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Iridium Catalysed Asymmetric Hydrogenation of Olefins and Isomerisation of Allylic Alcohols
Stockholm University, Faculty of Science, Department of Organic Chemistry.ORCID iD: 0000-0002-4465-6795
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work described in this thesis is focused on exploring the efficacy of asymmetric iridium catalysis in the hydrogenation of challenging substrates, including precursors to chiral sulfones and chiral cyclohexanes. Furthermore, iridium catalysis was used to isomerise allylic alcohols to aldehydes, and in a formal total synthesis of Aliskiren (a renin inhibitor). A large variety of unsaturated sulfones (cyclic, acyclic, vinylic, allylic and homoallylic) were prepared and screened in the iridium catalysed hydrogenation reaction using a series of previously developed N,P-ligated Ir-catalysts. The outcome was a highly enantioselective (>90% ee) protocol to prepare sulfones bearing chiral carbon scaffolds, sometimes having purely aliphatic substituents at the stereogenic centre. Furthermore, performing the Ramberg-Bäcklund reaction on the chiral products, under optimised conditions, produced cyclic and acyclic unsaturated derivatives without erosion of enantiomeric excess. This hydrogenation protocol was also successful in the hydrogenation of a number of cyclohexene-containing compounds. Minimally functionalised, functionalised and heterocycle-containing cyclohexenes were hydrogenated in up to 99% ee. Hitherto, both chiral sulfones and chiral cyclohexanes have been challenging targets for most catalytic asymmetric methodologies. Although the preparation of aldehydes and ketones by isomerisation of the corresponding allylic alcohol is well established, there has been limited success in the development of good enantioselective protocols. For the isomerisation of a number γ,γ-allylic alcohols to the corresponding chiral aldehydes, high enantioselectivities (up to >99% ee) and modest yields were achieved using an N,P-iridium catalyst. Noteworthy is the high selectivity obtained for isomerisation of and dialkyl γ,γ-allylic alcohols, which prior to this study had been difficult to isomerise in high enantioselectivity. Preparation of a key intermediate used in the synthesis of Aliskiren, a renin inhibitor drug was also accomplished. Using a convergent synthesis strategy, two allylic alcohol fragments were hydrogenated with high enantiomeric excess (>92% ee). These fragments were then joined using a Julia-Kocienski reaction, providing >95% geometry around the C=C bond, which was crucial for the subsequent steps in the synthesis.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2015. , 53 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-122419ISBN: 978-91-76492-79-6 (print)OAI: oai:DiVA.org:su-122419DiVA: diva2:866089
Public defence
2015-12-18, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16B, 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 5: Manuscript.

Available from: 2015-11-26 Created: 2015-10-30 Last updated: 2015-11-25Bibliographically approved
List of papers
1. Enantioselective Synthesis of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation: A Facile Approach to the Preparation of Chiral Allylic and Homoallylic Compounds
Open this publication in new window or tab >>Enantioselective Synthesis of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation: A Facile Approach to the Preparation of Chiral Allylic and Homoallylic Compounds
Show others...
2012 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 33, 13592-13595 p.Article in journal (Refereed) Published
Abstract [en]

A highly efficient and enantioselective Ir-catalyzed hydrogenation of unsaturated sulfones was developed. Chiral cyclic and acyclic sulfones were produced in excellent enantioselectivities (up to 98% ee). Coupled with the Ramberg–Bäcklund rearrangement, this reaction offers a novel route to chiral allylic and homoallylic compounds in excellent enantioselectivities (up to 97% ee) and high yields (up to 94%).

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-120540 (URN)10.1021/ja306731u (DOI)
Available from: 2015-09-11 Created: 2015-09-11 Last updated: 2017-12-04Bibliographically approved
2. Highly Enantioselective Asymmetric Isomerization of Primary AllylicAlcohols with an Iridium–N,P Complex
Open this publication in new window or tab >>Highly Enantioselective Asymmetric Isomerization of Primary AllylicAlcohols with an Iridium–N,P Complex
2011 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 17, 11143-11145 p.Article in journal (Refereed) Published
Abstract [en]

Highly enantioselective asym. isomerization of a range of E- and Z- trisubstituted primary allylic alcs. to the corresponding chiral aldehydes catalyzed by a N,​P-​ligated iridium complex is reported.  Notably, the selectivity of this catalyst was less sensitive to steric effects in the asym. isomerization of Z-​trisubstituted allylic alcs. than E-​trisubstituted compds.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-122304 (URN)10.1002/chem.201101524 (DOI)
Available from: 2015-10-28 Created: 2015-10-28 Last updated: 2017-12-01Bibliographically approved
3. An Enantioselective Approach to the Preparation of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation
Open this publication in new window or tab >>An Enantioselective Approach to the Preparation of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation
Show others...
2014 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 136, no 47, 16557-16562 p.Article in journal (Refereed) Published
Abstract [en]

Several chiral sulfonyl compounds were prepared using the iridium catalyzed asymmetric hydrogenation reaction. Vinylic, allylic and homoallylic sulfone substitutions were investigated, and high enantioselectivity is maintained regardless of the location of the olefin with respect to the sulfone. Impressive stereoselectivity was obtained for dialkyl substitutions, which typically are challenging substrates in the hydrogenation. As expected, the more bulky Z-substrates were hydrogenated slower than the corresponding E isomers, and in slightly lower enantioselectivity.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-111912 (URN)10.1021/ja5079877 (DOI)000345720500016 ()
Funder
Swedish Energy AgencySwedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:8;

Available from: 2015-01-12 Created: 2015-01-08 Last updated: 2017-12-05Bibliographically approved
4. 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, 7292-7296 p.Article 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%.

Keyword
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
5. Enantio- and Regioselective Hydrogenation of Minimally and Densely Decorated Unsaturated Carbocycles
Open this publication in new window or tab >>Enantio- and Regioselective Hydrogenation of Minimally and Densely Decorated Unsaturated Carbocycles
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Several cyclic prochiral olefins were successfully hydrogenated (>99 conv.,up to >99 % ee) using N,P-ligated iridium catalysts. Minimally functionalisedsubstrates (Class 1) were hydrogenated rapidly and in high ee, whichwas consistent with earlier reports. Substrates having functional groups(Class 2) and heterocycles (Class 3) attached to the unsaturated cycle, were43hydrogenated gradually over a period of time, however, high enantioselectivitywas still maintained (up to >99 % ee). This methodology is a highly practical,general and selective means of preparing chiral cyclohexanes.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-122417 (URN)
Available from: 2015-10-30 Created: 2015-10-30 Last updated: 2017-03-15Bibliographically approved

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