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Transition metal-catalyzed reduction of carbonyl compounds: Fe, Ru and Rh complexes as powerful hydride mediators
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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 [en]
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: urn:nbn:se:su:diva-75795ISBN: 978-91-7447-506-7 (print)OAI: oai:DiVA.org:su-75795DiVA: diva2:524015
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
List of papers
1. Mechanistic investigations into the asymmetric transfer hydrogenation of ketones catalyzed by pseudo-dipeptide ruthenium complexes
Open this publication in new window or tab >>Mechanistic investigations into the asymmetric transfer hydrogenation of ketones catalyzed by pseudo-dipeptide ruthenium complexes
2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 23, 5709-5718 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2009
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-31029 (URN)10.1002/chem.200802496 (DOI)
Available from: 2009-11-02 Created: 2009-11-02 Last updated: 2017-12-12Bibliographically approved
2. High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones: Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine
Open this publication in new window or tab >>High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones: Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine
Show others...
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.

Keyword
amino acids, asymmetric synthesis, enantioselectivity, hydrogenation, transition metals
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-84808 (URN)10.1002/cctc.201200308 (DOI)000311698800032 ()
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
3. Selective hydrosilylation of ketones catalyzed by in situ-generated iron NHC complexes
Open this publication in new window or tab >>Selective hydrosilylation of ketones catalyzed by in situ-generated iron NHC complexes
2011 (English)In: Applied organometallic chemistry, ISSN 0268-2605, E-ISSN 1099-0739, Vol. 25, no 10, 748-752 p.Article in journal (Refereed) Published
Abstract [en]

Aryl alkyl-, heteroaryl alkyl- and dialkyl ketones were readily reduced to their corresponding secondary alcohols in high yields, using the commercially available and inexpensive polymeric silane polymethylhydrosiloxane (PMHS), as reducing agent. The reaction is catalyzed by an in situ-generated iron complex, conveniently generated from iron(II) acetate and the commercially available N-heterocyclic carbene (NHC) precursor IPr·HCl.

Keyword
hydrosilylation, iron, carbenes, ketones, catalysis
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-62938 (URN)10.1002/aoc.1832 (DOI)000295294800003 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2011-10-05 Created: 2011-10-05 Last updated: 2017-12-08Bibliographically approved
4. Efficient and Selective Hydrosilylation of Carbonyls Catalyzed by Iron Acetate and N-Hydroxyethylimidazolium Salts
Open this publication in new window or tab >>Efficient and Selective Hydrosilylation of Carbonyls Catalyzed by Iron Acetate and N-Hydroxyethylimidazolium Salts
2012 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 354, no 1, 217-222 p.Article in journal (Refereed) Published
Abstract [en]

Aromatic aldehydes, along with aryl alkyl, heteroaryl alkyl, and dialkyl ketones were efficiently reduced to their corresponding primary and secondary alcohols, respectively, in high yields, using the commercially available and inexpensive polymeric silane, polymethylhydrosiloxane (PMHS), as reducing agent. The reaction is catalyzed by in situ generated iron complexes containing hydroxyethyl-functionalized NHC ligands. Turnover frequencies up to 600 h−1 were obtained

Keyword
aldehydes, carbenes, hydrosilylation, iron, ketones
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-75773 (URN)10.1002/adsc.201100606 (DOI)000299331300021 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2012-04-26 Created: 2012-04-26 Last updated: 2017-12-07Bibliographically approved

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