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Carbon-Carbon Bond Formation via Radical Cyclization and Transition Metal Catalysis
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (Prof. Lars Engmen)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Free radical cyclization methodology has been used extensively in synthesis for manipulation of complex molecules such as alkaloids, terpenes, carbohydrates, peptides and nucleic acids. The methodology has emerged as a result of work by physical organic chemists who determined rate constants for the most common radical reactions used in organic synthesis.

A novel route to cyclic imines based on 5-exo radical cyclization was explored. The radical precursors were imines prepared from allylamine and readily available a-phenylselenenyl ketones. The synthesis of conformationally constrained bicyclic nucleosides is also reported using 5-exo and 6-exo cyclizations of hexenyl and heptenyl radicals in thymidine nucleosides. The nucleosides were incorporated in a 15mer antisense oligonucleotide via solid-phase oligonucleotide synthesis. The AONs with the modifications were tested for target affinity and stability and compared with the well known LNA modified AONs. The thesis discusses the unique qualities of these novel molecules and presents them as potential candidates for antisense therapeutic agents.

Keeping up with the theme of intramolecular carbon-carbon bond formation, microwave induced carbodechalcogenation of chalcogenoanhydrides was explored. Poor generality in these reactions made us turn to transition metal catalysis for Sonogashira cross-coupling reactions using alkyl aryl and diaryl tellurides as coupling partners.

Place, publisher, year, edition, pages
2010. , p. 76
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 751
Keywords [en]
Radical cyclizations, transition metal catalysis
National Category
Chemical Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-123960ISBN: 978-91-554-7830-8 (print)OAI: oai:DiVA.org:uu-123960DiVA, id: diva2:316564
Public defence
2010-06-10, B42,BMC, BMC, Husargatan 3, Uppsala, Biomedical centre (BMC), 10:15 (English)
Opponent
Supervisors
Available from: 2010-05-20 Created: 2010-04-30 Last updated: 2018-06-04Bibliographically approved
List of papers
1. A radical cyclization route to cyclic imines
Open this publication in new window or tab >>A radical cyclization route to cyclic imines
2010 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 8, p. 1149-1151Article in journal (Refereed) Published
Abstract [en]

A novel route to cyclic imines based on 5-exo radical cyclization is explored. The radical precursors are imines prepared from allylamine and readily available alpha-phenylselenenyl ketones.

Keywords
Radicals, alpha-Phenylselenenyl ketones, Delta(1)-Pyrrolines, 5-exo cyclization
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-115968 (URN)10.1016/j.tetlet.2009.12.104 (DOI)000274710500003 ()
Available from: 2010-02-17 Created: 2010-02-17 Last updated: 2017-12-12Bibliographically approved
2. Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies
Open this publication in new window or tab >>Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies
Show others...
2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 26, p. 8362-8379Article in journal (Refereed) Published
Abstract [en]

Two unusual reactions involving the 5-hexenyl or the 6-heptenyl radical cyclization of a distant double bond at C4' and the radical center at C2' of the ribofuranose ring of thymidine have been used as key steps to synthesize North-type conformationally constrained cis-fused bicyclic five-membered and six-membered carbocyclic analogues of LNA (carbocyclic-LNA-T) and ENA (carbocyclic-ENA-T) in high yields. Their structures have been confirmed unambiguously by long range iH-13C NMR correlation (HMBC), TOCSY, COSY, and NOE experiments. The carbocyclic-LNA-T and carbocyclic-ENA-T were subsequently incorporated into the antisense oligonucleotides (AONs) to show that they enhance the Tm of the modified AON/RNA heteroduplexes by 3.5-5 °C and 1.5 °C/modification for carbocyclic-LNA-T and carbocyclic-ENA-T, respectively. Whereas the relative RNase H cleavage rates with carbocyclic-LNA-T, carbocyclic-ENA-T, aza-ENA-T, and LNA-T modified AON/RNA duplexes were found to be very similar to that of the native counterpart, irrespective of the type and the site modification in the AON strand, a single incorporation of carbocyclic-LNA and carbocyclic-ENA into AONs leads to very much more enhanced nuclease stability in the blood serum (stable >48 h) as compared to that of the native (fully degraded <3 h) and the LNA-modified AONs (fully degraded <9 h) and aza-ENA (≈85% stable in 48 h). Clearly, remarkably enhanced lifetimes of these carbocyclic-modified AONs in the blood serum may produce the highly desired pharmacokinetic properties because of their unique stability and consequently a net reduction of the required dosage. This unique quality as well as their efficient use as the AON in the RNase H-promoted cleavage of the target RNA makes our carbocyclic-LNA and carbocyclic-ENA modifications excellent candidates as potential antisense therapeutic agents.

National Category
Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-96273 (URN)10.1021/ja071106y (DOI)000247563700050 ()17552524 (PubMedID)
Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14Bibliographically approved
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