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Asymmetric transfer hydrogenation of ketones: Catalyst development and mechanistic investigation
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The development of ligands derived from natural amino acids for asymmetric transfer hydrogenation (ATH) of prochiral ketones is described herein. In the first part, reductions performed in alcoholic media are examined, where it is found that amino acid-derived hydroxamic acids and thioamides, respectively, are simple and versatile ligands that in combination with [RhCp*Cl2]2 efficiently catalyze this particular transformation. Selectivities up to 97% ee of the corresponding secondary alcohols are obtained, and it is furthermore observed that the two different ligand classes, albeit based on the same amino acid scaffold, give rise to products of opposite configuration.

The highly interesting enantioswitchable nature of the two abovementioned catalysts is studied in detail by mechanistic investigations. A structure/activity correlation analysis is performed, which reveals that the diverse behavior of the catalysts arise from different interactions between the ligands and the metal. Kinetic studies furthermore stress the catalyst divergence, since a difference in the rate determining step is established from initial rate measurements. In addition, rate constants are determined for each step of the overall reduction process.

In the last part, catalyst development for ATH executed in water is discussed. The applicability of hydroxamic acid ligands is further extended, and catalysts based on these compounds are found to be efficient and compatible with aqueous conditions. The structurally even simpler amino acid amide is also evaluated as a ligand, and selectivities up to 90% ee are obtained in the reduction of a number of aryl alkyl ketones. The very challenging reduction of dialkyl ketones is moreover examined in the Rh-catalyzed aqueous ATH, where a modified surfactant-resembling sulfonylated diamine is used as ligand, and the reaction is carried out in the presence of SDS-micelles. A positive effect is to some extent found on the catalyst performance upon addition of phase-transfer components, especially regarding the catalytic activity in the reduction of more hydrophobic substrates.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2011. , 49 p.
Keyword [en]
Asymmetric catalysis, reduction, amino acid, rhodium, mechanistic investigation, kinetic study
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-55412ISBN: 978-91-7447-234-9OAI: oai:DiVA.org:su-55412DiVA: diva2:405670
Public defence
2011-04-29, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 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 4: In press.Available from: 2011-04-07 Created: 2011-03-14 Last updated: 2011-05-25Bibliographically approved
List of papers
1. A Simple and Efficient Catalyst System for the Asymmetric Transfer Hydrogenation of Ketones
Open this publication in new window or tab >>A Simple and Efficient Catalyst System for the Asymmetric Transfer Hydrogenation of Ketones
2007 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, no 16, 2541-2544 p.Article in journal (Refereed) Published
Keyword
alcohols (benzene compounds);reduction, hydrogenation;diastereoselective syntheses, enantioselective syntheses (incl. cis/trans-isomerism)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-24562 (URN)10.1002/chin.200808080 (DOI)000250300100015 ()
Available from: 2007-11-22 Created: 2007-11-14 Last updated: 2011-03-24Bibliographically approved
2. Fine-tuning catalytic activity and selectivity-[Rh(amino acid thioamide)] complexes for efficient ketone reduction
Open this publication in new window or tab >>Fine-tuning catalytic activity and selectivity-[Rh(amino acid thioamide)] complexes for efficient ketone reduction
2009 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1873-3581, Vol. 50, no 46, 6321-6324 p.Article in journal (Refereed) Published
Abstract [en]

Amino acid-derived thioamides are prepared and evaluated as ligands in the rhodium-catalyzed asymmetric transfer hydrogenation of ketones in 2-propanol. It is found that increasing the steric bulk at the C-terminus of the ligand had a positive impact on both activity and selectivity in the reduction reaction. In order to find the optimum catalyst, a study is performed on a series of thioamide ligands having substituents of varying size.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-31031 (URN)10.1016/j.tetlet.2009.08.116 (DOI)000271055100027 ()
Available from: 2009-11-02 Created: 2009-11-02 Last updated: 2011-03-24Bibliographically approved
3. Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Amino Acid Derived Rhodium Complexes: On the Origin of Enantioselectivity and Enantioswitchability
Open this publication in new window or tab >>Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Amino Acid Derived Rhodium Complexes: On the Origin of Enantioselectivity and Enantioswitchability
Show others...
2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 42, 11197-11209 p.Article in journal (Refereed) Published
Abstract [en]

