Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Formal Total Synthesis of Aliskiren
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.ORCID-id: 0000-0002-4465-6795
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.ORCID-id: 0000-0002-1383-8246
2015 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, nr 19, s. 7292-7296Artikkel i tidsskrift (Fagfellevurdert) 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%.

sted, utgiver, år, opplag, sider
2015. Vol. 21, nr 19, s. 7292-7296
Emneord [en]
asymmetric synthesis, hydrogenation, iridium, olefination, total synthesis
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-117427DOI: 10.1002/chem.201406523ISI: 000353348100041PubMedID: 25783891OAI: oai:DiVA.org:su-117427DiVA, id: diva2:813477
Forskningsfinansiär
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Energy AgencyVINNOVAStiftelsen Olle Engkvist Byggmästare
Merknad

AuthorCount:4;

Tilgjengelig fra: 2015-05-22 Laget: 2015-05-19 Sist oppdatert: 2019-12-12bibliografisk kontrollert
Inngår i avhandling
1. Iridium Catalysed Asymmetric Hydrogenation of Olefins and Isomerisation of Allylic Alcohols
Åpne denne publikasjonen i ny fane eller vindu >>Iridium Catalysed Asymmetric Hydrogenation of Olefins and Isomerisation of Allylic Alcohols
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Department of Organic Chemistry, Stockholm University, 2015. s. 53
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-122419 (URN)978-91-76492-79-6 (ISBN)
Disputas
2015-12-18, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16B, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 5: Manuscript.

Tilgjengelig fra: 2015-11-26 Laget: 2015-10-30 Sist oppdatert: 2015-11-25bibliografisk kontrollert
2. Iridium Catalysed Asymmetric Hydrogenation of Olefins and Dynamic Kinetic Resolution in the Asymmetric Hydrogenation of Allylic Alcohols
Åpne denne publikasjonen i ny fane eller vindu >>Iridium Catalysed Asymmetric Hydrogenation of Olefins and Dynamic Kinetic Resolution in the Asymmetric Hydrogenation of Allylic Alcohols
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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. 

sted, utgiver, år, opplag, sider
Stockholm: Department of Organic Chemistry, Stockholm University, 2017. s. 52
Emneord
Iridium catalyst, asymmetric hydrogenation, dynamic kinetic resolution, allylic alcohol
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-140923 (URN)978-91-7649-744-9 (ISBN)978-91-7649-745-6 (ISBN)
Disputas
2017-05-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius Väg 16 B, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad

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

Tilgjengelig fra: 2017-04-07 Laget: 2017-03-23 Sist oppdatert: 2018-03-22bibliografisk kontrollert
3. Enantio- and Regioselective Iridium-Catalyzed Hydrogenation of Olefins: From Development to Total Synthesis
Åpne denne publikasjonen i ny fane eller vindu >>Enantio- and Regioselective Iridium-Catalyzed Hydrogenation of Olefins: From Development to Total Synthesis
2019 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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. 

sted, utgiver, år, opplag, sider
Stockholm: Department of Organic Chemistry, Stockholm University, 2019. s. 61
Emneord
Asymmetric hydrogenation, Iridium, Regioselectivity, Kinetic resolution, Total synthesis
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-163645 (URN)978-91-7797-588-5 (ISBN)978-91-7797-589-2 (ISBN)
Disputas
2019-03-12, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad

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

Tilgjengelig fra: 2019-02-15 Laget: 2019-01-23 Sist oppdatert: 2019-02-07bibliografisk kontrollert

Open Access i DiVA

Fulltekst mangler i DiVA

Andre lenker

Forlagets fulltekstPubMed

Søk i DiVA

Av forfatter/redaktør
Peters, Byron K.Liu, JianguoMargarita, CristianaAndersson, Pher G.
Av organisasjonen
I samme tidsskrift
Chemistry - A European Journal

Søk utenfor DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 242 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf