol. 9, no 1, p. 339-347Article in journal (Refereed) Published
Abstract
Identifiers
urn:nbn:se:uu:diva-92878 (URN)
Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
5. Rationally Designed Ligands for Asymmetric Iridium-Catalyzed Hydrogenation of Olefins
Open this publication in new window or tab >>Rationally Designed Ligands for Asymmetric Iridium-Catalyzed Hydrogenation of Olefins
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2004 In: Journal of the American Chemical Society, ISSN 0002-7863, Vol. 126, no 44, p. 14308-14309Article in journal (Refereed) Published
Abstract
Identifiers
urn:nbn:se:uu:diva-92879 (URN)
Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
6. Origin of Enantioselectivity in Ir-Catalyzed Asymmetric Hydrogenation of Tri-Substituted Olefins
Open this publication in new window or tab >>Origin of Enantioselectivity in Ir-Catalyzed Asymmetric Hydrogenation of Tri-Substituted Olefins
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Manuscript (Other academic)
Abstract
Identifiers
urn:nbn:se:uu:diva-92880 (URN)
Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
7. Mechanistic Insights into the Phosphine free RuCp*-Diamine Catalyzed Hydrogenation of Arylketones: An Experimental and Theoretical Study
Open this publication in new window or tab >>Mechanistic Insights into the Phosphine free RuCp*-Diamine Catalyzed Hydrogenation of Arylketones: An Experimental and Theoretical Study
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In: Journal of the American Chemical Society, ISSN 0002-7863Article in journal (Refereed) Submitted
Abstract
Identifiers
urn:nbn:se:uu:diva-92881 (URN)
Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved

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