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High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones: Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine
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.
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2012 (English)In: ChemCatChem, ISSN 1867-3880, E-ISSN 1867-3899, Vol. 4, no 12, 2082-2089 p.Article in journal (Refereed) Published
Abstract [en]

A total of 21 amino acid based ligands including hydroxy amide, thioamide, and hydroxamic acid functionalities, respectively, were combined with [Ru(p-cymene)Cl2]2 and [RhCp*Cl2]2, and used as catalysts for the asymmetric transfer hydrogenation of four different heteroaromatic ketones in 2-propanol. The reactions were performed on a Chemspeed automated high-throughput screening robotic platform. Optimal catalysts were identified for the individual heterocyclic substrate classes. Based on these results, the formal syntheses of the antidepressant drugs (R)-fluoxetine and (S)-duloxetine were conducted by using the found catalysts in the key reaction step, which results in high isolated yields (94?%) and excellent product enantioselectivities (>99?% ee) of the formed 1,3-amino alcohols.

Place, publisher, year, edition, pages
2012. Vol. 4, no 12, 2082-2089 p.
Keyword [en]
amino acids, asymmetric synthesis, enantioselectivity, hydrogenation, transition metals
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-84808DOI: 10.1002/cctc.201200308ISI: 000311698800032OAI: oai:DiVA.org:su-84808DiVA: diva2:581481
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:5;

Available from: 2013-01-02 Created: 2013-01-02 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Transition metal-catalyzed reduction of carbonyl compounds: Fe, Ru and Rh complexes as powerful hydride mediators
Open this publication in new window or tab >>Transition metal-catalyzed reduction of carbonyl compounds: Fe, Ru and Rh complexes as powerful hydride mediators
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A detailed mechanistic investigation of the previously reported ruthenium pseudo-dipeptide-catalyzed asymmetric transfer hydrogenation (ATH) of aromatic ketones was performed. It was found that the addition of alkali metals has a large influence on both the reaction rate and the selectivity, and that the rate of the reaction was substantially increased when THF was used as a co-solvent. A novel bimetallic mechanism for the ruthenium pseudo-dipeptide-catalyzed asymmetric reduction of prochiral ketones was proposed.

There is a demand for a larger substrate scope in the ATH reaction, and heteroaromatic ketones are traditionally more challenging substrates. Normally a catalyst is developed for one benchmark substrate, and a substrate screen is carried out with the best performing catalyst. There is a high probability that for different substrates, another catalyst could outperform the one used. To circumvent this issue, a multiple screen was executed, employing a variety of ligands from different families within our group’s ligand library, and different heteroaromatic ketones to fine-tune and to find the optimum catalyst depending on the substrate. The acquired information was used in the formal total syntheses of (R)-fluoxetine and (S)-duloxetine, where the key reduction step was performed with high enantioselectivities and high yield, in each case.

Furthermore, a new iron-N-heterocyclic carbene (NHC)-catalyzed hydrosilylation (HS) protocol was developed. An active catalyst was formed in situ from readily available imidazolium salts together with an iron source, and the inexpensive and benign polymethylhydrosiloxane (PMHS) was used as hydride donor. A set of sterically less demanding, potentially bidentate NHC precursors was prepared. The effect proved to be remarkable, and an unprecedented activity was observed when combining them with iron. The same system was also explored in the reduction of amides to amines with satisfactory results.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2012. 61 p.
Keyword
Asymmetric catalysis, amino acid, N-heterocyclic carbene, iron, ruthenium, rhodium, mechanistic investigation, kinetic study, asymmetric transfer hydrogenation, hydrosilylation
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-75795 (URN)978-91-7447-506-7 (ISBN)
Public defence
2012-06-07, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.

Available from: 2012-05-11 Created: 2012-04-27 Last updated: 2014-02-24Bibliographically approved

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