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Enantio- and Regioselective Ir-Catalyzed Hydrogenation of Di- and Trisubstituted Cycloalkenes
Stockholm University, Faculty of Science, Department of Organic Chemistry.ORCID iD: 0000-0002-4465-6795
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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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
2016. Vol. 138, no 36, p. 11930-11935
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-135188DOI: 10.1021/jacs.6b07291ISI: 000383410700067PubMedID: 27548029OAI: oai:DiVA.org:su-135188DiVA, id: diva2:1048614
Funder
Swedish Energy AgencySwedish Research CouncilKnut and Alice Wallenberg FoundationStiftelsen Olle Engkvist ByggmästareAvailable from: 2016-11-21 Created: 2016-11-01 Last updated: 2019-12-12Bibliographically approved
In thesis
1. Iridium Catalysed Asymmetric Hydrogenation of Olefins and Dynamic Kinetic Resolution in the Asymmetric Hydrogenation of Allylic Alcohols
Open this publication in new window or tab >>Iridium Catalysed Asymmetric Hydrogenation of Olefins and Dynamic Kinetic Resolution in the Asymmetric Hydrogenation of Allylic Alcohols
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
Iridium catalyst, asymmetric hydrogenation, dynamic kinetic resolution, allylic alcohol
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-140923 (URN)978-91-7649-744-9 (ISBN)978-91-7649-745-6 (ISBN)
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: 2020-05-04Bibliographically approved
2. The Use of N,P-Iridium and N,P-Palladium Complexes in Asymmetric Synthesis
Open this publication in new window or tab >>The Use of N,P-Iridium and N,P-Palladium Complexes in Asymmetric Synthesis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work presented in this thesis concerns asymmetric catalysis using chiral N,P-ligands and iridium or palladium transition metals. The first part  (Chapters 2 and 3) highlights the N,P-iridium catalyzed asymmetric hydrogenation of 1,4-cyclohexadienes having functionalized or unfunctionalized substituents, including allylsilane side chains. A series of N,P-iridium catalysts were synthesized and screened on a number of cyclohexadienes. The developed N,P-iridium catalysts have provided excellent chemo-, regio- and enantioselectivity for most of the products obtained. For substrates having an allylsilane sidechain, the chiral cyclic allylsilane products were used to induce stereocontrol in a subsequent Hosomi-Sakurai reaction using TiCl4 as Lewis acid and aldehydes as electrophiles. The corresponding homoallylic alcohols were obtained in good to excellent diastereoselectivity. 

The second part (Chapter 4) describes the N,P-iridium catalyzed asymmetric hydrogenation of various vinyl fluorides. A number of tri- and tetrasubstituted vinyl fluorides were synthesized and evaluated for the asymmetric hydrogenation. The corresponding saturated chiral fluoro compounds were obtained in very high enantioselectivity (up to 99% ee). The defluorination, usually known to occur under the catalytic hydrogenation conditions, were not observed for the majority of the substrates. 

Finally, Chapter 5 describes the application of N,P-ligands in the asymmetric cycloisomerization of 1,6-enynes using a palladium precatalyst. The enantioselectivities for the products were found to depend both on the substrate as well as the hydrogen source. These developed catalytic reactions provide attractive methods to create multiple stereogenic centers in a molecule in relatively few steps from readily available starting materials.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2018. p. 66
Keywords
Iridium, Asymmetric Hydrogenation, Palladium, Asymmetric Cycloisomerization and Hosomi-Sakurai Allylation
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-150602 (URN)978-91-7797-061-3 (ISBN)978-91-7797-062-0 (ISBN)
Public defence
2018-01-31, 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 3: Manuscript.

Available from: 2018-01-08 Created: 2017-12-27 Last updated: 2018-01-11Bibliographically approved
3. Enantio- and Regioselective Iridium-Catalyzed Hydrogenation of Olefins: From Development to Total Synthesis
Open this publication in new window or tab >>Enantio- and Regioselective Iridium-Catalyzed Hydrogenation of Olefins: From Development to Total Synthesis
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work presented in this thesis concerns the iridium-catalyzed asymmetric hydrogenation of cyclic olefins and allylic alcohols for the preparation of useful chiral intermediates with various substitution patterns. The strategy provides stereocontrol for both non-functionalized as well as functionalized substrates and aims to be implemented in the stereoselective preparation of chiral building blocks having more than one stereocenter. The first part (Chapter 2) is focused on the asymmetric hydrogenation of 1,4-cyclohexadienes bearing a number of different functionalities. The development of a novel set of imidazole-based Ir-N,P catalyst enabled the efficient and enantioselective hydrogenation of prochiral substrates. In addition, the challenging regioselective mono-hydrogenation of only one of the two trisubstituted double bonds of the diene was accomplished.

The sequential preparation of chiral cyclic allylsilanes by means of iridium-catalyzed asymmetric hydrogenation and their employment in the Hosomi-Sakurai reaction was also studied (Chapter 3). Several patterns of alkyl substitution on the prochiral olefins were evaluated and the hydrogenation afforded the allylsilanes in high conversions and excellent enantiomeric excesses. These chiral silanes were then used in the TiCl4-promoted allylation of aldehydes, which took place with high diastereoselectivity.

In Chapter 4, the kinetic resolution of allylic alcohols via asymmetric hydrogenation is described. High selectivity was observed for a broad range of substrates using a combination of an Ir-N,P catalyst and K2CO3 under mild reaction conditions. This highly efficient process is complementary to our previously reported asymmetric hydrogenation/DKR protocol. The final part (Chapter 5) covers the application of Ir-catalyzed hydrogenations as key steps in total synthesis. A sequential strategy involving enantio- and regioselective hydrogenations was successfully employed in the synthesis of the natural sesquiterpene (-)-Juvabione. In the following project, two allylic alcohols were hydrogenated to prepare chiral intermediates for a convergent formal synthesis of the renin inhibitor Aliskiren. 

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2019. p. 61
Keywords
Asymmetric hydrogenation, Iridium, Regioselectivity, Kinetic resolution, Total synthesis
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-163645 (URN)978-91-7797-588-5 (ISBN)978-91-7797-589-2 (ISBN)
Public defence
2019-03-12, 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 3: Manuscript.

Available from: 2019-02-15 Created: 2019-01-23 Last updated: 2020-05-11Bibliographically approved

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