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Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
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2008 (Engelska)Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 64, nr 37, s. 8746-8751Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The study of a series of palladium(0)-catalyzed C2-arylations of a 1-cyclopentenyl ether equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary is reported. Stereoselective Heck monoarylations were performed using aryl iodides under classical heating conditions for 1.7-3.0 h at 80 degrees C and in one case using 30 min of microwave irradiation at 110 degrees C. To further explore the scope and nature of this stereoselective methodology, aryl bromides were also utilized as arylating agents, using 20 min of microwave processing at 120-130 degrees C. High to excellent diastereopurities (90-98% de) were obtained according to H-1 NMR and GC-MS analyses. The prolinol fragment apparently controlled the chastereoselectivity of the Heck reaction by presenting the arylpalladium species from the preferred side of the double bond. By X-ray structure diffraction analysis of an N-quaternized Heck product, the absolute configuration of the new stereocenter was established as (R), Supporting a Si-face migratory insertion.

Ort, förlag, år, upplaga, sidor
2008. Vol. 64, nr 37, s. 8746-8751
Nyckelord [en]
Heck reaction, microwave, vinyl ether, palladium catalysis; stereoselective
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-104394DOI: 10.1016/j.tet.2008.06.099ISI: 000258841100022ISBN: 0040-4020 (tryckt)OAI: oai:DiVA.org:uu-104394DiVA, id: diva2:219730
Tillgänglig från: 2009-05-28 Skapad: 2009-05-28 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Ingår i avhandling
1. Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications
Öppna denna publikation i ny flik eller fönster >>Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules.

This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon.

In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant.

The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction.

Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted.

In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors.

Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2012. s. 90
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 162
Nyckelord
Mizoroki-Heck arylation, Suzuki coupling, domino reaction, stereoselective, palladium, chelation control, vinyl ether, HIV-protease inhibitors, HIV-integrase inhibitors
Nationell ämneskategori
Organisk kemi
Forskningsämne
Kemi med inriktning mot organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-173068 (URN)978-91-554-8370-8 (ISBN)
Disputation
2012-06-08, B42, Uppsala Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Anmärkning
The time 12:05 for the public defense mentioned in the thesis is incorrect. It will take place at 09:15, 2012-06-08.Tillgänglig från: 2012-05-16 Skapad: 2012-04-18 Senast uppdaterad: 2012-08-01Bibliografiskt granskad

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Trejos, AlejandroSävmarker, JonasLarhed, Mats

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