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Iridium Catalysed Asymmetric Hydrogenation of Olefins and Dynamic Kinetic Resolution in the Asymmetric Hydrogenation of Allylic Alcohols
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work described in this thesis is focused on exploring the efficacy of iridium-catalysed asymmetric hydrogenation of precursors to chiral alcohols and chiral cyclohexanes. A range of allylic alcohols including γ,γ-dialkyl allylic alcohols and (Z)-allylic alcohols were prepared and evaluated in the asymmetric hydrogenation using iridium catalysts resulting in chiral alcohols in high yields and excellent enantioselectivity. This methodology was applied in the formal synthesis of Aliskiren, an efficient renin inhibitor drug, using the asymmetric hydrogenation of an allylic alcohol as a key-step. Another project concerned the dynamic kinetic resolution of racemic secondary allylic alcohols using Ir-N,P catalysts under hydrogenation conditions. A range of secondary allylic alcohols and protected alcohols were evaluated in the asymmetric hydrogenation via dynamic kinetic resolution using Ir-N,P catalysts. The corresponding chiral saturated alcohols were formed in good yield with excellent diastereoselectivites (up to 95/5) and enantioselectivities (>99% ee). The last part of this thesis is directed towards the development of highly regio- and enantioselective asymmetric hydrogenation of 1,4-cyclohexadienes and its application in the preparation of useful chiral cyclohexenone intermediates. Non-functionalised, functionalised and heterocycle-containing cyclohexadienes were evaluated. Good yield of regioselectively mono-hydrogenated silyl protected enol ethers were obtained in most cases with excellent enantioselectivity. 

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2017. , p. 52
Keywords [en]
Iridium catalyst, asymmetric hydrogenation, dynamic kinetic resolution, allylic alcohol
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-140923ISBN: 978-91-7649-744-9 (print)ISBN: 978-91-7649-745-6 (electronic)OAI: oai:DiVA.org:su-140923DiVA, id: diva2:1084156
Public defence
2017-05-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius Väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 5: Manuscript.

Available from: 2017-04-07 Created: 2017-03-23 Last updated: 2018-03-22Bibliographically approved
List of papers
1. Asymmetric Hydrogenation of Allylic Alcohols Using Ir-N,P-Complexes
Open this publication in new window or tab >>Asymmetric Hydrogenation of Allylic Alcohols Using Ir-N,P-Complexes
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2016 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 6, no 12, p. 8342-8349Article in journal (Refereed) Published
Abstract [en]

In this study, a series of gamma,gamma-disubstituted and beta,gamma-disubstituted allylic alcohols were prepared and successfully hydrogenated using suitable N,P-based Ir complexes. High yields and excellent enantioselectivities were obtained for most of the substrates studied. This investigation also revealed the effect of the acidity of the N,P-Ir-complexes on the acid sensitive allylic alcohols. DFT Delta pK(a) calculations were used to explain the effect of the N,P-ligand on the acidity of the corresponding Ir-complex. The selectivity model of the reaction was used to accurately predict the absolute configuration of the hydrogenated alcohols.

Keywords
asymmetric synthesis, gamma-gamma-disubstituted allylic alcohols, beta-gamma-disubstituted allylic alcohols, DFT, iridium, hydrogenation
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-137577 (URN)10.1021/acscatal.6b02456 (DOI)000389399400039 ()
Funder
Swedish Research CouncilStiftelsen Olle Engkvist ByggmästareSwedish Energy Agency
Available from: 2017-01-10 Created: 2017-01-09 Last updated: 2018-05-14Bibliographically approved
2. Formal Total Synthesis of Aliskiren
Open this publication in new window or tab >>Formal Total Synthesis of Aliskiren
2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 19, p. 7292-7296Article in journal (Refereed) Published
Abstract [en]

The efficient and selective formal total synthesis of aliskiren is described. Aliskiren, a renin inhibitor drug, has received considerable attention, primarily because it is the first of the renin inhibitor drugs to be approved by the FDA. Herein, the formal synthesis of aliskiren by iridium-catalyzed asymmetric hydrogenation of two allylic alcohol fragments is reported. Screening a number of N,P-ligated iridium catalysts yielded two catalysts that gave the highest enantioselectivity in the hydrogenation, which gave the saturated alcohols in 97 and 93% ee. In only four steps after hydrogenation, the fragments were combined by using the Julia-Kocienski reaction to produce late-stage intermediate in an overall yield of 18%.

