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Aminocarbonylations of Alkenyl Phosphates, Chlorides, Bromides and Triflates with Mo(CO)6 as a Solid CO source
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2009 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 65, no 36, 7646-7652 p.Article in journal (Refereed) Published
Abstract [en]

Palladium-catalyzed aminocarbonylations of alkenyl chlorides, bromides, and triflates were investigated using Mo(CO)6 as a solid carbon monoxide source. The reactions afforded moderate to good yields producing a wide variety of acrylamides after 20 minutes of microwave irradiation. In addition, the aminocarbonylation reaction was, for the first time, expanded to include alkenyl phosphates as starting materials.

Place, publisher, year, edition, pages
2009. Vol. 65, no 36, 7646-7652 p.
Keyword [en]
Carbonylation, Microwave, Vinyl halides, Vinyl phosphates, Vinyl triflates, Alkenyl electrophiles, Palladium, Enolizable ketones
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-100358DOI: 10.1016/j.tet.2009.06.101ISI: 000269340000043OAI: oai:DiVA.org:uu-100358DiVA: diva2:210167
Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2013-07-04Bibliographically approved
In thesis
1. Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation
Open this publication in new window or tab >>Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tuberculosis (TB) is a major infectious disease, killing about 2 million people annually throughout the world. Today's TB treatment is a lengthy procedure involving a combination of antibiotics. No new TB drug has been introduced onto the market in the past 40 years, and the emergence of multi- and extensively drug-resistant TB calls for new drugs. Finding new drug targets is important and one such target is the Mycobacterium tuberculosis enzyme glutamine synthetase (GS), which catalyses the formation of glutamine from glutamic acid. In this work, novel GS inhibitors and new Pd(0)-catalyzed methods have been developed.

A microwave-enhanced Pd(0)-catalyzed α-arylation reaction was developed using water as solvent, and a phenylglycine scaffold was identified using structure-based design. A series of α-arylated phenylglycine derivates was produced at moderate to good yields. Some of these were biologically evaluated against GS.

A novel scaffold, 3-amino-imidazo[1,2-a]pyridine, was identified by high-throughput screening directed towards GS. This type of compound could be easily produced via a Ugi-type, microwave-promoted multi-component reaction in 20 min. The scaffold was investigated by changing one substituent at a time, and in an experimental design where 8 factors were varied in the same design. Several potent inhibitors were identified; amongst them the most potent inhibitor to date (IC50 = 0.38 µM). Two discrete structure-activity relationships were established, and one of the inhibitors was co-crystallized.

The first general aminocarbonylation of aryl chlorides and the first aminocarbonylation of alkenyl phosphates were developed. Alkenyl chlorides, bromides and triflates were investigated in the same transformation utilizing Mo(CO)6 as a solid carbon monoxide source. Two different Pd(0)-based catalytic systems were developed. A wide variety of aryl chlorides and amines could be transformed into the corresponding amides with good yields. The alkenyl substrates produced low to good yields.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 95
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-100377 (URN)978-91-554-7492-8 (ISBN)
Public defence
2009-05-15, B22, BMC, Husargatan3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-04-23 Created: 2009-03-31 Last updated: 2009-06-08Bibliographically approved

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Larhed, Mats

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