Amino acid based thioamides, hydroxamic acids, and hydrazides have been evaluated as ligands in the rhodium-catalyzed asymmetric transfer hydrogenation of ketones in 2-propanol. Catalysts containing thioamide ligands derived from L-valine were found to selectively generate the product with an R configuration (95 % ee), whereas the corresponding L-valine-based hydroxamic acids or hydrazides facilitated the formation of the (S)-alcohols (97 and 91 % ee, respectively). The catalytic reduction was examined by performing a structure–activity correlation investigation with differently functionalized or substituted ligands and the results obtained indicate that the major difference between the thioamide and hydroxamic acid based catalysts is the coordination mode of the ligands. Kinetic experiments were performed and the rate constants for the reduction reactions were determined by using rhodium–arene catalysts derived from amino acid thioamide and hydroxamic acid ligands. The data obtained show that the thioamide-based catalyst systems demonstrate a pseudo-first-order dependence on the substrate, whereas pseudo-zero-order dependence was observed for the hydroxamic acid containing catalysts. Furthermore, the kinetic experiments revealed that the rate-limiting steps of the two catalytic systems differ. From the data obtained in the structure–activity correlation investigation and along with the kinetic investigation it was concluded that the enantioswitchable nature of the catalysts studied originates from different ligand coordination, which affects the rate-limiting step of the catalytic reduction reaction.

Keyword
amino acids, asymmetric catalysis, kinetics;reaction mechanisms, rhodium
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-35766 (URN)10.1002/chem.200900548 (DOI)000271560000020 ()
Note
"Corrigendum" in Chemistry - A European Journal 2010, vol 16, nr 35, sid 10610.Available from: 2010-01-22 Created: 2010-01-20 Last updated: 2012-02-08Bibliographically approved
4. Amino acid-derived amides and hydroxamic acids as ligands for asymmetric transfer hydrogenation in aqueous media
Open this publication in new window or tab >>Amino acid-derived amides and hydroxamic acids as ligands for asymmetric transfer hydrogenation in aqueous media
2011 (English)In: Catalysis communications, ISSN 1566-7367, E-ISSN 1873-3905, Vol. 12, no 12, 1118-1121 p.Article in journal (Refereed) Published
Abstract [en]

Amides and hydroxamic acids derived from α-amino acids were evaluated as ligands in combination with rhodium and iridium half-sandwich complexes in asymmetric transfer hydrogenation (ATH) of ketones. The reactions were performed in aqueous media using lithium formate as hydride source. The catalyst systems turned out to be highly efficient and ees up to 90% were obtained.

Keyword
Asymmetric catalysis, reduction, ketones, iridium, rhodium
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-55570 (URN)10.1016/j.catcom.2011.03.032 (DOI)000292120300015 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2011-03-23 Created: 2011-03-21 Last updated: 2012-01-23Bibliographically approved
5. Rhodium-catalyzed asymmetric transfer hydrogenation of alkyl and aryl ketones in aqueous media
Open this publication in new window or tab >>Rhodium-catalyzed asymmetric transfer hydrogenation of alkyl and aryl ketones in aqueous media
2008 (English)In: Green Chemistry, ISSN 1463-9262, E-ISSN 1463-9270, Vol. 10, no 8, 832-835 p.Article in journal (Refereed) Published
Abstract [en]

A novel lipophilic rhodium catalyst was evaluated in the enantioselective transfer hydrogenation of ketones in water using sodium formate as the hydride donor, and in the presence of sodium docecylsulfonate. Alkyl alkyl ketones were reduced in good yields and in moderate to good enantioselectivities, and the reduction of aryl alkyl ketones proceeded with excellent enantioselectivity (up to 97% ee).

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-14482 (URN)10.1039/b806177g (DOI)000258038200003 ()
Available from: 2008-12-03 Created: 2008-12-03 Last updated: 2011-03-24Bibliographically approved

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