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Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 90 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 162
Keyword [en]
Mizoroki-Heck arylation, Suzuki coupling, domino reaction, stereoselective, palladium, chelation control, vinyl ether, HIV-protease inhibitors, HIV-integrase inhibitors
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-173068ISBN: 978-91-554-8370-8 (print)OAI: oai:DiVA.org:uu-173068DiVA: diva2:516760
Public defence
2012-06-08, B42, Uppsala Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note
The time 12:05 for the public defense mentioned in the thesis is incorrect. It will take place at 09:15, 2012-06-08.Available from: 2012-05-16 Created: 2012-04-18 Last updated: 2012-08-01Bibliographically approved
List of papers
1. Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller
Open this publication in new window or tab >>Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller
Show others...
2008 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 64, no 37, 8746-8751 p.Article in journal (Refereed) 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.

Keyword
Heck reaction, microwave, vinyl ether, palladium catalysis; stereoselective
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-104394 (URN)10.1016/j.tet.2008.06.099 (DOI)000258841100022 ()0040-4020 (ISBN)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
2. Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
Open this publication in new window or tab >>Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
2009 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, 7587-7589 p.Article in journal (Refereed) Published
Abstract [en]

A mild and novel palladium(II)-catalyzed domino Heck/Suzuki alpha,beta-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed alpha- or beta-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.

National Category
Pharmaceutical Sciences
Research subject
Organic Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-124718 (URN)10.1039/b918358b (DOI)000272238900039 ()20024288 (PubMedID)
Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2017-12-12Bibliographically approved
3. Chelation-Mediated Palladium(II)-Catalyzed Domino Heck-Mizoroki/Suzuki-Miyaura Reactions Using Arylboronic Acids: Increasing Scope and Mechanistic Understanding
Open this publication in new window or tab >>Chelation-Mediated Palladium(II)-Catalyzed Domino Heck-Mizoroki/Suzuki-Miyaura Reactions Using Arylboronic Acids: Increasing Scope and Mechanistic Understanding
2011 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, no 8, 2433-2438 p.Article in journal (Refereed) Published
Abstract [en]

A palladium(II)-catalyzed Heck-Mizoroki/Suzuki-Miyaura domino reaction involving metal coordinating dimethylaminoethyl vinyl ethers and a number of electron-rich and electron-deficient arylboronic acids has been developed. Through variation of the temperature and the concentration of the p-benzoquinone (p-Bq) ligand/reoxidant, conditions for the robust and convenient one-pot generation of diarylated-saturated ethers were identified. With the aid of coordination of the dimethylamino group to the arylpalladium intermediate, the otherwise predominant formation of the beta-arylated olefin could be reversed. A reaction route involving a chelation-controlled carbopalladation, providing a p-Bq stabilized six-membered palladacycle, followed by transmetalation and reductive elimination is suggested to explain the selective formation of saturated diarylated ether products.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-152784 (URN)10.1021/jo1018188 (DOI)000289187300004 ()21417443 (PubMedID)
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
4. Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids
Open this publication in new window or tab >>Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids
2012 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 1, no 1, 49-56 p.Article in journal (Refereed) Published
Abstract [en]

A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78% isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino b,a-diarylation–reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2012
Keyword
chirality, domino reactions, palladium, stereoselective catalysis, water effects
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-172735 (URN)10.1002/open.201100010 (DOI)000328606600008 ()
Available from: 2012-04-13 Created: 2012-04-13 Last updated: 2017-12-07Bibliographically approved
5. Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids
Open this publication in new window or tab >>Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids
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2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 15, 4714-4722 p.Article in journal (Refereed) Published
Abstract [en]

The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion sigma-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the s-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2012
National Category
Organic Chemistry Theoretical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:uu:diva-172740 (URN)10.1002/chem.201102678 (DOI)000302162500033 ()
Available from: 2012-04-13 Created: 2012-04-13 Last updated: 2017-12-07Bibliographically approved
6. Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
Open this publication in new window or tab >>Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
Show others...
2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 6, 2724-2736 p.Article in journal (Refereed) Published
Abstract [en]

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

Keyword
HIV, AIDS, protease inhibitor, aspartic protease, lactam, tertiary alcohol, X-ray
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-160186 (URN)10.1021/jm201620t (DOI)000301767000017 ()
Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2017-12-08Bibliographically approved
7. Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
Open this publication in new window or tab >>Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
Show others...
2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 16, 5125-9 p.Article in journal (Refereed) Published
Abstract [en]

A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-99766 (URN)10.1021/jm8003784 (DOI)000258637400032 ()18665580 (PubMedID)
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved

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