Keywords
asymmetric synthesis, hydrogenation, iridium, olefination, total synthesis
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-117427 (URN)10.1002/chem.201406523 (DOI)000353348100041 ()25783891 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Energy AgencyVINNOVAStiftelsen Olle Engkvist Byggmästare
Note

AuthorCount:4;

Available from: 2015-05-22 Created: 2015-05-19 Last updated: 2017-12-04Bibliographically approved
3. Iridium-catalyzed Asymmetric Hydrogenation of Allylic Alcohols via Dynamic Kinetic Resolution
Open this publication in new window or tab >>Iridium-catalyzed Asymmetric Hydrogenation of Allylic Alcohols via Dynamic Kinetic Resolution
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-140936 (URN)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-03-28Bibliographically approved
4. Enantio- and Regioselective Ir-Catalyzed Hydrogenation of Di- and Trisubstituted Cycloalkenes
Open this publication in new window or tab >>Enantio- and Regioselective Ir-Catalyzed Hydrogenation of Di- and Trisubstituted Cycloalkenes
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2016 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 36, p. 11930-11935Article in journal (Refereed) Published
Abstract [en]

A number of cyclic olefins Were prepared and evaluated for the asymmetric hydrogenation reaction using novel N,P-ligated iridium imidazote-based Catalysts (Crabtree type). The diversity of these cyclic olefins spanned those having little functionality to others bearing strongly coordinating substituents and heterocycles. Excellent enantioselectivities were observed both for substrates having little functionality (up to >99% ee) and for substrates possessing functional groups several carbons away from the olefin. Substrates having functionalities such as carboxyl groups, alcohols, or heterocycles in the vicinity of the C=C bond were hydrogenated in high enantiomeric excess (up to >99% ee). The hydrogenation was also found to be regioselective, and by controlling the reaction conditions, selective hydrogenation of one of two trisubstituted olefins can be achieved: Furthermore, trisubstituted olefins can be selectively hydrogenated in the presence of tetrasubstituted olefins.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-135188 (URN)10.1021/jacs.6b07291 (DOI)000383410700067 ()27548029 (PubMedID)
Funder
Swedish Energy AgencySwedish Research CouncilKnut and Alice Wallenberg FoundationStiftelsen Olle Engkvist Byggmästare
Available from: 2016-11-21 Created: 2016-11-01 Last updated: 2018-03-22Bibliographically approved
5. Regioselective Iridium-Catalyzed Asymmetric Monohydrogenation of 1,4-Dienes
Open this publication in new window or tab >>Regioselective Iridium-Catalyzed Asymmetric Monohydrogenation of 1,4-Dienes
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2017 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, no 41, p. 14470-14475Article in journal (Refereed) Published
Abstract [en]

A highly efficient regio- and enantioselective monohydrogenation of 1,4-dienes has been realized using an iridium catalyst with a chiral N,P-ligand under mild conditions. The substrate scope was studied and included both unfunctionalized as well as functionalized substituents on the meta- or para-position. Substrates having substituents with functionalities such as silyl protected alcohols or ketals were monohydrogenated in high regioselectivity and high enantiomeric excess (up to 98% ee).

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-149001 (URN)10.1021/jacs.7b06829 (DOI)000413503300025 ()28930455 (PubMedID)
Funder
Swedish Research CouncilStiftelsen Olle Engkvist ByggmästareSwedish Energy Agency
Available from: 2017-11-27 Created: 2017-11-27 Last updated: 2018-05-09Bibliographically approved

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